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0.457435 | 1f7490fa69a546e1a4b1c9c1e4d7b66d | A forest plot showing the effect sizes (ES) and confidence intervals (CI) of HRV indices compared between groups. The vertical solid black line represents a mean difference of zero or no effect. Each black diamond shows the standardized mean difference. The upper and lower range of the line connected to the diamond shows the 95% CI for the ES. Group 1: clinician-rated and self-rated depression; Group 2: only self-rated depression; Group 3: clinician-rated and self-rated anxiety; Group 4: only self-rated anxiety. HRV, heart rate variability; Mean HR, mean heart rate; Mean RR, mean of all RR intervals; SDRR, standard deviation of all RR intervals; SDSD, standard deviation of differences between adjacent RR intervals; RMSSD, root mean square of successive RR interval differences; pNN20, percentage of differences between adjacent RR intervals >20 ms; nHF, normalized high-frequency power; nLF, normalized low-frequency power; LF/HF, low- to high-frequency ratio. | PMC10109339 | fpsyt-14-1124550-g002.jpg |
0.488737 | 5acdf6a32c174d39865f7a5e795045b5 | A forest plot showing the effect sizes (ES) and confidence intervals (CI) of HRV indices compared between groups. The vertical solid black line represents a mean difference of zero or no effect. Each black diamond shows the standardized mean difference. The upper and lower range of the line connected to the diamond shows the 95% CI for the ES. Group A: no depression group; Group 2: only self-rated depression; Group B: no anxiety group; Group 4: only self-rated anxiety. HRV, heart rate variability; Mean HR, mean heart rate; Mean RR, mean of all RR intervals; SDRR, standard deviation of all RR intervals; SDSD, standard deviation of differences between adjacent RR intervals; RMSSD, root mean square of successive RR interval differences; pNN20, percentage of differences between adjacent RR intervals >20 ms; nHF, normalized high-frequency power; nLF, normalized low-frequency power; LF/HF, low- to high-frequency ratio. | PMC10109339 | fpsyt-14-1124550-g003.jpg |
0.528292 | c097c507f3a04d188a19ad92e113cb44 | The mean blood pressure (A) and heart rate (B) of Dahl-SS rats at baseline and at the end of the 6-week and 12-week dietary interventions. (C) Timeline of the protocol. HS: the group with high salt intake for 12 weeks, n=8; HLS: the group with high salt for the first 6 weeks, then low salt intake for the next 6 weeks, n=8; HB: the group with high salt intake plus Benazepril administered intragastrically for 12 weeks, n=9; HLB: the group with high salt for the first 6 weeks, then low salt intake for the next 6 weeks, and with Benazepril administration throughout 12 weeks, n=9. | PMC10110468 | ijmsv20p0572g001.jpg |
0.451991 | 4c980136e8a34e2ebb255d40474ed739 | NE-induced vasoconstriction and ACh-induced vasodilatation of MSAs. (A) NE-induced maximum percentage change of the MSA inner vasoconstriction. (B) Duration of NE-induced vasoconstriction, from the beginning of vasoconstriction to the end of artery diameter recovery. (C) ACh-induced maximum percentage change in MSA inner vasodilatation. (D) Duration of ACh-induced vasodilatation, from the beginning of ACh injection to the end of artery diameter recovery. The percentage change in vasoconstriction/vasodilatation was calculated as the percentage of MSA inner diameter changes after NE/ACh injection divided by the baseline inner diameter. NE and ACh were injected through a femoral vein (10 μg/kg). The second order branch of the mesenteric arteries was recorded by a high-speed camera attached to a microscope. The measurements of three MSA segments were averaged. HS: the group with high salt intake for 12 weeks, n=8; HLS: the group with high salt for the first 6 weeks, then low salt intake for the next 6 weeks, n=8; HB: the group with high salt intake plus Benazepril administered intragastrically for 12 weeks, n=9; HLB: the group with high salt for the first 6 weeks, then low salt intake for the next 6-week, and with Benazepril administration throughout 12 weeks, n=9. MSA: mesenteric small artery; NE: norepinephrine; ACh: acetylcholine. *: compared with HS group, P<0.05; **: compared with the HS group, P<0.01; #: compared with the HLB group, P<0.05; ##: compared with the HLB group, P<0.01; @: compared with the HB group, P<0.05. | PMC10110468 | ijmsv20p0572g002.jpg |
0.422869 | 4675ad0875b24bf6a1d0f7299151e3e4 | Blood perfusion of the MSAs was recorded by full-field laser perfusion imaging. The MSAs of the proximal small intestine were recorded continuously for at least 10 minutes before and after injection of NE or ACh. (A) The average percentage changes in blood perfusion after NE injection. (B) The maximum percentage changes in blood perfusion after NE injection. (C) The average percentage increase in blood perfusion induced by ACh. (D) The maximum percentage increase in blood perfusion induced by ACh. The percentage changes within the MSAs were calculated as the average change in blood perfusion within a thirty-second interval after drug injection divided by baseline blood perfusion (i.e., thirty seconds of blood perfusion before NE/ACh administration). The maximum percentage change was calculated as the maximum blood perfusion induced by ACh (or minimum blood perfusion induced by NA) divided by the baseline blood perfusion. The measurements of three MSA segments were averaged. HS: the group with high salt intake for 12 weeks, n=8; HLS: the group with high salt for the first 6 weeks, then low salt intake for the next 6 weeks, n=8; HB: the group with high salt intake plus Benazepril administered intragastrically for 12 weeks, n=9; HLB: the group with high salt for the first 6 weeks, then low salt intake for the next 6 weeks, and with Benazepril administration throughout 12 weeks, n=9. MSA: mesenteric small artery; NE: norepinephrine; ACh: acetylcholine. *: compared with the HS group, P<0.05; **: compared with the HS group, P<0.01; #: compared with the HLB group, P<0.05. | PMC10110468 | ijmsv20p0572g003.jpg |
0.433475 | 40d64a45339347798403ef95dda5d2e7 | Histological and immunohistochemical changes in the MSAs of Dahl-SS rats. The sectioned MSAs were stained with hematoxylin and eosin (HE), Masson's trichrome and immunohistochemistry (original magnification × 400, scale bar: 50 μm). For IHC, nuclei appeared brown in positive expression of MSA by immunohistochemistry assay. HS: the group with high salt intake for 12 weeks; HLS: the group with high salt for the first 6 weeks, then low salt intake for the next 6 weeks; HB: the group with high salt intake plus Benazepril administered intragastrically for 12 weeks; HLB: the group with high salt for the first 6 weeks, then low salt intake for the next 6 weeks, and with Benazepril administration throughout 12 weeks. MSA: mesenteric small artery; HE: hematoxylin and eosin; IHC: immunohistochemical staining; eNOS: endothelial nitric oxide synthase; ACE: angiotensin-converting enzyme; AT1R: angiotensin II type 1 receptor; AT2R: angiotensin II type 2 receptor. IMT/LD ratio: intima-media thickness/internal lumen diameter ratio; CD rate: collagen deposition rate. eNOS PE rate: positive expression rate of endothelial nitric oxide synthase; ACE PE rate: positive expression rate of angiotensin converting enzyme; AT1R PE rate: positive expression rate of angiotensin II type 1 receptor; AT2R PE rate: positive expression rate of angiotensin II type 2 receptor. *: compared with the HS group, P<0.05; **: compared with the HS group, P<0.01; #: compared with the HLB group, P<0.05; ##: compared with the HLB group, P<0.01; @: compared with the HB group, P<0.05; @@: compared with the HB group, P<0.01. | PMC10110468 | ijmsv20p0572g004.jpg |
0.522498 | 53220542061444e0b8e5e3c29845dd1a | NPs exposure increases SGLT2 expression in PCAECs. PCAECs were incubated in the presence of different NPs concentrations (1 and 10 μg/mL) for 24 h and level of SGLT1 and SGLT2 expression were determined by western blot. (a–b) Representative immunoblots of SGLT1 and SGLT2 with their respective cumulative data. Data are the mean ± SEM (n = 3–5). ##p < 0.01, ###p < 0.001 versus NC: negative control (complete media). | PMC10110533 | 41598_2023_33086_Fig1_HTML.jpg |
0.478669 | 79c42e7168d94edcabb1af174355223d | Inhibition of SGLT2 suppresses NPs-induced premature senescence in cultured and native ECs. (a) Cell viability of PCAECs with different doses of ENA. Data are the mean ± SEM (n = 6). ###p < 0.001 versus NC (complete media). (b–c) SA-β-gal activity was determined by X gal staining in PCA and PCAECs treated with or without NPs (10 μg/mL) alone or with ENA (0.01, 0.1, 1 μM) for 24 h. Representative staining images of PCAECs showing SA-β-gal (blue stain), and PCA rings, respectively; scale bar = 100 μM. (d) Cumulative SA‐β‐gal activity in PCAECs as a percentage of control. Results are expressed as mean ± SEM (n = 3–4). **p < 0.01; ***p < 0.001 versus PC: positive control (complete media + NPs 10 μg/mL), ###p < 0.001 vs. NC (complete media). | PMC10110533 | 41598_2023_33086_Fig2_HTML.jpg |
0.460775 | 9cfb6263bf044cccad98111a176bf8a4 | SGLT2 inhibition increases cell proliferation and down-regulates the cell cycle regulatory proteins expression altered by NPs exposure. (a) Cell proliferation of PCAECs treated with or without NPs (10 μg/mL) alone or with ENA (0.01, 0.1, 1 μM) for 24 h. Data are the mean ± SEM (n = 6). *p < 0.05; **p < 0.01 vs. PC (complete media + NPs 10 μg/mL); ##p < 0.01 vs. NC (complete media). (b-c) Representative immunoblots for cell cycle regulatory proteins: p53 and p21 (lower band) with their corresponding cumulative data. Data are the mean ± SEM (n = 3–4). *p < 0.05 versus PC; #p < 0.05 versus NC. | PMC10110533 | 41598_2023_33086_Fig3_HTML.jpg |
