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S0009279720310334 | Thromboembolism is a major cause of morbidity and mortality worldwide . Most therapeutic drugs for treating thrombosis can cause hemorrhage and have short half lives within human blood circulation resulting in a need to discover and develop novel anticoagulants antithrombotics . EuRP 61 has been isolated from a plant latex | A novel antithrombolytic protease derived from Euphorbia. latex. The enzyme exhibited fibrinolytic anticoagulant and antiplatelet activities. Its fibrinogenolytic activity was not abolished by blood circulating inhibitors. The enzyme appears safe for cell viability especially in human blood cells. |
S000927972031036X | Developing brain is very sensitive to the influence of environmental factors during gestation and the neonatal period . The aim of the study is to assess cobalt and iron accumulation in the brain as well as changes in the expression of iron regulatory proteins transferrin receptor 1 hepcidin and ferroportin in suckling mice . Perinatal exposure to cobalt chloride increased significantly cobalt content in brain tissue homogenates of 18 day old and 25 day old mice inducing alterations in brain iron homeostasis . Higher degree of transferrin receptor 1 expression was demonstrated in cobalt chloride exposed mice with no substantial changes between d18 and d25 mice . A weak ferroportin expression was found in 18 day old control and cobalt treated mouse brain . Cobalt exposure of d25 mice resulted in increased ferroportin expression in brain compared to the untreated age matched control group . Hepcidin level in cobalt exposed groups was decreased in d18 mice and slightly increased in d25 mice . The obtained data contribute for the better understanding of metal toxicity impact on iron homeostasis in the developing brain with further possible implications in neurodegeneration . | Late prenatal and early postnatal exposure to cobalt chloride increases significantly brain Co content in suckling mice. CoCl. provokes changes in the expression of iron regulatory proteins transferrin receptor 1 hepcidin and ferroportin. Cobalt toxicity affects iron homeostasis in the developing brain with further possible implications in neurodegeneration. |
S000927972031053X | The novel human coronavirus 2 called SARS CoV 2 is the causative agent of Coronavirus Induced Disease and has spread causing a global pandemic . Currently there is no vaccine to prevent infection nor any approved drug for the treatment . The development of a new drug is time consuming and can not be relied on as a solution in combatting the immediate global challenge . In such a situation the drug repurposing becomes an attractive solution to identify the potential of COVID 19 treatment by existing drugs which are approved for other indications . Here we review the potential use of rapamycin an mTOR inhibitor that can be repurposed at low dosages for the treatment of COVID 19 . Rapamycin inhibits protein synthesis delays aging reduces obesity in animal models and inhibits activities or expression of pro inflammatory cytokines such as IL 2 IL 6 and IL 10 . Overall the use of rapamycin can help to control viral particle synthesis cytokine storms and contributes to fight the disease by its anti aging and anti obesity effects . Since rapamycin targets the host factors and not viral machinery it represents a potent candidate for the treatment of COVID 19 than antiviral drugs as its efficacy is less likely to be dampened with high mutation rate of viral RNA . Additionally the inhibitory effect of rapamycin on cell proliferation may aid in reducing viral replication . Therefore by drug repurposing low dosages of rapamycin can be tested for the potential treatment of COVID 19 SARS CoV 2 infection . | Rapamycin an mTOR inhibitor can be repurposed for treatment of COVID 19. Rapamycin inhibits protein synthesis pro inflammatory cytokines and delays aging. Rapamycin action targeted on host factors and not viral machinery. Rapamycin act on cell proliferation may aid in reducing viral replication. |
S0009279720311108 | To investigate the effect of gamabufotalin on metastasis and modulation of stemness features in osteosarcoma and the molecular mechanisms underlying such effects . Human osteosarcoma U2OS MG 63cell lines were used in this study . Cell proliferation migration and invasion were determined by MTT assay wound healing assay and cell invasion assay respectively . The inhibitive effect of GBT on stemness was assessed by flow cytometry and mammosphere formation . The protein levels of related proteins were detected by western blotting analysis . The effect of GBT on tumorigenicity and metastasis was determined by immunofluorescence staining and immunohistochemistry We found that GBT suppressed the viability of U2OS MG 63cells in a time and dose dependent manner . Notably GBT had no effect on the viability of human fetal osteoblastic 1.19cells . Moreover GBT increased the width of wounds reduced the number of invasive osteosarcoma cells and reversed the epithelialmesenchymal transition phenotype . Notably we found that compared with hFOB1.19cells the levels of transforming growth factor periostin phosphorylated AKT Collectively our data demonstrated that GBT inhibited the viability and tumorigenesis capability of osteosarcoma cells by blocking the TGF periostin PI3K AKT signaling pathway . Therefore GBT may represent a promising therapeutic agent for the management of osteosarcoma . | Higher levels of TGF periostin p AKT PI3K were observed in osteosarcoma spheroids. The TGF periostin PI3K AKT pathway promotes osteosarcoma procession. GBT exerts an anti tumor effect by blocking osteosarcoma CSCs and invasion capacity. |
S0009279720311121 | Cisplatin is an antineoplastic drug well recognized for its success in the battle against several types of cancer in adult juvenile and child populations . Meanwhile this drug is also famous due to its serious side effects such as hepatotoxicity . This study evaluated the hepatoprotective effectiveness of Diphenyl Diselenide | Cisplatin induced metabolic disorders and oxidative damage in liver of rats. PhSe. and Ebselen preserved redox balance after cisplatin exposure. PhSe. and Ebselen PhSe. showed hepatoprotective effects against cisplatin. |
S0009279720311182 | Dextromethorphan is a cough suppressant available in many prescribed and over the counter medications . Adverse reactions induced by DM have been regularly reported including allergic skin reactions in some cases . However the underlying mechanisms of local anaphylaxis induced by DM have not been elucidated . In this study we found that DM could activate mast cells to increase calcium mobilization and release hexosaminidase histamine tumor necrosis factor MCP 1 and IL 8 in a dose dependent manner . The allergic reactions were confirmed by hind paw swelling and extravasation assay | Dextromethorphan DM was firstly found to induce anaphylaxis. and. MRGPRX2 was confirmed to be critical to anaphylaxis induced by DM. Close monitoring should be drawn on patients with drugs containing DM. |
S0009279720311285 | Artesunate is a kind of derivative of artemisinin which possesses potent anti cancer effect in addition to its anti malarial property . And autophagy was a highly conserved process exerting a double edged effect in cancer cell survival . Besides apoptosis is a programmed cell death program crucial to cell homeostasis . However the relations between autophagy and apoptosis and the role of artesunate in this interaction have not been elucidated in bladder cancer . In present study we used human bladder cancer cells to investigate that how artesunate would influence autophagy and apoptosis processes . We found that artesunate could inhibit the viability proliferation and migration of bladder cancer cells as well as induce autophagy in a time and dose dependent manner in addition the artesunate induced autophagy subsequently activated cells apoptosis . Furthermore we pretreated T24 and EJ cells with 3 Methyladenine or Rapamycin to inhibit or promote autophagy respectively leading to inhibited or increased apoptosis . Moreover pretreatment of these cell lines with Acadesine or Dorsomorphin to activate or inhibit the AMPK mTOR ULK1 pathway respectively also resulting in promotion or suppression in both autophagy and apoptosis . In the upstream ROS upregulation triggered by ART initiated AMPK mTOR ULK1 axis . However this initiative effect of ROS can be reversed by N Acetyl | Artesunate induce caspase dependent apoptosis in human bladder cancer cells. Artesunate time and dose dependently activated autophagy in human bladder cancer cells. Apoptosis in human bladder cancer cells were induced by artesunate activated autophagy. AMPK mTOR ULK1 pathway mediated artesunate induced autophagy dependent apoptosis in human bladder cancer cells. ROS plays a vital role in ART activated AMPK mTOR ULK1 pathway. |
S000927972031139X | Due to drug resistance and side effects the development of novel therapeutics for the treatment of lung cancer is still in an urgent need . Morusin a naturally occurring prenylated flavonoid isolated from the root bark of | Morusin induced apoptosis in A549 and NCIH292cells. Morusin induced autophagy in A549 and NCIH292cells. Modulation of MAPK ERK MAPK JNK and PI3K AKT NF B involved in morusin induced cell death. |
S0009279720311558 | The unfolded protein response is an emerging target pathway for cancer treatment owing to its ability to induce cell death . In our previous analysis of UPR modulating small molecules we had reported that piperazine oxalate derivative compounds are able to promote increased phosphorylation of eukaryotic translation initiation factor 2 alpha . In this study we found that AMC 04 induces apoptotic cell death | A new piperazine oxalate derivate AMC 04 induces apoptosis in human cancer cells. AMC 04 induces apoptosis. the activation of the ATF4 CHOP DR5 pathway. Induction of DR5 by AMC 04 is regulated by ROS mediated p38 activation. AMC 04 can bind to the histone methyltransferases revealed by molecular docking analysis. AMC 04 inhibits the H3K9 histone methyltransferase activity revealed by biochemical analysis. |
S0009279720311960 | Two types of cholinesterases are present in mammalian blood and tissues acetylcholinesterase and butyrylcholinesterase . While AChE regulates neurotransmission by hydrolyzing acetylcholine at the postsynaptic membranes and neuromuscular junctions BChE in plasma has been suggested to be involved in detoxifying toxic compounds . This study was undertaken to establish the identity of circulating ChE activity in plasmas from domestic animals by assessing sensitivity to AChE specific inhibitors and BChE specific inhibitors as well as binding to anti FBS AChE monoclonal antibodies . Based on the inhibition of ChE activity by ChE specific inhibitors it was determined that bovine ovine and caprine plasma predominantly contain AChE while porcine and equine plasma contain BChE . Three of the anti FBS AChE MAbs 4E5 5E8 and 6H9 inhibited 8598 of enzyme activity in bovine ovine and caprine plasma confirming that the esterase in these plasmas was AChE . These MAbs did not bind to purified recombinant human or mouse AChE demonstrating that these MAbs were specific for AChEs from ruminant species . These MAbs did not inhibit the activity of purified human BChE or ChE activity in porcine and equine plasma confirming that the ChE in these plasmas was BChE . Taken together these results demonstrate that anti FBS AChE MAbs can serve as useful tools for distinguishing between AChEs from ruminant and non ruminant species and BChEs . | Acetylcholinesterase is the predominant esterase in bovine ovine and caprine plasma. Porcine and equine plasma contain predominantly butyrylcholinesterase. Monoclonal antibodies MAbs against fetal bovine serum AChE inhibit AChEs from ruminants. MAbs against fetal bovine serum AChE do not cross react with BChE. Residues at positions 241 275 and 287 located near the entrance to the gorge contribute to the binding of MAbs to AChEs. |
S0009279720311984 | The calcineurin inhibitor cyclosporin A is one of the most common immunosuppressive agents used in organ transplantation . However its clinical use is often limited by several unwanted effects including nephrotoxicity and hepatotoxicity . By using immunohistochemical and ELISA techniques it was found that CsA administration causes a rapid activation of a disintegrin and metalloproteases 17 epidermal growth factor receptor and subsequent ERK1 2 phosphorylation in the liver and kidney of albino mice . Furthermore this study presents mechanistic relevance of this signaling cascade involving reactive oxygen species mediated ADAM 17 EGFR ERK1 2 activation as indicated by a clear reduction in ADAM 17 and EGFR activities as well as ERK1 2 phosphorylation when the animals pretreated with Polyethylene glycol superoxide dismutase before CsA administration . Collectively our findings demonstrate that CsA has the ability to activate ADAM 17 mediated EGFR ERK1 2 phosphorylation in the liver and kidney of albino mice in ROS dependent manner . Finally these data may support the concept of using antioxidant therapy as a valuable approach for the prevention of CsA induced nephrotoxicity and hepatotoxicity . | Cyclosporin A activates ADAM 17 in the liver and kidney of albino mice. Cyclosporin A activates EGFR in the liver and kidney of albino mice. Cyclosporin A activates ERK1 2 signaling cascade in the liver and kidney of albino mice. PEG SOD attenuates ADAM 17 EGFR ERK1 2 signaling induced by cyclosporine A. |
S0009279720312011 | Cell cycle dysregulation is the mainstay of aberrant cell proliferation which leads to tumor progression . Mutations in tumor cells initiate various dysregulated pathways and spontaneous over proliferation with genomic chromosomal instability . Despite advances in cancer therapy it has remained a medicinal challenge to treat . Besides the complexity of pathophysiological pathways behind cancer raises the need for novel multi target agents possessing fewer side effects . Alkaloid based therapies have been explored so far to target cell division in cancer including vinca alkaloids . As a class of hopeful carboline derivatives growing evidence has indicated their auspicious roles in combating cancer by inhibiting topoisomerase kinesin Eg5 telomerase cyclin dependent kinase IB kinase and polo like kinase 1 in the transition phases of cell cycle . In this review | carboline alkaloids are natural based promising agents with potential therapeutic applications. carbolines derivatives greatly ameliorate cell cycle dysregulations in cancer. carbolines suppress CDK PLK 1 IKK to exert their anti cancer effects. carboline alkaloids block Kinesin Eg5 DNA integration in combating cancer. carbolines inhibit TOPO telomerase to suppress cell cycle over activation. |
S000927972031276X | Ulcerative colitis is a chronic disease driven primarily by uncontrolled pervasive inflammatory responses affecting the colon and rectum . Currently available medications carry multiple detrimental adverse effects which have emphasized the mandatory need for safer and more efficient novel therapeutic alternatives . Melittin is the main constituent of bee venom and exhibits potent anti inflammatory properties . The antiulcerogenic effect of oral melittin was explored in the current study using the acetic acid induced colitis model . Increase in body weight and decrease in colon mass index were observed in the melittin group . Microscopically melittin ameliorated acetic acid induced histological damage . Melittin administration has efficiently amended the elevated levels of the cytokines tumor necrosis factor and interleukin 6 seen in the colitis group . This was accompanied by inhibition of the upstream signaling molecules Toll like receptor 4 tumor necrosis factor receptor associated factor mitogen activated protein kinase 38 and nuclear factor kappaB in the melittin group . Moreover treatment with melittin resulted in marked decrease in colonic level of prostaglandin E2 together with the enzymes involved in its synthesis secretory phospholipase A2 and cyclooxygenase 2 . Additionally melittin has attenuated acetic acid induced oxidative stress as manifested by the significant diminishment in malondialdehyde as well as the increase in superoxide dismutase and reduced glutathione levels . Therefore melittin mitigated UC pathogenesis and could be considered as a potent and promising therapeutic alternative for UC treatment . | Melittin exerted potent antiulcerogenic effect in acetic acid induced colitis model. Melittin amended the elevated levels of inflammatory cytokines. Melittin inhibited the upstream inflammatory molecules TLR4 TRAF6 p38 MAPK and NF B. Melittin reversed alterations in PGE2 and enzymes involved in its synthesis. Melittin attenuated oxidative stress and ameliorated histological damage in colitis. |
