RESUMO
Background: Tumor-Node-Metastasis (TNM) stage of gastric cancer (GC) is one of the main factors affecting clinical outcome. The aim of this study was to explore the targets related to TNM stage of GC, and screening natural bioactive drug. Methods: RNA sequencing data of the TCGA-STAD cohort were downloaded from UCSC database. Genes associated with TNM staging were identified by weighted gene co-expression network analysis (WGCNA). Univariate Cox regression, least absolute shrinkage and selection operator (LASSO), extreme gradient boosting (Xgboost), random forest (RF) and cytohubba plug-in of cytoscope were applied to screen hub genes. Natural bioactive ingredients were available from the HERB database. Molecular docking was used to evaluate the binding activity of active ingredients to the hub protein. CCK-8, flow cytometry, transwell and Western blot assays were used to analyze the effects of diosgenin on GC cells. Results: 898 TNM-related genes were screened out through WGCNA. Three genes associated with GC progression/prognosis were identified, including nuclear receptor subfamily 3 group C member 2 (NR3C2), solute carrier family 1 member 5 (SLC1A5) and FAT atypical cadherin 1 (FAT1) based on the machine learning algorithms and hub co-expression network analysis. Diosgenin had good binding activity with SLC1A5. SLC1A5 was highly expressed in GC and was closely associated with tumor stage, overall survival and immune infiltration of GC patients. Diosgenin could inhibit cell viability and invasive ability, promote apoptosis and induce cell cycle arrest in G0/G1 phase. In addition, diosgenin promoted cleaved caspase 3 expression and inhibited Ki67, cyclin D1, p-S6K1, and SLC1A5 expression levels, while the mTORC1 activator (MHY1485) reversed this phenomenon. Conclusion: For the first time, this work reports diosgenin may inhibit the activation of mTORC1 signaling through targeting SLC1A5, thereby inhibiting the malignant behaviors of GC cells.
Assuntos
Proliferação de Células , Diosgenina , Alvo Mecanístico do Complexo 1 de Rapamicina , Simulação de Acoplamento Molecular , Neoplasias Gástricas , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Neoplasias Gástricas/metabolismo , Humanos , Proliferação de Células/efeitos dos fármacos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Diosgenina/farmacologia , Diosgenina/química , Apoptose/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Progressão da Doença , Ensaios de Seleção de Medicamentos Antitumorais , Antígenos de Histocompatibilidade Menor/metabolismo , Antígenos de Histocompatibilidade Menor/genética , Relação Dose-Resposta a Droga , Células Tumorais CultivadasRESUMO
Acute kidney injury (AKI), if not well controlled, may progress to chronic kidney disease (CKD). Diosgenin is a natural phytosteroid sapogenin from plants. This study aimed to investigate the mechanistic effects of diosgenin on AKI and AKI related development of CKD. The mouse model of ischemia/reperfusion (I/R)-induced AKI was used, and its progressive changes were followed. Human renal proximal tubular epithelial cells were used, and hypoxia stimulation was applied to mimic the in vivo I/R. Diosgenin, given after renal injury, preserved kidney function, as evidenced by a reduction in serum levels of BUN, creatinine, and UACR in both acute and chronic phases of AKI. Diosgenin alleviated I/R-induced tubular injury and prevented macrophage infiltration and renal fibrosis in AKI mice. Furthermore, diosgenin also mitigated the development of CKD from AKI with reduced renal expression of inflammatory, fibrotic, and epithelial-mesenchymal transition markers. In human renal tubular epithelial cells, diosgenin downregulated the hypoxia-induced oxidative stress and cellular damages that were dependent on the NOX4/p65 signaling pathways. Taken together, diosgenin treatment reduced I/R-induced AKI and ameliorated the progression to CKD from AKI probably by modifying the NOX4/p65 signaling pathways.