0.446651 | 5fb68d8ece464f7dbfc24dbd2173799e | Enavogliflozin does not interfere with NPs uptake by PCAECs. (a) Representative confocal microscopy images of NPs internalization in PCAECs treated with or without NPs (10 μg/mL) alone and with ENA (1 μM) for 24 h. DAPI: diamidine-2-phenylindole dihydrochloride; MERGE: the merged image of NPs + DAPI; scale bar = 20 μM. (b) Representative histogram of NPs internalization analyzed with flow cytometry; (c) The mean of three independent experiments is presented as the relative mean fluorescence intensity (MFI). The values were normalized against the MFI of PC as a reference. The mean fluorescence intensity indicates the accumulation of NPs in cells. Data are the mean ± SEM (n = 3). ***p < 0.001 versus PC (complete media + NPs 10 μg/mL). | PMC10110533 | 41598_2023_33086_Fig4_HTML.jpg |
0.454795 | b8cf75872e03499ea3235b3af6ad1e68 | SGLT2 inhibition reduces NPs induced oxidative stress and prevents endothelial dysfunction. (a) Representative fluorescence microscopy images of DCF‐DA in live adherent ECs with corresponding 4′,6-Diamidino-2-phenylindole (DAPI) staining after the 24 h treatment of NPs (10 μg/mL) alone or with ENA (0.01, 0.1, 1 μM); scale bar = 500 μM. (b) Quantification of relative DCF-DA fluorescence intensity measured as a percentage of control. Data are the mean ± SEM (n = 5–6). *p < 0.05; ***p < 0.001 versus PC (complete media + NPs 10 μg/mL); ###p < 0.001 versus NC (complete media). (c) Representative microscopy images of ethidium fluorescence in arterial rings; scale bar = 100 μM. (d-f) Representative immunoblots of Nox2, p22phox (upper band) and eNOS proteins with their corresponding cumulative data. Data are the mean ± SEM (n = 3). *p < 0.05; **p < 0.01; ***p < 0.001 versus PC; #p < 0.05; ###p < 0.001 vs. NC. (g) Concentration-relaxation curve in response to BK after 24 h treatment with NPs (10 μg/mL) alone or with ENA (0.1 and 1 μM). Data are the mean ± SEM (n = 7–13). *p < 0.05; **p < 0.01 versus PC; ###p < 0.001 versus NC. | PMC10110533 | 41598_2023_33086_Fig5_HTML.jpg |
0.574019 | e4816ee21fe2420e85cf05b780e6d71e | Modelling the effect of 5HT2A-R activation on the whole-brain topographical distribution of entropy. (A) Resting state activity is simulated using the dynamic mean-Field (DMF) model, in which each region’s activity is represented by a time series of excitatory firing rates (constrained to 0–15 Hz for visualisation). The probability density function (PDF) and differential entropy (h(X)) of each region is then estimated, obtaining a topographical distribution of entropy values. (B) 5HT2A-R agonism is modelled as a receptor-density-dependent response gain modulation. Black line is the frequency–current (F–I) curve of a population without 5HT2A-R agonism, and coloured curves show the resulting F–I curves of regions with increasing 5HT2A-R agonism. (C) 5HT2A-R activation changes the topographical distribution of entropy with respect to resting state activity, which constitutes the main subject of analysis in this study. | PMC10110594 | 41598_2023_32649_Fig1_HTML.jpg |
0.403716 | f5db8b12a22849548b084766c1b51602 | Linear heterogeneous increase of entropy following 5HT2A-R activation. (A) Effect of 5HT2A-R agonism on the local entropy each of region in the AAL atlas. See Supplementary Table 1 for abbreviations. Bars indicate the (bilateral) average relative change in local entropy, \documentclass[12pt]{minimal}
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\begin{document}$$\Delta h_n$$\end{document}Δhn, and error bars indicate 1 standard deviation across 1000 simulations. (B) Histograms of local entropy values for the condition with (red) and without (blue) 5HT2A-R activation. 5HT2A-R activation increased both the average and the spread of the local entropy distribution. (C) Topographical map of entropy changes. Brain regions are coloured according to their \documentclass[12pt]{minimal}
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\begin{document}$$\Delta h_n$$\end{document}Δhn values. (D) 5HT2A-R agonism changed the topographical distribution of entropy in linear manner. Each circle indicates the averages of each region across 1000 simulations. | PMC10110594 | 41598_2023_32649_Fig2_HTML.jpg |
0.403285 | 68fdccf6fc5749cc82e0025bd6604ca6 | Changes in local entropy are explained best by connectivity strength, then receptor density. (A) Changes in entropy were overall independent from receptor density, although (B) they were well predicted by the connectivity strength of each region. We split into strength (blue and gray), and receptor dependent groups (red). The S\documentclass[12pt]{minimal}
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\begin{document}$$_1$$\end{document}1 and S\documentclass[12pt]{minimal}
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\begin{document}$$_2$$\end{document}2 groups showed no significant relationship with receptor density, while the R\documentclass[12pt]{minimal}
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\begin{document}$$_1$$\end{document}1 group were highly correlated with it. (C) Topographical localisation of the three groups, following the same colour code. S\documentclass[12pt]{minimal}
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\begin{document}$$_1$$\end{document}1 were mainly located in occipital, parietal and cingulate regions, while the R\documentclass[12pt]{minimal}
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\begin{document}$$_1$$\end{document}1 ones were in temporal and frontal ones. | PMC10110594 | 41598_2023_32649_Fig3_HTML.jpg |
0.419464 | 8ff6ff65feca45d5aa699c484611bf57 | Relative changes in entropy are partially reproduced by a strength-preserving null model of the connectome. (A–D) Connectivity matrices used to control the role of local properties of the connectome on \documentclass[12pt]{minimal}
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\begin{document}$$\Delta h_n$$\end{document}Δhn. See main text for the description of the matrices and randomisation algorithm. (E–G) Scatter plots of \documentclass[12pt]{minimal}
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\begin{document}$$\Delta h_n$$\end{document}Δhn for the human connectome against the three null models. DSPR yielded a high but not perfect correlation showing that local network properties of human connectome are necessary but not sufficient to capture the effect of 5HT2A-R activation. | PMC10110594 | 41598_2023_32649_Fig4_HTML.jpg |
0.449197 | bca55f460cb74ef0aeaeac78c83c207b | Case 2 AP and L X-ray after surgery | PMC10111707 | 13018_2023_3708_Fig1_HTML.jpg |
0.457332 | f7511fb2de9e4b3ca245097184a9bd58 | Case 2 AP and L at last follow-up | PMC10111707 | 13018_2023_3708_Fig2_HTML.jpg |
0.392888 | 5cd7f095db4e4857814943641b149a04 | Case 1 AP and L X-ray at last follow-up. A recurrence of foot deformity is visible | PMC10111707 | 13018_2023_3708_Fig3_HTML.jpg |
0.426103 | 769d068ca66748eb969e72b568a2ff09 | Case 1 AP and L X-ray after surgery | PMC10111707 | 13018_2023_3708_Fig4_HTML.jpg |
0.45713 | b913b2cc54344559ba5f906b67c36396 | Case 1 AP and L X-ray 6 months after surgery | PMC10111707 | 13018_2023_3708_Fig5_HTML.jpg |
0.47973 | 4591b1b5bdc349fba6252134d3ca1c43 | Case 1 AP and L X-ray before surgery (after 5 casts) | PMC10111707 | 13018_2023_3708_Fig6_HTML.jpg |
0.433189 | e30e48da329c484daa1cfa5a7d852391 | Case 2 AP and L X-ray before surgery | PMC10111707 | 13018_2023_3708_Fig7_HTML.jpg |
0.405272 | b6bbffcb86c44f7a88f00332d417b999 | The traditional H-shaped medical curriculum and a Z-shaped curriculum model [5] | PMC10111732 | 12909_2023_4221_Fig1_HTML.jpg |
0.419513 | 90068463d0524e1ba121d69561a41595 | Inflammation, atrophy, and fasciitis on lower limb MRI. An axial T1 image (A) demonstrates increased intramuscular fat signal bilaterally consistent with atrophy. An axial T2 fat saturated image (B) demonstrates diffuse muscular edema in all four compartments | PMC10111759 | 12969_2023_816_Fig1_HTML.jpg |
0.447004 | 718410d9dd624bd2b382f58864c7a131 | Gastrocnemius biopsy demonstrates granulomatous myositis with a histiocytic component with CD4+ T cell predominance. Left gastrocnemius biopsy revealed granulomatous myositis with perivascular inflammation (A, H&E, 100X) and extensive muscle fibrosis and fatty replacement (B, H&E, 40X). Special stains of the granulomas revealed a histiocytic component (C, CD68+ stain, 100X) with CD4+ T cell predominance (D, CD4+ stain, 100X). | PMC10111759 | 12969_2023_816_Fig2_HTML.jpg |
0.478691 | 7c37bc5cea5c4644959485ac5d4affe9 | Photomicrograph showing microscopic features of central giant cell granuloma (Haematoxylin and Eosin stain; Magnification 400×) | PMC10112111 | JOMFP-26-601b-g001.jpg |
0.461146 | 7e5424cdc9b145a2b2aac311d88fc5da | CD34 immunoexpression highlighting the blood vessels in CGCG (a: CD 34 in aggressive CGCG, b: CD 34 in non-aggressive CGCG) (Immunohistochemical stain; magnification 400×) | PMC10112111 | JOMFP-26-601b-g002.jpg |
0.465512 | 889c7774a9324512bd593a4dcf6cca61 | Importing the image to Image J software by dragging and dropping | PMC10112111 | JOMFP-26-601b-g003.jpg |
0.451314 | 5634f80b069f44afb414a8c0a98691ce | Opening the image in Image J software after dragging and dropping | PMC10112111 | JOMFP-26-601b-g004.jpg |
0.434207 | c1e2803b35ae45db982095ff2a454969 | Selection of the wand tool to trace the desired area in Image J | PMC10112111 | JOMFP-26-601b-g005.jpg |
0.430149 | 0976ab3fa67a45a8a7e946ee8ec892c3 | Tracing the perimeter of blood vessels | PMC10112111 | JOMFP-26-601b-g006.jpg |