S0009279720313363 | Cisplatin based chemotherapy is a common first line regimen for treating nonsmall cell lung cancer . However drug resistance is still a major problem . The purposes of this study were to evaluate whether sclareol can reverse cisplatin resistance and to investigate its possible mechanisms . A549 cells the human NSCLC cells with inherent cisplatin resistance were used to investigate synergistic effect of sclareol with cisplatin in cell proliferation and migration as well as its regulatory mechanisms in expression of excision repair cross complementation group 1 a cisplatin resistance associated molecule . Nude mice bearing subcutaneous A549 tumors were applied to investigate synergistic activity of sclareol in anti tumor . As comparing to the cisplatin alone group the treatment of cisplatin combined with sclareol significantly suppressed survival rate and cell migration of A549cells . Besides sclareol also exhibited suppression in ERCC1 expression by inhibiting AKT GSK3 AP1 Snail and JNK AP1 pathways . Furthermore the experimental data from | Drug resistance is still a critical issue in clinical chemotherapy. Platinum based compounds such as cisplatin are first line drugs for treating non small cell lung cancer NSCLC . Excision repair cross complementation group 1 ERCC1 a DNA repair enzyme involved in cisplatin resistance. Sclareol is a natural aromatic compound with the activity of suppressing ERCC1 expression. Sclareol can be used as an adjuvant drug to enhance cytotoxic effect of cisplatin in NSCLC chemotherapy. |
S0009279720313375 | acetic acids exhibit a wide range of pharmacological activities . Among them the only derivative used in clinical practice is the aldose reductase inhibitor epalrestat . Structurally related compounds 5 | Six rhodanine acetic acid derivatives were tested for aldose reductase inhibition. Four compounds inhibited aldose reductase more potently than epalrestat. Inhibition selectivity relative to aldehyde reductase exceeded that of epalrestat. Negligible cytotoxicity to the HepG2 cell line was recorded for all compounds. SAR evaluation indicated a way how to improve inhibition parameters further. |
S0009279720313922 | The on going pandemic of COVID 19 wreaked by a viral infection of SARS CoV 2 has generated a catastrophic plight across the globe . Interestingly one of the hallmarks of COVID 19 is the so called cytokine storm due to attack of SARS Cov 2 in the lungs . Considering mesenchymal stem cells therapy could contribute against SARS CoV 2 viruses attack because of their immune modulatory and anti inflammatory ability linked to their stemness to the arsenal of treatments for COVID 19 . Another novel therapeutic strategies include the blockade of rampant generation of pro inflammatory mediators like acute respiratory distress syndrome degradation of viral protein capsids by PROTACs composed of Ubiquitin proteasome framework and ubiquitination independent pathway directing the SARS CoV 2 nucleocapsid protein and proteasome activator etc . This review is consequently an endeavour to highlight the several aspects of COVID 19 with incorporation of important treatment strategies discovered to date and putting the real effort on the future directions to put them into the perspective . | Coronavirus disease COVID 19 emerged out as a potential global biological disaster caused by SARS CoV 2. Early detection of the SARS CoV 2 had a better prognosis for treatment strategies. Clinical trials among repurposed molecules had progressed with several methodological limitations. Systemic overview of various aspects in epidemiology and treatment strategies. Challenges and the future directions have also been discussed. |
S0009279720314216 | Ginsenoside Rb1 is the best constituent of ginseng and although it shows clinical efficacy as an antineoplastic antioxidative and antirheumatic agent its oral bioavailability is poor due to its limited solubility . In this study the solubility of GsRb1 was improved by encapsulating it in polymeric nanocapsules therefore improving the oral bioavailability . The encapsulation resulted in stable homogenous and well dispersed nano GsRb1 whose mean particle size and zeta potential were 183.9nm and 36.9mV respectively . A significant improvement was observed in the in vitro release profile of nano GsRb1 as compared to its free form . Our study also indicated a significant repression of the degradation of nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor alpha the nuclear factor kappa B signaling pathway NOD LRR and pyrin domain containing protein 3 inflammasome activation and the mitochondrial damage thereby reducing inflammation and gouty arthritis induced by monosodium urate when compared to free GsRb1 strongly suggesting that polymeric nano particles can be a novel approach for delivering the GsRb1 into the inflamed joints for a better treatment effectiveness . | GsRb1 is the best constituent of ginseng. GsRb1 oral bioavailability is poor due to its limited solubility. The solubility of GsRb1 was improved by encapsulating it in polymeric nanoparticles. Nano GsRb1 is a novel approach to deliver GsRb1. |
S0009279720314460 | A cellular model of cardiomyocytes and mitochondria isolated from mouse liver were used to understand the drug action of BPDZ490 and BPDZ711 two benzopyran analogues of the reference potassium channel opener cromakalim on mitochondrial respiratory parameters and swelling by comparing their effects with those of the parent compound cromakalim . For these three compounds the oxygen consumption rate was determined by high resolution respirometry and their impact on adenosine triphosphate production and calcium induced mitochondrial swelling was investigated . Cromakalim did not modify neither the OCR of H9c2 cells and the ATP production nor the Ca induced swelling . By contrast the cromakalim analogue BPDZ490 induced a strong increase of OCR while the other benzopyran analogue BPDZ711 caused a marked slowdown . For both compounds 1 displayed a biphasic behavior while 2 still showed an inhibitory effect . Both compounds 1 and 2 were also found to decrease the ATP synthesis with pronounced effect for 2 while cromakalim remained without effect . Overall these results indicate that cromakalim as parent molecule does not induce | New cromakalim analogues inhibit mitochondrial respiration rate with low toxicity. Benzopyran derivatives inhibit the Calcium induced swelling of mitochondria. Cromakalim. does not act on respiration rate and swelling of mitochondria. Benzopyran derivatives decrease the ATP synthesis. BPDZ490 behaves as a mild uncoupling agent and BPDZ711 as a strong inhibitor. |
S0009279720314617 | Irinotecan is widely prescribed for treatment of various intractable cancers such as advanced and metastatic colon cancer cells but its continuous treatment promotes the resistance development . In this study we established CPT11 resistant variants of three human colon cancer cell lines and found that gain of the resistance elicited an up regulation of aldo keto reductase 1C3 in the cells . Additionally the sensitivity to CPT11 toxicity was decreased and increased by overexpression and knockdown respectively of the enzyme . Moreover the resistant cells suppressed formation of reactive 4 hydroxy 2 nonenal by CPT11 treatment and the suppressive effect was almost completely abolished by addition of an AKR1C3 inhibitor . These results suggest that up regulated AKR1C3 contributes to promotion of the chemoresistance by detoxifying the reactive aldehyde . Western blot and real time polymerase chain reaction analyses and ATP binding cassette B1 functional assay revealed that among three ABC transporters ABCB1 was the most highly up regulated by development of the CPT11 resistance inferring a significant contribution of pregnane X receptor dependent signaling to the ABCB1 up regulation . The combined treatment with inhibitors of AKR1C3 and ABCB1 potently sensitized the resistant cells to CPT11 and its active metabolite SN38 . Taken together our results suggest that combination of AKR1C3 and ABCB1 inhibitors is effective as adjuvant therapy to enhance CPT11 sensitivity of intractable colon cancer cells . | Gain of CPT11 resistance up regulates AKR1C3 expression in colon cancer cells. AKR1C3 accelerates the resistance through metabolizing cytotoxic HNE. The CPT11 resistance is also ascribed to the ABCB1 up regulation via PXR activation. Treatment with inhibitors of AKR1C3 and ABCB1 overcomes the CPT11 resistance. Author statement. |
S0009279720314885 | Polo like kinase 1 is a prominent mediatory player during the cell cycle mitosis and cytokinesis in eukaryotic cells . Besides its physiological roles PLK1 expression is upregulated in a wide range of human malignant tumors and its overexpression worsens prognosis therefore specific inhibition of PLK1 in tumor cells is a fascinating approach for the development of novel chemotherapeutics . The present study elucidated the potential cytotoxic effects of a PLK1 inhibitor GSK461364A in five cancer cell lines including Raji K562 PC3 MCF 7 MDA MB 231 along with noncancerous L929cells by XTT assay . The cells were treated for 24h with GSK461364A at different concentrations ranged between 0.5 and 40M and significant cytotoxicity was observed in all treated groups with the IC | GSK461364A evaluated for antiproliferative activity against Raji K562 PC3 MCF 7 and MDA MB 231cell lines. GSK461364A exhibited the best cytotoxic activity against Raji cells. GSK461364A arrested the cells at G2 M phase of the cell cycle and caused DNA damage. GSK461364A also induced apoptosis and altered total oxidant status TOS in Raji cells. |
S0009279720315325 | Leishmaniasis is a parasitic neglected tropical disease and result in a broad spectrum of clinical manifestations ranging from a single ulceration to a progressive and fatal visceral disease . Comprising a limited and highly toxic therapeutic arsenal new treatments are urgently needed . Targeting delivery of drugs has been a promising approach for visceral leishmaniasis . Phosphatidylserine liposomes have demonstrated superior efficacy in VL targeting intracellular parasites in host cells through macrophage scavenger receptors . In this work we investigated the | Nanoliposomal nitazoxanide NTZ LP eliminates amastigotes of. The uptake of NTZ LP by infected macrophages is similar to uninfected cells. NTZ LP localizes in a closer proximity to the amastigotes inside the macrophages. NTZ LP reduces the parasite burden by 82 liver and 50 spleen of hamsters. |
S0009279720315593 | The present study aims to explore the effects of astaxanthin on the semen quality of diabetes mellitus KKAy mice . A total of 60 DM KKAy mice with similar body weights and initial blood glucose and serum lipid levels were assigned to four groups namely one control and three astaxanthin treatments . Results show that oral astaxanthin administration reduced fasting blood glucose and serum total cholesterol low density lipoprotein cholesterol insulin and nitrate oxide levels in the testis of DM KKAy mice . Astaxanthin also improved the high density lipoprotein cholesterol protein and superoxide dismutase levels in the testis serum interleukin 11 tumour necrosis factor and interferon levels and sperm density sperm movement and normal morphology rate of DM KKAy mice . Based on the results astaxanthin can effectively affect serum cytokines and ameliorate semen quality of DM KKAy mice thus it may be developed as an adjuvant drug to treat diabetes mellitus induced infertility . | Astaxanthin decreased fasting blood glucose of diabetes mellitus KKAy mice. Astaxanthin decreased serum lipid levels of diabetes mellitus KKAy mice. Astaxanthin improved sperm quality of diabetes mellitus KKAy mice. |
S0009279720315726 | 1 Methylpyrene is a ubiquitous environmental pollutant and rodent carcinogen . Its mutagenic activity depends on sequential activation by various CYP and sulfotransferase enzymes . Previously we have observed induction of micronuclei and mitotic arrest by 1 MP in a Chinese hamster derived cell line expressing both human CYP1A2 and SULT1A1 however the mode of chromosome damage and the involvement of mitotic tubulin structures have not been clarified . In this study we used immunofluorescent staining of centromere protein B with the formed micronuclei and that of and tubulin reflecting the structures of mitotic spindle and centrioles respectively in V79 hCYP1A2 hSULT1A1 cells . The results indicated that 1 MP induced micronuclei in V79 hCYP1A2 hSULT1A1 cells from 0.125 to 2M under a 24h 0h regime while in the parental V79 Mz cells micronuclei were induced by 1 MP only at concentrations8M in both cases the micronuclei induced by 1 MP were predominantly CENP B positive . Following 54h of exposure 1 MP induced mitotic spindle non congression and centrosome amplification in V79 hCYP1A2 hSULT1A1 cells and anaphase telophase retardation at concentrations0.125M with concentration dependence while in V79 Mz cells it was inactive up to 8M . This study suggests that in mammalian cells proficient in activating enzymes 1 MP may induce chromosome loss and mitotic disturbance probably by interfering with the mitotic spindle and centrioles . | 1 Methylpyrene is potently aneugenic in metabolism proficient mammalian cells. 1 Methylpyrene may disrupt mitotic apparatus by interfering with tubulin. 1 Methylpyrene may retard mitotic progression. |
S0009279720315799 | COVID 2019 pandemic is affecting people worldwide in the absence of an effective treatment strategy . Several suggestive therapeutic options through drug repurposing are recommended but a complete consensus is not reached . A combination of Hydroxychloroquine and Azithromycin has been widely tried and discussed but its administration has also led to potential adversities in patients . Studies are suggesting that most prominent adverse event with HCQ and AZM combination is QT interval prolongation . We studied interaction of HCQ with AZM and subsequent effect of this drug combination on QT interval prolongation . We performed system biological investigation of HCQ and AZM targets and screened important targets and pathways possibly involved in QT interval prolongation . The best core hub protein drug targets involved in QT interval prolongation were identified as HSP90AA1 exclusively associated with HCQ while AKT1 exclusively associated with AZM on the basis of node degree value . It was found that PI3K Akt VEGF ERBB2 pathways must be given consideration for understanding the role of HCQ and AZM in QT interval prolongation . | Hydroxychloroquine and azithromycin is widely tried for recent pandemic. It is discussed to prolong QT interval causing severe adverse events. Potential drug targets involved in this process were screened using system biology. Pathways were also screened for drug combination mediated adverse events. |
S0009279720316367 | DNA is the store house of all necessary hereditary information for growth of cells and tissues . Physiological functionality of DNA depends on its 3D helical structure and any distortion in a structure may lead to mutation and genomic instability that may translate into disease like cancer . In order to prevent DNA damage an exogenous compound is required that can either scavenge the excess free radicals or enhance the structural integrity of DNA through binding . In the present study the binding mechanism of ethyl pyruvate with DNA models using different spectroscopic techniques was investigated for their structural integrity . Besides 2 2 diphenyl 1 picrylhydrazyl and ferric reducing antioxidant power assays were performed to determine the antioxidant scavenging of EP . Plasmid DNA relaxation assay was performed to assess the radioprotection efficacy of EP in the plasmid DNA . Circular dichroism and UVVis absorbance spectroscopic data confirmed the conformation change in ctDNA upon binding with EP . The molecular docking visualized that EP stacks between the DNA bases with a glide score of 2.117 | CD and UVVis spectra of ctDNA indicated conformational change after EP binding. Docking showed EP binds reversibly as an intercalator and in a minor groove of DNA. EP is an effective antioxidant. EP significantly protects DNA against radiation induced damage. |
S0009279720316896 | Erythrocytes represent the main cell component in circulation and recently have become a topic of intensive scientific interest . The relevance of erythrocytes as a model for cytotoxicity screening of xenobiotics is under the spotlight of this review . Erythrocytes constitute a fundamental cellular model to study potential interactions with blood components of manifold novel polymer or biomaterials . Morphological changes subsequent disruption of RBC membrane integrity and hemolysis could be used to determine the cytotoxicity of various compounds . Erythrocytes undergo a programmed death which could serve as a good model for evaluating certain mechanisms which correspond to apoptosis taking place in nucleated cells . Importantly erythrocytes can be successfully used as a valuable cellular model in examination of oxidative stress generated by certain diseases or multiple xenobiotics since red cells are subjected to permanent oxidative stress . Additionally the antioxidant capacity of erythrocytes and the activity of anti oxidative enzymes could reflect reactive oxygen species generating properties of various substances and allow to determine their effects on tissues . The last part of this review presents the latest findings on the possible application of RBCs as drug delivery systems . In conclusion all these findings make erythrocytes highly valuable cells for | Erythrocytes are a valuable. model for cytotoxicity screening of xenobiotics. Erythrocytes can be used as a cellular model in examination of oxidative stress. Red blood cells can be successfully applied as drug delivery systems. Xenobiotics can interact with erythrocytes membrane and induce eryptosis. |
S0014483518303907 | Diabetic retinopathy is a microvascular complication of diabetes and one of the most common causes of blindness in active stage . This study is performed to explore the effects of microRNA 21 on retinal vascular endothelial cell viability and angiogenesis in rats with DR via the phosphatidylinositiol 3 kinase protein kinase B vascular endothelial growth factor signaling pathway by binding to phosphatase and tensin homolog | Roles of miR 21 in EC viability and angiogenesis of DR were studied. MiR 21 targeted. and repressed its expression. Increased miR 21 and reduced. expression were observed in rats with DR. Increased angiogenesis was observed in retina of rats with DR. Activated PI3K Akt VEGF axis induced VEGF mRNA transcription and expression. |
