Protective effects of Dioscin against sepsis-induced cardiomyopathy via regulation of toll-like receptor 4/MyD88/p65 signal pathway.

BACKGROUND: Dioscin has many pharmacological effects; however, its role in sepsis-induced cardiomyopathy (SIC) is unknown. Accordingly, we concentrate on elucidating the mechanism of Dioscin in SIC rat model. METHODS: The SIC rat and H9c2 cell models were established by lipopolysaccharide (LPS) induction. The heart rate (HR), left ventricle ejection fraction (LVEF), mean arterial blood pressure (MAP), and heart weight index (HWI) of rats were evaluated. The myocardial tissue was observed by hematoxylin and eosin staining. 4-Hydroxy-2-nonenal (4-HNE) level in myocardial tissue was detected by immunohistochemistry. Superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) activities in serum samples of rats and H9c2 cells were determined by colorimetric assay. Bax, B-cell lymphoma-2 (Bcl-2), toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), phosphorylated-p65 (p-p65), and p65 levels in myocardial tissues of rats and treated H9c2 cells were measured by quantitative real-time PCR and Western blot. Viability and reactive oxygen species (ROS) accumulation of treated H9c2 cells were assayed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and dihydroethidium staining assays. RESULTS: Dioscin decreased HR and HWI, increased LVEF and MAP, alleviated the myocardial tissue damage, and reduced 4-HNE level in SIC rats. Dioscin reversed LPS-induced reduction on SOD, CAT, GSH, and Bcl-2 levels, and increment on Bax and TLR4 levels in rats and H9c2 cells. Overexpressed TLR4 attenuated the effects of Dioscin on promoting viability, as well as dwindling TLR4, ROS and MyD88 levels, and p-p65/p65 value in LPS-induced H9c2 cells. CONCLUSION: Protective effects of Dioscin against LPS-induced SIC are achieved via regulation of TLR4/MyD88/p65 signal pathway.

Polyphyllin I alleviates neuroinflammation after cerebral ischemia-reperfusion injury via facilitating autophagy-mediated M2 microglial polarization.

Microglial activation and polarization play a central role in poststroke inflammation and neuronal damage. Modulating microglial polarization from pro-inflammatory to anti-inflammatory phenotype is a promising therapeutic strategy for the treatment of cerebral ischemia. Polyphyllin I (PPI), a steroidal saponin, shows multiple bioactivities in various diseases, but the potential function of PPI in cerebral ischemia is not elucidated yet. In our study, the influence of PPI on cerebral ischemia-reperfusion injury was evaluated. Mouse middle cerebral artery occlusion (MCAO) model and oxygen-glucose deprivation and reoxygenation (OGD/R) model were constructed to mimic cerebral ischemia-reperfusion injury in vivo and in vitro. TTC staining, TUNEL staining, RT-qPCR, ELISA, flow cytometry, western blot, immunofluorescence, hanging wire test, rotarod test and foot-fault test, open-field test and Morris water maze test were performed in our study. We found that PPI alleviated cerebral ischemia-reperfusion injury and neuroinflammation, and improved functional recovery of mice after MCAO. PPI modulated microglial polarization towards anti-inflammatory M2 phenotype in MCAO mice in vivo and post OGD/R in vitro. Besides, PPI promoted autophagy via suppressing Akt/mTOR signaling in microglia, while inhibition of autophagy abrogated the effect of PPI on M2 microglial polarization after OGD/R. Furthermore, PPI facilitated autophagy-mediated ROS clearance to inhibit NLRP3 inflammasome activation in microglia, and NLRP3 inflammasome reactivation by nigericin abolished the effect of PPI on M2 microglia polarization. In conclusion, PPI alleviated post-stroke neuroinflammation and tissue damage via increasing autophagy-mediated M2 microglial polarization. Our data suggested that PPI had potential for ischemic stroke treatment.

Polyphyllin I induces rapid ferroptosis in acute myeloid leukemia through simultaneous targeting PI3K/SREBP-1/SCD1 axis and triggering of lipid peroxidation.

