Xing Wang

Diabetic peripheral neuropathy (DPN) is a common and intractable chronic diabetic complication with complex pathogenesis and limited clinical treatments. Ferroptosis critically participates in the initiation and progression of DPN, while Ferrostatin-1 (Fer-1), a specific ferroptosis inhibitor that blocks iron-dependent lipid peroxidation, has an unclear therapeutic role in DPN. This study aimed to clarify the protective effects and molecular mechanisms of Fer-1 against DPN-induced pathological injuries. In vivo, DPN models were constructed in SD rats via intraperitoneal injection of 60 mg/kg streptozotocin, followed by 10 consecutive weeks of Fer-1 treatment at doses of 1 and 2 mg/kg/day. The results showed that Fer-1 did not affect the blood glucose and body weight of DPN rats, but improved impaired glucose tolerance, relieved mechanical and thermal hyperalgesia, accelerated nerve conduction velocity, and alleviated sciatic nerve morphological damage. In vitro, high glucose (100 mM)-induced injury in RSC96 Schwann cells was markedly rescued by gradient concentrations of Fer-1 (5, 12.5, 25 μM) after 48-hour intervention. Mechanistically, Fer-1 activated the Nrf2 signaling pathway and regulated ferroptosis-related protein expression, which elevated intracellular GSH content and SOD/GPX activities, reduced MDA levels, and suppressed oxidative stress and ferroptosis both in vivo and in vitro. Moreover, Nrf2 inhibitor ML385 partially reversed the protective effects of Fer-1 against high glucose-induced oxidative damage. Collectively, Fer-1 exerts protective effects on DPN by partially activating the Nrf2-mediated inhibition of oxidative stress and ferroptosis, providing a promising therapeutic candidate and theoretical foundation for DPN clinical treatment.

Gentiopicroside (GPS), derived from Gentiana manshurica, exhibits multiple pharmacological activities, such as anti‐inflammatory and antioxidant effects, but its role and mechanisms in treating type 2 diabetes mellitus (T2DM) remain unclear. This study explored GPS's therapeutic effects and underlying mechanisms in vitro and in vivo. In a T2DM mouse model induced by a high‐fat diet (HFD) and streptozotocin (STZ), the results demonstrated that GPS significantly relieved diabetic symptoms, corrected oral glucose tolerance impairment, enhanced insulin sensitivity, and ameliorated lipid metabolism disorders. GPS also increased the activities of antioxidant enzymes, elevated the levels of antioxidant substances, reduced malondialdehyde (MDA) in serum and liver, and ameliorated hepatic insulin resistance (IR). In palmitic acid (PA)‐induced HepG2 cells, GPS dramatically inhibited PA‐induced cytotoxicity and oxidative stress by increasing glutathione (GSH) levels and superoxide dismutase (SOD) activities while lowering malondialdehyde (MDA) levels, and reversed PA‐induced IR. Mechanistically, GPS regulated protein expression in the PI3K/AKT/Nrf2 pathway and promoted Nrf2 nuclear translocation in both models. More importantly, further studies revealed that LY294002 (a PI3K inhibitor) or ML385 (an Nrf2 inhibitor) suppressed the protective effects of GPS against PA‐induced hepatic oxidative damage. In conclusion, GPS alleviates hepatic oxidative damage, IR and delays the progression of T2DM through activating the PI3K/AKT/Nrf2 signaling pathway, providing an important foundation for further development and utilization of GPS. However, this study still has limitations including the lack of a positive control drug and insufficient exploration of the relevant molecular mechanisms, and will further improve the research and explore the clinical potential of GPS in the future.

