Search

Obesity is an important factor implicated in chronic kidney disease (CKD). Juglanin (Jug) is a natural compound extracted from the crude Polygonumaviculare, showing anti-inflammatory and anti-diabetic effects. However, whether Jug has protective effects against obesity-induced renal injury, little has been investigated. Herein, we attempted to explore the potential of Jug in mediating obesity-induced kidney disease in high fat diet (HFD)-challenged mice. Our results suggested that chronic HFD feeding markedly increased the body weights of mice compared to the ones fed with normal chow diet (NCD), along with significant glucose intolerance and insulin resistance. However, these metabolic disorders induced by HFD were effectively alleviated by Jug treatments in a dose-dependent manner. Moreover, HFD-challenged mice showed apparent histopathological changes in renal tissues with significant collagen accumulation, which were attenuated by Jug supplementation. In addition, Jug treatment decreased the expression levels of kidney injury molecule-1 (KIM-1), while increased nephrin and podocin expression levels in kidney of HFD-challenged mice, improving the renal dysfunction. Furthermore, HFD led to lipid deposition in kidney samples of mice by enhancing abnormal lipid metabolism. In addition, HFD promoted the releases of circulating pro-inflammatory cytokines, and enhanced the renal inflammation by activating nuclear factor-kappa B/histone deacetylase 3 (NF-κB/HDAC3) signaling. HFD-induced dyslipidemia and inflammation were considerably abrogated by Jug administration in mice. The protective effects of Jug against renal injury were confirmed in palmitate (PA)-stimulated HK2 cells in vitro mainly through suppressing the nuclear translocation of NF-κB and HDAC3, repressing inflammation and lipid accumulation eventually. Hence, Jug could ameliorate HFD-induced kidney injury mainly through blocking the NF-κB/HDAC3 nuclear translocation.

Air pollution containing particulate matter (PM) less than 2.5 μm (PM2.5) plays an essential role in regulating hepatic disease. However, its molecular mechanism is not yet clear, lacking effective therapeutic strategies. In this study, we attempted to investigate the effects and mechanisms of PM2.5 exposure on hepatic injury by the in vitro and in vivo experiments. At first, we found that PM2.5 incubation led to a significant reduction of nuclear factor erythroid-derived 2-related factor 2 (Nrf2), along with markedly reduced expression of different anti-oxidants. Notably, suppressor of IKKε (SIKE), known as a negative regulator of the interferon pathway, was decreased in PM2.5-incubated cells, accompanied with increased activation of TANK-binding kinase 1 (TBK1) and nuclear factor-κB (NF-κB). The in vitro studies showed that Nrf2 positively regulated SIKE expression under the conditions with or without PM2.5. After PM2.5 treatment, Nrf2 knockdown further accelerated SIEK decrease and TBK1/NF-κB activation, and opposite results were observed in cells with Nrf2 over-expression. Subsequently, the gene loss- and gain-function analysis demonstrated that SIKE deficiency further aggravated inflammation and TBK1/NF-κB activation caused by PM2.5, which could be abrogated by SIKE over-expression. Importantly, SIKE-alleviated inflammation was mainly dependent on TBK1 activation. The in vivo studies confirmed that SIKE- and Nrf2-knockout mice showed significantly accelerated hepatic injury after long-term PM2.5 exposure through reducing inflammatory response and oxidative stress. Juglanin (Jug), mainly isolated from Polygonum aviculare, exhibits anti-inflammatory and anti-oxidant effects. We found that Jug could increase Nrf2 activation, and then up-regulated SIKE in cells and liver tissues, mitigating PM2.5-induced liver injury. Together, all these data demonstrated that Nrf2 might positively meditate SIKE to inhibit inflammatory and oxidative damage, ameliorating PM2.5-induced liver injury. Jug could be considered as an effective therapeutic strategy against this disease by improving Nrf2/SIKE signaling pathway., Graphical abstract Image 1, Highlights • PM2.5 incubation inhibits Nrf2 and SIKE activation in vitro. • Nrf2 positively regulates SIKE expression in PM2.5-incubated cells. • SIKE-regulated inflammatory response requires TBK1 blockage in PM2.5-treated cells. • Juglanin treatment suppresses inflammation in PM2.5-incubated cells through increasing SIKE expression.

Excess high-fat diet (HFD) intake predisposes the occurrence of obesity-associated heart injury, but the mechanism is elusive. Fisetin (FIS), as a natural flavonoid, has potential activities to alleviate obesity-induced metabolic syndrome. However, the underlying molecular mechanisms of FIS against HFD-induced cardiac injury remain unclear. The present study was to explore the protective effects of FIS on cardiac dysfunction in HFD-fed mice. We found that FIS alleviated HFD-triggered metabolic disorder by reducing body weight, fasting blood glucose and insulin levels, and insulin resistance. Moreover, FIS supplements significantly alleviated dyslipidemia in both mouse hearts and cardiomyocytes stimulated by metabolic stress. FIS treatment abolished HFD-induced inflammatory response in heart tissues through suppressing TNF receptor-1/TNF receptor-associated factor-2 (Tnfr-1/Traf-2) signaling. Furthermore, FIS induced a strong reduction in the expression of fibrosis-related genes, contributing to the inhibition of fibrosis by inactivating transforming growth factor (Tgf)-β1/Smads/Erk1/2 signaling. Collectively, these results demonstrated that FIS could be a promising therapeutic strategy for the treatment of obesity-associated cardiac injury.

Astrocytes activation related NF-κB signaling and oxidative stress were treated as key target associated with PM2.5 threating nerve injury. Unfortunately, the underlying molecular mechanisms of interaction between NF-κB signaling, glial cells activation in neuroinflammation are still not absolutely explained. Fisetin, a natural flavonoid was found to be promote health, partly due to its ability in antioxidant and anti-inflammation. In this regard, we constructed fisetin nanoparticles (FN) to investigate the anti-inflammatory effect in PM2.5-induced mice. Accordingly, qPCR and western blot analysis indicated that astrocytes activation related NF-κB signaling and oxidative stress contributed to PM2.5-induced neuroinflammation, which were significantly suppressed by increasing concentration of FN treatment. Also, FN may directly enhance anti-oxidative stress and anti-inflammatory way to perform inhibitory effects on NF-κB related glial cells activation. Overall, here we identified a new mechanism of action of FN as potential anti-inflammatory product against PM2.5-induced neuroinflammation via regulation of astrocytes activation related NF-κB.