Acute myeloid leukemia (AML) is a malignant disease that is difficult to completely cure. Polyphyllin I (PPI), a steroidal saponin isolated from Paris polyphylla, has exhibited multiple biological activities. Here, we discovered the superior cytotoxicity of PPI on AML cells MOLM-13 with an IC50 values of 0.44 ± 0.09 µM. Mechanically, PPI could cause ferroptosis via the accumulation of intracellular iron concentration and triggering lipid peroxidation. Interestingly, PPI could induced stronger ferroptosis in a short time of about 6 h compared to erastin. Furthermore, we demonstrate that PPI-induced rapid ferroptosis is due to the simultaneous targeting PI3K/SREBP-1/SCD1 axis and triggering lipid peroxidation, and PI3K inhibitor Alpelisib can enhance the activity of erastin-induced ferroptosis. Molecular docking simulations and kinase inhibition assays demonstrated that PPI is a PI3K inhibitor. In addition, PPI significantly inhibited tumor progression and prolonged mouse survival at 4 mg/kg with well tolerance. In summary, our study highlights the therapeutic potential of PPI for AML and shows its unique dual mechanism.

Diosgenin improves post-myocardial infarction cardiac function via HAND2-induced angiogenesis.

While diosgenin has been demonstrated effective in various cardiovascular diseases, its specific impact on treating heart attacks remains unclear. Our research revealed that diosgenin significantly improved cardiac function in a myocardial infarction (MI) mouse model, reducing cardiac fibrosis and cell apoptosis while promoting angiogenesis. Mechanistically, diosgenin upregulated the Hand2 expression, promoting the proliferation and migration of endothelial cells under hypoxic conditions. Acting as a transcription factor, HAND2 activated the angiogenesis-related gene Aggf1. Conversely, silencing Hand2 inhibited the diosgenin-induced migration of hypoxic endothelial cells and angiogenesis. In summary, these findings provide new insights into the protective role of diosgenin in MI, validating its effect on angiogenic activity and providing a theoretical basis for clinical treatment strategies.

Dioscin alleviates aplastic anemia through regulatory T cells promotion.

Objectives: Aplastic anemia (AA) is one of the immune-mediated bone marrow failure disorders caused by multiple factors, including the inability of CD4 + CD25 + regulatory T cells (Tregs) to negatively regulate cytotoxic T lymphocytes (CTLs). Dioscin is a natural steroid saponin that has a similar structure to steroid hormones. The purpose of this study is to look into the effect of Dioscin on the functions of CD4 + CD25+ Tregs in the AA mouse model and explore its underlying mechanism.Methods: To begin with, bone marrow failure was induced through total body irradiation and allogeneic lymphocyte infusion using male Balb/c mice. After 14 consecutive days of Dioscin orally administrated, the AA mouse model was tested for complete blood counts, HE Staining of the femur, Foxp3, IL-10 and TGF-ß. Then CD4 + CD25+ Tregs were isolated from splenic lymphocytes of the AA mouse model, Tregs and the biomarkers and cytokines of Tregs were measured after 24 h of Dioscin intervention treatment in vitro.Results: Dioscin promotes the expression of Foxp3, IL-10, IL-35 and TGF-ß, indicating its Tregs-promoting properties. Mechanistically, the administration of Dioscin resulted in the alteration of CD152, CD357, Perforin and CD73 on the surface of Tregs, and restored the expression of Foxp3.Conclusion: Dioscin markedly attenuated bone marrow failure, and promoted Tregs differentiation, suggesting the maintenance of theimmune balance effect of Dioscin. Dioscin attenuates pancytopenia and bone marrow failure via its Tregs promotion properties.

Diosgenin Targets CaMKK2 to Alleviate Type II Diabetic Nephropathy through Improving Autophagy, Mitophagy and Mitochondrial Dynamics.

