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Background: The total flavones of Abelmoschus manihot (TFA), a compound that is extracted from Abelmoschus manihot , has been widely used in China to reduce podocyte injury in diabetic kidney disease (DKD). However, the mechanisms underlying the therapeutic action of this compound have yet to be elucidated. Podocyte pyroptosis is characterized by activation of the NLRP3 inflammasome and plays an important role in inflammation-mediated diabetic kidneys. Regulation of the PTEN/PI3K/Akt pathway is an effective strategy for improving podocyte damage in DKD. Previous research has also shown that N6-methyladenosine (m 6 A) modification is involved in DKD and that m 6 A-modified PTEN regulates the PI3K/Akt pathway. In this study, we investigated whether TFA alleviates podocyte pyroptosis and injury by targeting m 6 A modification-mediated NLRP3-inflammasome activation and PTEN/PI3K/Akt signaling. Methods: We used MPC-5 cells under high glucose (HG) conditions to investigate the key molecules that are involved in podocyte pyroptosis and injury, including activation of the NLRP3 inflammasome and the PTEN/PI3K/Akt pathway. We detected alterations in the levels of three methyltransferases that are involved in m 6 A modification. We also investigated changes in the levels of these key molecules in podocytes with the overexpression or knockdown of methyltransferase-like (METTL)3. Results: Analysis showed that TFA and MCC950 protected podocytes against HG-induced pyroptosis and injury by reducing the protein expression levels of gasdermin D, interleukin-1β, and interleukin-18, and by increasing the protein expression levels of nephrin, ZO-1, WT1 and podocalyxin. TFA and 740Y-P inhibited activation of the NLRP3 inflammasome via the PI3K/Akt pathway by inhibiting the protein levels of NIMA-related kinase7, NLRP3, ASC, and caspase-1, and by increasing the protein expression levels of p-PI3K and p-Akt. TFA improved pyroptosis and injury in HG-stimulated podocytes by regulating METTL3-dependent m 6 A modification. Conclusion: Collectively, our data indicated that TFA could ameliorate pyroptosis and injury in podocytes under HG conditions by adjusting METTL3-dependent m 6 A modification and regulating NLRP3-inflammasome activation and PTEN/PI3K/Akt signaling. This study provides a better understanding of how TFA can protect podocytes in DKD.

Abelmoschus manihot , an annual herbal flowering plant, is widely distributed throughout eastern Europe and in temperate and subtropical regions of Asia. Its flowers have been traditionally used for the treatment of chronic kidney disease in China. Currently, more than 128 phytochemical ingredients have been obtained and identified from the flowers, seeds, stems, and leaves of A. manihot . The primary components are flavonoids, amino acids, nucleosides, polysaccharides, organic acids, steroids, and volatile oils. A. manihot and its bioactive constituents possess a plethora of biological properties, including antidiabetic nephropathy, antioxidant, antiadipogenic, anti-inflammatory, analgesic, anticonvulsant, antidepressant, antiviral, antitumor, cardioprotective, antiplatelet, neuroprotective, immunomodulatory, and hepatoprotective activities, and have effects on cerebral infarction, bone loss, etc. However, insufficient utilization and excessive waste have already led to a rapid reduction of resources, meaning that a study on the sustainable use of A. manihot is urgent and necessary. Moreover, the major biologically active constituents and the mechanisms of action of the flowers have yet to be elucidated. The present paper provides an early and comprehensive review of the traditional uses, chemical constituents, pharmacological activities, and pharmaceutical, quality control, toxicological, and clinical settings to emphasize the benefits of this plant and lays a solid foundation for further development of A. manihot .

