4-octyl itaconate inhibits high glucose induced renal tubular epithelial cell fibrosis through TGF-ß-ROS pathway.

Diabetic kidney disease (DKD) is one of the most serious complications of diabetes and has become the leading cause of end-stage kidney disease, causing serious health damage and a huge economic burden. Tubulointerstitial fibrosis play important role in the development of DKD. Itaconate, a macrophage-specific metabolite, has been reported to have anti-oxidant, anti-inflammatory effects. However, it is unknown whether it perform anti-fibrotic effect in renal tubular epithelial cells. In this current study, we observed that in human renal tubular epithelial cells (HK2), high glucose induced an increase in transforming growth factor ß (TGF-ß) production, and upregulated the expressions of fibronectin and collagen I through the TGF-ß receptor as verified by administration of TGF-ß receptor blocker LY2109761. Treatment with 4-octyl itaconate (4-OI), a derivant of itaconic acid, reduced the TGF-ß production induced by high glucose and inhibited the pro-fibrotic effect of TGF-ß in a dose-dependent manner. In addition, we found that 4-OI exerted its anti-fibrotic effect by inhibiting the excessive production of ROS induced by high glucose and TGF-ß. In summary, 4-OI could ameliorate high glucose-induced pro-fibrotic effect in HK2 cell, and blocking the expression of TGF-ß and reducing the excessive ROS production may be involved in its anti-fibrotic effect.

Metformin and Fibrosis: A Review of Existing Evidence and Mechanisms.

Fibrosis is a physiological response to organ injury and is characterized by the excessive deposition of connective tissue components in an organ, which results in the disruption of physiological architecture and organ remodeling, ultimately leading to organ failure and death. Fibrosis in the lung, kidney, and liver accounts for a substantial proportion of the global burden of disability and mortality. To date, there are no effective therapeutic strategies for controlling fibrosis. A class of metabolically targeted chemicals, such as adenosine monophosphate-activated protein kinase (AMPK) activators and peroxisome proliferator-activated receptor (PPAR) agonists, shows strong potential in fighting fibrosis. Metformin, which is a potent AMPK activator and is the only recommended first-line drug for the treatment of type 2 diabetes, has emerged as a promising method of fibrosis reduction or reversion. In this review, we first summarize the key experimental and clinical studies that have specifically investigated the effects of metformin on organ fibrosis. Then, we discuss the mechanisms involved in mediating the antifibrotic effects of metformin in depth.

Function and Mechanism of Novel Histone Posttranslational Modifications in Health and Disease.

Histone posttranslational modifications (HPTMs) are crucial epigenetic mechanisms regulating various biological events. Different types of HPTMs characterize and shape functional chromatin states alone or in combination, and dedicated effector proteins selectively recognize these modifications for gene expression. The dysregulation of HPTM recognition events takes part in human diseases. With the application of mass spectrometry- (MS-) based proteomics, novel histone lysine acylation has been successively discovered, e.g., propionylation, butyrylation, 2-hydroxyisobutyrylation, ß-hydroxybutyrylation, malonylation, succinylation, crotonylation, glutarylation, and lactylation. These nine types of modifications expand the repertoire of HPTMs and regulate chromatin remodeling, gene expression, cell cycle, and cellular metabolism. Recent researches show that HPTMs have a close connection with the pathogenesis of cancer, metabolic diseases, neuropsychiatric disorders, infertility, kidney diseases, and acquired immunodeficiency syndrome (AIDS). This review focuses on the chemical structure, sites, functions of these novel HPTMs, and underlying mechanism in gene expression, providing a glimpse into their complex regulation in health and disease.

Impact of Exposure to Antibiotics During Pregnancy and Infancy on Childhood Obesity: A Systematic Review and Meta-Analysis.

OBJECTIVE: This study aimed to investigate whether antibiotic exposure during pregnancy and infancy was associated with childhood overweight or obesity. METHODS: PubMed, Embase, and Cochrane Library databases were searched from the inception date to April 18, 2019, to identify observational studies that investigated the association between antibiotic exposure during pregnancy and infancy and childhood overweight or obesity. After study selection and data extraction, the meta-analysis was conducted using Stata software version 12.0 (StataCorp LP, College Station, Texas). The evaluation of the methodological quality was carried out by AMSTAR 2 (Bruyère Research Institute, Ottawa, Ontario, Canada). RESULTS: A total of 23 observational studies involving 1,253,035 participants were included. The meta-analysis showed that prenatal exposure to antibiotics was not significantly associated with childhood overweight or obesity, whereas an increased risk of overweight or obesity was seen in subgroup analysis of the second trimester (risk ratio = 1.13; 95% CI: 1.06-1.22; P = 0.001). In contrast, antibiotic exposure during infancy could increase the risk of childhood overweight or obesity (risk ratio = 1.14; 95% CI: 1.06-1.23; P = 0.001). CONCLUSIONS: This meta-analysis found that antibiotic exposure during the second trimester and infancy could increase the risk of childhood overweight or obesity.