Chlorogenic acid alleviates renal fibrosis by reducing lipid accumulation in diabetic kidney disease through suppressing the Notch1 and Stat3 signaling pathway.

AIMS: Abnormal renal lipid metabolism causes renal lipid deposition, which leads to the development of renal fibrosis in diabetic kidney disease (DKD). The aim of this study was to investigate the effect and mechanism of chlorogenic acid (CA) on reducing renal lipid accumulation and improving DKD renal fibrosis. METHODS: This study evaluated the effects of CA on renal fibrosis, lipid deposition and lipid metabolism by constructing in vitro and in vivo models of DKD, and detected the improvement of Notch1 and Stat3 signaling pathways. Molecular docking was used to predict the binding between CA and the extracellular domain NRR1 of Notch1 protein. RESULTS: In vitro studies have shown that CA decreased the expression of Fibronectin, α-smooth muscle actin (α-SMA), p-smad3/smad3, alleviated lipid deposition, promoted the expression of carnitine palmitoyl transferase 1 A (CPT1A), and inhibited the expression of cholesterol regulatory element binding protein 1c (SREBP1c). The expression of Notch1, Cleaved Notch1, Hes1, and p-stat3/stat3 were inhibited. These results suggested that CA might reduce intercellular lipid deposition in human kidney cells (HK2) by inhibiting Notch1 and stat3 signaling pathways, thereby improving fibrosis. Further, in vivo studies demonstrated that CA improved renal fibrosis and renal lipid deposition in DKD mice by inhibiting Notch1 and stat3 signaling pathways. Finally, molecular docking experiments showed that the binding energy of CA and NRR1 was -6.6 kcal/mol, which preliminarily predicted the possible action of CA on Notch1 extracellular domain NRR1. CONCLUSION: CA reduces renal lipid accumulation and improves DKD renal fibrosis by inhibiting Notch1 and stat3 signaling pathways.

The association of milk products with rheumatoid arthritis: A cross-sectional study from NHANES.

OBJECTIVE: Milk products are a major part of the western diet, but the role of their effect in rheumatoid arthritis (RA) is controversial. The objective of this study was to explore the relationship between milk products and RA in the United States (US) population. METHODS: In the cross-sectional study, a total of 12,813 participants aged 20years or older were selected from the National Health and Nutrition Examination Survey (NHANES). Consumption of milk products was collected by personal interview, and RA status was obtained by self-reported questionnaires. The association between milk products and RA was estimated by using the weighted logistic regression model. RESULTS: We found a negative association of once a day or more milk products intake with self-reported RA prevalence (odds ratio [OR]: 0.68; 95% confidence interval [CI]: 0.53 to 0.86; P<0.001). A linear trend between consumption of milk products and the prevalence of RA (P<0.01) was also observed. In subgroup analysis, protective effects of milk products on RA were more pronounced in several groups (i.e., Mexican Americans, highly educated and drinking individuals, etc.). However, no interaction effect of stratification variables and the frequency of milk products intake with RA was detected. After imputing missing data, the sensitivity analysis showed the same association. CONCLUSION: This study suggested a negative association between consumption of milk products and RA among US population. Further investigations are warranted to validate the causal association and the underlying mechanism.

The role of inflammation in autoimmune disease: a therapeutic target.

Autoimmune diseases (AIDs) are immune disorders whose incidence and prevalence are increasing year by year. AIDs are produced by the immune system's misidentification of self-antigens, seemingly caused by excessive immune function, but in fact they are the result of reduced accuracy due to the decline in immune system function, which cannot clearly identify foreign invaders and self-antigens, thus issuing false attacks, and eventually leading to disease. The occurrence of AIDs is often accompanied by the emergence of inflammation, and inflammatory mediators (inflammatory factors, inflammasomes) play an important role in the pathogenesis of AIDs, which mediate the immune process by affecting innate cells (such as macrophages) and adaptive cells (such as T and B cells), and ultimately promote the occurrence of autoimmune responses, so targeting inflammatory mediators/pathways is one of emerging the treatment strategies of AIDs. This review will briefly describe the role of inflammation in the pathogenesis of different AIDs, and give a rough introduction to inhibitors targeting inflammatory factors, hoping to have reference significance for subsequent treatment options for AIDs.

Research progress of VEGFR small molecule inhibitors in ocular neovascular diseases.

Angiogenesis is the biological process in which existing blood vessels generate new ones and it is essential for body growth and development, wound healing, and granulation tissue formation. Vascular endothelial growth factor receptor (VEGFR) is a crucial cell membrane receptor that binds to VEGF to regulate angiogenesis and maintenance. Dysregulation of VEGFR signaling can lead to several diseases, such as cancer and ocular neovascular disease, making it a crucial research area for disease treatment. Currently, anti-VEGF drugs commonly used in ophthalmology are mainly four macromolecular drugs, Bevacizumab, Ranibizumab, Conbercept and Aflibercept. Although these drugs are relatively effective in treating ocular neovascular diseases, their macromolecular properties, strong hydrophilicity, and poor blood-eye barrier penetration limit their efficacy. However, VEGFR small molecule inhibitors possess high cell permeability and selectivity, allowing them to traverse and bind to VEGF-A specifically. Consequently, they have a shorter duration of action on the target, and they offer significant therapeutic benefits to patients in the short term. Consequently, there is a need to develop small molecule inhibitors of VEGFR to target ocular neovascularization diseases. This review summarizes the recent developments in potential VEGFR small molecule inhibitors for the targeted treatment of ocular neovascularization diseases, with the aim of providing insights for future studies on VEGFR small molecule inhibitors.

Circulating Copper and Liver Cancer.

The association between circulating copper and the risk of liver cancer has been investigated by previous studies, while the findings were inconsistent. Thus, we aimed to evaluate the association between circulating copper and liver cancer by using meta-analysis and Mendelian randomization (MR). For meta-analysis, PubMed and Web of Science were searched to identify eligible studies published before April 4, 2022. Standardized mean difference (SMD) with 95% confidence interval (CI) in circulating copper level between liver cancer patients and controls were pooled. Furthermore, we selected genetic instruments for circulating copper from a genome-wide association study (GWAS) to conduct MR analysis. The summary statistics related to liver cancer were obtained from two large independent cohorts, UKBB and FinnGen, respectively. MR analysis was performed mainly by inverse-variance weighted (IVW) approach, followed by maximum-likelihood method as sensitivity analysis. In meta-analysis of eight studies, circulating copper was found to be higher in liver cancer patients (SMD: 1.65; 95% CI: 0.65 to 2.65) with high heterogeneity (I2 = 96.40%, P = 0.001). However, inconsistent findings were observed among subgroups with high evidence. In MR analysis, genetically predicted circulating copper was not significantly associated with the risk of liver cancer by IVW in UKBB (OR: 1.38; 95% CI: 0.72 to 2.65) and FinnGen (OR: 1.10; 95% CI: 0.69 to 1.73) separately, and the pooled results produced similar results (OR: 1.18, 95% CI: 0.81 to 1.72). Moreover, non-significant finding was confirmed by using maximum-likelihood method. There is no sufficient evidence to demonstrate that high levels of circulating copper increase the risks of liver cancer.