To investigate the therapeutic effect of total flavones of Abelmoschus manihot (L.) Medic (TFA) on CCl 4 -induced liver fibrosis in mice, and to clarify the mechanism of action of TFA in ameliorating liver fibrosis by untargeted metabolomics and intestinal microbiota 16S rRNA sequencing, in order to provide an experimental basis for the clinical application of TFA in the treatment of liver fibrosis. To establish a mice model of CCl 4 -induced liver fibrosis, and liver injury was assessed through histopathology, liver function markers (ALT, AST), inflammatory cytokines, and oxidative stress indicators. Serum untargeted metabolomics was conducted via LC-MS/MS, and intestinal microbiota profiles were analyzed by 16S rRNA sequencing. TFA treatment significantly reduced ALT and AST levels by approximately 55% and 40%, respectively, and markedly ameliorated histopathological changes. It also attenuated oxidative stress and inflammation. Metabolomic analysis identified 83 differential metabolites, indicating that TFA restored disruptions in glycerophospholipid, tryptophan, and arachidonic acid metabolism. Gut microbiota sequencing showed that TFA increased beneficial bacteria and decreased harmful bacteria. Furthermore, TFA downregulated the expression of CYP1A1, CYP2E1, and ALOX15 in liver tissue, suggesting modulation of arachidonic acid metabolism. TFA alleviated CCl 4 -induced liver fibrosis in mice by reducing oxidative stress and inflammation, improving gut microbiota dysbiosis, and regulating host metabolism. These findings suggest that TFA may hold potential as a multi-target agent for liver fibrosis, although further studies are required to confirm its efficacy in other models and females.

Recently, progression of chronic renal failure (CRF) has been closely associated with gut microbiota dysbiosis and intestinal metabolite-derived microinflammation. In China, total flavones of (TFA), a component of , has been widely used to delay CRF progression in clinics for the past two decades. However, the overall therapeutic mechanisms remain obscure. In this study, we designed experiments to investigate the renoprotective effects of TFA in CRF progression and its underlying mechanisms involved in gut microbiota and microinflammation, compared with febuxostat (FEB), a potent non-purine selective inhibitor of xanthine oxidase. , the CRF rat models were induced by uninephrectomy, potassium oxonate, and proinflammatory diet, and received either TFA suspension, FEB, or vehicle after modeling for 28 days. , the RAW 264.7 cells were exposed to lipopolysaccharide (LPS) with or without TFA or FEB. Changes in parameters related to renal injury, gut microbiota dysbiosis, gut-derived metabolites, and microinflammation were analyzed . Changes in macrophage polarization and autophagy and its related signaling were analyzed both and . For the modified CRF model rats, the administration of TFA and FEB improved renal injury, including renal dysfunction and renal tubulointerstitial lesions; remodeled gut microbiota dysbiosis, including decreased and and increased ; regulated gut-derived metabolites, including d-amino acid oxidase, serine racemase, d-serine, and l-serine; inhibited microinflammation, including interleukin 1β (IL1β), tumor necrosis factor-α, and nuclear factor-κB; and modulated macrophage polarization, including markers of M1/M2 macrophages. More importantly, TFA and FEB reversed the expression of beclin1 (BECN1) and phosphorylation of p62 protein and light chain 3 (LC3) conversion in the kidneys by activating the adenosine monophosphate-activated protein kinase-sirtuin 1 (AMPK-SIRT1) signaling. Further, TFA and FEB have similar effects on macrophage polarization and autophagy and its related signaling . In this study, we demonstrated that TFA, similar to FEB, exerts its renoprotective effects partially by therapeutically remodeling gut microbiota dysbiosis and inhibiting intestinal metabolite-derived microinflammation. This is achieved by adjusting autophagy-mediated macrophage polarization through AMPK-SIRT1 signaling. These findings provide more accurate information on the role of TFA in delaying CRF progression.

To improve the drug delivery to the brain with borneol (Bo)-modified solid lipid nanoparticles (SLNs) of pueraria flavones (PTF) via intranasal administration. PTF-loaded SLNs were modified with Bo by physical and chemical methods to synthesize PTF-Bo-SA-SLNs and PTF-Bo-SLNs. The prepared SLNs were characterized and their brain delivery effects were evaluated and . There was a more pronounced accumulation of PTF-Bo-SA-SLNs in Caco-2 cells. Following intranasal administration, more coumarin-6 was found in the rat brain carried by Bo-SA-SLNs. Brain area under the curve and C of PTF-Bo-SA-SLN were 7.31- and 7.29-times higher than those of PTF-SLN, respectively. PTF-Bo-SA-SLNs are a promising therapeutic carrier for brain disease after intranasal administration.

