Diosmetin has therapeutic efficacy in colitis regulating gut microbiota, inflammation, and oxidative stress via the circ-Sirt1/Sirt1 axis.

Diosmetin (3',5,7 -trihydroxy-4'-methoxy flavone) is a natural flavonoid compound in the citrus species, it exhibits a variety of pharmacological activities, but little is known of its effects on colitis. In this study we evaluated the therapeutic effects of diosmetin on mouse models of chronic and acute colitis. Chronic colitis was induced in mice by drinking water containing 3% dextran sulfate sodium (DSS) from D0 to D8, followed by administration of diosmetin (25, 50 mg · kg-1 · d-1) for another 8 days. Acute colitis was induced by drinking water containing 5% DSS from D0 to D7, the mice concomitantly received diosmetin (25, 50 mg · kg-1 · d-1) from D1 to D7. During the experiments, body weight and disease activity index (DAI) were assessed daily. After the mice were sacrificed, colon tissue and feces samples were collected, and colon length was measured. We showed that in both models, diosmetin administration significantly decreased DAI score and ameliorated microscopic colon tissue damage; increased the expression of tight junction proteins (occludin, claudin-1, and zonula occludens-1), and reduced the secretion of proinflammatory cytokines IL-1ß, IL-6, TNF-α, and Cox-2 in colon tissue. We found that diosmetin administration remarkably inhibited colon oxidative damage by adjusting the levels of intracellular and mitochondrial reactive oxygen species, GSH-Px, SOD, MDA and GSH in colon tissue. The protection of diosmetin against intestinal epithelial barrier damage and oxidative stress were also observed in LPS-treated Caco-2 and IEC-6 cells in vitro. Furthermore, we demonstrated that diosmetin markedly increased the expression of Nrf2 and HO-1 and reduced the ratio of acetylated NF-κB and NF-κB by activating the circ-Sirt1/Sirt1 axis, which inhibited oxidative stress and inflammation in vivo and in vitro. Diosmetin reversed the effects of si-circSirt1 and si-Sirt1 in LPS-treated Caco-2 and IEC-6 cells. When the gut microbiota was analyzed in the mouse model of colitis, we found that diosmetin administration modulated the abundance of Bacteroidetes, Actinobacteria, Cyanobacteria and Firmicutes, which were crucial for inflammatory bowel disease. Our results have linked colitis to the circ-Sirt1/Sirt1 signaling pathway, which is activated by diosmetin. The results imply that diosmetin may be a novel candidate to alleviate DSS-induced colitis and can be a lead compound for future optimization and modification.

Isorhamnetin alleviates lipopolysaccharide-induced acute lung injury by inhibiting mTOR signaling pathway.

Aim: Acute Lung Injury (ALI) is an acute hypoxic respiratory insufficiency caused by various traumatic factors, manifested as progressive hypoxemia and respiratory distress, and lung imaging shows a heterogeneous osmotic outbreak. Isorhamnetin (ISO) is a flavonoid compound isolated and purified from medicinal plants, such as Hippophae rhamnoides L. and Ginkgo, and has multiple pharmacological functions, such as anti-tumor, anti-myocardial hypoxia, and cardiovascular protection. Our previous study has shown that ISO could attenuate lipopolysaccharide (LPS)-induced acute lung injury in mice, but its mechanism is not clear.Methods: In this study, we used LPS-induced mouse and cell models to research the mechanism of ISO alleviating acute lung injury.Results: The results showed that ISO could attenuate the injury of type II alveolar epithelial cells by inhibiting the TLR4/NF-κB pathway. Further studies showed that ISO could inhibit the activation of mTOR signal in vivo and in vitro and promote autophagy in alveolar epithelial cells to reduce lung injury caused by LPS. In addition, ISO could inhibit LPS-induced epithelial cell apoptosis.Conclusion: Overall, ISO could suppress injury and apoptosis of epithelial cells and activate autophagy to protect epithelial cells via inhibiting mTOR signal and attenuating LPS-induced acute lung injury in mice.