S0014483519300193 | Although acute hyperoxia hypoxia alternation can shift sharply physiological processes of vessel development e.g . oxygen induced retinopathy very little is known of metabolic products resulted from the neovascularization disorder . In this study the influence of abnormal oxygen exposures on the plasma metabolomic profiles of rats with OIR was investigated by the gas chromatography mass spectrometry . Rat pups were divided into four groups each with 12 individuals reared in room air and sampled at P12 exposed to high oxygen for 5 days and sampled at P12 reared in room air and sampled at P17 exposed to high oxygen for 5 days then followed by room air for 5 days and sampled at P17 . Plasma samples were analyzed with GC MS resulted in 122 metabolite species . Distinct differences in the plasma metabolome were found between groups of CT1 vs. HO1 and HO1 vs. HO2 by using univariate and multivariate analyses . Alternating hyperoxia hypoxia conditions induced significant changes of richness of proline ornithine and glutamine that were important components of arginine and proline metabolism pathway . These metabolites contributed largely to plasma sample classification determined with receiver operating characteristic curve analysis and were involved profoundly in the proline dependent production of reactive oxygen species related to the cellular redox reactions . Our results from the rat OIR model suggest proline and arginine and proline metabolism pathway as the potential biomarkers for human retinopathy of prematurity diagnosis . | Plasma metabolomics study of rats with oxygen induced retinopathy OIR . Distinct differences of plasma metabolome were found in vaso obeliteration and neovasculization phases of rat OIR. Proline and arginine and proline metabolism pathway might be important in occurrence and development of rat OIR . |
S0014483519302039 | Retinal ganglion cell degeneration leading to irreversible blindness in chronic optic neuropathies commonly begins with dendritic shrinkage followed by axon degeneration . Although limited axon regeneration in the optic nerve is possible with a genetic deletion of PTEN SOCS3 after optic nerve injury the roles of PTEN SOCS3 on dendritic preservation and regeneration remain unclear . This study investigated the effect of PTEN SOCS3 genetic deletion on the structural integrity of RGC dendrites and axons in the retina following optic nerve crush . Using time lapse | PTEN but not SOCS3 deletion ameliorates RGC dendritic shrinkage after ON crush. Rate of dendritic shrinkage in SOCS3 deleted RGCs are no different from control. SOCS3 deletion enhances axon regeneration in the optic nerve but not the retina. Intrinsic RGC axon and dendritic preservation mechanisms are molecularly distinct. PTEN deletion shows aberrant axon regeneration in retina 6 months after ON crush. |
S0014483519302441 | Congenital cataracts the most common cause of visual impairment and blindness in children worldwide have diverse etiologies . According to statistics analysis about one quarter of congenital cataracts caused by genetic defects . Various mutations of more than one hundred genes have been identified in hereditary cataracts so far . In this review we briefly summarize recent developments about the genetics molecular mechanisms and treatments of congenital cataracts . The studies of these pathogenic mutations and molecular genetics is making it possible for us to comprehend the underlying mechanisms of cataractogenesis and providing new insights into the preventive diagnostic and therapeutic approaches of cataracts . | Congenital cataracts represent the leading cause of visual disability in childhood. Genetic researches identified various mutations of associated genes acting through varied mechanisms in inherited cataract. Future studies in lens regeneration and anti aggregation drugs may provide new insights into treatment of congenital cataract. |
S0014483519302489 | We studied the early protein profile in the ocular tissue extracted after LASIK and SMILE surgery . SMILE and LASIK was performed in contralateral eyes and stromal tissue samples were collected from 10 eyes of 5 donors . The stromal tissue samples were analyzed using label free quantification approach and ITRAQ labelling approach in LC MS MS . Combined functional analysis revealed many differentially expressed proteins which were involved in important biological processes . About 117 unique differentially expressed proteins were identified using two different proteomic approaches . Collagens proteoglycans corneal crystallins were enriched and showed differential expression in SMILE and LASIK as compared to the non surgical control . Apart from these 14 3 3 class of proteins Lysozyme Macrophage Migratory Inhibitory Factor protein Pigment Epithelial Derived Factor were differentially expressed when compared between LASIK and SMILE . Peroxiredoxin 1 expression was found to be reduced in LASIK as compared to SMILE . The expression of Lysozyme C and Macrophage Migratory Inhibitory Factor inflammatory response was found to be less in SMILE as compared to LASIK . Western blot validation of specific markers such as Collagen IV Keratocan Lumican Aldehyde dehydrogenase 3 A1 Lysozyme C confirmed the differences in the protein levels observed in SMILE and LASIK operated tissues as compared to non surgical controls . In conclusion this study revealed the early molecular changes occurring in the cornea resulting from these two surgical procedures which may have implications on managing post operative complications . | Collagens proteoglycans corneal crystallins expressed differentially in SMILE and LASIK as compared to control. Reduced expression of proinflammatory factors and lesser reduction in neurotrophic markers in SMILE compared to LASIK. Novel factors 14 3 3 class of proteins PEDF associated with the immediate post surgical response may be important targets. Wound healing post SMILE surgery may be better resulting in reduced post operative complications when compared to LASIK. |
S0014483519302738 | Astigmatism is a refractive error due to meridional differences in refractive powers of lens or cornea . The resulting failure to focus image points in a single plane causes blurred vision at all distances . In this study using an animal model of lens induced astigmatism we tested the hypothesis that induced astigmatism is due to processing of astigmatic retinal image information by the brain which causes distorted growth in the anterior segment via centrifugal neural projections . To induce astigmatism 4.00DS 8.00DC crossed cylinder lens goggles were affixed over the right eyes of 7 day old chicks with the 8.00DC axis oriented vertically or horizontally the left eyes were without goggles . For all experiments refractive errors of both eyes were measured by streak retinoscopy before and after 1 week of lens wear . To test whether neuronal pathways between retina and brain are required axonal conduction within the eye was blocked by intravitreal injections of tetrodotoxin . TTX effectively blocked nerve conduction within the eye for 48h after injection . Goggled eyes developed astigmatism after treatment with TTX or PBS but not after excitotoxins . Our hypothesis was rejected . In this model the compensatory astigmatism induced by crossed cylinder lenses is intrinsic to the eye and mediated by visual processing in the retina . | Crossed cylinder lenses induced compensatory refractive astigmatism in chicks. This effect was prevented by excitotoxins which disrupt retinal image processing. This effect was not prevented by tetrodotoxin block of nerve conduction in the eye. Lens induced astigmatism in chicks is mediated by local signaling within the retina. |
S0014483519302945 | The bird retina offers an excellent model to investigate the mechanisms that coordinate the morphogenesis histogenesis and differentiation of neuron and glial cells . Although these developmental features have been intensively studied in the chicken | Altricial and precocial bird species differ in the timing of visual system maturation. Visual system development occurs faster in precocial bird species than in altricial bird species. Retinal neurogenesis is intense at perinatal stages in altricial bird species. |
S0014483519303185 | Limbal stem cells a subpopulation of limbal epithelial basal cells are crucial to the homeostasis and wound healing of corneal epithelium . The identification and isolation of LSCs remains a challenge due to lack of specific LSCs biomarkers . In this study Haematoxylin eosin 4 6 diamidino 2 phenylindole and immunohistochemistry stains were performed on the pre and post natal limbus tissues of mice which has the advantage of more controllable in term of sampling age relative to human origin . By morphological analysis we supported that there is an absence of the Palisades of Vogt in the mouse . The development of prenatal and neonatal cornea was dominated by its stroma whereas after eyelids opened at P14 the corneal epithelial cells quickly go stratification in response to the liquid air interface . Based on IHC staining we found that the expression of LSCs putative biomarkers in limbal epithelial basal cells appeared in chronological order as follows Vim p63 CK14 CK15 and in corneal epithelial basal cells were weakened in chronological order as follows Vim p63 CK15 CK14 which might also represent the stemness degree . Furthermore the dynamic spatial expression of the examined LSCs putative biomarkers during mouse development also implied a temporal restriction . The expression of Vim in epithelial cells of mouse ocular surface occurred during E12 E19 only . The expression of CK15 was completely undetectable in CECs after P14 whereas the others putative molecular markers of LSCs such as p63 and CK14 still remained weak expression suggesting that CK15 was suitable to serve as the mouse LSCs biomarkers after P14 . In this study our data demonstrated the dynamic spatiotemporal expression pattern of LSCs putative biomarkers in mouse was age related and revealed the time spectrum of the expression of LSCs in mouse which adds in our knowledge by understanding the dynamic expression pattern of biomarkers of stem cells relate to maintenance of their stemness . | The differentiation of CECs is related to eye opening in mice. Dynamic spatial expression pattern reveals a temporal restriction of LSCs putative biomarkers. The order of Vim p63 CK15 CK14 might represent the stemness degree in ocular surface during mouse development. |
S0014483519303586 | Glaucoma is a major cause of blindness and IOP reduction remains the only clinically validated therapy . In this study we analyze a novel IOP lowering strategy that uses a modest negative pressure applied locally to the periorbital region by a pair of goggles with each lens individually connected to a programmable pump . Motivated by clinical data showing an IOP reduction we used an existing validated lumped parameter model of the eye to understand the putative mechanism of this treatment . The model considers aqueous humor dynamics episcleral venous pressure and changes in ocular blood volume to describe how IOP changes with time in response to an external perturbation . We find that clinical data are qualitatively and quantitatively consistent with model predictions if we include two primary mechanisms in the model first negative pressure application causes a relatively rapid increase in globe volume accompanied by increased blood volume in the eye . Second negative pressure application reduces episcleral venous pressure causing a slower adjustment of IOP due to altered aqueous humor dynamics . These results provide testable hypotheses that hopefully will lead to a fuller experimentally driven understanding of how negative periocular pressure influences IOP . Evaluating the long term effects of such treatments on glaucoma patients requires further clinical study . | A novel strategy for IOP management has been recently proposed patients wear goggles to deliver a modest negative pressure to the anterior globe and orbit. We used a lumped parameter mathematical model to investigate possible mechanisms of IOP lowering in this treatment. Model predictions are consistent with clinical data if we include ocular blood volume changes and reduction of episcleral venous pressure. The long term benefit for vision preservation of goggle wear remains to be determined but these results motivate further clinical studies. |
S0014483519303768 | Rhegmatogenous retinal detachment is the most common type of RD the separation of neurosensory retina from the underlying retinal pigment epithelium . The RRD patients can be benefited from appropriate treatment if detected early especially for the people predicted at high risk . In this study we aimed to investigate the genetic association and clinical correlation of collagen type II alpha 1 | rs1793958 variant is significantly associated with reduced risk of RRD in southern Chinese population. RRD patients carrying rs1793958G allele have milder RD severity compared to those carrying the wildtype AA genotype. RRD patients have poorer visual acuity and lower intraocular pressure in their surgical eyes compared to the fellow eyes. |
S0014483519303793 | Age related macular degeneration is a predominant cause of visual deficit in aged population . Abnormal accumulation of cholesterol including oxidized low density lipoprotein underneath the retinal pigment epithelium cells contributes to the development of AMD . Gypenosides are glycosides extracted from | Gypenosides enhance cholesterol efflux in retinal pigment epithelium cells. Gypenosides reduce uptake and accumulation of oxidized LDL in retinal pigment epithelium cells. Gypenosides suppress oxidized LDL induced ROS production in retinal pigment epithelium cells. Gypenosides inhibit oxidized LDL induced inflammation in retinal pigment epithelium cells. |
S0014483519303975 | Uveitis is usually considered as a vision threatening multiple system intraocular inflammatory disease . Among uveitis VogtKoyanagiHarada disease and Behcet s disease are common non infectious uveitis entities . Although the exact pathogenesis of uveitis is not yet clear it is acknowledged that the combination of a certain genetic or epigenetic factors with an imbalance in the regulation of the immune response leads to the development of this disease . HLA genes show a strong association with both VKH disease and BD in multiple ethnic populations . Candidate association studies based on a pathogenesis hypothesis laid the foundation for genetic research of uveitis and identified a large number of genes associated with VKH disease or BD including SUMO4 MCP 1 and CTLA4 . Genome wide association study provided a powerful tool for genome wide level analysis to explore the genetic predisposition for uveitis and revealed several genes to be associated with uveitis including IL23R C1orf141 STAT4 and ADO ZNF365 EGR2 . Another variant type the so called copy number variants in IL17F IL23A and C4A also showed an association with uveitis . Additionally epigenetic factors such as DNA methylation and ncRNAs play important roles in the development of uveitis . The application of new technologies such as whole exome sequencing and whole genome sequencing and other epigenetic modifications such as N6 methyl adenosine modification of mRNAs will be helpful to discover new pathogenic risk genes for uveitis . The understanding of the genetic and epigenetic mechanisms in uveitis may provide a foundation to find novel targets and to develop new strategies in the treatment of uveitis in the near future . | Summary SNPs genes associated with VKH disease and BD were enumerated. Summary CNVs genes associated with VKH disease and BD were generalized. Epigenetic factors especially DNA methylation and ncRNAs were closely related to VKH disease and BD. |
S0014483519304014 | In this study we evaluated the effect of placenta derived Mesenchymal Stem Cells versus placebo in improving corneal transparency following experimental injury in an ex vivo organ culture model of post mortem human corneas . We also compared the influence of MSCs on the basic histopathology of the cornea and the immunohistochemistry markers of fibrotic corneal scarring . Mesenchymal Stem Cells extracted from the placenta were isolated and expanded in vitro . Five pairs of post mortem human corneas harvested for the corneal transplant of equal grade were included in the study . Corneas of the same pair were randomly assigned to either the case arm or the control arm . All corneas underwent a standardized superficial keratectomy 4mm in diameter . The case and control arm corneas received an intrastromal injection of MSCs and placebo respectively . The corneal button was maintained in an organ culture system for 28 days under the standard protocol . Laser light was passed through the corneas mounted on a self styled modified artificial anterior chamber . Image analysis was used to quantify corneal transparency . Haematoxylin Eosin staining and Immunohistochemistry was done for Alpha SMA . Laser scatter measurements were measured using Image Analysis . The difference in the mean of Full Width Half Maximum Max intensity and Red pixel intensity between the cases and the controls was 101.5 16.3 and 11.4 respectively which was found to be statistically significant . Histopathology showed a disorganized Bowman s layer in the controls as compared to the cases . Alpha Smooth Muscle Actin at the injury site stained 3 in all controls as compared to 1 in the cases showing a statistically significant difference . Based on our findings we consider that placenta derived Mesenchymal Stem Cells can alter evolving corneal scarring into a more favourable outcome with better corneal transparency and lesser fibrotic corneal scarring . | Mesenchymal Stem Cells show reduced corneal scarring. Corneal transparency increases significantly with Mesenchymal Stem Cells. Histopathological staining shows marked difference between cases and controls. |