0.458509 | 114bd57e605e4b18b78af46e4991ce51 | Selection of the tools, ‘Analyse’ followed by ‘Measure’ to obtain the area of the traced blood vessel | PMC10112111 | JOMFP-26-601b-g007.jpg |
0.405634 | ffcd21848d9246a2bb3c4c3a5200d33e | Vascular area obtained in the dialogue box | PMC10112111 | JOMFP-26-601b-g008.jpg |
0.472996 | e888245d5dad44a6977f83fc050565ee | Immunoexpression of α-SMA in CGCG cases (a: Score 1, b: Score 2, c: Score 3, d: Score 4) (Immunohistochemical stain; magnification 400×) | PMC10112111 | JOMFP-26-601b-g009.jpg |
0.435222 | c930918f1ba94e2c87be64e1f88844d7 | FZD4 expression is increased in ECs exposed to disturbed flow and regulates pro-inflammatory signalling. (A,B) Protein lysates were obtained from (A) HAECs exposed to DF and UF for 24–72 h or from (B) HAECs exposed to DF, UF or static conditions for 72 h. FZD4 expression was analysed by western blotting using calnexin (A) or PDHX (B) as a loading control. Data were analysed by two-tailed paired t-test at each time point (n=4) (A) or one-way ANOVA with Tukey's multiple comparison test (n=3) (B). Representative blots are shown in the panels above. (C) Aortas from juvenile pigs were fixed and sections cut from regions exposed to DF or UF. Sections were stained with anti-FZD4 and anti-β-catenin antibodies. Nuclei were stained with DAPI. Tissue sections were imaged en face and mean fluorescence intensity quantified in three fields of view for each flow region (n=4; analysis by Mann–Whitney test; representative images are shown). Scale bars: 50 µm. (D,E) RNA (D) or protein lysates (E) were prepared from ECs transfected with FZD4 siRNA (siFzd4) or scrambled (scr) controls and exposed to DF or UF for 48 h. Gene expression was determined by qRT-PCR using GAPDH as a housekeeping gene (n=6–8; analysis by Kruskal–Wallis test) (D). Expression of VCAM1 was assessed by western blotting using calnexin as a loading control (n=7; analysis by Mann–Whitney test; representative blots are shown in the panel) (E). All data are presented as mean±s.e.m and all n-values represent independent biological replicates. ns, not significant; *P<0.05; **P<0.01; ***P<0.001. | PMC10112981 | joces-136-260449-g1.jpg |
0.477817 | 801a86ecb7904153bb046f3fc58ebae6 | RSPO-3 expression is increased in ECs exposed to disturbed flow and regulates the expression of FZD4. (A–D) Lysates were obtained from HAECs exposed to DF and UF for 72 h. (A) RNA lysates were prepared and the expression of (A) FZD4 (n=16), (B) ZNRF3 (n=6) and (C) RSPO-3 (n=10) was determined by qRT-PCR using GAPDH as a housekeeping gene (analysis by Wilcoxon matched-pairs signed-rank test). (D) Protein lysates were prepared and analysed by western blotting using an anti-RSPO-3 antibody. Calnexin (CNX) was used as a loading control (n=8; analysis by two-tailed paired t-test; representative blots are shown in the panel above). (E–G) HAECs were transfected with RSPO-3 siRNA (siRSPO-3) or scrambled controls (scr) and exposed to flow for 48 h. Protein lysates were prepared from ECs exposed to DF and analysed by western blotting using antibodies against RSPO-3 (E) and FZD4 (F). Calnexin was used as a loading control (n=3–4; analysis by Mann–Whitney test; representative blots are shown in the panels above). (G) RNA was isolated from ECs exposed to DF and expression of pro-inflammatory genes determined by qRT-PCR using GAPDH as a housekeeping gene (n=3–4; analysis by Mann–Whitney test). All data are presented as mean±s.e.m. and all n-values represent independent biological replicates. ns, not significant; *P<0.05; **P<0.01; ****P<0.0001. | PMC10112981 | joces-136-260449-g2.jpg |
0.427593 | cab653b0121645f8a4a12d573a2823b7 | β-catenin activity is increased in ECs exposed to disturbed flow in a FZD4-dependent manner. (A–D) HAECs were exposed to flow for 72 h and treated with iCRT5 (50 µM) for the last 24 h of flow exposure. ‘Veh’, vehicle control. (A) HAECs were transfected with TCF reporter constructs 24 h prior to flow exposure. Lysates were prepared from cells exposed to DF and firefly and Renilla luciferase activity was recorded. Ratios were corrected for the protein content of lysates. Results shown are relative to the DF control (n=4; analysis by Mann–Whitney test). (B,C) RNA was harvested from ECs exposed to DF and UF and gene expression determined by qRT-PCR using GAPDH as a housekeeping gene (n=4–8; analysis by two-way ANOVA with Tukey's multiple comparison test). (C) HAECs were treated with TNFα for the final 24 h of flow exposure. RNA was harvested from ECs exposed to DF (n=3–4; analysis by one-way ANOVA with Tukey's multiple comparison test). Con, control. (D) The number of adherent calcein-labelled THP-1 monocytes was determined in four fields of view following treatment with iCRT5 for the final 24 h of flow exposure or for the full duration. Representative fluorescence images for DF control, iCRT5 (24 h) and TNFα (positive control) are shown; phase-contrast images are also included to show the presence of the intact EC monolayer. Scale bar: 200 µm. Results are shown relative to untreated controls (n=7; analysis by Mann–Whitney test). (E) HAECs were transfected with FZD4 siRNA (siFzd4) or scrambled control plus TCF reporter constructs and exposed to flow for 48 h. Lysates were prepared as for A. Results are shown relative to DF control (n=6; analysis by Kruskal–Wallis test). (F,G) HAECs were transfected with FZD4 or RSPO-3 siRNA or scrambled control and exposed to flow for 48 h. (F) Lysates were prepared from ECs exposed to DF and analysed by western blotting using an anti-β-catenin antibody. PDHX was used as a loading control (n=3–4; analysis by Mann–Whitney test). (G) Transcript levels of β-catenin (CTNNB1) were assessed by qRT-PCR using GAPDH as a housekeeping gene (n=5; analysis by Mann–Whitney test). All data are presented as mean±s.e.m. and all n-values represent independent biological replicates. ns, not significant; *P<0.05; **P<0.01; ***P<0.001; ****P<0.0001. | PMC10112981 | joces-136-260449-g3.jpg |
0.476848 | 0b7b6a23351e44458bfc331c1af0545d | WNT5A expression is increased in ECs exposed to disturbed flow. (A,B) HAECs were exposed to flow for 72 h and the expression of WNT5A was quantified in cells exposed to DF or UF by (A) qRT-PCR using GAPDH as a housekeeping gene (n=8; analysis by Wilcoxon signed-rank test) or (B) western blot using an anti-WNT5A antibody. Calnexin (CNX) was used as a loading control (n=8; analysis by Wilcoxon signed-rank test). (C,D) HAECs were transfected with WNT5A siRNA (siWnt5a) or scrambled controls and exposed to flow for 48 h. (C) WNT5A expression was assessed by western blotting using calnexin as a loading control (n=5; analysis by Mann–Whitney test). (D) Gene expression was determined by qRT-PCR using GAPDH as a housekeeping gene (n=4–5; analysis by Mann–Whitney test). (E,F) HAECs were exposed to flow for 72 h in the presence of sFRP-1 (200 µg ml−1) for the duration of flow exposure. (E) HAECs were transfected with TCF reporter constructs 24 h prior to flow exposure. Lysates were prepared from cells exposed to DF and firefly and Renilla luciferase activity was recorded. Ratios were corrected for protein content of lysates. Results are shown relative to the DF control (n=3; analysis by Mann–Whitney test). (F) Gene expression was determined by qRT-PCR using GAPDH as a housekeeping gene (n=3–4; analysis by Mann–Whitney test). All data are presented as mean±s.e.m. and all n-values represent independent biological replicates. *P<0.05; **P<0.01. | PMC10112981 | joces-136-260449-g4.jpg |
0.434929 | fbbd3101b883431e9816639130333ca1 | Disturbed flow inhibits the β-catenin destruction complex in a FZD4-, RSPO-3- and Ryk-dependent manner. (A,B) GSK3β phosphorylation was quantified by western blotting using anti-phospho GSK3β Ser9 and anti-GSK3β (total) antibodies in protein lysates from HAECs exposed to (A) DF and UF for 72 h or (B) DF for 48 h following transfection with FZD4 or RSPO-3 siRNA or scrambled controls. Calnexin (CNX) was used as a loading control. Results are shown relative to the DF control (A, n=9, analysis by Wilcoxon signed-rank test; and B, n=4, analysis by Mann–Whitney test). (C,D) HAECs were exposed to flow for 72 h and IWR-1 (10 µM) was added for the final 24 h of flow exposure. (C) HAECs were transfected with TCF reporter constructs 24 h prior to flow exposure. Lysates were prepared from cells exposed to DF and firefly and Renilla luciferase activity was recorded. Ratios were corrected for protein content of lysates. Results are shown relative to DF control (n=5; analysis by two-tailed unpaired t-test). (D) Gene expression was determined by qRT-PCR using GAPDH as a housekeeping gene (n=4; analysis by two-tailed unpaired t-test). (E,F) Lysates were obtained from ECs exposed to DF and UF for 72 h and (E) phosphorylated (n=8) or (F) total (n=5) LRP6 levels assessed by western blot using PDHX as a loading control (analysis by Wilcoxon signed-rank test). (G) HAECs were exposed to flow for 72 h and treated with DKK-1 (250 ng ml−1) f for the last 24 h of flow exposure. RNA was harvested from ECs exposed to DF and gene expression assessed by qRT-PCR using GAPDH as a housekeeping gene (n=4–5; analysis by Mann–Whitney test). (H–K) Lysates were obtained (H) from HAECs exposed to DF and UF for 72 h or (I–K) from HAECs exposed to DF for 48 h following transfection with Ryk siRNA (siRyk) or scrambled controls. (H–J) Expression of proteins was determined by western blotting using antibodies targeting (H,I) Ryk (n=3–4) or (J) β-catenin (n=3). PDHX or calnexin was used as a loading control (representative blots are shown in the panels above; n=3-4; analysis by Mann–Whitney test). (K) VCAM1 expression was assessed by qRT-PCR using GAPDH as a housekeeping gene (n=4; analysis by Mann–Whitney test). All data are presented as mean±s.e.m. and all n-values represent independent biological replicates. ns, not significant; *P<0.05; **P<0.01. | PMC10112981 | joces-136-260449-g5.jpg |
