Norkurarinone and isoxanthohumol inhibit high glucose and hypoxia-induced angiogenesis via improving oxidative stress and regulating autophagy in human retinal microvascular endothelial cells.

Diabetic retinopathy (DR) is one of the most serious complications of diabetic microangiopathy. Recent studies have shown its close association with high glucose-induced oxidative stress and autophagy disorder. Previous studies showed that various compounds of flavonoids of Sophora flavescens Aiton extracted using ethyl acetate (SFE) could cross the blood-retinal barrier, exerting favorable effects on retinal tissue disorders and angiogenesis in rats with DR. However, the mechanism and the specific material basis for SFE are still unclear. Here, we established the in vitro DR model of human retinal microvascular endothelial cell (HRMECs) induced by high glucose and hypoxia (HGY), screened out the potential pharmacodynamic components of SFE viz. norkurarinone (NKR) and isoxanthohumol (IXM), and proved that they could improve the pathological features of angiogenesis. Further, we explored the mechanism of action of NKR and IXM, investigating their effects on cellular oxidative stress and autophagy levels under HGY conditions. Finally, the role of the PI3K/AKT/mTOR signaling pathway in the regulation of cell autophagy by NKR and IXM was evaluated. Collectively, NKR and IXM could improve cellular oxidative stress state and activate PI3K/AKT/mTOR signaling pathway to regulate autophagy dysregulation, thus playing a significant role in protecting HRMECs from HGY-caused angiogenesis.

Total flavonoids of Sophora flavescens and kurarinone ameliorated ulcerative colitis by regulating Th17/Treg cell homeostasis.

ETHNOPHARMACOLOGICAL RELEVANCE: Ulcerative colitis (UC) is relevant to dysregulation of inflammation and immune processes. Sophora flavescens Aiton is a classic medicine widely used in the treatment of UC in ancient and modern China, alkaloids and flavonoids are the main components. Previous studies reveal that Sophora flavescens Aiton total flavonoids extracts (SFE) exert an anti-UC effect by regulating the intestinal microbe structure and restoring the balance of the "host-microbe" co-metabolic network in UC mice. However, whether SFE influences immune inflammation remains unclear, which is the core link to UC disease. It also remains to be verified flavonoids are the material basis that plays a role in SFE. AIM OF THE STUDY: To identify the action mechanism of the immune-inflammatory regulation of SFE and its main active component Kurarinone against UC. METHODS: This study constructed UC mice and abnormal immune RAW 264.7 cell models, and subsequently used western blotting and flow cytometry (FCM) to evaluate the effects of SFE on the NF-κB pathway and the regulation of immunity in UC mice. Kurarinone was screened from flavonoid compounds of SFE by lipopolysaccharide (LPS)-induced RAW 264.7 cells, and its effect was subsequently investigated in UC mice. Western blotting, ELISA, FCM, and RT-PCR were used to determine the regulation of Kurarinone on the Th17/Treg differentiation and the JAK2/STAT3 signaling pathway. RESULTS: SFE regulated the differentiation of Th17/Treg in peripheral blood and inhibited immune-inflammatory response to treat UC. Various flavonoid components in SFE inhibited the synthesis of IL-6 and TNF-α in RAW 264.7 cells, among which Kurarinone had better effect. This study revealed the therapeutic effects of Kurarinone in UC mice for the first time. Kurarinone promoted the secretion of SIgA to improve the regulation of the intestinal mucosal barrier and resistance to pathogens. It also regulated the transcription level of RORγt and Foxp3 in colon, decreased the expression of pro-inflammatory factor IL-17A and up-regulated the expression of immunosuppressive factors TGF-ß1 and IL-10 in colon. Furthermore, Kurarinone restored intestinal immune system homeostasis by down-regulating the JAK2/STAT3 signaling pathway and regulating the balance of Th17/Treg cell differentiation in UC. CONCLUSIONS: SFE, especially the flavonoid ingredients represented by Kurarinone, has significant effects on immunoregulation against UC. And their mechanism of effect is related to inhibiting the activation of JAK2/STAT3 signaling pathway and regulating differentiation of Th17/Treg cells. KEYWORK: Immunoregulatory; Kurarinone; Th17 cells; Treg cells; Ulcerative colitis.

Effect of the ethyl acetate extract of Sophora flavescens Aiton on diabetic retinopathy based on untargeted retinal metabolomics.

