Diabetic nephropathy (DN) together with glomerular hyperfiltration has been implicated in the development of diabetic microangiopathy in the initial stage of diabetic diseases. Increased amounts of urinary protein in DN may be associated with functional and morphological alterations of podocyte, mainly including podocyte hypertrophy, epithelial-mesenchymal transdifferentiation (EMT), podocyte detachment, and podocyte apoptosis. Accumulating studies have revealed that disruption in multiple renal signaling pathways had been critical in the progression of these pathological damages, such as adenosine monophosphate-activated kinase signaling pathways (AMPK), wnt/β-catenin signaling pathways, endoplasmic reticulum stress-related signaling pathways, mammalian target of rapamycin (mTOR)/autophagy pathway, and Rho GTPases. In this review, we highlight new molecular insights underlying podocyte injury in the progression of DN, which offer new therapeutic targets to develop important renoprotective treatments for DN over the next decade.

Membranous nephropathy (MN) is the major cause of nephrotic syndrome with special pathological features, caused by the formation of immune complexes in the space between podocytes and the glomerular basement membrane. In idiopathic membranous nephropathy (IMN) the immune complexes are formed by circulating antibodies binding mainly to one of two naturally-expressed podocyte antigens: the M-type receptor for secretory phospholipase A2 (PLA2R1) and the Thrombospondin type-1 domain-containing 7A (THSD7A). Formation of antibodies against PLA2R1 is much more common, accounting for 70-80% of IMN. However, the mechanism of anti-podocyte antibody production in IMN is still unclear. In this review, we emphasize that the exposure of PLA2R1 is critical for triggering the pathogenesis of PLA2R1-associated MN, and propose the potential association between inflammation, pollution and PLA2R1. Our review aims to clarify the current research of these precipitating factors in a way that may suggest future directions for discovering the pathogenesis of MN, leading to additional therapeutic targets and strategies for the prevention and early treatment of MN.

Purpose: Intestinal epithelial barrier dysfunction is crucial in the pathogenesis of intestinal and systemic diseases. Ferulic acid (FA) possesses promising antioxidant activities. In a previous study, we demonstrated potentially protective effects of FA against heat stress-induced intestinal epithelial barrier dysfunction in IEC-6 cells. However, the underlying mechanisms are unclear. The present study aimed to elucidate whether FA protects IEC-6 cells from heat stress-induced intestinal epithelial barrier dysfunction via antioxidative mechanisms. Materials and methods: IEC-6 cells were pretreated with FA prior to hyperthermia exposure at 42 °C for 6 h, and the levels of intracellular reactive oxygen species (ROS), malondialdehyde (MDA), nitrogen oxide (NO), and superoxide dismutase (SOD) activity were analyzed. The intestinal epithelial barrier function was determined by transepithelial electrical resistance (TER) values and 4-kDa fluorescein isothiocyanate-dextran (FD4) flux in IEC-6 cell monolayers. Expression of related proteins was detected by Western blotting. Results: FA suppressed heat stress-induced intestinal oxidative stress damage by reducing ROS, MDA and NO production, while enhancing SOD activity. Furthermore, FA treatment strengthened intestinal barrier function via increasing the phosphorylation levels of Akt, nuclear factor-erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1) protein expression, which was reversed by zinc protoporphyrin (an HO-1 inhibitor). Additionally, LY294002, a specific PI3K/Akt inhibitor, significantly suppressed FA-induced Nrf2 nuclear translocation and HO-1 protein expression and inhibited FA-induced occludin and ZO-1 protein expression. Conclusions: FA protected against heat stress-induced intestinal epithelial barrier dysfunction via activating the PI3K/Akt-mediated Nrf2/HO-1 signaling pathway in IEC-6 cells.