0.40282 | 3323a88b8311414c99df2827b0e64048 | β-catenin activity increases permeability in ECs exposed to disturbed flow and alters cytoskeletal and junctional organisation. (A–E) HAECs were exposed to flow for 72 h and treated with iCRT5 (50 µM) for the last 24 h of flow exposure. (A) FITC–avidin was added to monolayers immediately after flow cessation. Images show areas where FITC–avidin binds to biotinylated gelatin underlying ECs. Cells were counterstained with an anti-VE-cadherin antibody (images shown are maximum projections of z-stacks). Scale bars: 200 µm. (B) Accumulation of FITC–avidin was quantified by determining the intensity of FITC–avidin in maximum projections and shown relative to the DF vehicle control (n=5; analysis by two-way ANOVA with Tukey's multiple comparison test). (C–E) ECs were fixed and stained with an anti-VE-cadherin antibody and DRAQ5 nuclear stain with (C) an anti-ZO-1 antibody, (D) Alexa Fluor 488–Phalloidin or (E) an anti-vinculin antibody (representative images from four independent experiments). Scale bars: 50 µm. All data are presented as mean±s.e.m. and all n-values represent independent biological replicates. **P<0.01. | PMC10112981 | joces-136-260449-g6.jpg |
0.458573 | ffdf302c53c042f7b444c575a50bd77e | Knockdown of FZD4 or WNT5A alters organisation of the cytoskeleton and vinculin in ECs exposed to disturbed flow. (A–D) HAECs were exposed to disturbed flow for 48 h following transfection with siRNAs targeting (A–C) FZD4 (siFzd4) or (D) WNT5A (siWnt5a) and compared to scrambled RNA-transfected control (scr). ECs were fixed and stained with an anti-VE-cadherin antibody and DRAQ5 nuclear stain with (A) anti-ZO-1, (B,D) Alexa Fluor 488–Phalloidin or (C) anti-vinculin antibody (representative images from four independent experiments). Scale bars: 50 µm. (E) HAECs were exposed to flow for 72 h and treated with iCRT5 (50 µM) for the last 24 h of flow exposure. RNA was harvested from ECs exposed to DF and gene expression assessed by qRT-PCR using GAPDH as a housekeeping gene (n=4–6; analysis by Mann–Whitney test). All data are presented as mean±s.e.m. and all n-values represent independent biological replicates. *P<0.05; **P<0.01. | PMC10112981 | joces-136-260449-g7.jpg |
0.410741 | 4b4fc985e78e4179be91ff7cfdf96715 | Proposed pathway of disturbed flow-dependent FZD4-β-catenin signalling. Disturbed flow increases the expression of FZD4 via an RSPO-3-dependent mechanism. Activation of FZD4 by WNT5A inhibits the GSK3β-axin-APC destruction complex, promoting the stabilisation and nuclear translocation of β-catenin. Increased transcriptional activity of β-catenin promotes endothelial dysfunction via increased pro-inflammatory signalling and barrier disruption. The targets of inhibitors used in this study are shown at relevant points in the pathway. Image created with BioRender.com and published with a BioRender content licence for use in academic journals. | PMC10112981 | joces-136-260449-g8.jpg |
0.455869 | 066d9d5a0ff44f098f1a62913b20e98b | DNMT3B-catalyzed SMAD7 DNA methylation correlates with poor prognosis of LAD patients.a, b Analysis of SMAD7 expression in 517 cases of LAD tissue and 59 cases of adjacent normal lung tissue (a), and 59 pairs of human LAD tissue and adjacent normal lung tissue (b) in the TCGA LUAD datasets. c Kaplan-Meier analysis (Log-rank test) of the 5-year overall survival of LAD patients in the TCGA LUAD datasets, who were divided into low or high SMAD7 expression subgroups. d, e Correlation between SMAD7 mRNA levels and the average beta-values (DNA methylation level) of the selected 6 methylation probes in 460 cases of LAD tissues in the TCGA LUAD datasets (d), and analysis of the average beta-values of the 6 probes against LAD tissues and adjacent normal lung tissues in the TCGA LUAD datasets (e). f, g Correlation between SMAD7 mRNA level and the average DNA methylation level of SMAD7 in 5 cases of normal lung tissues and 28 cases of our collected LAD cohort (f), and analysis of the average DNA methylation level of SMAD7 in adjacent normal lung tissues and LAD tissues in the cohort (g). h, i Kaplan-Meier analysis (Log-rank test) of the 5-year overall survival (left panel) and recurrence-free survival (right panel) of LAD patients in the TCGA LUAD datasets, who were divided into low or high SMAD7 methylation level subgroups. j, k Western blotting (WB) and qPCR analyses showed the effect of silencing DNMT3A and DNMT3B on the protein and mRNA level of SMAD7 in A549 and HCC827 cells with indicated treatments. l Bisulfite-sequencing PCR (BSP) validated the DNA methylation levels of region 1 of SMAD7 gene locus in A549 and HCC827 cells with indicated treatments. m, n WB and qPCR analysis showed the effect of overexpressing DNMT3A or DNMT3B on the protein and mRNA level of SMAD7 in A549 and HCC827 cells with indicated treatments. o BSP validated the DNA methylation level of region 1 of SMAD7 gene locus in A549 and HCC827 cells with indicated treatments. For aforementioned WB, qPCR and BSP assays, cells were treated with TGF-β1 at final concentration of 5 ng/mL for 48 h before the indicated assays were performed (j–o). Error bars represent mean ± SD. Two-tailed unpaired Student’s t-test (a, e and g), two-tailed paired Student’s t-test (b), and two-way ANOVA multiple comparison analysis (k, l, n, and o), respectively, were used for statistical analysis. **P < 0.01; *P < 0.05; ns, not significant, P > 0.05. | PMC10113255 | 41421_2023_528_Fig1_HTML.jpg |
0.475282 | 998b1d5993884dccb457e20cae5d8efa | PHF14 is identified as a novel binding partner of DNMT3B.a Putative bound proteins of DNMT3B were analyzed by IP-MS assay. Representative image was derived from 3 independent experiments. b, c Immunoprecipitation assays with Flag-tagged PHF14 and HA-tagged DNMT3B, respectively, in LAD cells and 293FT cells validated an interaction between PHF14 and DNMT3B. Incubation of IgG-conjugated beads with cell lysates was employed as the negative control in these assays. Representative blots were derived from 3 independent experiments. d WB analysis showed the effect of overexpressing (left panel) or knocking out PHF14 (right panel) on the protein level of SMAD7 in indicated LAD cells. e qPCR analysis showed the effect of overexpressing PHF14 on the mRNA level of SMAD7 in Calu3 and HCC827 cells with indicated treatments. f BSP validated the DNA methylation level of region 1 of SMAD7 gene locus in Calu3 and HCC827 cells with indicated treatments. g Measurement of SBE-luciferase activity showed relative TGF-β signaling activates in Calu3 and HCC827 cells with indicated treatments. h qPCR analysis showed the effect of knocking out PHF14 on the mRNA level of SMAD7 in A549 and PC9 cells with indicated treatments. i BSP validated the DNA methylation level of region 1 of SMAD7 gene locus in A549 and PC9 cells with indicated treatments. j Measurement of SBE-luciferase activity showed relative TGF-β signaling activates in A549 and PC9 cells with indicated treatments. For aforementioned WB, qPCR, BSP and SBE-luciferase activity assays, cells were treated with TGF-β1 at final concentration of 5 ng/mL for 48 h before the indicated assays were performed (d–j). Error bars represent means ± SD derived from three independent experiments. Two-way ANOVA multiple comparison analysis was used for statistical analysis. **P < 0.01; ns, not significant, P > 0.05. | PMC10113255 | 41421_2023_528_Fig2_HTML.jpg |
0.436428 | ff1d7c18738f40cda4068e5938ae0c25 | PHF14 facilities DNMT3B-mediated DNA methylation of SMAD7.a Representative images of subcellular localization of endogenous PHF14 in A549 cells and Flag-tagged PHF14 in 293FT cells (five random fields of view per slice, scale bar: 30 μm). b ChIP-qPCR assays validated the effect of overexpressing PHF14 (left) or knocking out PHF14 (right) on the occupancy of DNMT3B on region 1 of SMAD7 gene locus in indicated cells. c BSP validated the DNA methylation level of region 1 of SMAD7 gene locus in Calu3 and HCC827 cells with indicated treatments. d ChIP-qPCR assays validated the occupancy of Flag-tagged PHF14 on region 1 of SMAD7 gene locus in Calu3 and HCC827 cells with indicated treatments. e, f qPCR and WB analysis showed the mRNA and protein levels of SMAD7 in Calu3 and HCC827 cells with indicated treatments. g BSP validated the DNA methylation level of region 1 of SMAD7 gene locus in Calu3 and HCC827 cells with indicated treatments. h, i qPCR and WB analysis showed the mRNA and protein levels of SMAD7 in Calu3 and HCC827 cells with indicated treatments. V or shV represents control vectors for overexpression or shRNA knockdown, respectively. For aforementioned WB, qPCR, ChIP-qPCR and BSP assays, cells were treated with TGF-β1 at final concentration of 5 ng/mL for 48 h before the indicated assays were performed (b–i). Error bars represent means ± SD derived from three independent experiments. Two-way ANOVA multiple comparison analysis was used for statistical analysis. **P < 0.01; *P < 0.05; ns, not significant, P > 0.05. | PMC10113255 | 41421_2023_528_Fig3_HTML.jpg |