S0014483519304075 | Pre harvest burning of sugarcane fields produces large amounts of air pollutants which are known to cause health problems including ocular surface abnormalities . In this study we evaluated the effect of biomass burning on mucus quality and mucin gene expression in the conjunctiva of sugarcane workers and residents of an adjacent town . Impression cytology samples of the inferior tarsal and bulbar conjunctiva of 78 SWs and 32 RTs were collected before and immediately after a 6 month harvest period . The neutral acid and total mucus content of goblet cells was determined by PAS and AB staining . The levels of MUC5AC MUC1 and MUC16 mRNA in the conjunctiva were measured by real time PCR . Compared to RTs SWs had higher levels of bulbar acid mucus and MUC16 mRNA and tarsal MUC5AC mRNA at T2 and lower levels of neutral mucus at T1 and T2 . In the SW group MUC1 mRNA levels were higher at T2 than at T1 but the levels of neutral and acid mucus were similar . In the RT group acid mucus decreased and neutral mucus increased in the bulbar and tarsal conjunctiva at T2 . In conclusion our findings show that sugarcane harvesting is associated with abnormalities in mucus quality and content and changes in mucin mRNA levels on the ocular surface . This may help explain the ocular inflammatory signs and symptoms observed in subjects exposed to air pollutants and high temperatures from sugarcane biomass burning . | Sugarcane burning is known to produce large amounts of air pollutants at the harvest season. Impression cytology of bulbar and tarsal conjunctiva of sugarcane workers and residents nearby town were collected. The samples were processed to analysis the mucus profile neutral acid and the MUC1 MUC5AC and MUC16 mRNA levels. Sugarcane workers had lower levels of conjunctiva neutral mucus than the town residents before and after the harvest season. Sugarcane harvesting decreased acid and increased neutral mucus and MUC5AC mRNA levels in the conjunctiva in town residents. |
S0014483519304099 | The objectives of the present work were to assess by spectral domain optical coherence tomography the changes in thickness of the outer nuclear layer the ONL photoreceptor inner segment and the retinal thickness as a function of age in the normal canine retina . OCT retinal scans extending from the edge of the optic nerve head along the superior and inferior meridians were captured in both eyes of 17 normal dogs at age ranging from 4 to 119 weeks . The different parameters along the superior and the inferior regions were determined following manual segmentation using the Heidelberg Eye Explorer software . Changes in thickness with age were modeled using one phase exponential decay models . | Changes by OCT of the ONL ONL IS and retinal thickness of the canine retina. Thinning of retinal thickness occurs early in life. The superior retina is thicker than the inferior. The decline was modeled fitting a one phase decay model. |
S0014483519304117 | Elevated intraocular pressure is the primary risk factor for glaucoma and is the only treatable feature of the disease . There is a correlation between elevated pressure and homeostatic reductions in the aqueous humor outflow resistance via changes in the extracellular matrix of the trabecular meshwork . It is unclear how these extracellular matrix changes affect segmental patterns of aqueous humor outflow nor do we understand their causal relationship . The goal of this study was to determine whether there are changes in the segmental outflow regions with perfusion in normal eyes and whether these regions change during the IOP homeostatic response to elevated pressure . Using human anterior segment perfusion organ culture we measured the amount of high flow intermediate flow and low flow regions before and after 7 days of perfusion at either physiologic pressure or at elevated pressure . We found a small but significant decrease in the amount of HF regions over 7 days perfusion at 1x pressure and a twofold increase in the amount of MF regions over 7 days perfusion at 2x pressure . Small positional differences or shifts in the specific location of HF MF or LF occurred on a per eye basis and were not found to be statistically significant across biological replicates . Differences in the amount of segmental flow regions of contralateral eyes flowed at 1x pressure for 7 days were small and not statistically significant . These results demonstrate that perfusion at physiologic pressure had little effect on the distribution and amount of HF MF and LF regions . However the overall amount of MF regions is significantly increased in response to perfusion at elevated pressure during IOP homeostatic resistance adjustment . The amount of both HF and LF regions was decreased accordingly suggesting a coordinated response in the TM to elevated pressure . | Segmental flow regions of the TM are relatively stable after 7 days of perfusion. Intermediate flow regions are increased after perfusion at elevated pressure. These dynamic changes are part of the normal homeostatic response to pressure. Contralateral eyes show small differences in amounts of flow regions. |
S0014483519304154 | Microglial cells are important contributors to the neuroinflammation and blood vessel damage that occurs in ischemic retinopathies . We hypothesized that key effectors of the renin angiotensin aldosterone system angiotensin II and aldosterone increase the density of microglia in the retina and stimulate their production of reactive oxygen species as well as pro angiogenic and pro inflammatory factors . Two animal models were studied that featured up regulation of Ang II or aldosterone and included transgenic Ren 2 rats which overexpress renin and Ang II in tissues including the retina and Sprague Dawley rats with ischemic retinopathy and infused with aldosterone . Complementary studies were performed in primary cultures of retinal microglia from neonatal Sprague Dawley rats exposed to hypoxia 0.5 O | Angiotensin II and aldosterone increased the density of microglia in the retina. Blockade of the angiotensin type 1 receptor and aldosterone reduced reactive oxygen species and the expression of NADPH oxidase NOX isoforms in retinal microglia exposed to hypoxia. Blockade of the angiotensin type 1 receptor and aldosterone reduced the protein levels of pro angiogenic and pro inflammatory factors produced by retinal microglia in response to hypoxia. |
S0014483519304208 | Ocular rigidity is thought to play a role in the pathogenesis of glaucoma but the lack of reliable non invasive measurements has been a major technical challenge . We recently developed a clinical method using optical coherence tomography time lapse imaging and automated choroidal segmentation to measure the pulsatile choroidal volume change and calculate OR using Friedenwald s equation . Here we assess the validity and repeatability of this non invasive technique . We also propose an improved mathematical model of choroidal thickness to extrapolate V from the pulsatile submacular choroidal thickness change more accurately . The new mathematical model uses anatomical data accounting for the choroid thickness near the equator . The validity of the technique was tested by comparing OR coefficients obtained using our non invasive method OR | Clinical validation of a non invasive method for measuring ocular rigidity. Strong correlation between OR coefficients obtained non invasively and invasively. Integrated choroidal anatomy to improve our mathematical model and OR measurements. The method is reproducible and can be used to measure OR accurately. |
S001448351930435X | Porcine models of ophthalmological diseases are often used in pre clinical translational studies due to pigs similarities to humans . In particular the iodoacetic acid model of photoreceptor degeneration seems to mimic well the endstage phenotype of human pathologies as retinitis pigmentosa and age related macular degeneration with high potential for prosthesis retinal devices testing . IAA is capable of inducing photoreceptor death by blockage of glycolysis and its effects on the retina have been described . Nonetheless up to date literature lacks of a comprehensive morpho functional characterization of the entire visual system of this model . This gap is particularly critical for prosthesis testing as inner retinal structures and optic pathways must be preserved to elicit cortical responses and restore vision . In this study we investigated the functional and anatomical features of the visual system of IAA treated pigs and compared them to control animals . IAA was administered intravenously at 12mg kg control animals received saline solution . Electrophysiological analyses included full field and pattern electroretinograms and flash visually evoked potentials . Histological evaluations were performed on the retina and the optic pathways and included thickness of the different retinal layers ganglion cells count and immunohistochemistry for microglial cells macroglial cells and oligodendrocytes . The histological results indicate that IAA treatment does not affect the morphology of the inner retina and optic pathways . Electrophysiology confirms the selective rod and partial cone degeneration but is ambiguous as to the functionality of the optic pathways seemingly preserved as indicated by the still detectable fVEPs . Overall the work ameliorates the characterization of such rapid and cost effective model providing more strength and reliability for future pre clinical translational trials . | Iodoacetic acid 12mg kg does not alter the morphology of the inner retina and optic pathways. Functionality of the optic pathway seems to be impaired as confirmed by weak residual flash visually evoked potentials. This photoreceptor degeneration model seems to be suitable for retinal prosthesis preclinical testing. |
S0014483519304415 | Childhood glaucoma is an important cause of blindness world wide . Eleven genes are currently known to cause inherited forms of glaucoma with onset before age 20 . While all the early onset glaucoma genes cause severe disease considerable phenotypic variability is observed among mutations carriers . In particular | Eleven genes responsible for childhood forms of glaucoma are currently known. Variable clinical features can be observed in patients with mutations in childhood glaucoma genes. mutations can cause ocular and systemic disease. mutations causing ocular disease and hearing loss are primarily located in the forkhead domain. |
S0014483519304427 | Death of retinal photoreceptors is the basis of prevalent blinding diseases . Since steroids might have a therapeutic role in retinal degenerations we compared the protective effects of dexamethasone and progesterone on photoreceptor death induced by mifepristone and light exposure . | Dexamethasone progesterone protect 89 photoreceptors in mifepristone light injured retinas. Photoreceptor protection correlated with steroid specific changes in cell death regulators. Steroid dependent protection might also be associated to changes in rhodopsin and GR. |
S0014483519304580 | Neuronal excitotoxicity caused by over activation of N Methyl D Aspartate receptors is an important risk factor for the retinal ganglion cells death in glaucoma . D serine played a role as a key co agonist for NMDA receptor activity and neurotoxicity . Our previous studies have demonstrated that increased D serine and serine racemase expression in the retina of the chronic intraocular hypertension model were detected . D amino acid oxidase treatment significantly increased RGCs survival in the glaucomatous eyes . However the molecular mechanism remains unclear . In the present study we investigated the extracellular signal regulated protein kinase1 2 signaling pathway involved in DAAO neuroprotective effects on RGC survival and explore the effect of inhibited ERK1 2 phosphorylation on RGC survival and Mller cell activation in a COH rat model . We found that ERK1 2 phosphorylation and p38 kinase phosphorylation increased in the COH model while c Jun N terminal kinase phosphorylation didn t change . DAAO treatment induced ERK 1 2 MAP kinase phosphorylation and its upstream regulator p MEK increased in the COH model . The increased p ERK was mainly located in retinal Mller cells . In contrast p JNK and p p38 protein expression was not significantly different under these conditions . Quantitative analysis of RGC survival by fluorescent labeling and TdT mediated dUTP nick end labeling assays confirmed that p ERK1 2 inhibition by PD98059 attenuates DAAO mediated reductions in RGC apoptosis . Additionally p ERK1 2 inhibition induced elevated glial fibrillary acidic protein expression in Mller cells in the COH model . Together these results suggest that the ERK1 2 signaling pathway is involved in DAAO s neuroprotective effects on RGC survival . | Phosphorylation of ERK 1 2 and p38 increased in the COH model but not JNK. DAAO treatment induced the phosphorylation of ERK 1 2 in the COH model. ERK inhibitor PD98059 attenuated DAAO mediated reduction in RGC apoptosis. Inhibition of p ERK induced elevated GFAP expression in Mller cells in the COH model. |
S0014483519304609 | Elevated inflammatory cytokines contribute to the pathogenesis of various retinal diseases such as diabetic retinopathy retinal vasculitis and retinitis . However the underlying mechanism of retinal inflammation remains largely unknown . Recent studies demonstrated that acetylcholinesterase is an inflammatory indicator in central neural system . This study was aimed to dissect the role of ACHE in retinal inflammation and its mechanism of action . Retinal inflammation was induced by intravitreal injection of tumor necrosis factor in heterozygous ACHE knockdown mice ACHE | A novel function of ACHE in regulating retinal inflammation via NF B signaling. ACHE inhibition attenuating TNF induced retinal inflammation and vascular leakage likely through suppression of NF B signaling activation. Donepezil as a promising therapeutic agent for retinal inflammatory diseases. |
S0014483519304610 | Retinal detachment induces ischemia and oxygen deficiency in the retina and results in multiple pathological events photoreceptor cell degeneration and death is the eventual cause of vision decline . In this study we investigated the therapeutic effects of mesenchymal stem cell derived exosomes in a rat retinal detachment model . The model was developed using a subretinal injection of 1 hyaluronic acid in male Sprague Dawley rats . MSC Exos were sub retinally injected at the time of retinal separation to study their therapeutic function . The retinal expression levels of inflammatory cytokines TNF IL 1 and MCP 1 were detected by RT PCR the autophagy related protein 5 and microtubule associated protein 1 light chain 3 beta were detected by Western blot and apoptosis was examined using TUNEL assays at 3 days following RD . Retinal structure was observed at 7 days post RD . Proteomic analysis was also performed to detect proteins carried by MSC Exos using iTRAQ based technology combined with one dimensional nano LC nano ESI MS MS. We found that expression of TNF and IL 1 were significantly reduced the LC3 II to LC3 I ratio was enhanced and cleavage of Atg5 was decreased after MSC Exo treatment . Treatment with MSC Exos also suppressed photoreceptor cell apoptosis and maintained normal retinal structure when compared to control groups . Proteomic analysis revealed that MSC Exos contained proteins with anti inflammatory neuroprotective and anti apoptotic effects . These results suggest that MSC Exos have therapeutic effects on RD induced retinal injury and can be used to reduce effects of retinal detachment on photoreceptor cell degeneration in patients . | In this study we investigated the therapeutic effects of mesenchymal stem cell derived exosomes MSC Exos in a RD model. MSC Exos reduced retinal inflammation enhanced autophagy suppressed apoptosis and maintained retinal structure. Proteomic analysis revealed MSC Exos contained proteins that have therapeutic effects. |