Caffeoylquinic acids (CQAs) are main constituents in many herbal medicines with various biological and pharmacological effects. However, CQAs will degrade or isomerize when affected by temperature, pH, light, etc. In this study, high-performance liquid chromatography with photodiode array detection (HPLC-PDA) and high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) was utilized to study the stability and degradation of CQAs (three mono-acyl CQAs and four di-acyl CQAs) under various ordinary storage conditions (involving different temperatures, solvents, and light irradiation). The results indicated that the stability of CQAs was mainly affected by temperature and light irradiation, while solvents did not affect it in any obvious way under the conditions studied. Mono-acyl CQAs were generally much more stable than di-acyl CQAs under the same conditions. Meanwhile, the chemical structures of 30 degradation products were also characterized by HPLC-MSⁿ, inferring that isomerization, methylation, and hydrolysis were three major degradation pathways. The result provides a meaningful clue for the storage conditions of CQAs standard substances and samples.

Intestinal barrier dysfunction is an important clinical problem in various acute and chronic pathological conditions. Ferulic acid (FA) can attenuate the intestinal epithelial barrier dysfunction, however, the underlying mechanism remains unclear. The present study aimed to uncover the protective effect of FA on intestinal epithelial barrier dysfunction in a Caco-2 cell model of lipopolysaccharide (LPS) stimulation and the underlying mechanism. Caco-2 cells were pretreated with FA and then exposed to LPS stimulation. The barrier function of Caco-2 cells was evaluated by measuring trans-epithelial resistance (TER) and 4-kDa fluorescein isothiocyanate (FITC)-dextran (FD4) flux, and analyzing the tight junction protein expression and structure. The results showed that decreased TER and increased FITC-FD4 flux were observed in Caco-2 cells stimulated with LPS, but these effects were attenuated by FA pretreatment. FA pretreatment inhibited LPS-induced decrease in occludin and ZO-1 mRNA and protein expression. LPS stimulation decreased miR-200c-3p expression, whereas this decrease was inhibited by FA pretreatment. Furthermore, overexpression of miR-200c-3p strengthened the protective effects of FA on LPS-induced Caco-2 cell barrier dysfunction by decreasing epithelial permeability, increasing occludin and ZO-1 protein expression, and maintaining of ZO-1 protein distribution, while suppression of miR-200c-3p reversed the protective effects of FA. LPS treatment increased the expression of PTEN protein and decreased expression of phosphorylated PI3K and AKT proteins. However, pretreatment of FA inhibited expression of PTEN protein and promoted activation of PI3K/AKT signaling pathway in the LPS-treated Caco-2 cells, and this regulatory effect of FA on the PTEN/PI3K/AKT signaling pathway was strengthened or weakened by miR-200c-3p overexpression or suppression, respectively. Our findings suggested that in Caco-2 cells, FA promotes activation of PI3K/AKT pathway by miR-200c-3p-mediated suppression of the negative mediator PTEN, which, in turn, maintains TJ function and thus ameliorates LPS-induced intestinal epithelial barrier dysfunction.

Background: Resting-state functional magnetic resonance imaging (fMRI) studies have uncovered the disruptions of functional brain networks in primary insomnia (PI) patients. However, the etiology and pathogenesis underlying this disorder remains ambiguous, and the insomnia related symptoms are influenced by a complex network organization in the brain. The purpose of this study was to explore the abnormal intrinsic functional hubs in PI patients using a voxel-wise degree centrality (DC) analysis and seed-based functional connectivity (FC) approach. Methods: A total of 26 PI patients and 28 healthy controls were enrolled, and they underwent resting-state fMRI. Degree centrality was measured across the whole brain, and group differences in DC were compared. The peak points, which significantly altered DC between the two groups, were defined as the seed regions and were further used to calculate FC of the whole brain. Later, correlation analyses were performed between the changes in brain function and clinical features. Results: Primary insomnia patients showed DC values lower than healthy controls in the left inferior frontal gyrus (IFG) and middle temporal gyrus (MTG) and showed a higher DC value in the right precuneus. The seed-based analyses demonstrated decreased FC between the left MTG and the left posterior cingulate cortex (PCC), and decreased FC was observed between the right precuneus and the right lateral occipital cortex. Reduced DC in the left IFG and decreased FC in the left PCC were positively correlated with the Pittsburgh sleep quality index and the insomnia severity index. Conclusions: This study revealed that PI patients exhibited abnormal intrinsic functional hubs in the left IFG, MTG, and the right precuneus, as well as abnormal seed-based FC in these hubs. These results contribute to better understanding of how brain function influences the symptoms of PI.