0.389428 | d15372b19ce4476cbf5e7e9e97410193 | PHF14 serves as a CG-rich motif reader to recruit DNMT3B on SMAD7 gene.a Schematic diagram of the truncated PHF14 protein constructions. Interactions between DNMT3B and various Flag-tagged truncated PHF14 constructions were evaluated by co-IP assays in 293FT cells without (b) or with DNase I treatment (c). d Wall-eye stereo view of the predicted interaction between the α-helix of PHF14 ePHD domain (right) and the major groove of DNA helix (left), in which key residues are shown as sticks, hydrogen bonds are shown as black dashes (upper panel), and electrostatic surface view of PHF14 ePHD domain bound to DNA helix (lower panel) was also shown. e Interactions between PHF14 ePHD domain or full-length PHF14 with unmethylated/methylated CG-rich oligonucleotides probes or AT-rich oligonucleotides probe were evaluated by EMSA using purified proteins. f, g Interactions between wild-type or mutated E430AK435A PHF14 ePHD domain or full-length PHF14 with unmethylated CG-rich oligonucleotides probes were evaluated by EMSA using purified proteins. Shifted DNA indicates protein-bound oligonucleotide probes, and free DNA indicates protein-free oligonucleotide probes. h SPR analysis measuring the affinity and kinetics of the interaction between PHF14 ePHD domain with CG-rich oligonucleotides probe. PHF14 ePHD domain was immobilized on a CM5 chip. i ChIP-qPCR assays validated the occupancy of Flag-tagged PHF14 on region 1 of SMAD7 gene locus in Calu3 and HCC827 cells with indicated treatments. j ChIP-qPCR assays validated the recruitment of DNMT3B on region 1 of SMAD7 gene locus in Calu3 and HCC827 cells with indicated treatments. k BSP validated the DNA methylation level of region 1 on SMAD7 gene locus in Calu3 and HCC827 cells with indicated treatments. l, m WB and qPCR analysis showed the effect of expressing wild-type or mutated PHF14 on the protein and mRNA levels of SMAD7 in Calu3 and HCC827 cells with indicated treatments. n Measurement of SBE-luciferase activity showed relative TGF-β signaling activates in Calu3 and HCC827 cells with indicated treatments. For aforementioned WB, qPCR, ChIP-qPCR, BSP and SBE-luciferase activity assays, cells were treated with TGF-β1 at final concentration of 5 ng/mL for 48 h before the indicated assays were performed (i–n). Error bars represent means ± SD derived from three independent experiments. Two-way ANOVA multiple comparison analysis was used for statistical analysis. **P < 0.01; ns, not significant, P > 0.05. | PMC10113255 | 41421_2023_528_Fig4_HTML.jpg |
0.414689 | 212c3763ef5b494cbbf627879b331aec | PHF14 promotes TGF-β-induced colony formation, invasion and migration of LAD cells in vitro.a, b Representative images and quantification of colony formation assays on A549 and PC9 cells with indicated treatments. c, d Representative images and quantification of invading cells in five random fields of matrigel-coated transwell assays performed on A549 and PC9 cells with indicated treatments. e, f Representative micrographs and quantification of wound healing assays performed on A549 and PC9 cells with indicated treatments. Images were photographed 24 h after wounds were scratched using pipette tips. g, h Representative images and quantification of colony formation assays performed on Calu3 and HCC827 cells with indicated treatments. i, j Representative images and quantification of invading cells in five random fields of matrigel-coated transwell assays performed using Calu3 and HCC827 cells with indicated treatments. k, l Representative micrographs and quantification of wound healing assays performed on Calu3 and HCC827 cells with indicated treatments. Images were photographed 24 h after wounds were scratched using pipette tips. PHF14, SMAD7 or shRNA of DNMT3B were ectopically stably transduced into indicated cells using lentiviral vectors. Prior to the cell functional assays, cells were pre-treated with TGF-β1 at final concentration of 5 ng/mL for 24 h, and this treatment was sustained throughout the assays (a–l). Scale bar: 100 μm (c, i), 300 μm (f, l). Error bars represent means ± SD derived from three independent experiments. Two-way ANOVA multiple comparison analysis was used for statistical analysis. **P < 0.01. | PMC10113255 | 41421_2023_528_Fig5_HTML.jpg |
0.490818 | 79f1076174cb4a1abb195a0d1848af51 | PHF14 promotes TGF-β-induced systemic metastases of LAD cells in vivo.a, b TGF-β1-overexpressing A549 and PC9 cells with PHF14 knocked out or corresponding vector-control cells labeled with reporting luciferase were injected via cardiac ventricle into nude mice (n = 5 per group). Representative bioluminescent images of systemic metastasis are shown (a), and quantitation of bioluminescent intensities were analyzed by ROI tools (b). c Metastatic bone lesions in mice intracardially injected with indicated cells were confirmed by micro-CT imaging and H&E staining. d Kaplan-Meier analysis (Log-rank test) of metastasis-free and overall survival of nude mice intracardially injected with indicated TGF-β1-overexpressing A549 and PC9 cells. e, f TGF-β1-overexpressing Calu3 and HCC827 cells labeled with luciferase reporter following indicated treatments were injected via cardiac ventricle into nude mice (n = 5 per group). Representative bioluminescent images of systemic metastasis are shown (e), and quantitation of bioluminescent intensities were analyzed by ROI tools (f). g Metastatic bone lesions in mice intracardially injected with the indicated cells were confirmed by micro-CT imaging and H&E staining. h Kaplan-Meier analysis (Log-rank test) of metastasis-free and overall survival of nude mice intracardially injected with indicated TGF-β1-overexpressing Calu3 and HCC827 cells. TGF-β1, PHF14, SMAD7 or shRNA of DNMT3B were ectopically stably expressed in indicated cell lines by using lentivirus. Scale bar: 100 μm. Error bars represent means ± SD derived from independent experiments. Two-way ANOVA multiple comparison analysis was used for statistical analysis. **P < 0.01; *P < 0.05. | PMC10113255 | 41421_2023_528_Fig6_HTML.jpg |
0.426234 | 238a046908a9413eb5b3ee0e3345630d | SMAD7 and PHF14 are diagnostic and prognostic biomarkers for LAD progression.a, b Analysis of PHF14 expression in 517 cases of LAD tissue and 59 cases of adjacent normal lung tissue (a), and 59 pairs of paired human LAD tissue and adjacent normal lung tissue (b) using the TCGA LUAD datasets. c–f WB and qPCR analysis showed that the expression of PHF14 is upregulated in LAD tissues compared with adjacent non-cancerous lung tissues in 8 cases of freshly collected LAD specimens, and in LAD cell lines compared with primary NLEC. g, h Kaplan-Meier analysis (Log-rank test) of the 5-year overall survival (left panel) and recurrence-free survival (right panel) of LAD patients in the TCGA LUAD datasets, who were divided into low or high PHF14 expression subgroups. i, j Representative IHC images show that PHF14 expression was inversely associated with the level of SMAD7 in LAD specimens with high DNMT3B expression, and the correlation between the expression levels of PHF14 and SMAD7 was not significant in those expressing low DNMT3B. Four representative cases are shown, scale bar: 50 μm. k GSEA analysis indicated that the PHF14 level positively correlated with TGF-β-mediated transcription using the TCGA LUAD dataset. The defined “high” and “low” expression levels of PHF14 were stratified by the median expression level. l Analysis of the SMAD7 ctDNA methylation level from our collected cohort, including 12 cases normal serum samples, 19 cases serum samples from non-metastatic LAD patients and 27 cases serum samples from metastatic LAD patients. m Analysis of the SMAD7 methylation level of ctDNA from 14 pairs serum samples of LAD patients before and after surgical resection of cancer. n Kaplan-Meier analysis (Log-rank test) of the 5-year overall survival of LAD patients in our collected LAD cohort, who were divided into two subgroups with low or high SMAD7 ctDNA methylation level. Two-tailed unpaired Student’s t-test (a), two-tailed paired Student’s t-test (b, m), cross-tabulation with two-tailed Chi-square test (j) and two-way ANOVA multiple comparison analysis (l) were used for statistical analysis. **P < 0.01; ns, not significant, P > 0.05. | PMC10113255 | 41421_2023_528_Fig7_HTML.jpg |
0.420102 | 91d8b15292bc4fe5b43a5c797c67aa1d | Flowchart (CCA cholangiocarcinoma, GEP NEN gastroenteropancreatic neuroendocrine neoplasm, HCC hepatocellular carcinoma, PDAC pancreatic ductal adenocarcinoma, ptx patients) | PMC10113327 | 10585_2023_10201_Fig1_HTML.jpg |
0.403324 | 1fbe024c6e5648cf94bee5d0c74d2015 | Kaplan–Meier curves of A brain metastasis-free survival (BMFS) and B overall survival (OS) according to different tumor entities (BMFS brain metastasis-free survival, CCA cholangiocarcinoma, GEP NEN gastroenteropancreatic neuroendocrine neoplasm, HCC hepatocellular carcinoma, OS overall survival, PDAC pancreatic ductal adenocarcinoma) | PMC10113327 | 10585_2023_10201_Fig2_HTML.jpg |
0.475701 | 914ab79372254697ab1ab3d6ee5203fb | Kaplan–Meier curves of overall survival (OS) according to treatment of brain metastases (BSC best supportive care, OS overall survival, WBRT whole brain radiotherapy) | PMC10113327 | 10585_2023_10201_Fig3_HTML.jpg |
0.458512 | 4b16317c42c94467b706035804704e82 |
In vitro chromosomal aberration and micronucleus studies: evaluation and summary of test results from 15 studies | PMC10113887 | EFS2-21-e06857-g001.jpg |
0.496414 | d7125e7273db40db8589509b2f8d6705 | Derivation from the overall enveloped and averaged cpfs of probabilities for the estimated lowest BMD across the 21 primary clusters being below the RP (see text for explanation)
The percentages shown in blue are probabilities for the estimated lowest BMD across the 21 primary clusters being below the RP derived from the lower and upper bounds of the overall enveloped cpf (probabilities 5% and 100%) and the lower and upper bounds of the overall averaged cpf (probabilities 56% and 72%).