S0014483519304683 | Neuropathic dry eye is one of the most frequently seen complications after corneal refractive surgery however its incidence decreases in a significant manner along the first six months postoperative reaching between 10 and 45 incidence . However little is known on the inflammatory status of the ocular surface during this recovery process . We aim to analyze the clinical and tear molecule concentration changes along six months after advanced surface ablation for myopia correction in a prospective study including 18 eyes of 18 subjects who bilaterally underwent advanced surface ablation corneal refractive surgery . Clinical variables and a panel of 23 pro and anti inflammatory cytokines chemokines concentration in tears preoperatively and at 1 3 and 6 months postoperatively were evaluated . We found that uncorrected distance visual acuity improved significantly from baseline at 1 month visit symptoms improved and tear osmolarity decreased significantly from baseline at 3 month visit and there was a decrease in mechanical corneal threshold between 1 month and 3 and 6 month visits . Regarding tear molecules IL 4 IL 5 IL 6 IL 13 IL 17A and IFN tear levels were significantly increased at all the three visits compared to preoperative levels at V0 IL 2 and VEGF were also significantly increased at 1 month and 6 month visits but not at 3 month visit whereas IL 9 IL 10 and IL 12 were only significantly increased at 6 month visit . Although we found that there is a recovery in clinical variables at 6 months postoperatively ocular surface homeostasis is not completely restored as it can be seen by the changes in concentration of some pro and anti inflammatory molecules measured in tears . | Clinical variables completely restore after 6 months of ASA refractive surgery. Some tear pro inflammatory cytokines chemokines do not recover their basal values. Ocular surface homeostasis is not completely restored after 6 months of ASA surgery. |
S0014483519304701 | The eye is a very important organ in the human body which is affected by various external factors . One of these factors is the sunlight which can cause the visual impairment and as well as the increase in the oxidative stress . The heme oxygenase I plays a very important role in the fight against the oxidative stress . The HO enzyme catalyses the degradation of the heme to the ferrous iron the biliverdin and the carbon monoxide . The HO 2 is the isoform HO 1 and is mainly constitutively expressed . We have studied the changes in the HO 1 and the HO 2 in the retina on the level of the RNA and the protein in the summer and in the winter season . The retina of the eye was obtained from the breeding pigs in concern | HO enzyme is a protective protein against oxidative stress and main producer of CO recognized as anti depression factor. Seasonal variation in HO expression in retina tissue was investigated. Changes in the gene expression and protein synthesis of HO 1 and HO 2 isoforms were characterized. The impact of some factors such as the length of the light day and biological clock on the HO synthesis was discussed. |
S0014483519304725 | Adaptation to changes in ambient light intensity in retinal cells and circuits optimizes visual functions . In the retina light adaptation results in changes in light sensitivity and spatiotemporal tuning of ganglion cells . Under light adapted conditions contrast sensitivity of ganglion cells is a bandpass function of spatial frequency in contrast dark adaptation reduces CS especially at higher spatial frequencies . In this work we aimed to understand intrinsic neuromodulatory mechanisms that underlie retinal adaptation to changes in ambient light level . Specifically we investigated how CS is affected by dopamine nitric oxide and modifiers of electrical coupling through gap junctions under different conditions of adapting illumination . | The optokinetic response is useful for assessing retinal function s in chicks. Dopamine and nitric oxide modulate high photopic adaptation in retinal circuits. Dopamine does this by stimulating nitric oxide release. Blocking connexin35 mediated cell cell coupling simulates high photopic adaptation. The chick has untapped potential as a model for retinal research. |
S0014483519304798 | Our previous work reported that minocycline induced inhibition of microglial activation aggravated visual injury in an oxygen induced retinopathy animal model . We hypothesized that minocycline might have aggravated injury to the photoreceptor . Some patients who use minocycline to treat acne complain of visual impairment however no studies have addressed minocycline toxicity to photoreceptors . Here we identified mechanistic effect of minocycline on photoreceptor apoptosis . The results of Cell Counting Kit 8 and Ki67 staining demonstrated that minocycline inhibited the proliferation of 661W cells and flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling demonstrated that minocycline promoted cell apoptosis . Additionally minocycline administration activated signaling associated with endoplasmic reticulum stress the pancreatic ER kinase like ER kinase eukaryotic translation initiation factor 2 CCAAT enhancer binding protein homologous protein cascade which represented the key mechanism underlying the initiation of apoptosis . Moreover we observed downregulated nuclear factor erythroid 2 related factor 2 after administration of minocycline for 12h and Nrf2 transferred from nuclear to cytoplasm after 6h indicating that Nrf2 in nuclear may alleviated the pro apoptotic effect of minocycline on photoreceptor cells . Upregulating Nrf2 inhibited apoptosis in minocycline treated 661W cells . These represent the first data demonstrating minocycline toxicity to photoreceptors via its pro apoptotic effects through the regulation of ER stress pathways . | Minocycline inhibits photoreceptor cell proliferation and promotes apoptosis. Minocycline treatment promotes ER stress mediated apoptosis. and. Minocycline regulates Nrf2 levels to mediate ER stress levels. |
S0014483519304816 | Age related macular degeneration is a complex disease with multiple genetic and environmental risk factors . In the age of molecular genetics many investigators have established a link between genes and development or progression of the disease . This later evolved to determine whether phenotypic features of AMD have distinct genetic profiles . Molecular genetics have subsequently been introduced as factors in risk assessment models increasing the predictive value of these tools . Models seek to predict either development or progression of disease and different AMD related genes aid our understanding of these respective features . Several investigators have attempted to link molecular genetics with treatment response but results and their clinical significance vary . Ocular and systemic biomarkers may interact with established genes promising future routes of ongoing clinical assessment . Our understanding of AMD molecular genetics is not yet sufficient to recommend routine testing despite its utility in the research setting . Clinicians must be wary of misusing population based risk models from genetic and biomarker associations as they are not necessarily relevant for individual counseling . This review addresses the known uses of predictive genetics and suggests future directions . | We continue to explore the genetic architecture that underlies the development of age related macular degeneration AMD . Genetics based risk models for the onset of AMD differ from those that predict the risk of AMD progression. Genetic profiling of individuals who may benefit from nutritional supplements has been shown to be unwarranted at this time. Molecular genetic variants in the future may have value in guiding current therapies with anti VEGF medications. This brief review addresses these issues and the current limitations of molecular genetics for the precision care of AMD. |
S0014483519304828 | Acylated lysine residues represent major chemical modifications in proteins . We investigated the malonylation and propionylation of lysine residues in the proteins of aging human lenses . Western blot results showed that the two modifications are present in human lens proteins . Liquid chromatography mass spectrometry results showed 418 and 432pmol mg protein of MalK and PropK respectively in human lens proteins with no apparent changes related to aging . Mass spectrometry results revealed that MalK and PropK modified lysine residues are present in all major crystallins other cytosolic proteins and membrane and cytoskeletal proteins of the lens . Several mitochondrial and cytosolic proteins in cultured human lens epithelial cells showed MalK and PropK modifications . Sirtuin 3 and sirtuin 5 were present in human lens epithelial and fiber cells . Moreover lens epithelial cell lysate deacylated propionylated and malonylated lysozyme . The absence of SIRT3 and SIRT5 led to higher PropK and MalK levels in mouse lenses . Together these data suggest that MalK and PropK are widespread modifications in lens and SIRT3 and SIRT5 could regulate their levels in lens epithelial cells . | SIRT3 and SIRT5 are present in human lenses and they are catalytically active in epithelial cells but not in fiber cells. Malonylation and propionylation of lysine residues occurs in human lens proteins and the levels of MalK and PropK do not change significantly during aging. The absence of SIRT3 and SIRT5 leads to increased propionylation and malonylation proteins in mouse lenses. |
S0014483519304920 | Administration of RC28 E a VEGF bFGF dual decoy receptor have shown relative therapeutic value in ocular in vivo models including laser induced choroidal neovascularization in monkeys and streptozotocin induced diabetic retinopathy in rats . In the present study we have elucidated the pharmacokinetics profiles of RC28 E at the systemic vitreous and aqueous humor after administration in a primate model | Drug could rapidly distribute into focus of eye after intravitreal administration. Exposure in choroid and retina could reach efficacy dose. Approximately one quarter drug enters blood circulation system through the blood ocular barrier. |
S0014483519304981 | Proliferative vitreoretinopathy is a blinding fibrotic eye disease that develops in 810 of patients who undergo primary retinal detachment reparative surgery and in 4060 of patients with open globe injury . At present there is no pharmacological treatment for this devastating disease . Vitreal growth factors activate their respective receptors of cells in the vitreous trigger their downstream signaling transduction Akt and drive cellular responses intrinsic to the pathogenesis of PVR . PI3Ks play a central role in experimental PVR . However which isoform are involved in PVR pathogenesis remain unknown . Herein we show that p110 a catalytic subunit of receptor regulated PI3K isoform is highly expressed in epiretinal membranes from patients with PVR and that idelalisib a specific inhibitor of PI3K effectively inhibits vitreous induced Akt activation proliferation migration and contraction of retinal pigment epithelial cells derived from an epiretinal membrane of a PVR patient . Small molecules of kinase inhibitors have shown great promise as a class of therapeutics for a variety of human diseases . The data herein suggest that idelalisib is a promising PVR prophylactic . | p110d is highly expressed in epiretinal membranes from patients with PVR. p110 is highly expressed in cultured cells from epiretinal membranes from patients with PVR. Idelalisib specifically inhibits vitreous induced Akt activation. Idelalisib effectively prevents vitreous induced proliferation migration and contraction of RPEs derived from an epiretinal membrane of a PVR patient. The data suggest that idelalisib is a promising PVR prophylactic. |
S0014483519305135 | The purpose of the current work was to utilize a three dimensional corneal epithelial tissue model to study dry eye disease and oxidative stress related corneal epithelial injuries for the advancement of ocular therapeutics . Air liquid interface cultures of normal human corneal epithelial cells were used to produce 3D corneal epithelial tissues appropriate for physiologically relevant exposure to environmental factors . Oxidative stress was generated by exposing the tissues to non toxic doses of ultraviolet radiation hydrogen peroxide vesicating agent nitrogen mustard or desiccating conditions that stimulated morphological cellular and molecular changes relevant to dry eye disease . Corneal specific responses including barrier function tissue viability reactive oxygen species accumulation lipid peroxidation cytokine release histology and gene expression were evaluated . 3D corneal epithelial tissue model structurally and functionally reproduced key features of molecular responses of various types of oxidative stress induced ocular damage . The most pronounced effects for different treatments were UV irradiation intracellular ROS accumulation hydrogen peroxide exposure barrier impairment and IL 8 release nitrogen mustard exposure lipid peroxidation and IL 8 release desiccating conditions tissue thinning a decline in mucin expression increased lipid peroxidation and IL 8 release . Utilizing a PCR gene array we compared the effects of corneal epithelial damage on the expression of 84 oxidative stress responsive genes and found specific molecular responses for each type of damage . The topical application of lubricant eye drops improved tissue morphology while decreasing lipid peroxidation and IL 8 release from tissues incubated at desiccating conditions . This model is anticipated to be a valuable tool to study molecular mechanisms of corneal epithelial damage and aid in the development of therapies against dry eye disease oxidative stress and vesicant induced ocular injuries . | Physiologically relevant organotypic normal human corneal epithelial tissue model. Realistic exposures to environmental factors low humidity UV harmful agents. 3D tissues reproduce key features of oxidative stressinduced ocular damage. Specific cellular and molecular responses to different types of oxidative stress. Regulation of oxidative stress responsive genes following an oxidative damage. |
S0014483519305160 | The avascular cornea trabecular meshwork and lens obtain iron an essential biometal from the aqueous humor . The mechanism by which this exchange is regulated however is unclear . Recently we reported that non pigmented ciliary epithelial cells express ferroportin an iron export protein modulated by hepcidin the master regulator of iron homeostasis secreted mainly by the liver . Here we explored whether ciliary epithelial and other cells in the anterior segment synthesize hepcidin suggesting local regulation of iron exchange at this site . Human and bovine eyes were dissected to isolate the ciliary body corneal endothelial TM lens epithelial and outer epithelial cell layer of the iris . Total mRNA and protein lysates were processed to evaluate the synthesis and expression of hepcidin the iron regulatory peptide hormone Fpn the only known iron export protein ceruloplasmin a ferroxidase necessary for iron export transferrin receptor a major iron uptake protein and ferritin a major iron storage protein . A combination of techniques including reverse transcription polymerase chain reaction of total mRNA Western blotting of protein lysates and immunofluorescence of fixed tissue sections were used to accomplish these goals . RT PCR of isolated tissue samples revealed hepcidin specific mRNA in the CB TM CE and LE of the bovine eye . Western blotting of protein lysates from these tissues showed reactivity for hepcidin Fpn ferritin and TfR . Western blotting and immunohistochemistry of similar tissues isolated from cadaveric human eyes showed expression of hepcidin Fpn and Cp in these samples . Notably Fpn and Cp were expressed on the basolateral membrane of non pigmented ciliary epithelial cells facing the AH . Synthesis and expression of hepcidin and Fpn in the ciliary epithelium suggests local regulation of iron transport from choroidal plexus in the ciliary body to the AH across the blood aqueous barrier . Expression of hepcidin and Fpn in CE TM and LE cells indicates additional regulation of iron exchange between the AH and cornea TM and lens suggesting autonomous regulation of iron homeostasis in the anterior segment . Physiological and pathological implications of these observations are discussed . | Hepcidin is synthesized locally by cells of the anterior eye segment AS . Co expression of ferroportin suggests autonomous regulation of iron in the AS. Hepcidin is upregulated by IL6 implicating iron in inflammation of the AS. |
S0014483519305214 | Diabetic retinopathy is triggered by retinal cell damage stimulated by the diabetic milieu including increased levels of intraocular free fatty acids . Free fatty acids may serve as an initiator of inflammatory cytokine release from Mller cells and the resulting cytokines are potent stimulators of retinal endothelial pathology such as leukostasis vascular permeability and basement membrane thickening . Our previous studies have elucidated a role for peroxisome proliferator activated receptor in promoting several steps in the pathologic cascade in DR including angiogenesis and expression of inflammatory mediators . Furthermore PPAR is a known target of lipid signaling suggesting a potential role for this transcription factor in fatty acid induced retinal inflammation . Therefore we hypothesized that PPAR stimulates both the induction of inflammatory mediators by Mller cells as well the paracrine induction of leukostasis in endothelial cells by Mller cell inflammatory products . To test this we used the PPAR inhibitor GSK0660 in primary human Mller cells human retinal microvascular endothelial cells and mouse retina . We found that palmitic acid activation of PPAR in HMC leads to the production of pro angiogenic and or inflammatory cytokines that may constitute DR relevant upstream paracrine inflammatory signals to EC and other retinal cells . Downstream EC transduce these signals and increase their synthesis and release of chemokines such as CCL8 and CXCL10 that regulate leukostasis and other cellular events related to vascular inflammation in DR. Our results indicate that PPAR inhibition mitigates these upstream as well as downstream inflammatory signaling events elicited by metabolic stimuli and inflammatory cytokines . Therefore our data suggest that PPAR inhibition is a potential therapeutic strategy against early DR pathology . | The PPAR inhibitor GSK0660 inhibits palmitic acid stimulated inflammatory mediator production by Mller cells. GSK0660 inhibits TNF induced leukocyte adhesion in both HRMEC and mouse retina. GSK0660 blocks TNF induced leukostasis by modulating the levels of CCL8 and CXCL10. GSK0660 s effects on retinal cells are mediated by both PPAR dependent and PPAR independent pathways. |