Diabetic nephropathy (DN) is a worldwide health problem with increasing incidence. Diosgenin (DIO) is a natural active ingredient extracted from Chinese yams (Rhizoma dioscoreae) with potential antioxidant, anti-inflammatory, and antidiabetic effects. However, the protective effect of DIO on DN is still unclear. The present study explored the mitigating effects and underlying mechanisms of DIO on DN in vivo and in vitro. In the current study, the DN rats were induced by a high-fat diet and streptozotocin and then treated with DIO and metformin (Mef, a positive control) for 8 weeks. The high-glucose (HG)-induced HK-2 cells were treated with DIO for 24 h. The results showed that DIO decreased blood glucose, biomarkers of renal damage, and renal pathological changes with an effect comparable to that of Mef, indicating that DIO is potential active substance to relieve DN. Thus, the protective mechanism of DIO on DN was further explored. Mechanistically, DIO improved autophagy and mitophagy via the regulation of the AMPK-mTOR and PINK1-MFN2-Parkin pathways, respectively. Knockdown of CaMKK2 abolished AMPK-mTOR and PINK1-MFN2-Parkin pathways-mediated autophagy and mitophagy. Mitophagy and mitochondrial dynamics are closely linked physiological processes. DIO also improved mitochondrial dynamics through inhibiting fission-associated proteins (DRP1 and p-DRP1) and increasing fusion proteins (MFN1/2 and OPA1). The effects were abolished by CaMKK2 and PINK1 knockdown. In conclusion, DIO ameliorated DN by enhancing autophagy and mitophagy and by improving mitochondrial dynamics in a CaMKK2-dependent manner. PINK1 and MFN2 are proteins that concurrently regulated mitophagy and mitochondrial dynamics.

Diosgenin attenuates nonalcoholic hepatic steatosis through the hepatic FXR-SHP-SREBP1C/PPARα/CD36 pathway.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and has no approved treatment. The hepatic farnesoid X receptor (FXR) is one of the most promising therapeutic targets for NAFLD. Diosgenin (DG), a natural compound extracted from Chinese herbal medicine, is very effective in preventing metabolic diseases. Our research aims to determine the effects and molecular mechanisms of DG on NAFLD in vivo and in vitro. The effect of DG on hepatic steatosis was evaluated in Sprague‒Dawley (SD) rats induced by a high-fat diet (HFD) and in HepG2 cells exposed to free fatty acids (FFAs, sodium oleate:sodium palmitate = 2:1). DG treatment efficiently managed hepatic lipid deposition in vivo and in vitro. Mechanistically, DG upregulated the expression of FXR and small heterodimer partner (SHP) and downregulated the expression of genes involved in hepatic de novo lipogenesis (DNL), including sterol regulatory element-binding protein 1C (SREBP1C), acetyl-CoA carboxylase 1 (ACC1), and fatty acid synthase (FASN). Moreover, DG promoted the expression of peroxisome proliferator-activated receptor alpha (PPARα), which is related to fatty acid oxidation. In addition, DG inhibited the expression of the CD36 molecule (CD36) related to fatty acid uptake. However, hepatic FXR silencing weakened the regulatory effects of DG on these genes. Collectively, our data show that DG has a good effect on alleviating nonalcoholic hepatic steatosis via the hepatic FXR-SHP-SREBP1C/PPARα/CD36 pathway. DG promises to be a novel candidate FXR activator that can be utilized to treat NAFLD.

Diosgenin restores memory function via SPARC-driven axonal growth from the hippocampus to the PFC in Alzheimer's disease model mice.

Central nervous system axons have minimal capacity to regenerate in adult brains, hindering memory recovery in Alzheimer's disease (AD). Although recent studies have shown that damaged axons sprouted in adult and AD mouse brains, long-distance axonal re-innervation to their targets has not been achieved. We selectively visualized axon-growing neurons in the neural circuit for memory formation, from the hippocampus to the prefrontal cortex, and showed that damaged axons successfully extended to their native projecting area in mouse models of AD (5XFAD) by administration of an axonal regenerative agent, diosgenin. In vivo transcriptome analysis detected the expression profile of axon-growing neurons directly isolated from the hippocampus of 5XFAD mice. Secreted protein acidic and rich in cysteine (SPARC) was the most expressed gene in axon-growing neurons. Neuron-specific overexpression of SPARC via adeno-associated virus serotype 9 delivery in the hippocampus recovered memory deficits and axonal projection to the prefrontal cortex in 5XFAD mice. DREADDs (Designer receptors exclusively activated by designer drugs) analyses revealed that SPARC overexpression-induced axonal growth in the 5XFAD mouse brain directly contributes to memory recovery. Elevated levels of SPARC on axonal membranes interact with extracellular rail-like collagen type I to promote axonal remodeling along their original tracings in primary cultured hippocampal neurons. These findings suggest that SPARC-driven axonal growth in the brain may be a promising therapeutic strategy for AD and other neurodegenerative diseases.

