PMID: 

Life Sci. 2020 Jan 15 ;241:117115. Epub 2019 Nov 29. PMID: 31790685

Abstract Title: 

The potential of Diosgenin in treating psoriasis: Studies from HaCaT keratinocytes and imiquimod-induced murine model.

Abstract: 

AIMS: Psoriasis is a cutaneous disease mainly characterized by keratinocyte hyperproliferation, abnormal epidermal differentiation, inflammation and angiogenesis. In this study, we aimed to report the therapeutic potential of Diosgenin on psoriasis-like models and explore the underlying mechanisms.MAIN METHODS: For in vitro studies, we initially evaluated the bioeffects of Diosgenin on keratinocytes by detecting the cell viability, cell cycle and apoptosis in HaCaT cells. To mimic psoriatic conditions, we established hyperproliferative model by stimulating HaCaT cells with LPS/IL-22 and inflammatory model by LPS/TNF-α stimulation. Meanwhile, differentiation in HaCaT cells and angiogenesis in HUVECs/HMEC-1 were observed. The influence of Diosgenin on above-mentioned conditions was examined. For in vivo studies, we dosed imiquimod (IMQ) -induced mice with Diosgenin and conducted hematoxylin-eosin (HE), TUNEL assay and immunohistochemistry (IHC) to evaluate histological changes, apoptosis and the status of keratinocyte proliferation, epidermal differentiation, vascularity and cutaneous inflammatory cell infiltration respectively.KEY FINDINGS: Results showed that Diosgenin inhibited HaCaT cell growth through cell cycle arrest and NFκB inhibition while induced apoptosis by regulating Caspase3, Bax and Bcl-2 protein expression. After Diosgenin treatment, NFκB nuclear translocation and IL-22 receptor dependent pathways were suppressed in LPS/IL-22 induced HaCaT cells respectively. Furthermore, Diosgenin downregulated proinflammatory cytokines through TLR4/Myd88 inhibition and upregulated several differentiation markers' expression in HaCaT cells. Additionally, Diosgenin inhibited vascular formation partially by reducing the VEGF-α expression in keratinocytes. In animal studies, Diosgenin attenuated psoriatic lesions on mice accordingly.SIGNIFICANCE: This study suggests that Diosgenin might be a promising candidate for developing anti-psoriatic agents.

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PMID: 

Onco Targets Ther. 2019 ;12:9093-9104. Epub 2019 Nov 4. PMID: 31806994

Abstract Title: 

Diosgenin Suppresses Cholangiocarcinoma Cells Via Inducing Cell Cycle Arrest And Mitochondria-Mediated Apoptosis.

Abstract: 

Purpose: Diosgenin (DSG) is the precursor of steroid hormones and plays a crucial part in the proliferation of various carcinomas including human colorectal cancer and gastric carcinoma. Nevertheless, its specific features and mechanisms in human cholangiocarcinoma (CCA) remain unknown.Methods: MTS assay, colony-forming assay, and EdU assay were performed to determine the role of DSG on the progression of human CCA cells. The distributions of cell cycle, the ratio of apoptosis, and the mitochondrial membrane potential (ΔΨm) were studied by flow cytometry (FCM). AO/EB and Hoechst 33258 staining were performed to observe the morphological features of cell apoptosis. TEM was performed to observe the ultrastructures of QBC939 and HuCCT1 cells. The mRNA and protein expression of mitochondrial apoptotic pathway and GSK3β/β-catenin pathway were further confirmed by qPCR and Western blotting. The xenograft tumor model of HuCCT1 cells was built. Immunohistochemistry of tumor tissues was performed.Results: Our results indicated that DSG inhibited the progression of six CCA cell lines. In vivo tumor studies also indicated that DSG significantly inhibited tumor growth in xenografts in nude mice. The expression of mitosis-promoting factor cyclinB1 was decreased along with the elevating level of cell cycle inhibitor p21, resulting in arresting CCA cell cycles at G2/M phase. Furthermore, DSG induced apoptosis with the increased expressions of cytosol cytochrome C, cleaved-caspase-3, cleaved-PARP1 and the Bax/Bcl-2 ratio. Mechanistically, our study showed that GSK3β/β-catenin pathway was involved in the apoptosis of CCA cells. Thus, DSG might provide a new clue for the drug therapy of CCA.Conclusion: In our data, DSG was found to have efficient antitumor potential of human CCA cells in vitro and in vivo.