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and a leading cause of vision impairment and blindness, which lacks effective diagnostic measures and therapeutic options. Sophora flavescens Aiton or "Kushen" is a traditional Chinese medicine used since ancient times, either alone or in combination, to clear heat, dampness, and tearing, and to treat ocular diseases and improve eyesight. Additionally, the flavonoids of Sophora flavescens Aiton extracted using ethyl acetate (EtOAc) (SFE) is effective in managing diabetes and diabetic vascular complications. In this study, we explored the pharmacodynamic effects and material basis of action of SFE on DR for the first time and elucidated the mechanism based on untargeted retinal metabolomics. Results from the pharmacodynamic studies showed that SFE could reduce blood glucose levels in rats, regulate serum lipopolysaccharide, tauroursodeoxycholic acid, and trimethylamine oxide levels, and significantly improve the structure of retina in rats with DR. Moreover, SFE could protect the blood-retinal barrier, reduce angiogenesis and capillary formation, and inhibit retinal nerve cell apoptosis. A total of 13 compounds were identified in the aqueous humor and retina, which were dihydroflavonoid, isoflavonoid, pterostane flavonoid, chalcone, and dihydroflavonol derivatives. In addition, 39 differential metabolites were screened based on retinal metabolomics data and 23 were found to be affected by SFE, indicating its anti-DR effect by regulating the synthetic metabolic pathways, including lactose, bile acid, glycerophospholipid, arginine, purine, and pyrimidine metabolism pathways. Collectively, our findings elucidated the effects, material basis, and treatment mechanism of SFE on DR systematically and could lay the foundation for promoting the clinical application of Sophora flavescens Aiton.

The experience of urgent dialysis patients with end-stage renal disease: A qualitative study.

PURPOSE: Taiwan is among the countries with the highest global prevalence of chronic renal disease. However, when advised to undergo dialysis therapy, patients with end-stage renal disease often hesitate. Attitudes toward medication and Taiwanese cultures are the main reasons for this delay, and delay conditioning requires urgent dialysis. This study aimed to explore the experience of urgent dialysis patients with end-stage renal disease. METHODS: This study used a purposive sampling strategy with semi-structured interviews leading to in-depth interviews. Patients were recruited from the nephrology ward and hemodialysis center of a northern Taiwanese hospital. All participants were aged over 20 years with end-stage renal disease. Although advised by doctors to undergo dialysis, these patients delayed their treatment and later suffered severe complications. After emergency hospitalization, the patients' condition improved. Data were analyzed by content analysis. RESULTS: Interviews with five participants suffering from end-stage renal disease identified six themes: "experiencing a sudden jolt," "silent organ brings the most pain," "feeling angry: why me?," "facing a dilemma," "taking risks," and "facing consequences." CONCLUSION: These patients delayed their treatment and later suffered severe complications, even though doctors advised them to undergo dialysis. Health professionals play an important role in communication and coordination, assisting patients in coping with their situation. The analysis of the reasons for the delay in undergoing dialysis, therefore, should help health professionals provide proper guidance and care to patients who are faced with the decision to accept dialysis treatment.

Construction of a "Bacteria-Metabolites" Co-Expression Network to Clarify the Anti-Ulcerative Colitis Effect of Flavonoids of Sophora flavescens Aiton by Regulating the "Host-Microbe" Interaction.

Ulcerative colitis (UC) is considered an immune disease, which is related to the dysbiosis of intestinal microbiota and disorders of the host immune system and metabolism. Sophora flavescens Aiton has been used for the clinical treatment of UC in China and East Asia for thousands of years. It has many traditional prescriptions and modern preparations, and its curative effects are definite. We are the first to report that the flavonoids in Sophora flavescens (S. flavescens) Aiton EtOAc extract (SFE) could potentially attenuate the dextran sodium sulfate-induced UC in mice, which changed the current understanding of considering alkaloids as the only anti-UC pharmacological substances of S. flavescens Aiton. Based on the 16S rRNA gene sequencing and metabolomic analysis, it was found that the anti-UC effects of SFE were due to the regulation of gut microbiota, reversing the abnormal metabolisms, and regulation of the short-chain fatty acids synthesis. Notably, according to the interaction networks of specific bacteria and "bacteria and metabolites" co-expression network, the SFE could enrich the abundance of the commensal bacterium Lactobacillus, Roseburia, norank_f__Muribaculaceae, Anaerotruncus, Candidatus_Saccharimona, and Parasutterella, which are proposed as potentially beneficial bacteria, thereby playing vital roles in the treatment of UC.