Protective effect of Idelalisib on carbon tetrachloride-induced liver fibrosis via microRNA-124-3P/phosphatidylinositol-3-hydroxykinase signalling pathway.

Liver fibrosis is the repair process of abnormal connective tissue hyperplasia after liver damage caused by different causes. Inhibition of PI3K/Akt signalling pathway can reduce the deposition of extracellular matrix, inhibit the proliferation of hepatic stellate cells (HSCs), and promote its apoptosis to achieve the purpose of therapy. This study aimed to investigate the effect of Idelalisib (PI3K inhibitor) on carbon tetrachloride (CCl4 )-induced liver fibrosis in mice. We used CCl4 -induced liver fibrosis mouse model in vivo and TGF-ß1-stimulated HSCs to evaluate the antifibrosis activity of Idelalisib. In vivo, Idelalisib significantly alleviated CCl4 -induced liver damage, collagen deposition, and hydroxyproline accumulation in mice. Immunohistochemistry and Western blot results showed that Idelalisib could significantly inhibit the expressions of COL1 and α-SMA in a concentration-dependent manner. In cell experiments, Idelalisib significantly inhibited the expressions of COL1, SMA, and p-Smad3 in TGF-ß-induced HSCs, thereby inhibiting HSC activation. Flow cytometry and Western blot results showed that Idelalisib significantly promoted TGFß-induced apoptosis of HSCs after 48 h of administration, but had no significant effect after 24 h. Idelalisib promoted the apoptosis of activated HSCs by inhibiting the PI3K/Akt/FOXO3 signalling pathway. To further explore the mechanism by which Idelalisib inhibited PI3K, we predicted the miRNA targeting PI3K through the database and crossed it with the down-regulated miRNA reported in liver fibrosis mice in the past five years. Finally, we identified miR-124-3p and miR-143-3p. We then demonstrated that Idelalisib significantly promoted miR-124-3p and miR-142-3p in vitro and in vivo. Dual-luciferase report analysis showed that Idelalisib significantly inhibited luciferase activity but had no significant effect on the luc-MUT transfection assay. Finally, we demonstrated that Idelalisib reversed the effects of miR-124-3p inhibitor on the PI3K/Akt/FOXO3 asterisk pathway and caspase-3. Idelalisib has potential as a candidate drug for alleviating liver fibrosis.

Byakangelicin protects against carbon tetrachloride-induced liver injury and fibrosis in mice.

Liver fibrosis is a disease caused by long-term damage that is related to a number of factors. The current research on the treatment of liver fibrosis mainly focuses on the activation of hepatic stellate cell, in addition to protecting liver cells. byakangelicin has certain anti-inflammatory ability, but its effect on liver fibrosis is unclear. This study aims to explore whether byakangelicin plays a role in the development of liver fibrosis and to explore its mechanism. We determined that byakangelicin has a certain ability to resist fibrosis and reduce liver cell damage in a model of carbon tetrachloride-induced liver fibrosis in mice. Thereafter, we performed further verification in vitro. The signalling pathways of two important pro-fibrotic cytokines, transforming growth factor-ß and platelet-derived growth factor, were studied. Results showed that byakangelicin can inhibit related pathways. According to the hepatoprotective effect of byakangelicin observed in animal experiments, we studied the effect of byakangelicin on 4-HNE-induced hepatocyte (HepG2) apoptosis and explored its related pathways. The results showed that byakangelicin could attenuate 4-HNE-induced hepatocyte apoptosis via inhibiting ASK-1/JNK signalling. In conclusion, byakangelicin could improve carbon tetrachloride-induced liver fibrosis and liver injury by inhibiting hepatic stellate cell proliferation and activation and suppressing hepatocyte apoptosis.

Discovery of new Lenalidomide derivatives as potent and selective GSPT1 degraders.