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PMID: 

Int J Mol Sci. 2019 Dec 25 ;21(1). Epub 2019 Dec 25. PMID: 31881805

Abstract Title: 

Induction of G2/M Phase Arrest by Diosgenin via Activation of Chk1 Kinase and Cdc25C Regulatory Pathways to Promote Apoptosis in Human Breast Cancer Cells.

Abstract: 

The anti-tumor activity of diosgenin, a new steroidal constituent present in fenugreek, on two human breast cancer cell lines, MCF-7 and Hs578T, was studied. Diosgenin treatment resulted in cell growth inhibition, cell cycle arrest, and apoptosis in concentration- and time-dependent manners in both cell lines. Western blot analyses of whole cell lysates for cell cycle proteins showed that diosgenin altered phosphorylated cyclin checkpoint1 (p-Chk1) and cyclin B expression, which resulted in G2/M phase blockade. Mechanistically, Cdc25C-Cdc2 signaling was involved in inactivating Chk1by p53-dependence in MCF-7 cells and p21-dependence in Hs578T cells that are p53-deficient. Moreover, diosgenin induced a significant loss of the mitochondrial membrane potential in breast cancer cells, and prominently affected cell death through down-regulation of the anti-apoptotic protein, Bcl-2. This released cytochrome c and activated the caspase signaling cascade. Taken together, these findings reveal that the anti-proliferative activity of diosgenin involves the induction of G2/M phase arrest via modulating the Cdc25C-Cdc2-cyclin B pathway and mitochondria-mediated apoptosis in human breast cancer cell lines. This suggests the potential usefulness of diosgenin in treating breast cancer.

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PMID: 

J Steroid Biochem Mol Biol. 2019 Dec 30 ;198:105575. Epub 2019 Dec 30. PMID: 31899316

Abstract Title: 

The role of diosgenin in diabetes and diabetic complications.

Abstract: 

Diabetes mellitus is a chronic and common metabolic disease that seriously endangers human health. Hyperglycemia and long-term metabolic disorders in diabetes will cause damage to the whole body tissues and organs, resulting in serious complications. Nowadays, drugs for treating diabetes on the market has strong side effects, new treatments thus are urgently needed. Natural therapy of natural ingredients is a promising avenue, this is because natural ingredients are safer and they also show strong activity in the treatment of diabetes. Diosgenin is such a very biologically active natural steroidal sapogenin. The research of diosgenin in the treatment of diabetes and its complications has been widely reported. This article reviews the effects of diosgenin through multiple targets and multiple pathways in diabetes and its complications which including diabetic nephropathy, diabetic liver disease, diabetic neuropathy, diabetic vascular disease, diabetic cardiomyopathy, diabetic reproductive dysfunction, and diabetic eye disease.

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PMID: 

Arch Gynecol Obstet. 2019 Nov 16. Epub 2019 Nov 16. PMID: 31734759

Abstract Title: 

Menstrual problems in adolescence: relationship to serum vitamins A and E, and systemic inflammation.

Abstract: 

BACKGROUND: Vitamin status and inflammatory mechanisms may be related to menstrual cycle abnormalities. We investigated the associations between serum fat soluble vitamin (vitamins A and E) concentrations and biomarkers of inflammation and antioxidant status with menstrual characteristics, primary dysmenorrhea (PD) and premenstrual syndrome (PMS) in healthy adolescents.METHODS: A total of 897 adolescent girls either suffering from PMS (n = 134), PD (n = 322), PMS and PD (n = 293) or healthy adolescents (n = 148) were recruited. Serum vitamin A and E, high-sensitivity C-reactive protein (hs-CRP), antibody titers to Hsp27 (anti-Hsp27), serum prooxidant-antioxidant balance (PAB), WBC, mean platelet volume (MPV), and platelet distribution width (PDW) and RBC distribution width (RDW) were measured. Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and RDW-to-platelet ratio (RPR) were calculated.RESULTS: Girls with long bleeding periods had lower concentrations of serum vitamin E compared to those who reported a normal period duration. There were significantly differences between the groups reporting oligomenorrhea, regular menses and polymenorrhea with respect to NLR, RPR, MPV and PDW. Logistic regression demonstrated that the presence of both PMS and PD was positively related to higher serum hs-CRP, PAB and NLR, while serum vitamin A level was inversely related to the presence of PMS.CONCLUSIONS: We found that serum vitamin A, hs-CRP, PAB and NLR are significantly associated with the presence of PMS and PD. Inflammatory processes may contribute to the etiology, symptoms and severity of menstrual disorders. Prospective studies are needed to elucidate the possibility of targeting oxidative stress and inflammatory process for the amelioration of menstrual symptoms.