S001448351930541X | Previous metabolomics studies from our lab found altered plasma levels of bile acids in patients with age related macular degeneration compared to controls . In this study we investigated the ability of the bile acid taurocholic acid to inhibit features of AMD modeled | TCA protects RPE monolayer tight junctions. TCA inhibits VEGF induced cell migration in choroidal endothelial cells. TCA inhibits VEGF induced tube formation in choroidal endothelial cells |
S0014483519305469 | The accumulation of chondroitin sulfate proteoglycans in the glial scar following acute damage to the central nervous system limits the regeneration of injured axons . Given the rich diversity of CSPG core proteins and patterns of GAG sulfation identifying the composition of these CSPGs is essential for understanding their roles in injury and repair . Differential expression of core proteins and sulfation patterns have been characterized in the brain and spinal cord of mice and rats but a comprehensive study of these changes following optic nerve injury has not yet been performed . Here we show that the composition of CSPGs in the optic nerve and retina following optic nerve crush in mice and rats exhibits an increase in aggrecan brevican phosphacan neurocan and versican similar to changes following spinal cord injury . We also observe an increase in inhibitory 4 sulfated GAG chains which suggests that the persistence of CSPGs in the glial scar opposes the growth of CNS axons thereby contributing to the failure of regeneration and recovery of function . | Chondroitin sulfate proteoglycans in the optic nerve are upregulated following a crush injury. Proteoglycan expression is associated with astrogliosis. Different proteoglycan core proteins are localized differentially in the optic nerve. There is a major increase in 4 sulfated glycosaminoglycans. Optic nerve crush stimulates an increase in chondroitin sulfate proteoglycans in the retina. |
S0014483519305470 | The interaction of keratocytes with extracellular matrix components plays an important role in the maintenance of corneal transparency and shape as well as in the healing of corneal wounds . In particular the interaction of these cells with collagen and cell mediated collagen contraction contribute to wound closure . Endo180 is a receptor for collagen that mediates its cellular internalization . We have now examined the role of Endo180 in collagen contraction mediated by corneal fibroblasts . Antibodies to Endo180 inhibited the contractile activity of mouse corneal fibroblasts embedded in a three dimensional collagen gel and cultured in the presence of serum with this effect being both concentration and time dependent and essentially complete at an antibody concentration of 0.2g ml . Whereas corneal fibroblasts cultured in a collagen gel manifested a flattened morphology with prominent stress fibers under control conditions they showed a spindlelike shape with few stress fibers in the presence of antibodies to Endo180 . Antibodies to Endo180 had no effect on the expression of smooth muscle actin or the extent of collagen degradation in collagen gel cultures of corneal fibroblasts . Immunohistofluorescence analysis did not detect the expression of Endo180 in the unwounded mouse cornea . However Endo180 expression was detected in keratocytes migrating into the wound area at 3 days after a corneal incisional injury . Together our results suggest that Endo180 is required for the contraction of collagen matrix mediated by corneal fibroblasts and that its expression in these cells may contribute to the healing of corneal stromal wounds . | Endo180 is required for collagen gel contraction mediated by corneal fibroblasts. Endo180 is up regulated in migrating keratocytes during corneal wound healing. Interaction of Endo180 with collagen influences corneal fibroblast morphology. |
S0014483519305664 | Vision loss is a devastating consequence of systemic hypoxia but the cellular mechanisms are unclear . We investigated the impact of acute hypoxia in the retina and optic nerve . We induced systemic hypoxia 10 O | Acute systemic hypoxia led to glial response in the visual system. Hypoxia induced astrocyte stress and reactivity in the unmyelinated optic nerve. Hypoxia led to loss of oligodendrocytes in the myelinated optic nerve. |
S0014483519305676 | The eye lens is mainly composed of crystallins which undergo modifications such as oxidation deamidation and isomerization with aging . Asp58 Asp76 Asp84 and Asp151 residues of A crystallin are site specifically isomerized to L iso D and D iso isomers in aged related cataract lenses . In addition an A6680 peptide corresponding to the 6680 | A substation to the L iso form at Asp76 in A6680 peptides changed its properties. The A6680 peptide containing L iso Asp76 gains chaperone activity. The A6680 peptide containing L iso Asp76 has sheet structure. |
S0014483519305779 | Our study aimed to reveal the underlying pathologic mechanisms of thyroid associated ophthalmopathy by integrative transcriptomics and proteomic analysis of extraocular muscles . The study involved 11 TAO patients and 11 control donors . Total RNA was extracted from EOM samples of 5 TAO patients and 5 control individuals for gene microarray analysis to reveal differentially expressed genes . Concurrently EOM samples from 3 TAO patients and 3 control individuals were lysed for quantitative proteomic analysis . Differentially expressed genes and proteins were identified followed by functional and pathway enrichment analysis and protein protein interaction network construction . Concordance between proteins and transcripts was examined and functional annotations were conducted . Expressions of versican and lipocalin 1 in EOM samples from another 3 TAO patients and 3 control individuals were measured by western blotting . In total 952 genes and 137 proteins were identified as differentially expressed as well as 96 differentially expressed proteins without significantly changed mRNA abundance . Proteins mainly related to the composition and contraction force of the muscle fibers were significantly up regulated in EOM samples of TAO as well as those associated with cell adhesion . In addition differentially expressed proteins related to the components and metabolism of extracellular matrix were identified . Similarly expressions of genes involved in cell adhesion and ECM metabolism were significantly different between EOM samples of TAO patients and controls . Western blotting verified that VCAN involved in ECM proteoglycans and diseases associated with glycosaminoglycan metabolism was markedly higher in EOM samples of TAO whereas LCN1 was obviously decreased . In conclusion this study demonstrated the significantly altered cellular components of EOM muscle contraction cell adhesion and ECM metabolism which might be involved in the pathologic mechanisms and or consequences of TAO . | Proteomic analysis revealed differentially expressed proteins mainly related to component and contraction of EOM from TAO. Gene microarray analysis identified differentially expressed genes mainly involved in cell adhesion and ECM metabolism. Western blotting verified the up regulation and down regulation of versican and lipocalin 1 respectively in EOM from TAO. |
S0014483519305846 | In order to study the pathophysiological alterations of the ciliary body during persistent hypotony it is necessary to develop an animal model without CB injury . In this study we successfully established a modified model of persistent hypotony without CB injury in New Zealand rabbits . A 23 gauge pars plana vitrectomy was performed and a trocar formed fistula was allowed to remain | A model of hypotony without ciliary body injury is essential. We established a model of persistent hypotony without ciliary body injury. This is the only animal model that simulates secondary changes of hypotony. This model represents a valuable tool for studying hypotony. |
S0014483519305871 | Glaucoma is an age related neurodegenerative disease that is commonly associated with sensitivity to intraocular pressure . The disease selectively targets retinal ganglion cells and constituent axons . RGC axons are rich in voltage gated sodium channels which are essential for action potential initiation and regeneration . Here we identified voltage dependent sodium channel NaV1.2 in the retina examined how this channel contributes to RGC light responses and monitored NaV1.2 mRNA and protein expression in the retina during progression of modeled glaucoma . We found NaV1.2 is predominately localized in ganglion cell intraretinal axons with dispersed expression in the outer and inner plexiform layers . We showed Phrixotoxin 3 a potent NaV1.2 channel blocker significantly decreased RGC electrical activity in a dose dependent manner with an I | Voltage gated sodium NaV channel 1.2 is localized predominately in ganglion cell intraretinal axons. Retinal ganglion cell light responses are modulated by the NaV1.2 channel specific blocker Phrixotoxin 3. Elevating intraocular pressure for four weeks decreases NaV1.2 protein expression in the retina. |
S0014483519305913 | The reactive oxygen species producing enzyme NADPH oxidase 4 is upregulated in response to TGF in lens epithelial cells | Nox4 is not essential but involved in TGF induced lens EMT. Nox4 deficiency delays the onset of TGF induced cataract. In situ Nox2 upregulation may compensate for a loss of Nox4 expression. ERK1 2 signaling is required for TGF Smad2 3 signaling. |
S0014483519306001 | Optic fissure closure defects result in uveal coloboma a potentially blinding condition affecting between 0.5 and 2.6 per 10 000 births that may cause up to 10 of childhood blindness . Uveal coloboma is on a phenotypic continuum with microphthalmia and anophthalmia the so called MAC spectrum . This review gives a brief overview of the developmental biology behind coloboma and its clinical presentation spectrum . Special attention will be given to two prominent syndromic forms of coloboma namely CHARGE | Uveal coloboma a rare potentially blinding condition affecting between 0.5 and 2.6 per 10 000 births. Isolated and syndromic cases of uveal coloboma. Current knowledge on the genetics of human uveal coloboma with a specific focus on CHARGE and COACH syndromes. Approaches to identify genes involved in optic fissure closure using animal models. Live imaging of zebrafish eye development to understand optic fissure closure. |
S0014483519306177 | This study was conducted to evaluate the impact of varying scleral material properties on the biomechanical response of the cornea under air puff induced deformation . Twenty pairs of human donor eyes were obtained for this study . One eye from each pair had its sclera stiffened using 4 glutaraldehyde while the fellow eye served as control for uniaxial strip testing . The whole globes were mounted in a rigid holder and intraocular pressure was set using a saline column . Dynamic corneal response parameters were measured before and after scleral stiffening using the CorVis ST a dynamic Scheimpflug analyzer . IOP was set to 10 20 30 and 40mmHg with at least 3 examinations performed at each pressure step . Uniaxial tensile testing data were fit to a neo Hookean model to estimate the Young s modulus of treated and untreated sclera . Scleral Young s modulus was found to be significantly correlated with several response parameters including Highest Concavity Deformation Amplitude Peak Distance Highest Concavity Radius and Stiffness Parameter Highest Concavity . There were significant increases in SP HC after scleral stiffening at multiple levels of IOP while no significant difference was observed in the corneal Stiffness Parameter Applanation 1 at any level of IOP . Scleral mechanical properties significantly influenced the corneal deformation response to an air puff . The stiffer the sclera the greater the constraining effect on corneal deformation resulting in lower displaced amplitude . This may have important clinical implications and suggests that both corneal and scleral material properties contribute to the observed corneal response in air puff induced deformation . | Highlight 1 Altering scleral stiffness significantly impacted corneal deformation response. Highlight 2 Corneal deformation response is due to coupling of corneal and scleral properties. Highlight 3 Highest Concavity response parameters may be sensitive to scleral changes. |
S0014483519306207 | Myopic children have larger ciliary muscles than non myopic children suggesting that the ciliary muscle may have an impact on or be affected by refractive error development . The guinea pig represents an attractive model organism for myopia development research . The purpose of the study was to investigate whether form deprivation induced myopia in one or more strains of guinea pig causes thickening of the ciliary muscle as seen in human myopia . Thirty nine guinea pigs were bred from in house progenitors obtained from Cincinnati Children s Hospital and the United States Army . At 24 days of age the right eyes of animals were exposed to form deprivation for 7 days while the fellow eyes served as controls . Refractive error was determined with retinoscopy while vitreous chamber depth and axial length were determined with A scan ultrasound . Ciliary muscle characteristics were determined histologically with antibody labeling and analyzed according to whether the animal developed axial myopia or was unresponsive . This analysis method yielded four groups with Group 1 having no induced myopia but with axial elongation Group 2 having myopia without vitreous or axial elongation Group 3 having myopia with either vitreous or axial elongation and Group 4 having myopia with both vitreous and axial elongation . There were no post treatment inter ocular differences between strains or for the overall group of animals for any ciliary muscle variable however a higher response group number in multivariate ordinal regression was related to having a treated compared to fellow eye that had a lower smooth muscle actin concentration with a shorter ciliary muscle length and a less oblate eye shape . Guinea pig ciliary muscle length and smooth muscle actin concentration were significantly less in the treated eyes of axially myopic animals suggesting that 7 days of form deprivation induced ciliary muscle cellular atrophy or inhibited ciliary muscle growth . Form deprivation myopia in the guinea pig does not result in the increase in ciliary muscle thickness associated with human juvenile and adult myopia . | Induced axial myopia in guinea pigs results inciliary muscle morphological changes that differ from human myopia. Induced ciliary muscle changes suggest atrophy or inhibited muscle growth. New guinea pig strains were described for myopia development research. |
S0014483519306232 | Corneal neovascularization is a common sight threatening pathology that can be induced by a variety of inflammatory and angiogenic stimuli . Current CNV treatments include anti inflammatory drugs and antibody based inhibitors of vascular endothelial growth factor . However these are not always effective and novel therapeutic approaches are needed . Previous work has indicated a role for nucleolin in VEGF mediated neoangiogenesis in a suture induced CNV model . The major goal for this current study is to test the effect of AS1411 a NCL binding DNA aptamer that has reached human clinical trials on neovascularization in a murine model of VEGF mediated CNV . Our results show that topical administration of AS1411 can significantly inhibit corneal neovascularization in this model . Mechanistic studies indicate that AS1411 reduces the VEGF stimulated proliferation migration and tube formation of primary cells obtained from human limbus stroma . AS1411 treatment also significantly reduced VEGF stimulated induction of miR 21 and miR 221 in HLSC suggesting a role for these pro angiogenic miRNAs in mediating the effects of AS1411 in this system . In sum this new research further supports a role for NCL in the molecular etiology of CNV and identifies AS1411 as a potential anti angiogenic CNV treatment that works by a novel mechanism of action . | Treatment with topical nucleolin binding aptamer AS1411 decreased corneal neovascularization. AS1411 is able to reduce migration proliferation and tube formation of VEGF stimulated human limbal stromal cells HLSC . miRNA 21 and 221 reduction by AS1411 on VEGF HLSC explains in part the effect of AS1411 on corneal neovascularization. |
S0014483519306281 | Multiple retinal cells harbor a circadian oscillator including retinal pigment epithelial cells . However little is known about the functions that are regulated by the RPE clock . The aim of this study was to investigate whether the circadian clock in the RPE regulates the transport of glucose and its glycolytic metabolic by product lactate . To that end we first characterized the mRNA expression profile of glucose and monocarboxylate transporters in ARPE 19cells . We found that | The. and. transporter genes are highly expressed in ARPE 19cells. RPE monolayer organization is necessary for rhythmic transporter expression. POS incubation affects transporter expression in a time dependent manner. RPE mediated transport is rhythmic for lactate but not for glucose. |