| PMC10113887 | EFS2-21-e06857-g002.jpg |
0.452349 | 1b81aaae78f940a0b9e4bda010f56534 | Lower and upper bounds for the overall enveloped and averaged cpfs quantifying uncertainty about the estimated lowest BMD across the 21 primary clusters considered in the uncertainty analysis
The solid black curves show the lower and upper bounds for the overall enveloped cpf resulting from the range of judgements between WG experts (lower and upper refer to relative position on the vertical axis). The red dashed curves show the lower and upper bounds of the overall averaged cpf, where judgements of different experts for each cluster were aggregated by averaging.
| PMC10113887 | EFS2-21-e06857-g003.jpg |
0.402465 | 3b765b597d104625b2a5b28ce9a0881f | Combination of the enveloped cpfs for the 21 individual clusters to obtain lower and upper enveloped cpfs for the estimated lowest BMD across all clusters
The black curves in the graphs show the lower and upper bounds of the enveloped cpf for the estimated lowest BMD across all clusters for endpoints that occur in animals and are relevant and adverse for humans, assuming that the experts’ judgements for different clusters are independent. The coloured curves show the lower and upper bounds of the enveloped cpfs for the individual clusters, from which the combined cpfs are calculated. The curves for each cluster are identified by the combination of line type (solid, dashed, etc.) and colour, as shown by the legend on the right.
| PMC10113887 | EFS2-21-e06857-g004.jpg |
0.414919 | a3bcc579af7f474fb6d9e33f0da7d3f7 | Judgements of the experts for Question 3: their probability that the lowest BMD of all those endpoints that occur in animals tested with BPA and are both relevant and adverse for humans is below the RP of 8.2 ng BPA/kg bw per day (HED), taking account of the 21 clusters assessed for Questions 1 and 2 and the additional uncertainties listed in Table D.5
| PMC10113887 | EFS2-21-e06857-g005.jpg |
0.435576 | 2478a632f7de4abcbc225ab9667ef85c | Parametric distributions fitted to the judgements of 16 experts for Question 2 for the cluster allergic lung inflammation
Note: The odd‐looking distribution with a sharp peak near the centre of the graph is mixture of two normal distributions which provided the best fit to the judgements of this expert (expert C), shown in Annex K. Sensitivity analysis showed that using these fitted distributions or the histograms provided by the experts made no material difference to the results (see later).
| PMC10113887 | EFS2-21-e06857-g006.jpg |
0.448329 | 18775cdddc8245a9bee3ee365edc127f |
In vivo chromosomal aberration and micronucleus studies: evaluation and summary of test results from 11 studies | PMC10113887 | EFS2-21-e06857-g007.jpg |
0.437139 | 53816919c31e432ba6bba13d570cfdb5 | Diagram of the conceptual model for the uncertainty analysis of the hazard assessment for HOCs other than genotoxicity, the uncertainty analysis for which was conducted separately and is described in Section 2.3.4.2. See text for further explanation | PMC10113887 | EFS2-21-e06857-g010.jpg |
0.456218 | ff7095617b45450ba0d1e8b9f168536a | Key endpoints and effect sizes considered by the experts when assessing Question 2 for the cluster allergic lung inflammation
Labels on the horizontal axis comprise study reference identification number (RefID), endpoint, tier of study (from WoE assessment), sex and species. Percentages shown by BMDU and BMDL symbols refer to the BMR on which they are based; percentages shown by NOAEL and LOAEL symbols refer to the effect size at that dose as % change from the control group, estimated by EFSA from the original study (na = not available).
| PMC10113887 | EFS2-21-e06857-g011.jpg |
0.445162 | a0a99b0a25a547a6958d060b883b2e00 | Criteria for evaluating if there is a significant dose–response | PMC10113887 | EFS2-21-e06857-g012.jpg |
0.436546 | bdc721ff173e403b8bf5ff254bfa3841 | Effect of including (solid curves) or excluding (dashed curves) allergic lung inflammation on the enveloped cpfs (left‐hand graph) and averaged cpfs (right‐hand graph) for the estimated lowest BMD across all the assessed clusters. Lower and upper bounds are shown for each cpf. See text for further explanation | PMC10113887 | EFS2-21-e06857-g013.jpg |
0.373592 | d290d8f7d274473f928a2f8b3a415a25 | Impact of excluding different clusters on the 5th percentile of the overall enveloped cpf (upper panel) and overall averaged cpf (lower panel) for the estimated lowest BMD across clusters
Each bar shows the lower and upper bound for the fifth percentile when the indicated cluster was excluded. The bottom bar (‘all’) shows the result when no clusters were omitted.
| PMC10113887 | EFS2-21-e06857-g014.jpg |
0.44769 | 3e4c6faa541d44d09691b9905de945c8 | Results from fitting a restricted cubic spline using 3 and 4 knots to the data from figure 8A (Montévil et al., 2020 [RefID 13788]) | PMC10113887 | EFS2-21-e06857-g015.jpg |
0.396809 | 755e490104304690a8eb45612fa86dc0 | Parametric distributions fitted to the judgements of 16 experts for Question 2 for the cluster cellular immunity | PMC10113887 | EFS2-21-e06857-g016.jpg |
0.493275 | 44bbf1058b3b425c968f3eebb62e80ef | Example of the results of combining one expert's judgements on Questions 1 and 2 for five immunotoxicity clusters; see text for explanation | PMC10113887 | EFS2-21-e06857-g018.jpg |
0.429996 | 1dd1072fb9fc4992ad8e6e635910b3b0 | Sensitivity analysis assessing the impact of hypothetical dependencies between allergic lung inflammation and cellular immunity on the overall enveloped cpf (left hand graph) and overall averaged cpf (right hand graph). See text for explanation | PMC10113887 | EFS2-21-e06857-g019.jpg |
0.5211 | 6b5cff7bda1542959af051e93760fee1 |
In vitro comet assay: evaluation and summary of test results from 22 studies | PMC10113887 | EFS2-21-e06857-g020.jpg |
0.437959 | 23b8f903617f4e8282289dd7a5d5b4f1 | Experts’ approximate probabilities, for each cluster, that there is at least one endpoint in the WoE table for the cluster that occurs in animals tested with BPA and is relevant and adverse in humans
Each bar represents the range of % probability for the specified cluster and expert (expert A, B etc.).
| PMC10113887 | EFS2-21-e06857-g021.jpg |
0.480112 | ae85a5af8a3d462aa6142aa3b8144d5c |
In vivo comet assay: evaluation and summary of test results from 21 studies | PMC10113887 | EFS2-21-e06857-g022.jpg |
0.389047 | f41c9b1b41f24c78b729f8346c231e06 | Application of PBPK model of Karrer et al. (2018) [RefID 12289] to check linearity | PMC10113887 | EFS2-21-e06857-g023.jpg |
0.434542 | a454a2c9604b4aa0852fef9aa92758e3 | Sensitivity analysis assessing the impact on the overall enveloped cpf (left hand graph) and overall averaged cpf (right hand graph) of using fitted parametric distributions (red curves) or the histograms provided by the experts (black curves) for Question 2 | PMC10113887 | EFS2-21-e06857-g024.jpg |
0.402834 | 9e48e03355b748d4a9c5b0f3d3a99702 | Example illustrating how different experts’ judgements for the same cluster were combined by two alternative methods: enveloping (black curves) and unweighted averaging (blue curves). See text for explanation | PMC10113887 | EFS2-21-e06857-g025.jpg |
0.39664 | 480b8a6fbc0243cc8fff9f99222202ea | Impact of excluding different clusters on the 50th percentile of the overall enveloped cpf (upper panel) and overall averaged cpf (lower panel) for the estimated lowest BMD across clusters
Each bar shows the lower and upper bound for the fifth percentile when the indicated cluster was excluded. The bottom bar (‘all’) shows the result when no clusters were omitted.
| PMC10113887 | EFS2-21-e06857-g026.jpg |
0.497097 | 8191820c951b4c02b6a0c5bee694ea12 | Two examples, for different clusters and experts, of elicited probability distributions for the estimated lowest BMD of those endpoints in the cluster that occur in animals tested with BPA and is both relevant and adverse for humans
Each graph shows the histogram provided by a single expert, and the parametric distribution that was subsequently fitted to their judgements.