Assuntos
Injúria Renal Aguda , Diosgenina , Camundongos Endogâmicos C57BL , NADPH Oxidase 4 , Insuficiência Renal Crônica , Transdução de Sinais , Diosgenina/farmacologia , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Animais , Humanos , Camundongos , Transdução de Sinais/efeitos dos fármacos , NADPH Oxidase 4/metabolismo , NADPH Oxidase 4/genética , Masculino , Estresse Oxidativo/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Fator de Transcrição RelA/genética , Progressão da Doença , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Linhagem CelularRESUMO
INTRODUCTION: Dioscin, a natural steroid saponin, has anticancer, anti-inflammatory, anti-hyperlipidemic, and glycemic capabilities. This study focused on dioscin roles and its related mechanisms in experimental lupus nephritis. MATERIALS AND METHODS: Lupus-prone NZB/W F1 mice were intragastrically administered with dioscin, prednisone or vehicle, and kidney, urine and blood samples were harvested after the mice were sacrificed. Proteinuria, blood urea nitrogen (BUN), creatinine, anti-dsDNA, IL-1ß, and IL-18 levels in serum as well as IFN-γ, IL-6, IL-17 and TNF-α levels in kidney tissues were assessed. Renal histopathology was examined through hematoxylin-eosin staining. IgG and C3 expression in kidney was evaluated using immunofluorescence staining. The number of glomerular F4/80-positive cells and NLRP3-positive cells was determined by immunohistochemical staining. The protein expression was examined by western blotting. RESULTS: Dioscin alleviated lupus nephritis in NZB/W F1 mice. Dioscin declined serum anti-dsDNA level, prevented deposition of immune complexes in renal glomeruli, and inhibited the inflammatory response and infiltration of macrophages into mouse kidneys. Dioscin inhibited NF-κB and NLRP3 inflammasome in NZB/W F1 mice. CONCLUSIONS: Dioscin ameliorates lupus nephritis through inhibition of NLRP3 inflammasome and NF-κB signaling.
Assuntos
Diosgenina , Inflamassomos , Nefrite Lúpica , Camundongos Endogâmicos NZB , NF-kappa B , Proteína 3 que Contém Domínio de Pirina da Família NLR , Animais , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , NF-kappa B/metabolismo , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Diosgenina/análogos & derivados , Diosgenina/farmacologia , Diosgenina/uso terapêutico , Camundongos , Feminino , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismoRESUMO
BACKGROUND: Fenugreeks (Trigonella L. spp.), belonging to the legume family (Fabaceae), are well-known multipurpose crops that their materials are currently received much attention in the pharmaceutical and food industries for the production of healthy and functional foods all over the world. Iran is one of the main diversity origins of this valuable plant. Therefore, the aim of the present study was to explore vitamins, minerals, and fatty acids profile, proximate composition, content of diosgenin, trigonelline, phenolic acids, total carotenoids, saponins, phenols, flavonoids, and tannins, mucilage and bitterness value, and antioxidant activity of the seed of thirty populations belonging to the ten different Iranian Trigonella species. RESULTS: We accordingly identified notable differences in the nutrient and bioactive compounds of each population. The highest content (mg/100 g DW) of ascorbic acid (18.67 ± 0.85â22.48 ± 0.60) and α-tocopherol (31.61 ± 0.15â38.78 ± 0.67) were found in the populations of T. filipes and T. coerulescens, respectively. Maximum content of catechin was found in the populations of T. teheranica (52.67 ± 0.05â63.50 ± 0.72 mg/l). Linoleic acid (> 39.11% ± 0.61%) and linolenic acid (> 48.78 ± 0.39%) were the main polyunsaturated fatty acids, with the majority in the populations of T. stellata (54.81 ± 1.39â63.46 ± 1.21%). The populations of T. stellata were also rich in trigonelline (4.95 ± 0.03â7.66 ± 0.16 mg/g DW) and diosgenin (9.06 ± 0.06â11.03 ± 0.17 mg/g DW). CONCLUSIONS: The obtained data provides baseline information to expand the inventory of wild and cultivated Iranian Trigonella species for further exploitation of rich chemotypes in the new foods and specific applications.