Diosgenin reduces bone loss through the regulation of gut microbiota in ovariectomized rats.

Diosgenin (DIO) is an aglycone of steroid saponins acquired from plants, including Dioscorea alata, Smilax China, and Trigonella foenum graecum, acting as an anti-osteoporosis, anti-diabetic, anti-hyperlipidemic, anti-inflammatory. Recent studies have demonstrated that DIO reduces bone loss. This study aimed to investigate the effects of DIO on the gut microbiota (GM) of ovariectomized (OVX) osteoporotic rats. Female Sprague-Dawley rats were randomly divided into sham operation (sham + vehicle group) or ovariectomy. For 12 weeks, OVX rats were treated using a vehicle (OVX + vehicle group) and DIO (OVX + DIO group). Subsequently, ELISA was conducted to determine serum estradiol levels, micro-CT scanning was performed to evaluate bone quality, and feces were collected for metagenomics sequencing to examine the structure and function of GM. Raw reads were filtered to remove chimera sequences. Operational taxonomic units (OTUs) were clustered in the filtered reads. A Venn diagram analysis was conducted to study the common and unique OTUs in the sham + vehicle, OVX + vehicle, and OVX + DIO groups. LEfSe analysis was conducted to evaluate the specific GM of the three groups. The GM functions were analyzed using the KEGG and CAZy databases. After a 12-week treatment, DIO administration prevented OVX-induced weight gain and increased the estradiol levels. DIO treatment improved the bone microstructure and structural parameters of rat tibias. Metagenomics sequencing results identified 1139, 1207, and 1235 operational taxonomic units (OTUs) in the sham + vehicle, OVX + vehicle, and OVX + DIO groups, respectively. The percentage of common OTUs was 41.2%. Treatment with DIO restored the composition of GM in OVX rats by increasing the abundance of Coriobacteriia Adlercreutzia, Romboutsia, and Romboutsia_idealis and reducing the abundance of Betaproteobacteria, Gammaproteobacteria, Methanobacteria, Bacteroides, Phocaeicola, Alistipes, Bacteroids_uniformis, Bacteroids_xylanisolvens. The anti-osteoporosis effect of DIO can be regulated through environmental information processing, organismal Systems, Cellular Processes, human diseases, metabolism, and genetic information processing. Meanwhile, treatment with DIO improved GM homeostasis by increasing the metabolism of carbohydrates, other amino acids, and glycans and reducing translation, energy metabolism, and nucleotide metabolism. DIO can reduce bone loss by regulating the structural composition and function of GM, a novel strategy for preventing osteoporosis.

Anticancer Activity of Diosgenin and Its Molecular Mechanism.

Diosgenin, a steroidal sapogenin, obtained from Trigonella foenum-graecum, Dioscorea, and Rhizoma polgonati, has shown high potential and interest in the treatment of various cancers such as oral squamous cell carcinoma, laryngeal cancer, esophageal cancer, liver cancer, gastric cancer, lung cancer, cervical cancer, prostate cancer, glioma, and leukemia. This article aims to provide an overview of the in vivo, in vitro, and clinical studies reporting the diosgenin's anticancer effects. Preclinical studies have shown promising effects of diosgenin on inhibiting tumor cell proliferation and growth, promoting apoptosis, inducing differentiation and autophagy, inhibiting tumor cell metastasis and invasion, blocking cell cycle, regulating immunity and improving gut microbiome. Clinical investigations have revealed clinical dosage and safety property of diosgenin. Furthermore, in order to improve the biological activity and bioavailability of diosgenin, this review focuses on the development of diosgenin nano drug carriers, combined drugs and the diosgenin derivatives. However, further designed trials are needed to unravel the diosgenin's deficiencies in clinical application.