Introduction: Diphenyl diselenide (DPDS) ameliorates nephropathy in streptozotocin (STZ)-induced type 1 diabetic rats by inhibiting oxidative stress and inflammatory reactions. However, it has not been clarified whether DPDS alleviates type 1 diabetic kidney disease (DKD) is related to the inhibition of extracellular matrix (ECM) production and the regulation of intestinal flora disorder.Methods: The present study investigated the effects of DPDS on ECM generation in the kidney and intestinal microflora composition in feces. The rats were orally administered DPDS or metformin for eight weeks. Various indices were measured to assess the severity of renal injury. After euthanizing the rats, oxidative stress markers in serum and kidney were assessed using biochemical methods, and the expressions of ECM-related proteins in kidney were analyzed using Western blot. Additionally, 16S rRNA high-throughput sequencing was used to evaluate the diversity and composition of the intestinal flora in feces.Results: The results showed DPDS and metformin improved the DKD in STZ rats, as evidenced by decreased blood glucose, BUN, urine volume, urine microalbumin, urinary β2 microglobulin, and improvement of renal pathological morphology. Furthermore, DPDS intervention markedly reduced the protein expression of α-SMA, COI Ⅳ, FN, and vimentin in the kidneys. Besides, DPDS not only improved dyslipidemia in STZ diabetic rats, but also enhanced the activities of antioxidant enzymes, decreased the level of MDA in serum and kidney, and regulated the expression of proteins related to the Nrf2/Keap1 signaling pathway in the kidney. Moreover, we found that DPDS could selectively improve the relative abundance of probiotics as well as the diversity of flora, thus ameliorating the intestinal microbial composition of the STZ rats, significantly regulating the intestinal microbial homeostasis.Discussion: Overall, DPDS inhibited ECM production and improved renal pathological changes, which may be related to reducing oxidative stress damage in the kidney and improving intestinal flora imbalance, providing data support for the further development and application of DPDS in DKD.

Introduction: Diarrhea is a common clinical condition that can potentially be fatal. Current treatment options often have side effects, such as constipation and vomiting, and there remains a need for more effective therapies. Pickled vegetables, a famous traditional food in China, have been suggested in clinical studies to alleviate diarrhea in children, particularly through the use of pickle water (PW). However, the pharmacological effects and mechanisms of PW on intestinal health remain unclear. This study aimed to explore the protective effects of PW on castor oil-induced diarrhea in ICR mice and to investigate its potential mechanisms.Methods: To evaluate the antidiarrheal effects of PW, we used a castor oil-induced diarrhea model in ICR mice. Various indices were measured to assess the severity of diarrhea. After euthanizing the mice, oxidative stress markers in the ileum were assessed using biochemical methods, and the expression of tight junction-related proteins in the ileum was analyzed using Western blot. Additionally, 16S rRNA high-throughput sequencing was used to evaluate the diversity and composition of the intestinal flora.Results: The results showed that PW supplementation reduced body weight without significantly affecting organ index and liver function in the castor oil-induced diarrhea mice. PW also effectively reduced the dilution rate, diarrhea index, average loose stool grade, propelling distance of carbon powder, and intestinal propulsive rate while improving the pathological abnormality in the ileum. Furthermore, PW enhanced the activities of total antioxidant capacity (T-AOC), glutathione peroxidase (GSH-PX), and catalase (CAT) while reducing malonaldehyde (MDA) levels. PW also increased the expression of tight junction proteins zonula occludens-1 (ZO-1) and occludin in the ileum. Additionally, the analysis of 16S rDNA revealed that PW increased both α and β diversity, improved the composition of the intestinal flora, and restored it to a normal level.Discussion: Collectively, dietary PW administration ameliorates Castor oil-induced diarrhea by restoring tight junctions between intestinal mucosal cells, suppressing oxidative stress, and regulating the composition of intestinal flora. These findings suggest that PW may be a promising strategy for managing diarrhea.

Hyperglycemia, oxidative stress, and inflammation play key roles in the onset and development of diabetic complications such as diabetic nephropathy (DN). Diphenyl diselenide (DPDS) is a stable and simple organic selenium compound with anti-hyperglycemic, anti-inflammatory, and anti-oxidative activities. Nevertheless, in vitro, the role and molecular mechanism of DPDS on DN remains unknown. Therefore, we investigated the effects of DPDS on tert-butyl hydrogen peroxide (t-BHP)-induced oxidative stress and lipopolysaccharide (LPS)-induced inflammation in rat glomerular mesangial (HBZY-1) cells and explored the underlying mechanisms. DPDS attenuated t-BHP-induced cytotoxicity, concurrent with decreased intracellular ROS and MDA contents and increased SOD activity and GSH content. Moreover, DPDS augmented the protein and mRNA expression of Nrf2, HO-1, NQO1, and GCLC in t-BHP-stimulated HBZY-1 cells. In addition, DPDS suppressed LPS-induced elevations of intracellular content and mRNA expression of interleukin (IL)-6, IL-1β and TNF-α. Furthermore, LPS-induced NFκB activation and high phosphorylation of JNK and ERK1/2 were markedly suppressed by DPDS in HBZY-1 cells. In summary, these data demonstrated that DPDS improves t-BHP-induced oxidative stress by activating the Nrf2/Keap1 pathway, and also improves LPS-induced inflammation via inhibition of the NFκB/MAPK pathways in HBZY-1 cells, suggesting that DPDS has the potential to be developed as a candidate for the prevention and treatment of DN.