S0014483519306542 | The lamina cribrosa in glaucoma is with augmented production of extracellular matrix proteins and connective tissue fibrosis . Fundamental pathological mechanisms for this fibrosis comprise fibrotic growth factors and oxidative stress . Transient receptor potential canonical channels channels play a key role in ECM fibrosis . Here we study TRPC expression in glaucomatous LC cells and investigate the role of TRPC in oxidative stress induced profibrotic ECM gene transcription and cell proliferation in normal LC cells . Age matched human LC cells were used . Hydrogen peroxide H | The lamina cribrosa in glaucoma is associated with increased extracellular matrix production and connective tissue fibrosis. Underlying pathological mechanisms of fibrosis include oxidative stress. TRPC channels play a key role in ECM fibrosis. TRPC1 C6 expression is enhanced in glaucoma LC cells. TRPC1 C6 contribute to H. induced ECM gene transcription involving the Ca. NFATc3 signaling pathway. TRPC1 C6 might constitute important therapeutic targets to prevent ECM remodeling and fibrosis in glaucoma optic neuropathy. |
S0014483519306608 | A recently described subtype of foveal hypoplasia with congenital nystagmus and optic nerve decussation defects was found to be associated with mutations in the Five Israeli families with congenital foveal hypoplasia were studied two of Karait Jewish origins and three of Indian Jewish origins . Subjects underwent a comprehensive ophthalmic examination including retinal photography and ocular coherence tomography . Molecular analysis including whole exome sequencing and screening of the Eight affected individuals were identified all had congenital nystagmus and all but one had hypoplastic foveal pits . Anterior segment dysgenesis was observed in only one patient one had evidence of developmental delay and another displayed early age related macular degeneration . Molecular analysis revealed a recently described homozygous mutation c.95T G p.Ile32Ser in two families of Jewish Indian descent and the same mutation in two families of Karaite Jewish descent . In a patient with only one pathogenic mutation a possible partial clinical expression of the disorder was seen . One patient of Jewish Indian descent was found to be compound heterozygous for c.95T G p.Ile32Ser and a novel mutation c.490 491delCT p.L164Vfs 41 . In five unrelated families with congenital nystagmus and foveal hypoplasia mutations in the | Foveal hypoplasia is a congenital disorder characterized by a lack of foveal depression in the foveal area. This study describes five unrelated families with foveal hypoplasia and nystagmus associated with SLC38A8 gene mutations. Expression in both Indian and Karaite Jewish ethnicities could be suggestive for common ancestry. A novel mutation c.490 491delCT is identified in the SLC38A8 gene. Expression in both Indian and Karaite Jewish ethnicities could be suggestive for common ancestry. A novel mutation c.490 491delCT is identified in the SLC38A8 gene. |
S0014483519306633 | The gut microbiota and its influence on host metabolism are considered to be an environmental factor that contributes to the progression of many immune and neurodegenerative diseases . However the features of the GM and serum metabolites in Primary open angle glaucoma patients have not been clearly elucidated . The purpose of this research is to explore the gut microbial composition and serum metabolic phenotype in POAG patients . 16S rRNA V4 genes of bacteria from the fecal samples of 30 POAG patients and 30 healthy subjects were sequenced by the Illumina MiSeq platform and then analyzed by QIIME . Their serum samples were analyzed by gas chromatography mass spectrometry based metabolomics . The association between gut microbial species and host circulating metabolites and clinical phenotypes was also analyzed . Compared with controls | POAG patients have different gut microbiota and serum metabolites with healthy subjects. Gut microbiota and host metabolism might be linked with glaucoma. Gut microbiota and metabolites targeted interventions of glaucoma should be considered in future. |
S0014483519306700 | Keratoconus is a controversial ophthalmological disease often considered both multifactorial and multigenic with poor or not entirely understood etiopathogenesis . Corneal collagen crosslinking procedure is the most common surgical therapy for KC which both slows corneal thinning and halts disease progression . While extensive studies provide consistent evidence on systemic oxidative stress in KC patients and animal models little is known on the tear fluid oxidative stress markers such as antioxidant enzymes activity or lipid peroxidation markers . Also little is known considering the oxidative status dynamics following CXL . In this way we aimed to evaluate three oxidative stress markers in the tears of KC patients before and after CXL procedure . | Oxidative stress is an important component of keratoconus pathological development. Corneal collagen crosslinking procedure is the most efficient treatment for keratoconus. Oxidative status changes can be observed in the tears of patients with keratoconus in a direct correlation to Amsler Krumeich stages. Oxidative status changes can be observed as further as 3 months following corneal collagen crosslinking procedure in the tears of keratoconus patients. Corneal collagen crosslinking induced oxidative stress could show a dependency with keratoconus severity. |
S0014483519306724 | Quantitative analysis of aqueous humor was performed to investigate glucose metabolism in patients with central retinal vein occlusion and to explore metabolic changes after anti vascular endothelial growth factor treatment . AH samples were collected from 35 patients . Participants diagnosed with CRVO were compared to participants who underwent cataract surgery . Thirteen of the participants with CRVO received second round anti VEGF treatments . Ultra high performance liquid chromatography tandem mass spectrometry was used to quantify metabolites of the AH . Central macular thickness and retinal ganglion cell layer thickness were measured using spectral domain optical coherence tomography . Thirteen metabolites involved in glucose metabolism were identified . Among these metabolites succinate glutamate and glutamine were significantly decreased for the CRVO group . The | Succinate glutamate and glutamine were significantly low in patients with CRVO. The ketoglutarate citrate ratio was positively correlation with glutamine levels. Lactate levels increased significantly after intravitreal anti VEGF administration. The change in CMT was negatively correlated with lactate increase. RGC thickness was negatively correlated with increased glucose and glutamine levels. |
S0014483519306785 | Glaucoma is a progressive neurodegenerative process affecting the retinal ganglion cells and the optic nerve . Oxidative stress has been implicated in glaucoma pathogenesis and iron is a potent generator of oxidative stress . The oral iron chelator deferiprone is protective against retinal degenerations associated with oxidative stress . To test whether DFP could be protective in glaucoma we used microbead injections to induce elevated intraocular pressure in a cohort of 3 month old C57BL 6J mice . One eye of each animal was injected with magnetic microbeads resulting in ocular hypertension for 7 weeks while the fellow eye was injected with saline and served as a normotensive internal control . While half of the cohort received oral DFP the other half did not and served as controls . After 8 weeks Brn3a immunolabeling of flat mounted retinas was used for manual RGC quantification . Axon counts were obtained from thin sections of optic nerves using the AxonJ plugin for ImageJ . DFP administration was protective against RGC and optic nerve loss in the setting of elevated IOP . These results suggest that iron chelation by DFP may provide glaucoma neuroprotection . | Oral DFP improved RGC survival in a microbead induced mouse model of glaucoma. DFP administration preserved retinal ganglion cells and optic nerve axons in hypertensive glaucomatous eyes. Iron chelation may be neuroprotective in glaucoma. |
S0014483519306797 | Experimental evidence suggests that dopamine modulates refractive eye growth . We evaluated whether increasing endogenous DA activity using pharmacological or genetic approaches decreased myopia susceptibility in mice . First we assessed the effects of systemic L 3 4 dihydroxyphenylalanine injections on form deprivation myopia in C57BL 6J WT | Systemic L DOPA administration prevents form deprivation myopia in mice. The dopamine packaging protein VMAT2 may affect early form deprivation myopia. Endogenously increased dopamine activity prevents form deprivation myopia in mice. |
S0014483519306839 | Retinal ischemia is a common condition that may lead into vision impairment and blindness . In this study we evaluated changes separately in On and Off visual responses induced by retinal ischemia . To do this reversible retinal ischemia was induced in anaesthetized rats by increasing the intraocular pressure until the eye fundus became whitish for either 30 or 60min . Both electroretinogram and multiunit neuronal activity in the superior colliculus were recorded simultaneously for at least 20min before during and after ischemia . In addition in normal eyes intravitreal glycine injections were performed to further investigate the mechanisms involved in this process . We found that collicular Off responses were more sensitive to ischemia than On responses . The Off response was the first one to decay at the time ischemia was induced and the last to recover after blood reperfusion . The duration of ischemia also differentially affected both responses . After 30min of ischemia 14 of SC recordings failed to recover Off responses . After 1h of ischemia the percentage of recordings that failed to recover Off responses increased to 50 . Post ischemic ERGs remained unaltered in all cases . Intravitreal Gly injections caused suppression of Off responses in the SC . Higher doses caused suppression of both On and Off responses in the SC but with no effect on the ERG at the doses tested . In summary Off responses were more sensitive than On responses to ischemia suggesting that different mechanisms drive the two types of responses . The recovery of transitory ischemia was not complete in the SC responses whereas the ERG remained unaltered suggesting that retinal damage produced by ischemia is more prominent in ganglion cells . Our results provide critical information for understanding ischemia repercussions and visual processing in the early visual system . | Collicular Off responses were more sensitive than ON responses to ischemia. Duration of ischemia differentially affected both responses On and Off . Recovery of ischemia was not complete in the SC whereas the ERG remained unaltered. |
S0014483519306967 | Orbital venous malformations are the most common benign orbital vascular disorders in adults and are characterized as enlarging encapsulated vascular neoplasms . These painless lesions grow slowly and become symptomatic with proptosis or visual disturbance . However the pathogenic mechanism and diagnostic markers of OVMs remain poorly understood . To identify potential pathways involved in OVM formation a cDNA microarray analysis was conducted with OVM samples and normal vascular tissues . These data were deposited in the National Omics Data Encyclopedia database . These pathway expression data were further confirmed by reverse transcription qPCR in an OVM cohort . To explore the diagnostic markers in OVM an angiogenesis antibody array was analyzed . The altered factors were further validated by enzyme linked immunosorbent assay in the OVM cohort . Transcriptome screening revealed upregulated autophagy and VEGF pathways and downregulated Hippo Wnt hedgehog and vascular smooth muscle contraction signaling pathways in OVM samples . Furthermore plasma EGF and Leptin levels were significantly elevated in OVM patients . Here for the first time we revealed the transcriptional background and plasma diagnostic markers in OVM providing a novel understanding of OVM pathogenesis and facilitating the early diagnosis of OVM . | Transcriptome screening revealed 2 upregulated and 4 downregulated signaling pathways in OVM samples. E2F1 was identified as the key transcriptional factor in regulating aberrant expression of lncRNAs. The plasma EGF and Leptin levels were significantly elevated in OVM patients. |
S0014483519306979 | Multiple aspects of cornea development including the innervation of the cornea by trigeminal axons are sensitive to embryonic levels of thyroid hormone . Although previous work showed that increased TH levels could enhance the rate of axonal extension within the cornea in a thyroxine dependent manner details underlying the stimulatory effect of TH on cornea innervation are unclear . Here by examining the effects throughout all stages of cornea innervation of the two main THs triiodothyronine and T4 we provide a more complete characterization of the stimulatory effects of TH on corneal nerves and begin to unravel the underlying molecular mechanisms . During development trigeminal axons are initially repelled at the corneal periphery and encircle the cornea in a pericorneal nerve ring prior to advancing into the corneal stroma radially from all along the nerve ring . Overall exogenous T3 led to pleiotropic effects throughout all stages of cornea innervation whereas the effects of exogenous T4 was confined to timepoints following completion of the nerve ring . Specifically exogenous T3 accelerated the formation of the pericorneal nerve ring . By utilizing | Pericorneal nerve ring formation was accelerated and corneas became precociously innerved in T3 treated embryos. T3 acts as a trophic factor to directly stimulate trigeminal nerve growth. Robo Slit pathway expression is reduced in eyefronts following T3 exposure. Growth rate and defasciculation of nerves increased within T3 or T4 treated corneas. KSPG CSPG and sulfation enzyme levels were modulated in T3 and T4 treated corneas. |
S0014483519307031 | Piezo channel is one of the mechanosensitive channels that senses pressure and shearing stress . Previous reports show that Piezo channel is expressed in many tissues such as skin and lung and they have many important roles . In addition the mRNA of | Piezo 1 2 were expressed in the cornea trabecular meshwork lens epithelial cells and on the retinal ganglion cell layer. Yoda 1 suppressed neurite outgrowth in retinal ganglion cells. GsMTx4 promoted neurite outgrowth in retinal ganglion cells. |
S0014483519307110 | The purpose of this study was to investigate the role of exosomes derived from platelet rich plasma in the regulation of the fibrogenic activity of Mller cells and the underlying mechanism . We studied the effects of PRP Exos on the fibrogenic activity of human retinal Mller cells in vitro . PRP Exos were isolated from the plasma of diabetic rats and normal control rats and then observed by transmission electron microscopy . After treatment with DM PRP Exos or Nor PRP Exos the proliferation and migration of hMCs were measured in vitro . Western blotting was conducted to assess the levels of fibrogenic molecules and activation of Yes associated protein and the PI3K Akt signalling pathway . In cultured hMCs DM PRP Exos but not Nor PRP Exos effectively increased the proliferative and migratory activities and improved connective tissue growth factor and fibronectin expression . Genetic and pharmacological suppression of YAP could reduce the proliferative and migratory activities of hMCs induced by DM PRP Exo . Additionally YAP knockdown inhibited the DM PRP Exo induced up regulation of CTGF and fibronectin . Furthermore DM PRP Exo induced PI3K Akt signalling mediated YAP activation and the expression of CTGF and fibronectin . In summary DM PRP Exos through YAP activation enhance both the proliferation and fibrogenic activity of Mller cells via the PI3K Akt pathway . | We firstly studied the role of PRP Exos in the regulation of fibrogenic activity of Mller cells and its mechanism. PRP Exos from diabetic rats could effectively increase proliferative and migratory activities of Mller cells. PRP Exos may contribute to the activation of YAP and promote the fibrogenic activity via the PI3K Akt pathway. |
S001448351930716X | As the peroxisome proliferator activated receptor alpha agonist fenofibrate has been widely used to be a good lipid regulating drug in the clinical application . In this study we investigated the mechanism by which keratocytes inhibit the corneal neovascularization through PPAR activation . To do this the CNV model was established by alkali burn followed by being divided into three groups including control fenofibrate and vehicle group . The expression of VEGFr3 MMP13 and PPAR in corneas of normal mouse and alkali burned mouse was determined via quantitative RT PCR and Western blot analysis . The CNV area was observed under a slit lamp microscope . The location of PPAR expression in the corneas was determined via immunohistochemistry . In cultured primary keratocytes the effect of fenofibrate on PPAR VEGFr3 and MMP13 expression was determined by qRT PCR and WB . Besides PPAR knockout mouse CNV and keratocytes model were established to further confirm the effect of PPAR on VEGFr3 and MMP13 expression . We found that PPAR was expressed in epithelium stroma and endothelium of the normal cornea however with relatively low level in the corneal stroma . Meanwhile its expression was decreased markedly in the cornea during the stage of CNV formation . After treatment of fenofibrate PPAR expression was promoted and the expression of VEGFr3 and MMP13 was inhibited in both CNV mice model and primary keratocytes and CNV areas were decreased in CNV mice model . However the results in PPAR CNV and keratocytes model were opposite . Our results suggest that keratocytes could promote the expression of VEGFr3 and MMP13 and CNV formation through PPAR downregulation . | PPAR gene knockout promoted the CNV induced by VEGFr3 and MMP13. PPAR activation inhibited the CNV via downregulating VEGFr3 and MMP13 expression. PPAR gene knockout could promote the VEGFr3 and MMP13 expression in keratocytes. Fenofibrate decreased VEGFr3 and MMP13 expression levels in keratocytes. |