| PMC10113887 | EFS2-21-e06857-g028.jpg |
0.445651 | 347097e8b84448fb953d2a6793d0fc0f | Cumulative probability functions (cpfs) quantifying uncertainty about the estimated lowest BMD across the 21 primary clusters considered in the uncertainty analysis
The dashed black curves show the lower and upper envelope for the cpf resulting from the range of judgements between WG experts (lower and upper refer to relative position on the vertical axis). The red solid curves show the lower and upper bounds of the averaged cpf, where judgements of different experts for each cluster were aggregated by averaging. Blue dotted lines show probabilities for the estimated lowest BMD across all clusters being below the RP of 8.2 ng BPA/kg bw per day (HED). Green solid lines show probabilities for the estimated lowest BMD across all clusters being below the RP when an additional UF of 2 is applied, as discussed in Section 3.2.4. Subtracting these probabilities from 100% gives the corresponding probabilities for the estimated lowest BMD across all clusters being above the RP.
| PMC10113887 | EFS2-21-e06857-g029.jpg |
0.441212 | eab98793426f412f872bcc3a737026fc | Key endpoints and effect sizes considered by the experts when assessing Question 2 for the cluster cellular immunity
Labels on the horizontal axis comprise study reference identification (RefID) number, endpoint, tier of study (from WoE assessment), sex and species, and developmental stage or chosen BMR value. Percentages shown by BMDU and BMDL symbols refer to the BMR on which they are based; percentages shown by NOAEL and LOAEL symbols refer to the effect size at that dose as % change from the control group, estimated by EFSA from the original study.
| PMC10113887 | EFS2-21-e06857-g030.jpg |
0.425451 | c3ed5e69d2cb4b0591921faeda698352 | Effects in germ cells: summary of evaluation and results from five studies | PMC10113887 | EFS2-21-e06857-g031.jpg |
0.38349 | dfd885c75a964a7289ad6830f0c92820 | Results of excluding allergic lung inflammation plus one additional cluster (indicated on the vertical axis) on the fifth percentile of the overall enveloped cpf (upper panel) and overall averaged cpf (lower panel) for the estimated lowest BMD across clustersEach bar shows the lower and upper bound for the fifth percentile when allergic lung inflammation plus the indicated cluster were excluded. The bottom bar (‘all’) shows the result when only allergic lung inflammation was omitted. | PMC10113887 | EFS2-21-e06857-g032.jpg |
0.525893 | 13b6332308814030869da5d131edca89 | Comparison of probability ranges provided by the experts for Question 3 with the probability ranges calculated from their assessments for Questions 1 and 2, showing the adjustments made by the experts to account for the additional uncertainties listed in Table D.5
| PMC10113887 | EFS2-21-e06857-g033.jpg |
0.41535 | 9aba5f39d9634b3a8d94d9189167e86e | Summary of distributions fitted to each experts’ judgements, for each cluster, for the estimated lowest BMD in the cluster for endpoints that occur in animals tested with BPA and is relevant and adverse in humans
Each bar represents the 90% probability interval of the distribution for the specified cluster and expert (expert A, B etc.).
| PMC10113887 | EFS2-21-e06857-g035.jpg |
0.438474 | 77d29bc2f3be41cdbb086ad012000bde | (a) Shiny tight skin with generalized hyperpigmentation, calcinosis cutis over wrist and elbow, salt-and-pepper dyspigmentation over the right side of the scalp near the temple. (b) Septate or branching pattern of salt-and-pepper dyspigmentation on the right side of the forehead near the hairline. (c) Ulcerated calcinosis cutis over the elbow | PMC10115323 | IDOJ-14-299-g001.jpg |
0.443405 | e3d6c8b60aa74a8093ec00f04219c5a6 | (a): Polarized Dermoscopy at 10× (DermLite DL3) from the center of salt-and-pepper dyspigmentation revealing three concentric zones around a follicle, namely, outermost hexagonal rims of white areas (green arrow), middle circular zone of pigment retention (red arrow), and an innermost zone of whitish perifollicular halo (blue arrow). There is also the presence of pseudo reticular brown areas along the course of superficial veins corresponding to the site of the groove sign (yellow arrow). (b): Polarized Dermoscopy at 10× (DermLite DL3) from the periphery of salt-and-pepper dyspigmentation at the trunk revealing multiple brown dots (black arrow) arranged regularly within white areas (red stars). (c): Onychoscopy at 10× (DermLite DL3) showing dilated nail-fold capillaries (white arrow), avascular areas with capillary dropouts in proximal nail fold (red arrow), and cuticle (black arrow). There is also presence of onychomadesis (blue arrow). (d): Enlarged calcified lymph nodes (egg-shell calcification) and nodules in upper lobes in mediastinum suggestive of silicosis, as seen on high-resolution computed tomography scan of the chest. (e): Histopathological analysis revealing epidermal thinning, reduced and pulled appendages, dermal lymphocytic infiltration, and homogenous edematous collagen bundles (hematoxylin and eosin stain, 400×) | PMC10115323 | IDOJ-14-299-g002.jpg |
0.449573 | e42a0294739f4ad488328001d7598a35 | Effect of the antioxidant ascorbic acid (AA) on the antimicrobial activity of the bioinspired peptides. AA was added before (pre), co-incubated (co), and 1 and 2 h after (post) the addition of RR (A) and D-RR (B) to Candida tropicalis, and before (pre) and co-incubated (co) the addition of WR (C) to Candida albicans cells. The colony forming units (CFU) values are means ± SD. The data from co-incubation were obtained from Table 1. **P < 0.01; *** P < 0.001; **** P < 0.0001. (ns) indicates not significantly different. The assay is representative of an independent assay out of three | PMC10115610 | 12602_2023_10064_Fig1_HTML.jpg |
0.384347 | 921a741f51de41eebfe0d6446c8858f5 | Morphological changes and size reduction in the yeast cells treated with the bioinspired peptides. A Microscopic images of Candida tropicalis cells treated with 27.5 µM RR and 23 µM D-RR. Scale bar represents 10 µm. AA, ascorbic acid, AcA, acetic acid. B Length of the longitudinal and transverse axes in C. tropicalis cells. C Microscopic images of Candida albicans cells treated with 27.5 µM WR. D Length of the longitudinal and transverse axes of C. albicans cells. A, B Note the granularity of the cytoplasm and the reduction in cell size. C, D The percentage numbers indicate a reduction of the axis in relation to their respective controls. Controls correspond to yeast cells cultivated in medium, control+ correspond to AcA or heat or Triton X-100 treatments. **** P < 0.0001. (ns) indicates not significantly different. The average size of each sample for C. tropicalis for longitudinal axis is: control 7.8 µm, AcA 6.3 µm, RR 5.5 µm, RR + AA 6.5 µm, D-RR 5.1 µm, D-RR + AA 6.1 µm. The average size of each sample for C. tropicalis for transversal axis is: control 4.7 µm, AcA 4.3 µm, RR 3.6 µm, RR + AA 4.5 µm, D-RR 3.4 µm, D-RR + AA 4.5 µm. The average size of each sample for C. albicans for longitudinal axis is: control 5.4 µm, AcA 3.7 µm, WR 3.3 µm, WR + AA 3.3 µm. The average size of each sample for C. albicans for the transversal axis is: control 3.9 µm, AcA 2.9 µm, WR 2.6 µm, WR + AA 2.0 µm. The assay is representative of an independent assay out of three | PMC10115610 | 12602_2023_10064_Fig2_HTML.jpg |
0.409095 | 5a380ecfaa3f4d62b1e98e0fc11405b6 | Mitochondrial functionality in opportunistic yeast (A, B, C, and D
Candida tropicalis, E and F Candida albicans) cells treated with bioinspired peptides RR, D-RR, and WR lethal dose. A, C, and E Microscopic images of yeast cells; Mitotracker Red FM fluorescence in the cytoplasm indicates mitochondrial functionality. Scale bar represents 10 µm. Note the hyperpolarization of the mitochondrial membranes of the treated yeast cells. Ascorbic acid (AA) reversed the hyperpolarization. Control+ corresponds to Triton X-100 treatment. Controls correspond to yeast cells cultivated in a medium. B, D, and F Determination of mitochondrial metabolic activity using WST-1. The values above the test bars indicate the mitochondrial activity compared to the control. Controls correspond to yeast cells cultivated in medium, control+ correspond to acetic acid (AcA) or Triton X-100 treatments. **** P < 0.0001; The assay is representative of an independent assay out of three | PMC10115610 | 12602_2023_10064_Fig3_HTML.jpg |
0.444377 | b408a8ec9d8747eabaf9d79ddcb4e89d | Cell death analysis in Candida tropicalis cells treated with RR lethal dose. A Microscopic images of yeast cells; FITC-VAD-FMK green fluorescence in the cytoplasm indicates metacaspase activation. Scale bar represents 10 µm. B Number of cells with activated metacaspases, determined after cell count in random DIC and fluorescence fields as observed in A. Different letters indicate a statistically significant difference. P < 0.05. C Viability assay with C. tropicalis incubated with RR at its time of death (6 h) and control in the presence of the pan-caspase inhibitor Z-VAD-FMK. Colony forming units (CFU) values are means ± SD. (nd), not determined (excessive number of grown colonies that prevented colony counting). (D) Detection of chromatin condensation by DAPI staining. Note that the control cells present a round-shaped nucleus with an even fluorescent signal, whereas the peptide-treated cells present a stronger and more punctual staining indicating chromatin condensation. Scale bar represents 10 µm. A–D Controls correspond to yeast cells cultivated in medium. A, B, D control+ corresponds to acetic acid (AcA) treatment. The assay is representative of an independent assay out of three | PMC10115610 | 12602_2023_10064_Fig4_HTML.jpg |