G1 to S phase transition 1 (GSPT1) is the requisite release factor for the translation termination. GSPT1 is identified as an oncogenic driver of several types of cancer and considered to be a promising cancer therapeutic target. Although two selective GSPT1 degraders were advanced into clinical trials, neither of them has been approved for clinical use. Here we developed a series of new selective GSPT1 degraders, among which the optimal compound 9q potently induced degradation of GSPT1 with a DC50 of 35 nM in U937 cells, and showed good selectivity in the global proteomic profiling study. Mechanism studies revealed that compound 9q induced GSPT1 degradation through the ubiquitin-proteasome system. Consistent with its potent GSPT1 degradation activity, compound 9q displayed good antiproliferative activities against U937 cells, MOLT-4 cells, and MV4-11 cells, with IC50 values of 0.019 µM, 0.006 µM, and 0.027 µM, respectively. Compound 9q also dose-dependently induced G0/G1 phase arrest and apoptosis in U937 cells.

FOXO3 regulates Smad3 and Smad7 through SPON1 circular RNA to inhibit idiopathic pulmonary fibrosis.

Forkhead box protein O3 (FOXO3) has good inhibition ability toward fibroblast activation and extracellular matrix, especially for the treatment of idiopathic pulmonary fibrosis. How FOXO3 regulates pulmonary fibrosis remains unclear. In this study, we reported that FOXO3 had binding sequences with F-spondin 1 (SPON1) promoter, which can activate its transcription and selectively promote the expression of SPON1 circRNA (circSPON1) but not mRNA expression. We further demonstrated that circSPON1 was involved in the extracellular matrix deposition of HFL1. In the cytoplasm, circSPON1 directly interacted with TGF-ß1-induced Smad3 and inhibited the activation of fibroblasts by inhibiting nuclear translocation. Moreover, circSPON1 bound to miR-942-5p and miR-520f-3p that interfered with Smad7 mRNA and promoted Smad7 expression. This study revealed the mechanism of FOXO3-regulated circSPON1 in the development of pulmonary fibrosis. Potential therapeutic targets and new insights into the diagnosis and treatment of idiopathic pulmonary fibrosis based on circRNA were also provided.

Inhibitory effect of Idelalisib on selenite-induced cataract in Sprague Dawley rat pups.

PURPOSE: The aim of this study was to evaluate the therapeutic effect of Idelalisib, Apelisib and Copanlisib on 8-day-old cataract SD rat pups. MATERIALS AND METHODS: The rat model induced by sodium selenate (Na2SeO3) was used in this study. Experimental animals were randomly divided into five groups with eight animals in each group. They were control group, Na2SeO3 group, Idelalisib group, Apelisib group and Copanlisib group. On days 3, 5 and 7, all rats in Na2SeO3, Idelalisib, Apelisib and Copanlisib groups were given subcutaneous injection into the nape with Na2SeO3 and control group was given the same amount of saline. For days 1-14, Idelalisib, Apelisib and Copanlisib were given by intragastric administration, respectively, and the same amount of saline was given to the control group and Na2SeO3 group. On the 15th day of the experiment, we selected the Idelalisib group with the best effect from all groups, separated their lenses, and further analyzed the crystal proteins, oxidative damage and apoptosis indexes. RESULTS: The survival rate of rats in control and Idelalisib groups was 100%, the Na2SeO3 group was 37.5%, the Apelisib group was 25%, and the Copanlisib group was 0. According to the rat survival rate and lens score, we selected Idelalisib for further analysis of the crystallin, oxidative damage and apoptosis indexes. The results suggested that Na2SeO3 leads to cataract formation and crystallin precipitation. The levels of antioxidant enzymes GSH and SOD were decreased in the Na2SeO3 group, Nrf-2 and HO-1 were downregulated, Keap1 upregulated, and cleaved caspase-3 and Bax/Bcl-2 upregulated. Idelalisib significantly improved crystallin insolubility, reduced oxidative damage, and inhibited lens apoptosis. CONCLUSION: In summary, Idelalisib can significantly improve the progression of Na2SeO3-induced cataract in rats. In the future, it may be a potential effective drug candidate for the clinical treatment of cataract.