S0014483519307171 | The transparent and refractive properties of the ocular lens are dependent on its precise cellular structure supported by the regulation of lens cellular processes of proliferation and differentiation that are essential throughout life . The ERK MAPK signalling pathway plays a crucial role in regulating lens cell proliferation and differentiation and in turn is regulated by inhibitory molecules including the Spred family of proteins to modulate and attenuate the impact of growth factor stimulation . Given Spreds are strongly and distinctly expressed in lens along with their established inhibitory role in a range of different tissues we investigated the role these antagonists play in regulating lens cell proliferation and differentiation and their contribution to lens structure and growth . Using established mice lines deficient for either or both Spred 1 and Spred 2 we demonstrate their role in regulating lens development by negatively regulating ERK1 2 activity . Mice deficient for both Spred 1 and Spred 2 have impaired lens and eye development displaying irregular lens epithelial and fibre cell activity as a result of increased levels of phosphorylated ERK1 2 . While Spred 1 and Spred 2 do not appear to be necessary for induction and early stages of lens morphogenesis nor for the formation of the primary fibre cells they are required for the continuous embryonic growth and differentiation of the lens . | The loss of Spreds results in a small lens eye phenotype. Spreds negatively regulate ERK1 2 signalling. Spreds negatively regulate lens epithelial cell proliferation. Spreds 1 and 2 complement each other in lens development. |
S0014483519307213 | Autophagy plays critical roles in various ocular diseases including age related macular degeneration . Tie2 expressing macrophages play crucial roles in angiogenesis . To investigate the role of TEMs and autophagy in the development of AMD we employed macrophage specific Tie2 knockout mice and used a laser induced choroidal neovascularization . The results showed that TEMs can promote CNV formation by up regulating the level of autophagy . These results were further verified by in vitro cell experiments that peritoneal macrophages from Tie2 knockout mice can inhibit the expression of autophagy related factors and inhibit the expression of angiogenic factor of VEGF by activating AMPK signaling pathway . Our results suggest that TEMs and macrophage Tie2 signal mediated autophagy play critical role in experimental CNV and they may be novel preventive targets for AMD treatment . | Knockdown of Tie2 expressing macrophagesin the laser induced CNVmicesuppress angiogenesisby reducing VEGF and autophagy. Supernatant from Tie2 knockoutmacrophagesinhibited migration tube formation VEGF and autophagyof bEnd.3 cells. Peritoneal macrophages from Tie2 knockout mice inhibitVEGFand autophagyby AMPK signaling pathway. |
S0014483519307298 | Elastic fibres provide tissues with elasticity and flexibility . In the healthy human cornea elastic fibres are limited to the posterior region of the peripheral stroma but their specific functional role remains elusive . | mg. mice showed abnormalities in corneal thickness from embryonic development through to adulthood. Elastic fibres were evident from E16.5 in both the WT and mg. mouse corneas. Adult mg. mouse corneas exhibited a disorganised elastic fibre network with unusually high levels of branching. The disrupted collagen arrangement seen in adult mg. mice corneas is likely linked to lower levels of decorin in these corneas. |
S001448351930733X | Various severe ocular diseases are associated with an elevated intravitreal expression of VEGF A which increases the permeability of retinal endothelial cells or retinal pigment epithelial cells | Blocking VEGFR2 efficiently reverts VEGF induced dysfunction of cells of the BRB. Additional blocking of other non tyrosine kinase receptors is not superior. Inhibiting VEGFR2 does not alter vitality of REC or RPE cells. Long term cultivated ARPE 19cells respond differently to VEGF A than short term cultivated ones. |
S0014483519307353 | Persistent non infectious uveitis has a significant morbidity but the extent to which this is accompanied by inflammation driven remodelling of the tissue is unclear . To address this question we studied a series of samples selected from two ocular tissue repositories and identified 15 samples with focal infiltration . Eleven of fifteen contained lymphocytes both B cells and T cells . In 20 of the samples there was evidence of ectopic lymphoid like structures with focal aggregations of B cells and T cells segregated into anatomically different adjacent zones . To investigate inflammation in the tissue an analysis of 520 immune relevant transcripts was carried out and 24 genes were differentially upregulated compared with control tissue . Two of these were increased in ocular inflammation compared to control immune tissue . We demonstrate that in a significant minority of patients chronic persistent uveitis leads to dysregulation of ocular immune surveillance characterized by the development of areas of local ectopic lymphoid like structures which may be a target for therapeutic intervention directed at antibody producing cells . | Active inflammation continues in cases of persistent uveitis. Some patients develop ectopic lymphoid like structure. In these cases targeting B cells may be beneficial. |
S0014483519307377 | Imaging techniques have revolutionised the assessment of retinal disease in humans and animal models . Here we describe a novel technique for the | Mouse models of RP that express GFP within rods allow spatiotemporal assessment of retinal degeneration. using cSLO. Mean grey values derived from the resulting images represent global indices of overall photoreceptor survival. This allows simple and objective mapping of focal photoreceptor loss or preservation following experimental intervention. |
S0014483519307432 | Methamphetamine an addictive stimulant of neurotransmitters is associated with cardiovascular and neurological diseases . METH induced ophthalmic complications are also present but have been insufficiently investigated . The purpose of this study is to investigate the retinal effects of METH . C57BL 6 mice were administrated progressively increasing doses of METH by repetitive intraperitoneal injections for 5 days . Retinal degeneration was examined by morphological changes and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling assay . Norepinephrine levels were measured by ELISA protein expression levels were determined by immunoblot and immunostaining and gelatinase activity was examined by zymography . The thickness of the retina and the number of nuclei in the inner and outer nuclear layers were decreased by METH . Retinal cell death and astrocyte activation by METH treatment were confirmed by TUNEL assay and glial fibrillary acidic protein expression respectively . Increased tumor necrosis factor protein in the retina and elevated norepinephrine levels in plasma were found in METH treated mice . Platelet endothelial cell adhesion molecule 1 protein expression level was decreased in the retina and central retinal artery by METH treatment along with the endothelial proteoglycans glypican 1 and syndecan 1 . Moreover a regulator of the extracellular matrix matrix metalloproteinase 14 in the retina and MMP 2 and MMP 9 in plasma were increased by METH treatment . In conclusion METH administration is involved in retinal degeneration with a vascular loss of PECAM 1 and the glycocalyx in the CRA and retina and an increase of MMPs . | Methamphetamine induces retinal neurodegeneration in mice. PECAM 1 and glycocalyx are lost from retinal vessels and central retinal artery following methamphetamine administration. Methamphetamine increases MMP 14 levels in the retina and MMP 2 and MMP 9 levels in plasma. |
S0014483519307444 | The present study was designed to investigate the effect of topical erythropoietin on the healing process of induced necrotizing scleritis and to evaluate the ocular side effects of this treatment modality in a rabbit model . Necrotizing scleritis was induced in 8 New Zealand albino rabbits . The animals were then randomly divided into one of two groups a treated group administered a topical erythropoietin containing cellulose based gel every 8h or a control group treated with a cellulose based gel without erythropoietin every 8h . The sizes of the lesions measured at different time points were compared between the groups . After three months the rabbits eyes were enucleated and histologically and immunohistochemically evaluated for angiogenesis and apoptosis . The lesions were completely vascularized in all eyes of the treated group and 50 of eyes of the control group . The mean interval from the induction of scleral necrosis to a complete improvement was 28 days in the treated group and 62.5 days in the control group . Histological examination revealed that erythropoietin enhanced the improvement of necrotizing scleritis by stimulating angiogenesis and reducing apoptosis . Neovascularization of the cornea iris or retina was not observed in the treated group . We observed a significantly faster recovery to complete improvement of necrotizing scleritis in rabbit eyes treated with erythropoietin compared to those of the control group . Treated eyes had a higher rate of complete healing and had no ocular safety concerns . This therapeutic modality represents a promising treatment for scleral necrosis following various types of ocular surgery . | Topical erythropoietin increased the rate of healing in induced necrotizing scleritis in rabbit eyes. The effect of erythropoietin was mediated by the inhibition of inflammation and apoptosis and stimulation of angiogenesis. Neovascularization of the cornea iris or retina was not observed in the treated eyes. |
S0014483519307511 | Loss of choriocapillaris in advanced age related macular degeneration is well documented but changes in early AMD have not been quantified . Postmortem eyes from donors with clinically documented early AMD were examined in choroidal whole mounts to determine the area pattern and severity of CC loss . Choroids from postmortem human eyes without AMD and from eyes with a Grade 2 clinical classification of early AMD were immunolabeled with | There is significant loss of submacular choriocapillaris in subjects with early AMD compared to control subjects. On the contrary there was no vascular pathology in paramacular choriocapillaris of the AMD subjects. Attenuation of choriocapillaris was associated with arteriosclerotic and hypertensive changes in Sattler s layer arterioles. Some of the areas of choriocapillaris loss had early choroidal neovascularization formations. |
S0014483519307535 | Corneal neovascularization can cause abnormal blood vessels to grow in the normally transparent and translucent cornea leading to various sight threatening eye diseases . microRNAs and circular RNAs are known to play essential roles in the regulation of numerous biological functions . It is urgently needed to understand the molecular mechanism of miRNAs and circular RNAs in the corneal neovascularization . We aimed to elucidate the role of a specific a circular RNA cZNF609 in the corneal neovascularization . cZNF609 and miR 184 levels were determined by RT qPCR . Luciferase reporter assay and RNA immunoprecipitation assay were conducted to verify the target of cZNF609 . The biological function of cZNF609 and miR 184 were assessed via cell proliferation migration and tube formation assays in vitro as well as the corneal suture model in vivo . The up regulation of cZNF609 and down regulation of miR 184 were observed during corneal neovascularization . cZNF609 acted as a miR 184 sponge to block miR 184 activity . Overexpression of miR 184 suppressed HCEKs cell proliferation migration in vitro and angiogenesis in vivo . The miR 184 mediated inhibition effect can be rescued through the re introduction of cZNF609 . Mechanically cZNF609 miR 184 interaction regulated the downstream Akt and VEGF signaling pathway . Intervention of cZNF609 and miR 184 may serve as a potential strategy for pathological corneal neovascularization treatment . | CZNF609 acted as a miR 184 sponge to block miR 184 activity. Overexpression of miR 184 suppressed HCEKs cell proliferation migration in vitro and angiogenesis in vivo. The miR 184 mediated inhibition effect can be rescued through the re introduction of cZNF609. |
S0014483519307687 | To investigate the protective effect of inhibiting miR 181a on diabetic corneal nerve in mice we chose male C57BL 6 mice with streptozotocin induced diabetes as animal models . The expression of miR 181a in trigeminal ganglion tissue of diabetic mice was detected by real time PCR . In vitro we cultured mouse trigeminal ganglion neurons and measured the neuronal axon growth when treated under miR 181a antagomir and negative conditions . Immunofluorescence showed a significant increase in neuronal axon length in trigeminal ganglion cells treated with miR 181a antagomir . In animal models we performed epithelial scraping and subconjunctival injection of the miR 181a antagomir and miRNA antagomir NTC to observe the corneal nerve repair by corneal nerve staining . miR 181a antagomir subconjunctival injection significantly increased the corneal epithelium healing of diabetic mice compared with that of the NTC group . Meanwhile corneal nerve staining showed that the repair of corneal nerve endings was significantly promoted . As the targets of the 181a ATG5 and BCL 2 were previously identified . The results of Western blot showed that the expression of autophagy associated protein ATG5 and LC3B II and the expression of anti apoptotic protein Bcl 2 were decreased in the high glucose cell culture environment and the diabetic TG tissue . The expression of ATG5 LC3B II and Bcl 2 were significantly increased after miR 181a antagomir treatment compared with negative control group . This study showed that inhibition of miR 181a expression in diabetic mice could increase ATG5 mediated autophagic activation BCL 2 mediated inhibition of apoptosis and promote the growth of trigeminal sensory neurons and the regeneration of corneal nerve fibers . It has a protective effect on diabetic corneal neuropathy . | We evaluated the expression of miR 181a which is significantly different between normal and diabetic mice in trigeminal ganglion tissue. The target genes of miR 181a were predicted by bioinformatics software Atg5 and Bcl 2 were identified as potential targets. This study demonstrated that inhibiting the expression of miR 181a in a diabetic mouse models can increase Atg5 mediated activation of autophagy and the Bcl 2 mediated inhibition of apoptosis which has a protective effect. |
S0014483519307729 | Retinal detachment results in disruption of retinal physiology and visual function . Although surgical intervention has been well developed to restore the retinal anatomic structure post op progression of visual function decline is prominent in a large proportion of patients . Therefore the establishment of a disease model that accurately mimics RD pathogenesis is crucial to mechanistic study and drug screening . General protocols to induce RD in mice are frequently associated with complications leading to model instability and reduced reproducibility . In this study we established a stable and reproducible mice RD model with a detached area of over 90 and rare complications . Briefly the modified method was realized by vitreous humor extraction to reduce intraocular pressure followed by directly visible hyaluronic acid injection into subretinal space . The detachment of retina was confirmed by fundus photography and progressive thinning of the outer nuclear layer was determined by HE staining . Apoptotic signals were prominent in the ONL . Consistently visual function was significantly compromised as determined by ERG . Moreover retinal vasculature appeared to remodel and acquired winding twisted and dilated structures illustrated by 3D reconstruction . In addition activation of Mller cells and microglia and infiltration of blood derived macrophages were detected locally . Collectively we have established a modified protocol to model RD with increased stability reproducibility and fewer complications and 3D high resolution imaging and reconstruction of vasculature could provide new tools to evaluate this model . | A modified model of retinal detachment in mice was established to better mimic pathogenesis. Vitreous humor extraction followed by visible hyaluronic acid injection increased the stability of model. Retinal vasculature after retinal detachment was evaluated by 3D imaging and reconstruction. |
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