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PMID: 

J Proteome Res. 2020 Jan 15. Epub 2020 Jan 15. PMID: 31940440

Abstract Title: 

Alterations of brain quantitative proteomics profiling revealed the molecular mechanisms of diosgenin against cerebral ischemia reperfusion effects.

Abstract: 

Diosgenin (DIO), the starting material for the synthesis of steroidal anti-inflammatory drugs in pharmaceutical industry, has been previously demonstrated to display pharmaceutical effects against cerebral ischemic reperfusion (I/R). However, the alterations of brain proteome profiles underlying this treatment remain elusive. In the present study, the proteomics analysis of the brain tissues from I/R rats after DIO treatment was performed by an integrated TMT-based quantitative proteomic approach coupled with LC-MS/MS technology. A total of 5043 proteins (ProteomeXchange identifier: PXD016303) were identified, of which 58 common differentially expressed proteins (DEPs) were significantly dysregulated in comparison between Sham verse I/R and I/R verse DIO. The 8 validated proteins including EPG5, STAT2, CPT1A, EIF2AK2, GGCT, HIKESHI, TNFAIP8, and EMC6 by qPCR and Western blotting consistently supported the TMT-based proteomic results, which were mainly associated with autophagy and inflammation response. Considering the anti-inflammatory characters of DIO, the biological functions of STAT2 and HIKESHI that are the probably direct anti-inflammatory targets were further investigated during the course of I/R treated with DIO. In addition, the combination of verified STAT2 and HIKESHI in peripheral blood samples from stroke patients resulted in AUC value of 0.765 with P

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PMID: 

Eur J Pharmacol. 2020 Jan 20:172942. Epub 2020 Jan 20. PMID: 31972180

Abstract Title: 

Apoptotic, necrotic, and antiproliferative activity of diosgenin and diosgenin glycosides on cervical cancer cells.

Abstract: 

(25R)-spirost-5-en-3β-ol, also known as diosgenin (DSG), exerts antiproliferative activity on diverse cell lines, induces apoptosis, and acts as a chemopreventative agent. However, the relationship between DSG glycosides and apoptotic, necrotic, and antiproliferative activity remains unclear. It is in this regard thatwe report the antiproliferative, necrotic, and apoptotic activities of DSG and its glycoside derivatives: (25R)-spirost-5-en-3β-yl O-β-D-glucopyranoside (3GD), (25R)-spirost-5-en-3β-yl O-α-L-rhamnopyranosyl-(1 → 4)-β-D-glucopyranoside (3GRD); and (25R)-spirost-5-en-3β-yl O-α-L-rhamnopyranosyl-(1 → 2)-O-[α-L-rhamnopyranosyl-(1 → 4)]-β-D-glucopyranoside), also known as dioscin (DSC), in in vitro assays of cervical HeLa and CaSki cancer cells. The results demonstrated that DSG glycosidic derivatives preserved their antiproliferative activity. However, in both cancer cell lines, 3GD and 3GRD were less potent than DSG, while DSC was more potent than DSG. With respect to necrotic activity, all tested compounds showed no or low activity on the two cervical cancer cell lines. Regarding apoptosis, the results showed that DSG glycosides were better apoptosis-inducers than DSG, suggesting that glucose and rhamnose residues play a central role in enhancing the apoptotic activity of DSG. Finally, DSG and its glycosidic derivatives were shown to affect the proliferative potential of lymphocytes (non-tumour cells) to a lesser extent than cancer cells, suggesting that these compounds have selective action. In conclusion, the results indicate that DSG and its glycosidic derivatives are promising anticancer compounds since they are compounds with low necrotic activity and selective action.

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PMID: 

Phytother Res. 2020 Jan ;34(1):193-200. Epub 2019 Nov 17. PMID: 31736181

Abstract Title: 

Acanthopanax senticosus polysaccharide regulates the intestinal homeostasis disruption induced by toxic chemicals in Drosophila.

Abstract: 

The intestinal epithelium provides the first line of defense against pathogens and toxic compounds. The ingestion of toxic compounds causes an enhanced epithelial cell death and an excessive proliferation of intestinal stem cells, eventually resulting in the disruption of gut homeostasis. In this study, Drosophila gut inflammation model induced by toxic compounds was exploited to analyze the ameliorative effect of Acanthopanax senticosus polysaccharide on the disruption of gut homeostasis. As a result, it was found that A. senticosus polysaccharide can significantly increase the survival rate of Drosophila adults as well as reduce the excessive proliferation and differentiation of intestinal stem cells through epidermal growth factor receptor, jun-N-terminal kinase, and Notch signaling pathways under the exposure totoxic compounds dextran sodium sulfate. Moreover, the polysaccharide effectively decreased the epithelial cell death and the accumulation of reactive oxygen species and antimicrobial peptides induced by sodium dodecyl sulfate. In addition, it was found that A. senticosus polysaccharide can extendthe lifespan of only female flies but not male flies. In conclusion, A. senticosus polysaccharide has an obvious protective effect on the gut homeostasis of Drosophila melanogaster.