Network Analysis of Anti-inflammatory Phytochemicals and Omics Data for Rheumatoid Arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that affects the synovial joints. Nearly 1.6 billion patients are affected by RA worldwide and the incidence of RA is about 0.5 to 1%. Recent studies reveal that immune cell responses and secretion of inflammatory factors are important for the control of RA. METHODS: In this study, a set of 402 phytochemicals with anti-inflammatory properties and 16 target proteins related to anti-inflammatory diseases were identified from the literature and they were subjected to network analysis. The protein-protein interaction (PPI) network was constructed using STRING (Search Tool for the Retrieval of Interacting Genes database) database. Visualization of the target gene-phytochemical network and its protein-protein interaction network was conducted using Cytoscape and further analyzed using MCODE (Molecular Complex Detection). The gene ontology and KEGG pathway analysis was performed using DAVID tool. RESULTS: Our results from the network approach indicate that the phytochemicals such as Withanolide, Diosgenin, and Butulin could act as potential substitute for anti-inflammatory drugs, including DMARDs. Genes such as Mitogen-activated protein kinase (MAPK) and Interleukin were found as hub genes and acted as best inhibitors for the target protein pathways. Curcumin, Catechin was also found to be involved in various signaling pathways such as NF-kappa B signaling pathway, ErbB signaling pathway and acted as the best inhibitor along with other candidate phytochemicals. CONCLUSION: In the current study, we were able to identify Withanolide, Diosgenin, and Butulin as potential anti-inflammatory phytochemicals and determine their association with key pathways involved in RA through network analysis. We hypothesized that natural compounds could significantly contribute to the reduction of dosage, improve the treatment and act as a therapeutic agent for more economical and safer treatment of RA.

Gut microbiota mediated inflammation, neuroendocrine and neurotrophic functions involved in the antidepressant-like effects of diosgenin in chronic restraint stress.

BACKGROUND: Diosgenin is a well-known steroid saponin possessing neuroprotective activities. However, it is unknown whether diosgenin could alleviate depression-like symptoms. METHODS: The antidepressant-like effect of diosgenin was investigated in mice induced by chronic restraint stress. The effects of diosgenin on behaviors, inflammation, neuroendocrine, neurotrophic function, and gut microbiota were evaluated. RESULTS: The results showed that diosgenin alleviated the depressive-like behaviors in mice. In addition, diosgenin was found to reduce serum concentrations of proinflammatory cytokines and the activity of the hypothalamic-pituitary-adrenal (HPA) axis. Besides, diosgenin could activate hippocampal brain-derived neurotrophic factor (BDNF)/TrkB/ERK/CREB signaling pathway and improve the expression of postsynaptic protein PSD95. Meanwhile, the neurogenesis which was inhibited by chronic restraint stress, was totally reversed by diosgenin. Moreover, diosgenin increased the abundance of phylum Firmicutes and the genus Lactobacillus in stressed mice. The results further showed that diosgenin caused a strong correlation between gut microbiota composition and inflammation, the HPA axis activity, or hippocampus neurotrophic function. LIMITATIONS: Only male mice were used for evaluation in the present study, which limits the understanding of effects of diosgenin on the both sexes. In addition, the results only indicate microbiota at the phylum or genus mediate the regulation of neuroinflammation, neuroendocrine, and neurotrophic function, but does not elucidate how microbiota modulate the systems via their primary or secondary metabolites. CONCLUSIONS: The present study shows that diosgenin exerts the antidepressant activity, which is associated with the enhancement of neurotrophic function and the inhibition of inflammatory and neuroendocrine activities via the regulation of gut microbiota.

Diosgenin Ameliorated Type II Diabetes-Associated Nonalcoholic Fatty Liver Disease through Inhibiting De Novo Lipogenesis and Improving Fatty Acid Oxidation and Mitochondrial Function in Rats.