Pinocembrin relieves lipopolysaccharide and bleomycin induced lung inflammation via inhibiting TLR4-NF-κB-NLRP3 inflammasome signaling pathway.

Inflammation is a defense response of the body to stimuli. Lung injury caused by external stimuli can stimulate inflammatory cells to accumulate at the site of injury and secrete cytokines. Pinocembrin is a flavonoid with anti-inflammatory effects. Based on previous studies, we further explored the anti-inflammatory mechanisms of pinocembrin in vitro and in vivo. In vitro studies indicated that pinocembrin inhibited lipopolysaccharide (LPS)-stimulated inflammatory response in macrophages. In vivo studies also showed that pinocembrin could reduce LPS and bleomycin (BLM) induced lung inflammatory response in mice. Further mechanistic studies indicated that pinocembrin could regulate the TLR4-NF-κB signaling pathway and suppressed the activation and assembly of NLRP3 inflammasomes. In summary, pinocembrin could relieve pulmonary inflammatory response induced by LPS and BLM mainly via inhibiting TLR4-NF-κB-NLRP3 inflammasome axis. These results contribute to the understanding of the anti-inflammatory mechanisms of pinocembrin and serve as reference for future research on pinocembrin.

Protective Effect of Arbidol Against Pulmonary Fibrosis and Sepsis in Mice.

From the perspective of epidemiology, viral immunology and current clinical research, pulmonary fibrosis may become one of the complications of patients with Coronavirus Disease 2019 (COVID-19). Cytokine storm is a major cause of new coronavirus death. The purpose of this study was to explore the effects of antiviral drug arbidol on cytokine storm and pulmonary fibrosis. Here, we use a mouse model of bleomycin-induced pulmonary fibrosis and a mouse model of fecal dilution-induced sepsis to evaluate the effects of arbidol on pulmonary fibrosis and cytokine storm. The results showed that arbidol significantly reduced the area of pulmonary fibrosis and improved lung function (reduced inspiratory resistance, lung dynamic compliance and forced vital capacity increased). Treatment with arbidol promoted reduced sepsis severity 48 h after sepsis induction, based on weight, murine sepsis score and survival rate. Arbidol observably alleviates inflammatory infiltrates and injury in the lungs and liver. Finally, we also found that arbidol reduced serum levels of pro-inflammatory factors such as TNF-α and IL-6 induced by fecal dilution. In conclusion, our results indicate that arbidol can alleviate the severity of pulmonary fibrosis and sepsis, and provide some reference for the treatment of cytokine storm and sequelae of pulmonary fibrosis in patients with COVID-19.

Microwave-assisted synthesis of mesoporous Co3O4 nanoflakes for applications in lithium ion batteries and oxygen evolution reactions.

Mesoporous Co3O4 nanoflakes with an interconnected architecture were successfully synthesized using a microwave-assisted hydrothermal and low-temperature conversion method, which exhibited excellent electrochemical performances as anode materials in lithium ion batteries and as catalysts in the oxygen evolution reaction (OER). Field-emission scanning electron microscopy (FESEM) and transmission electron microscopy (TEM) observations showed the unique interconnected and mesoporous structure. When employed as anode materials for lithium ion batteries, mesoporous Co3O4 nanoflakes delivered a high specific capacity of 883 mAh/g at 0.1C current rate and stable cycling performances even at higher current rates. Post-mortem analysis of ex situ FESEM images revealed that the mesoporous and interconnected structure had been well maintained after long-term cycling. The mesoporous Co3O4 nanoflakes also showed both OER active properties and good catalytic stability. This could be attributed to both the stability of unique mesoporous structure and highly reactive facets.