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PMID: 

Neoplasma. 2019 Jul 23 ;66(4):555-563. Epub 2019 Mar 30. PMID: 30943746

Abstract Title: 

Acanthopanax senticosus polysaccharide suppressing proliferation and metastasis of the human non-small cell lung cancer NCI-H520 cells is associated with Wnt/β-catenin signaling.

Abstract: 

Lung cancer (LC) is the highest lethality in all tumors. Non-small cell lung cancer (NSCLC) accounts for about 80% of all LC. Acanthopanax senticosus polysaccharide (ASPS) is extracted from the root of Acanthopanax senticosus (AS). Herein, we examined the effect and molecular mechanism of ASPS on NSCLC. The proliferation, invasion and migration of NCI-H520 cells were detected by cell counting kit-8 (CCK-8), transwell assay and wound healing assay, respectively. The epithelial-mesenchymal transition (EMT) and Wnt/β-catenin pathway-related factors were evaluated using quantitative real-time PCR (QRT-PCR) and western blot assay. Our results observed that ASPS significantly decreased the proliferation of cells at 24 and 48 h. Moreover, ASPS markedly repressed the invasion and migration capacities of cells in aconcentration-dependent manner. Besides, ASPS obviously down-regulated the levels of matrix metalloproteinase-2 (MMP-2), MMP-9, fibronectin 1 (FN1), vimentin, wnt3a, phosphorylated-glycogen synthase kinase 3β (p-GSK3β) and cyclin D1, whereas, up-regulating E-cadherin level. The level of GSK3β was not changed in the different groups. ASPS conspicuously inhibited the abilities of proliferation and metastasis in human non-small cell lung cancer cell line NCI-H520 possibly by suppressing Wnt/β-catenin pathway mediated-EMT.

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PMID: 

J Ethnopharmacol. 2019 Sep 15 ;241:111969. Epub 2019 May 22. PMID: 31125596

Abstract Title: 

Mass spectrometry-based urinary metabolomics for the investigation on the mechanism of action of Eleutherococcus senticosus (Rupr.&Maxim.) Maxim. leaves against ischemic stroke in rats.

Abstract: 

ETHNOPHARMACOLOGICAL RELEVANCE: As a traditional Chinese medicine, Eleutherococcus senticosus (Rupr.&Maxim.) Maxim. leaves (ESL) can treat ischemic, neurasthenia, and hypertension diseases. However, only few studies have been conducted on the mechanism of action of ESL for ischemic disease treatment.AIM OF THE STUDY: This study aimed to discover the potential biomarkers in the rats caused by ischemic stroke and build a gene-enzyme-biomarker network to explore the mechanism of ESL treatment on ischemic stroke further.MATERIALS AND METHODS: The urinary metabolomics strategy was developed by combining UPLC-Q-TOF/MS with multivariate data analysis. The gene-enzyme-biomarker network was built by Cytoscape 3.6.0 on the basis of the potential biomarkers filtered out via urinary metabolomic analysis. Then, the potential target enzymes of ESL in the treatment of ischemic stroke were selected for further validation analysis via the ELISA kits.RESULTS: A total of 42 biomarkers associated with ischemic stroke have been identified, among which 38 species can be adjusted by ESL, including 5'-methylthioadenosine, prostaglandin A2, l-methionine, aldosterone, 11b-hydroxyprogesterone, prostaglandin E3, dehydroepiandrosterone, taurine, 5-methoxyindoleacetate, and p-cresol glucuronide. These biomarkers were involved in several metabolic pathways, including taurine and hypotaurine, arachidonic acid, cysteine and methionine, steroid hormone biosynthesis, tryptophan, and tyrosine metabolism pathways. The gene-enzyme-biomarker network was built, and three predicted target proteins, including cyclooxygenase-2 (COX-2), monoamine oxidase (MAO), and nitric oxide synthase (NOS), were selected as the potential target enzymes for ESL in ischemic stroke treatment.CONCLUSIONS: All results showed that ESL can play a therapeutic role in treating ischemic stroke through different pathways. This study will provide an overall view of the mechanism underlying the action of ESL against ischemic stroke.

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