Dapagliflozin prevents kidney podocytes pyroptosis via miR-155-5p/HO-1/NLRP3 axis modulation.

Diabetic nephropathy (DN) is a significant clinical microvascular complication associated with diabetes mellitus (DM), and end-stage diabetes giving rise to kidney failure is developing into the major etiological factor of chronic kidney failure. Dapagliflozin is reported to limit podocyte damage in DM, which has proven to protect against renal failure. Mounting evidence has demonstrated that pyroptosis is associated with DM progression. Nevertheless, whether pyroptosis causes DN and the underlying molecular pathways remain obscure. In this study, we aimed to explore the antipyroptotic attributes of dapagliflozin and elucidate the underlying mechanisms of kidney damage in diabetes. In vivo, experiments were conducted in streptozotocin (STZ)-induced type 2 diabetic mice, which were administered dapagliflozin via gavage for 6 weeks. Subsequently, the specific organizational characteristics and expression of pyroptosis-related genes were evaluated. Intragastric dapagliflozin administration markedly reduced renal tissue injury. Meanwhile, dapagliflozin also attenuated the expression level of pyroptosis associated genes, including ASC, cleaved Caspase-1, GSDMD N-termini, NLRP3, IL-18, and IL-1ß in renal tissue of dapagliflozin-treated animals. Similar antipyroptotic effects were observed in palmitic acid (PA)-treated mouse podocytes. We also found that heme oxygenase 1 (HO-1) enhanced the protection of mouse podocyte clone 5 cells (MPC5). Moreover, miR-155-5p inhibition increased pyroptosis in PA-treated MPC5 cells, suggesting that miR-155-5p acts as an endogenous stimulator that increases HO-1 expression and reduces pyroptosis. Hence, our findings imply that dapagliflozin inhibits podocyte pyroptosis via the miR-155-5p/HO-1/NLRP3 axis in DM. Furthermore, dapagliflozin substitution may be regarded as an effective strategy for preventing pyroptosis in the kidney, including a therapeutic option for treating pyroptosis-related DN.

Coumaroyl and feruloyl flavonoid glycosides from the male flowers of Ginkgo biloba L. and their inhibitory activity against α-glucosidase.

Four flavonoid glycosides containing coumaroyl or feruloyl groups were isolated from the male flowers of Ginkgo biloba L., and compounds 3 and 4 were identified as novel compounds. The inhibitory activities against α-glucosidase were investigated by docking studies, in vitro assays and kinetic studies. The docking results showed that all compounds mainly formed hydrogen-bond and π-π-stacking interactions with α-glucosidase. Compound 4 had the lowest binding energy and maximum number of hydrogen bonds. Subsequently, the in vitro assays showed that compound 4 exhibited the strongest inhibitory potency. Finally, the kinetic studies indicated the inhibitory mode of compounds 1-4 against α-glucosidase were mixed types of competitive and non-competitive. Together, these findings suggested that the isolated flavonoid glycosides in this study, especially compound 4, have potential as α-glucosidase inhibitors.

Photoprotection of maqui berry against ultraviolet B-induced photodamage in vitro and in vivo.

Ultraviolet B (UVB) irradiation-induced DNA damage, oxidative stress, inflammatory processes, and skin pigmentation cause pigmented spots, wrinkles, inflammation, and accelerated skin aging and cancer. Maqui berry (Aristotelia chilensis) is a natural antioxidant, anticancer, and anti-inflammatory food. We investigated the photoprotective properties of the ethyl acetate fraction of maqui berry ethanol extract (MEE) in vitro and in vivo. Spectrophotometric measurements revealed dominant extinction profile of MEE in the UVB range. MEE clearly reversed the DNA damage induced by UVB irradiation in HaCaT cells by upregulating endogenous cellular enzymatic and non-enzymatic antioxidant systems containing superoxide dismutase, catalase, and glutathione and reducing the production of nitric oxide. Moreover, MEE treatment enhanced the antioxidant ability and weakened lipid peroxidation in BALB/c mice exposed to UVB radiation. It also down-regulated interleukin (IL)-6 and tumor necrosis factor-α levels and up-regulated IL-4 levels. Moreover, MEE inhibited the UVB-triggered activation of ERK and p38 MAPK. These data suggest that MEE is an effective agent against UVB-induced photodamage.

Maqui berry exhibited therapeutic effects against DSS-induced ulcerative colitis in C57BL/6 mice.

Maqui berry (Aristotelia chilensis) is an edible berry. The study aimed to explore the therapeutic effect of maqui berry on inflammatory bowel disease. Maqui berry water extract was separated by multiple solvents extraction. The chemical bases, antioxidant and anti-inflammatory properties of different extract fractions were then compared. Dextran sodium sulfate (DSS)-induced ulcerative colitis mice were used for the pharmacological activity test in vivo. Experimental results showed that the ethyl acetate fraction of maqui berry water extract (MWE) was rich in phenols and exhibited good antioxidant and anti-inflammatory activities. MWE considerably reduced the expression of COX2 and IL-6 in LPS-stimulated RAW 264.7 cells. Inflammatory bowel disease index, MDA, NO, i-NOS, and COX2 in colon tissues and MPO, TNF-α, and IL-1ß in blood serums were remarkably decreased in the treatment group compared to in the model group (p < 0.05). Intestinal histopathological damage was significantly alleviated in the treatment group, and the expression of occludin was increased (p < 0.05). MWE treatment alleviated the imbalance of gut microbiota caused by DSS injury. Overall, MWE plays a therapeutic role in ulcerative colitis through its anti-inflammatory effect, reduces immune stress, and regulates gut microbiota.

The protective effects of Cichorium glandulosum seed and cynarin against cyclophosphamide and its metabolite acrolein-induced hepatotoxicity in vivo and in vitro.

Cyclophosphamide (CP) is a widely utilized chemotherapy drug. CP and its metabolite, acrolein, could induce hepatotoxicity. In this study, Cichorium glandulosum seed (CGS) effectively mitigated CP-induced hepatotoxicity in mice. Protection of cynarin, the major compound of CGS, against acrolein cytotoxicity in HepG2 cells was studied. Pretreatment with cynarin could improve cell survival against acrolein cytotoxicity. Cynarin restored the balance of glutathione (GSH) and reactive oxygen species (ROS), and inhibited mitochondrial depolarization. The kinetics of Nrf2 expression in cytosolic and nuclear fractions were observed after acrolein exposure. Intracellular Nrf2 expression was triggered within 6 h of exposure but did not translocate to the nucleus. Cynarin pretreatment ameliorated the expression and activity of GSH S-transferase and triggered Nrf2 nuclear translocation. In conclusion, treatment with CGS and cynarin protects liver injury against CP and acrolein hepatotoxicity via improvement of GSH activity and activation of the Nrf2 pathway.