Purslane is a traditional Chinese medicine with a long-standing history of efficacy in the management of dermatological conditions such as vitiligo. However, the molecular mechanisms underlying its therapeutic effects on vitiligo remain unclear. Therefore, the present study explored these mechanisms using network pharmacology, molecular docking and in vitro experiments. Following the screening process, seven principal active components were identified, namely kaempferol, hesperetin, luteolin, quercetin, arachidonic acid, cycloartenol and β-sitosterol. In addition, six key targets, namely AKT1, tumor protein p53, peroxisome proliferator-activated receptor γ (PPARG), estrogen receptor 1, prostaglandin-endoperoxidase synthase 2 and mitogen-activated protein kinase 1, and eight pathways in purslane-based vitiligo treatment were identified. Network pharmacology and molecular docking demonstrated that flavonoids are the key components of purslane likely to mitigate oxidative stress damage in vitiligo. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that the phosphatidylinositol 3-kinase (PI3K)/AKT, p53 and PPARG signaling pathways are associated with purslane components and vitiligo. In vitro experiments revealed that purslane total flavones (PTF) increased cell viability, decreased ROS levels and increased antioxidant enzyme activities in H2O2-induced B16F10 cells. In addition, PTF activated the PI3K/AKT signaling pathway in H2O2-induced B16F10 cells, and the antioxidant effect of PTF was attenuated by a PI3K/AKT inhibitor. In conclusion, the findings of the present study suggest that the flavonoids of purslane contribute, at least in part, to its therapeutic effectiveness in vitiligo by mitigating oxidative stress in melanocytes through the PI3K/AKT signaling pathway.

Total flavone of (TFA), the effective constituents extracted from Flos , has been reported to inhibit inflammation. However, the effect of TFA on ulcerative colitis (UC) progression in patients with depression is unknown. The purpose of our research was to explore the anti-UC effects of TFA in the context of depression in mice with UC by regulating the gut microbiota to drive the intestinal barrier. In this study, chronic stress (CS) and dextran sodium sulfate (DSS) were used to induce depression and UC, respectively, in C57BL/6J mice. Fecal microbiota transplantation (FMT) was used to evaluate how treating mice modeling UC and depression with TFA effected their gut microbiota. Our results showed that TFA effectively improved UC aggravated by CS. In addition, TFA treatment improved the depression-like phenotype, the disturbed gut microbiota, and the intestinal barrier function in CS mice. It is worth noting that FMT from the CS mice to the receptor group further aggravated the damage of the intestinal barrier and the disturbance of the gut microbiota in the recipient DSS mice, thus further aggravating UC, however, treatment of the intervention of TFA in the CS fecal microbiota transplant with TFA also played its therapeutic outcome. Taken together, our results show that CS disrupts the gut microbiota, triggers intestinal barrier injury and aggravates DSS colitis, while TFA is a promising drug for the treatment of UC in patients with depression.