Diosgenin (DIO) is a dietary and phytochemical steroidal saponin representing multiple activities. The present study investigated the protective effect of DIO on type II diabetes-associated nonalcoholic fatty liver disease (D-NAFLD). The rat model was established by high-fat diet and streptozotocin injection and then administered DIO for 8 weeks. The results showed that DIO reduced insulin resistance index, improved dyslipidemia, and relieved pancreatic damage. DIO decreased hepatic injury markers, including aspartate aminotransferase (AST) and alanine aminotransferase (ALT). H&E staining showed that DIO relieved hepatic lipid deposition. Mechanistically, DIO inhibited hepatic de novo lipogenesis (DNL) and increased fatty acid ß-oxidation (FAO) through regulation of the AMPK-ACC/SREBP1 pathway. Endoplasmic reticulum (ER) stress was inhibited by DIO through regulation of PERK and IRE1 arms, which may then inhibit DNL. DIO also decreased reactive oxygen species (ROS) and enhanced the antioxidant capacity via an increase in Superoxide dismutase (SOD), Catalase (CAT), and Glutathione peroxidase (GPx) activities. The mitochondria are the site for FAO, and ROS can damage mitochondrial function. DIO relieved mitochondrial fission and fusion disorder by inhibiting DRP1 and increasing MFN1/MFN2 expressions. Mitochondrial apoptosis was then inhibited by DIO. In conclusion, the present study suggests that DIO protects against D-NAFLD by inhibiting DNL and improving FAO and mitochondrial function.

Evaluation of the antibacterial and inhibitory activity of NorA and MepA efflux pumps from Staphylococcus aureus by diosgenin.

The increase in bacterial resistance to available antibiotics has driven several researchers to search for new agents with therapeutic properties. Diosgenin is a naturally occurring steroidal saponin that has demonstrated several pharmacological properties. In the present study, we report the antimicrobial activity of diosgenin against the standard and multidrug-resistant bacteria of Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus, in addition to the efflux pump inhibitory activity against Staphylococcus aureus strains carrying NorA and MepA pumps. For this purpose, the broth microdilution method was used, from which the value of the Minimum Inhibitory Concentration (MIC) was obtained, and this was associated with subinhibitory concentration (MIC/8) with antibiotic of clinical use and ethidium bromide for strains carrier by efflux pump. Diosgenin showed antimicrobial activity for standard S. aureus bacteria and potentiating activity in association with gentamicin and ampicillin for P. aeruginosa multidrug-resistant bacteria, it also showed potentiation in association with norfloxacin against the E. coli strain and gentamicin against the S. aureus strain. Antimicrobial activity against efflux pump-bearing strains revealed that saponin did not interfere with the efflux pump mechanism or intervened antagonistically. Thus, saponin has shown to be very promising against bacterial resistance in association with aminoglycoside, fluoroquinolones and beta-lactam, however additional studies should be carried out to better elucidate the mechanism of action of diosgenin.

Therapeutic potential and research progress of diosgenin for lipid metabolism diseases.

Diosgenin, a steroidal saponin, is a natural product found in many plants. Diosgenin has a wide range of pharmacological activities, and has been used to treat cancer, nervous system diseases, inflammation, and infections. Numerous studies have shown that diosgenin has potential therapeutic value for lipid metabolism diseases via various pathways and mechanisms, such as controlling lipid synthesis, absorption, and inhibition of oxidative stress. These mechanisms and pathways have provided ideas for researchers to develop related drugs. In this review, we focus on data from animal and clinical studies, summarizing the toxicity of diosgenin, its pharmacological mechanism, recent research advances, and the related mechanisms of diosgenin as a drug for the treatment of lipid metabolism, especially in obesity, hyperlipidemia, nonalcoholic fatty liver disease, atherosclerosis, and diabetes. This systematic review will briefly describe the advantages of diosgenin as a potential therapeutic drug and seek to enhance our understanding of the pharmacological mechanism, recipe-construction, and the development of novel therapeutics against lipid metabolism diseases.

Dioscin ameliorates cisplatin-induced intestinal toxicity by mitigating oxidative stress and inflammation.

