Serotonin enhances the production of type IV collagen by human mesangial cells

Serotonin enhances the production of type IV collagen by human mesangial cells.BackgroundThe plasma concentration of 5-hydroxytryptamine (5-HT) in diabetic patients is higher than that in normal subjects. Since recent reports have demonstrated the presence of 5-HT2A receptor in glomerular mesangial cells, it is possible that 5-HT may be involved in the development of diabetic nephropathy through the 5-HT2A receptor in mesangial cells. Because expansion of the glomerular mesangial lesion is a characteristic feature of diabetic nephropathy, we examined the effect of 5-HT on the production of type IV collagen by human mesangial cells.MethodsHuman mesangial cells were incubated with 5-HT with or without 5-HT receptor antagonists, protein kinase C (PKC) inhibitor or transforming growth factor-β (TGF-β) antibody. Type IV collagen mRNA and protein concentration in medium were measured by Northern blot analysis and enzyme-linked immunosorbent assay (ELISA), respectively. TGF-β mRNA and bioactivity in the medium were measured by Northern blot analysis and bioassay using mink lung epithelial cells, respectively.Results5-HT stimulated the production of type IV collagen by human mesangial cells, which was inhibited by ketanserin and sarpogrelate hydrochloride, 5-HT2A receptor antagonists, but not by ondansetron, a 5-HT3 receptor antagonist. 5-HT increased the bioactivities of both active and total TGF-β. However, the 5-HT-enhanced production of type IV collagen was completely inhibited by an anti-TGF-β antibody. Furthermore, a PKC inhibitor, calphostin C, inhibited the 5-HT-induced increase in type IV collagen secretion, and the activity of membrane PKC was increased by 5-HT. Phorbol ester activated type IV collagen production as well as active and total TGF-β. Calphostin C completely inhibited the 5-HT-enhanced activity of active TGF-β, but did not inhibit exogenous TGF-β-induced increase in type IV collagen secretion.ConclusionsOur results suggest that 5-HT-enhanced production of type IV collagen by human mesangial cells is mediated by activation of PKC and subsequent increase in active TGF-β activity

Trapping of CDC42 C-terminal variants in the Golgi drives pyrin inflammasome hyperactivation

CDC42-C末端異常症に於ける炎症病態を解明 --ゴルジ体への異常蓄積がパイリンインフラマソーム形成を過剰促進--. 京都大学プレスリリース. 2022-05-02.Mutations in the C-terminal region of the CDC42 gene cause severe neonatal-onset autoinflammation. Effectiveness of IL-1β–blocking therapy indicates that the pathology involves abnormal inflammasome activation; however, the mechanism underlying autoinflammation remains to be elucidated. Using induced-pluripotent stem cells established from patients carrying CDC42[R186C], we found that patient-derived cells secreted larger amounts of IL-1β in response to pyrin-activating stimuli. Aberrant palmitoylation and localization of CDC42[R186C] protein to the Golgi apparatus promoted pyrin inflammasome assembly downstream of pyrin dephosphorylation. Aberrant subcellular localization was the common pathological feature shared by CDC42 C-terminal variants with inflammatory phenotypes, including CDC42[*192C*24] that also localizes to the Golgi apparatus. Furthermore, the level of pyrin inflammasome overactivation paralleled that of mutant protein accumulation in the Golgi apparatus, but not that of the mutant GTPase activity. These results reveal an unexpected association between CDC42 subcellular localization and pyrin inflammasome activation that could pave the way for elucidating the mechanism of pyrin inflammasome formation

Effect of a stearic acid-rich, structured triacylglycerol on plasma lipid concentrations

Background: Structured lipids are being incorporated into foods to reduce their energy value. One such lipid is rich in stearic acid.Objective: The objective of this study was to compare the effects on plasma lipids of a stearic acid&ndash;rich triacylglycerol and a fat rich in palmitic acid in hypercholesterolemic subjects.Design: Fifteen subjects with an average plasma cholesterol concentration of 6.13 &plusmn; 0.80 mmol/L initially ate a low-fat diet for 2 wk (run-in period), followed in random order and blinded fashion by 2 high-fat diets (for 5 wk each) containing foods derived from margarines rich either in palmitic acid or in the structured, stearic acid&ndash;rich triacylglycerol.Results: Plasma cholesterol concentrations with the low-fat, the stearic acid&ndash;rich, and the palmitic acid&ndash;rich diets were not significantly different (5.35 &plusmn; 0.83, 5.41 &plusmn; 0.78, and 5.52 &plusmn; 0.68 mmol/L, respectively) but were significantly lower (P &lt; 0.001) than those measured during the habitual diet period (ie, 2 wk before the study began). Neither HDL cholesterol nor plasma triacylglycerol differed significantly among the 3 study diets.Conclusion: A similar increase in the intake of stearic and palmitic acids (differing by &lt;5% of total energy) to ensure a high fat intake resulted in plasma total and LDL-cholesterol concentrations that did not differ significantly from concentrations measured during a period of low-fat intake.<br /

"This Is Fake News": Characterizing the Spontaneous Debunking from Twitter Users to COVID-19 False Information

False information spreads on social media, and fact-checking is a potential countermeasure. However, there is a severe shortage of fact-checkers; an efficient way to scale fact-checking is desperately needed, especially in pandemics like COVID-19. In this study, we focus on spontaneous debunking by social media users, which has been missed in existing research despite its indicated usefulness for fact-checking and countering false information. Specifically, we characterize the tweets with false information, or fake tweets, that tend to be debunked and Twitter users who often debunk fake tweets. For this analysis, we create a comprehensive dataset of responses to fake tweets, annotate a subset of them, and build a classification model for detecting debunking behaviors. We find that most fake tweets are left undebunked, spontaneous debunking is slower than other forms of responses, and spontaneous debunking exhibits partisanship in political topics. These results provide actionable insights into utilizing spontaneous debunking to scale conventional fact-checking, thereby supplementing existing research from a new perspective