A recent clinical study demonstrated that Huangkui capsule (with its bioactive constituents being total flavones extracted from (L.), TFA) combined with irbesartan provides effective therapy for type 2 diabetes (T2D) patients with diabetic nephropathy (DN). This study aimed to elucidate the therapeutic mechanisms of TFA in DN through the modulation of the gut-kidney axis. The db/db mice were administered TFA, irbesartan, or vehicle. Urinary albumin-creatinine ratio (UACR) was measured by the enzyme-linked immunosorbent assay (ELISA). Intestinal bacterial composition was analyzed using 16S rRNA sequencing. Serum metabolites were quantified via LC-ESI-MS/MS. Kidney transcriptomics were assessed using Illumina platform-based RNA sequencing. Administration of TFA reduced the UACR in db/db mice and significantly altered intestinal flora composition. Specifically, TFA elevated the abundance of Dietzia, Faecium, Streptococcus, and Blautia while reducing Bacteroidetes, Firmicutes, Enterobacteriaceae, Rikenellaceae, Fusivibrio, and Treponema. In serum metabolomic analysis, TFA increased the levels of quercetin 3-glucuronide and n-cinnamyl glycine but decreased cortisol concentrations. Concurrently, renal transcriptomics revealed the downregulation of key genes, including retnlg, ngp, mpo, camp, ctsg, elane, s100a8, s100a9, trem1, and mmp7, which primarily function in pathways related to neutrophil extracellular trap formation, steroid hormone biosynthesis, and cortisol synthesis/secretion. In contrast, irbesartan treatment did not significantly affect blood pressure or specific renal gene pathways in db/db mice. TFA attenuates diabetic nephropathy (DN) progression through pharmacological mechanisms involving three key axes: (1) modulation of intestinal flora composition, (2) regulation of circulating metabolites, and (3) suppression of renal gene activity pathways. These findings highlight the gut-kidney axis as a central therapeutic target for TFA in DN management.

This study aimed to investigate the effect of total flavonoids of Choerospondias axillaris (TFC) on myocardial infarction (MI)-induced cardiac dysfunction, interstitial fibrosis and inflammatory reaction and further to clarify the potential signaling pathway involved. Rats were subjected to MI via coronary artery occlusion. The model establishment was confirmed by the occurrence of ST-segment elevation in electrocardiogram. Then, TFC was administrated at doses of 75, 150 and 300 mg/kg for 28 consecutive days (gavage). Body weight and heart weight were recorded. Hemodynamics, infarct size and myocardial fibrosis were examined. Blood samples were collected to determine tumor necrosis factor- α (TNF- α ) and interleukin 6, 10 (IL-6, IL-10) levels. The expressions of matrix metalloproteinases-2, 9 (MMP-2, 9), phosphor-IKB α (p-IKB α) and transforming growth factor-β1 (TGF-β1) were assayed by Western blot. The results indicated that TFC significantly improved cardiac dysfunction, the heart coefficient and myocardial fibrosis in MI rat. TFC also decreased the levels of TNF- α and IL-6, but increased IL-10 content. Moreover, treatment with TFC protected the heart from chronic MI injury by decreasing the expressions of MMP-2, 9, TGF-β1 and p-IKB α . The results suggested that TFC attenuated cardiac dysfunction and myocardial interstitial fibrosis by modulating nuclear factor-kappa B (NF-κB) signaling pathway.

Choerospondias axillaris (Guangzao) is a medicinal plant used in Mongolia, and its fruit is commonly used for the treatment of cardiovascular diseases in clinic. The constituents responsible for this effect are always conceded to be the total flavonoids of C. axillaries (TFC). The present study was to evaluate the preventive effect of TFC on acute myocardial infarction induced by ischemia/reperfusion (I/R) in rats and the possible signaling pathway involved. The model of myocardial I/R was caused by occlusion of the left anterior descending coronary artery for 30 min followed by reperfusion for 2 h. Cardiac dysfunction, infarct size, pathologic histology and apoptosis were examined. Heart tissues were homogenized for biochemistry assays and Western blots analysis. The results indicated that pretreatment with TFC strongly improved cardiac function, obviously reduced heart pathologic lesion in I/R rat hearts. TFC also could protect the heart from I/R injury by increasing the levels of catalase, glutathione peroxidase and superoxide dismutase in heart homogenate, and decreasing that of malondialdehyde level. These beneficial effects were associated with the decrease in TUNEL-positive nuclear staining, Bax and caspase-3 levels, and the increase in Bcl-2 expression. Moreover, TFC counteracted the I/R-induced decreased activation of p38 mitogen-activated protein kinase (MAPK) and Jun N-terminal kinase. These data suggested that TFC improved I/R-induced myocardium impairment via anti-oxidative and anti-apoptotic activities, and this beneficial effects were intervened by MAPK signaling pathway.