Cisplatin is the most widely prescribed drug in chemotherapy, but its gastrointestinal toxicity reduces therapeutic efficacy. Oxidative stress and inflammation are considered to be the main pathogenesis of cisplatin-induced intestinal toxicity. Dioscin is a steroidal saponin with potential anti-cancer, antioxidant, and anti-inflammatory activities. In this study, we established a rat model of intestinal injury by tail vein injection of cisplatin, and intragastrically administered dioscin to evaluate its effect on intestinal injury. Biochemical markers, western blotting, qRT-PCR and histopathological staining were used to analyze intestinal injury according to various molecular mechanisms. The results revealed that dioscin significantly inhibited cisplatin-induced intestinal mucosal damage and decreased DAO levels in rats. Furthermore, dioscin activated the Nrf2/HO-1 pathway to increase the level of antioxidant enzymes and reduce the levels of MDA and H2O2. In addition, dioscin pretreatment significantly reduced ileum epithelial NLRP3 inflammasome formation and decreased the levels of inflammatory factors compared with the cisplatin group. In parallel, Nrf2 inhibitor ML385 blocked the therapeutic effect of dioscin in rat with cisplatin-induced intestinal toxicity. In terms of mechanisms, dioscin reversed cisplatin-induced up-regulation of MAPKs and up-regulated p-PI3K and p-AKT levels. Meanwhile, dioscin potently promoted Wnt3A/ß-catenin signaling to relieve cisplatin-induced proliferation inhibition. In conclusion, our study suggests that dioscin could ameliorate the cisplatin-induced intestinal toxicity by reducing oxidative stress and inflammation.

Diosgenin and Its Analogs: Potential Protective Agents Against Atherosclerosis.

Atherosclerosis is a chronic inflammatory disease of the artery wall associated with lipid metabolism imbalance and maladaptive immune response, which mediates most cardiovascular events. First-line drugs such as statins and antiplatelet drug aspirin have shown good effects against atherosclerosis but may lead to certain side effects. Thus, the development of new, safer, and less toxic agents for atherosclerosis is urgently needed. Diosgenin and its analogs have gained importance for their efficacy against life-threatening diseases, including cardiovascular, endocrine, nervous system diseases, and cancer. Diosgenin and its analogs are widely found in the rhizomes of Dioscore, Solanum, and other species and share similar chemical structures and pharmacological effects. Recent data suggested diosgenin plays an anti-atherosclerosis role through its anti-inflammatory, antioxidant, plasma cholesterol-lowering, anti-proliferation, and anti-thrombotic effects. However, a review of the effects of diosgenin and its natural structure analogs on AS is still lacking. This review summarizes the effects of diosgenin and its analogs on vascular endothelial dysfunction, vascular smooth muscle cell (VSMC) proliferation, migration and calcification, lipid metabolism, and inflammation, and provides a new overview of its anti-atherosclerosis mechanism. Besides, the structures, sources, safety, pharmacokinetic characteristics, and biological availability are introduced to reveal the limitations and challenges of current studies, hoping to provide a theoretical basis for the clinical application of diosgenin and its analogs and provide a new idea for developing new agents for atherosclerosis.

Diosgenin: An Updated Pharmacological Review and Therapeutic Perspectives.

Plants including Rhizoma polgonati, Smilax china, and Trigonella foenum-graecum contain a lot of diosgenin, a steroidal sapogenin. This bioactive phytochemical has shown high potential and interest in the treatment of various disorders such as cancer, diabetes, arthritis, asthma, and cardiovascular disease, in addition to being an important starting material for the preparation of several steroidal drugs in the pharmaceutical industry. This review aims to provide an overview of the in vitro, in vivo, and clinical studies reporting the diosgenin's pharmacological effects and to discuss the safety issues. Preclinical studies have shown promising effects on cancer, neuroprotection, atherosclerosis, asthma, bone health, and other pathologies. Clinical investigations have demonstrated diosgenin's nontoxic nature and promising benefits on cognitive function and menopause. However, further well-designed clinical trials are needed to address the other effects seen in preclinical studies, as well as a better knowledge of the diosgenin's safety profile.