0.416639 | 991a4ecfe2864fab866037917e6f4c94 | Cell death analysis in Candida albicans cells treated with WR lethal dose. A Microscopic images of yeast cells; FITC-VAD-FMK green fluorescence in the cytoplasm indicates metacaspase activation. Scale bar represents 10 µm. B Number of cells with activated metacaspases, determined after cell count in random DIC and fluorescence fields as observed in A. Different letters indicate a statistically significant difference. P < 0.05. C Viability assay with C. albicans incubated with WR at its time of death (1 h) and control in the presence of the pan caspase inhibitor Z-VAD-FMK. Colony forming units (CFU) values are means ± SD. (nd), not determined (excessive number of grown colonies that prevented colony counting). D Detection of chromatin condensation by DAPI staining. Note that the control cells present a round shaped nucleus with an even fluorescent signal, whereas the peptide-treated cells present a stronger and more punctual staining indicating chromatin condensation. Scale bar represents 10 µm. A–D Controls correspond to yeast cells cultivated in medium. A, B, D control+ corresponds to acetic acid (AcA) treatment. The assay is representative of an independent assay out of three | PMC10115610 | 12602_2023_10064_Fig5_HTML.jpg |
0.45154 | e7586804b872402792971cb08338acfc | Cell death analysis in Candida tropicalis cells treated with D-RR lethal dose. A Microscopic images of yeast cells; FITC-VAD-FMK green fluorescence in the cytoplasm indicates metacaspase activation. Scale bar represents 10 µm. B Number of cells with activated metacaspases, determined after cell count in random DIC and fluorescence fields as observed in A. Different letters indicate a statistically significant difference. P < 0.05. A, B Ascorbic acid (AA) reversed the metacaspase activation. C Viability assay with C. tropicalis incubated with D-RR at its time of death (3 h) and control in the presence of the pan caspase inhibitor Z-VAD-FMK. Colony forming units (CFU) values are means ± SD. (nd), not determined (excessive number of grown colonies that prevented colony counting). D Detection of chromatin condensation by DAPI staining. Note that the control cells present a round-shaped nucleus with an even fluorescent signal, whereas the peptide-treated cells present a stronger and more punctual staining indicating chromatin condensation. Scale bar represents 10 µm. A–D Controls correspond to yeast cells cultivated in medium. A, B, D control+ corresponds to acetic acid (AcA) treatment. The assay is representative of an independent assay out of three | PMC10115610 | 12602_2023_10064_Fig6_HTML.jpg |
0.449982 | 64f5a67c0a824468ab397204664a705f | Schematic depiction of the proposed model describing the mechanism of action of RR and D-RR on Candida tropicalis, and WR on Candida albicans. Based on the results present study using probes to cellular process (ROS, mitochondrial hyperpolarization, cell size reduction/vacuolization, chromatin condensation, accidental cell death, metacaspase activation) and inhibitors (ascorbic acid, metacaspase inhibitor) allowed to differentiate the type of cell death promoted by each peptide | PMC10115610 | 12602_2023_10064_Fig7_HTML.jpg |
0.532456 | 60bbee42c683401a9ee086341ec72fed | A healthy microbiota consists of a balance of Gram-positive and Gram-negative bacteria; in which hepcidin, iron (Fe3+), IL-6, and TMAO levels express a normal state of balance. Whereas a dysbiosis state indicates an increase of gram-negative bacteria and elevated hepcidin levels resulting in excessive iron accumulation. This stimulates high ferritin levels which promotes less cognitive decline and therefore excess hepcidin production. The synthesis of hepcidin is rapidly increased by infection and inflammation in which elevated IL-6 levels initiate a pro-inflammatory cascade. With IL-6 upregulation occurring in the liver, the higher levels of TMA become oxidized to TMAO. Circulation of TMAO initiated in the small intestine initiates an inflammatory state. | PMC10116142 | jad-92-jad220224-g001.jpg |
0.493726 | 719c9acb7c9c4bb9926c454419b53620 | The liver in a healthy state contains baseline hepcidin, IL-6, and TMA levels which supports a balance of healthy and dysbiotic bacteria. Iron levels are slightly higher in the healthy state than a dysbiotic state as hepcidin is upregulated in a dysbiotic state. In the dysbiotic state, IL-6 is also upregulated in the liver, and higher levels of TMA are sent to the liver to be oxidized to TMAO. TMAO is sent to the small intestines which ultimately causes inflammation and the overgrowth of dysbiotic bacteria. | PMC10116142 | jad-92-jad220224-g002.jpg |
0.514971 | 2b2a7501bae143cca360665bf6fa063d | In a state of a healthy microbiota, ferritin, hepcidin, IL-6, and iron are all at baseline levels. In a state of dysbiotic microbiota, the brain responds preventatively by upregulating ferritin and hepcidin levels, as well as IL-6. This is done via the astrocytes (purple) and microglia (red). In the neuron (dark yellow), iron is upregulated as well in the setting of neuroinflammation. Amyloid plaques can also be seen in the dysbiotic state as above. | PMC10116142 | jad-92-jad220224-g003.jpg |
0.458545 | cb2612a139114bf38ba2af654d6a111a | The endocrine summary of the gut-brain axis (GBA) involves an endocrine and neural communication between the brain, liver and intestines via several biomolecules and the vagus nerve. The arrows in this figure indicate the flow of each biomolecule. An overproduction of TMAO signifies overdevelopment of pathogenic gut bacteria and induces activation of macrophages, onsetting the secretion of IL-6, thus, initiating collective activation of microcascade inflammatory responses to absorb bacteria in attempt to mediate gut dysbiosis. IL-6 is unregulated in inflammation and involved in the regulation of neural processes. As the liver produces hepcidin, the sustained overproduction of hepcidin and IL-6 is stimulated throughout blood circulation. The hepcidin ascending to the brain is derived from circulation and further expressed through the production of iron-load and inflammation. The brain’s reactivity in response to overproduction sequesters iron to neurons. The activation of hepcidin results in the shutdown of ferroportin in neural cells. The increase of iron in neural cells activates an oxidative state in the brain. The brain is highly susceptible to oxidative damage. Imbalance of gut dysbiosis, thus, plays a major role in the pathophysiology and pathogenic mechanism for neurodegenerative diseases as a primary contributor. | PMC10116142 | jad-92-jad220224-g004.jpg |
0.431299 | 676a129261854b14a06614f16d960833 | Normal mBDNF signaling pathway. mBDNF activates the TrkB signaling pathway which in turn activates the MAPK/ERK, PI3K/Akt, and PLC-γ pathways. These pathways work together to regulate important cognitive functions such as LTP formation and neurogenesis. | PMC10116142 | jad-92-jad220224-g005.jpg |
0.41114 | d1250dafc29a4e57bf58eedff874160e | mBDNF signaling pathway under HFHS diet conditions. This diet causes gut dysbiosis, which decreases levels of mBDNF. These decreased mBDNF levels downregulate the TrkB signaling pathway and ultimately the MAPK/ERK, PI3K/Akt, and PLC-γ pathways, causing a multitude of problems such as increased susceptibility to cell death, dysregulation of CREB and transcription factors, as well as a decrease in LTP and neurogenesis. | PMC10116142 | jad-92-jad220224-g006.jpg |
0.442109 | 5311de25ddad4fe3becab996029ca2e5 | The neural summary of the gut-brain axis. Gut endocrine cells are activated by mature mBDNF or inhibited by proBDNF, which in turn activate or inhibit vagal nerve communication to the brain respectively. Additionally, afferent vagal nerve fibers stimulate efferent vagal nerve fibers via the inflammatory reflex. | PMC10116142 | jad-92-jad220224-g007.jpg |
0.50578 | 168a7f4e531245d9afce42f02904950c | Summary of healthy (left) and dysbiotic (right) states of the gut-brain axis. The left region of the figure depicts the brain, liver, and gut at optimal health whereas the right region represents the brain, liver, and gut in dysbiotic states. The brain, in a state of a healthy microbiota, ferritin, hepcidin, IL-6, and iron are all at baseline levels. The liver in a healthy state contains baseline hepcidin, IL-6, and TMA levels which supports a balance of healthy and dysbiotic bacteria. Iron levels are slightly higher in the healthy state than a dysbiotic state as hepcidin is upregulated in a dysbiotic state. In addition, a healthy microbiota consists of a balance of Gram-positive and Gram-negative bacteria; in which hepcidin, iron (Fe3+), IL-6, and TMAO levels express a normal state of balance. The right region of the figure depicts the brain in a state of dysbiotic microbiota. The brain responds preventatively by upregulating ferritin and hepcidin levels, as well as IL-6. This is done via the astrocytes (purple) and microglia (red). In the neuron (dark yellow), iron is upregulated as well in the setting of neuroinflammation. Amyloid plaques can also be seen in the dysbiotic state as above. Below, the liver is illustrated in a state of dysbiosis. IL-6 is upregulated, and higher levels of TMA are sent to the liver to be oxidized to TMAO. TMAO is sent to the small intestines which ultimately causes inflammation and the overgrowth of dysbiotic bacteria. Most importantly, the dysbiotic microbiota indicates an increase of gram-negative bacteria and elevated hepcidin. Whereas a dysbiosis state indicates an increase of gram-negative bacteria and elevated hepcidin levels resulting in excessive iron accumulation. This stimulates high ferritin levels which promotes less cognitive decline and therefore excess hepcidin production. The synthesis of hepcidin is rapidly increased by infection and inflammation in which elevated IL-6 levels initiate a pro-inflammatory cascade. With IL-6 upregulation occurring in the liver, the higher levels of TMA become oxidized to TMAO. Circulation of TMAO initiated in the small intestine initiates an inflammatory state. | PMC10116142 | jad-92-jad220224-g008.jpg |
0.474155 | eb484a9bae844477a47346a6ed976478 | PRISMA flow diagram. | PMC10116858 | fpsyg-14-1124650-g0001.jpg |
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