In vivo antihyperglycaemic and antihyperlipidemic activities and chemical constituents of Solanum anomalum.

Solanum anomalum is a plant used ethnomedically for the treatment of diabetes. The study was aimed to validate ethnomedical claims in rat model and identify the likely antidiabetic compounds. Leaf extract (70-210 mg/kg/day) and fractions (140 mg/kg/day) of S. anomalum were evaluated in hyperglycaemic rats induced using alloxan for effects on blood glucose, lipids and pancreas histology. Phytochemical characterisation of isolated compounds and their identification were performed using mass spectrometry and NMR spectroscopy. Bioinformatics tool was used to predict the possible protein targets of the identified bioactive compounds. The leaf extract/fractions on administration to diabetic rats caused significant lowering of fasting blood glucose of the diabetic rats during single dose study and on repeated administration of the extract. The hydroethanolic leaf extracts also enhanced glucose utilization capacity of the diabetic rats and caused significant lowering of glycosylated hemoglobin levels and elevation of insulin levels in the serum. Furthermore, triglycerides, LDL-cholesterol, and VLDL-cholesterol levels were lowered significantly, while HDL-cholesterol levels were also elevated in the treated diabetic rats. There was absence or few pathological signs in the treated hyperglycaemic rat pancreas compared to that present in the pancreas of control group. Diosgenin, 25(R)-diosgenin-3-O-α-L-rhamnopyranosyl-(1→4)-ß-D-glucopyranoside, uracil, thymine, 1-octacosanol, and octacosane were isolated and identified. Protein phosphatases along with secreted proteins are predicted to be the major targets of diosgenin and the diosgenin glycoside. These results suggest that the leaf extract/fractions of S. anomalum possess antidiabetic and antihyperlipidemic properties, offer protection to the pancreas and stimulate insulin secretion, which can be attributable to the activities of its phytochemical constituents.

Diosgenin inhibits ER stress-induced inflammation in aorta via iRhom2/TACE mediated signaling in experimental diabetic rats: An in vivo and in silico approach.

Hyperglycemia, hyperlipidemia, and atherosclerotic lesions may cause inflammation, which leads to chemokine production and changes in vascular responses. Hyperglycemia can impair normal protein folding by producing reactive oxygen species (ROS) and interacting with various signaling molecules, resulting in the activation of ER stress responses, that stimulates NF-kB, which regulates the expression of numerous genes involved in inflammation and vascular remodeling. Our previous studies have shown that diosgenin has a protective effect against streptozotocin (STZ) - induced oxidative damage in rat aorta. However, the therapeutic role of diosgenin on iRhom2/TACE signaling which has primarily been linked to the endoplasmic reticulum (ER)-stress induced inflammation is unknown. Diosgenin was administered (40 mg/kg b. wt, orally, for 4 weeks) to STZ-induced male albino rats. Fasting plasma glucose, blood pressure, nitrite level, lipid profile, and lipoprotein were assessed. Serum insulin and pro-inflammatory markers were analyzed using ELISA, mRNA and protein expression of iRhom2/TACE signaling molecules were analyzed using RT-PCR and western blotting analysis respectively. In silico study was also performed to find out the possible binding affinity of diosgenin with the ER stress signaling molecules. Through regulation of the iRhom2/TACE signaling molecules, diosgenin lowered dyslipidemia, hypertension, and pro-inflammatory cytokines (TNF-α, IL-1, IL-6, and IL-4) in the aorta of STZ induced diabetic rats. Results of molecular docking analysis also confirmed the potential binding interaction with iRhom2/TACE and TNF- α. These in silico and in vivo results indicated that a change in lipid profile and hypertension led to diabetes-related inflammation by promoting ER stress and, as a result, accelerating the aorta by generating proinflammatory cytokines and lipid deposition. This study concludes that diosgenin attenuates ER stress-induced inflammation in diabetic rat aorta by modulating the expression of pro-inflammatory, iRhom2/TACE mediated mechanism and hence diosgenin can be a therapeutic drug for the treatment of diabetes-induced inflammation.