Assuntos
Alcaloides , Antioxidantes , Diosgenina , Ácidos Graxos , Sementes , Trigonella , Antioxidantes/metabolismo , Alcaloides/análise , Irã (Geográfico) , Sementes/química , Ácidos Graxos/análise , Trigonella/química , Minerais/análise , Fenóis/metabolismo , Nutrientes/análiseRESUMO
BACKGROUD: Arsenic trioxide (ATO), the first-line drug in treating acute premyelogenous leukemia, has the profound side effect of inducing endothelial mesenchymal transition (EndMT) and causing cardiac fibrosis. Diosgenin (DIO), a pharmaceutical compound found in Paris polyphylla, exhibits promising potential in safeguarding cardiovascular health by mitigating EndMT. PURPOSE: This study aims to explore the role and mechanism of DIO in ATO-induced myocardial fibrosis to provide a novel therapeutic agent for ATO-induced cardiac fibrosis. METHODS: Wistar rats were given DIO by gavage and ATO by tail vein. Cardiac function and fibrosis were evaluated by echocardiography and Masson's trichrome staining in rats. Human aortic endothelial cells (HAECs) were utilized to analyze ATO-induced EndMT in vitro. The cytoskeleton of HAECs was visualized using F-actin staining to observe cell morphology, while Dil-Ac-LDL staining was employed to assess cell functionality. EndMT-related factors (CD31 and α-SMA), glucocorticoid receptor (GR) and interleukin-6 (IL-6) were detected by immunofluorescence and Western blot in vivo and in vitro. Furthermore, GR was knocked down by si-GR, and IL-6 was blocked by IL-6 neutralizing antibody to verify their role in the effect of DIO on ATO-induced EndMT in HAECs. RESULTS: DIO exhibited significant efficacy in ATO-induced damage to both cardiac diastolic and systolic function, along with mitigating cardiac fibrosis. Additionally, DIO alleviated the loss of cytoskeletal anisotropy and enhanced the uptake of Dil-Ac-LDL in HAECs. Furthermore, it reversed the ATO-induced downregulation of endothelial-specific markers CD31 and GR, while suppressing the upregulation of mesenchymal markers α-SMA and IL-6, both in vivo and in vitro. Notably, the protective effect of DIO was compromised upon knockdown of GR, which also led to a reversal of DIO-induced IL-6 downregulation. Furthermore, the neutralization of IL-6 with specific antibodies abolished the ATO-induced changes related to EndMT. CONCLUSION: In this study, we clarified the protective effect of DIO on ATO-induced myocardial fibrosis against EndMT via the GR/IL-6 axis for the first time and provided a potential therapeutic agent for preventing heart damage caused by ATO.
Assuntos
Trióxido de Arsênio , Diosgenina , Células Endoteliais , Fibrose , Ratos Wistar , Animais , Fibrose/tratamento farmacológico , Humanos , Masculino , Diosgenina/farmacologia , Diosgenina/análogos & derivados , Células Endoteliais/efeitos dos fármacos , Ratos , Interleucina-6/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Actinas/metabolismo , Miocárdio/patologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Transição Endotélio-MesênquimaRESUMO
The aim of this study was to investigate the effects of polyphyllin â ¦ (PP â ¦) on proliferation, apoptosis, and cell cycle of diffuse large B-cell lymphoma (PLBCL) cell lines U2932 and SUDHL-4. The DLBCL cell lines were divided into a control group and a PPâ ¦ group, and experiments were conducted using MTT assay, flow cytometry, and Western blotting.Results showed that compared with the control group, PPâ ¦ significantly inhibited the proliferation of U2932 and SUDHL-4 cells (P<0.05). Apoptosis assays demonstrated that treatment with 0.50 and 1.00 µmol/L PP â ¦ significantly increased the apoptosis rates of both cell lines (P<0.05), upregulated apoptosis-related proteins, and downregulated Bcl-2 protein level (P<0.05). Cell cycle analysis revealed that PPâ ¦ treatment led to an increase in G0/G1-phase cells (P<0.05) and a decrease in G2/M-phase cells (P<0.05), significantly downregulated cyclin D1, CDK4, CDK6, and survivin protein expression (P<0.05). In conclusion, PPâ ¦ exerted anti-lymphoma effects by inhibiting proliferation, promoting apoptosis, and inducing G0/G1 phase arrest in DLBCL cells.
Assuntos
Apoptose , Ciclo Celular , Proliferação de Células , Linfoma Difuso de Grandes Células B , Humanos , Linfoma Difuso de Grandes Células B/metabolismo , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Ciclo Celular/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Diosgenina/farmacologia , Diosgenina/análogos & derivados , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/metabolismoRESUMO
The prevalence of nonalcoholic fatty liver disease (NAFLD) has been increasing worldwide in recent years, causing severe economic and social burdens. Therefore, the lack of currently approved drugs for anti-NAFLD has gradually gained attention. SIRT1, as a member of the sirtuins family, is now the most widely studied in the pathophysiology of many metabolic diseases, and has great potential for preventing and treating NAFLD. Natural products such as Diosgenin (DG) have the potential to be developed as clinical drugs for the treatment of NAFLD due to their excellent multi-target therapeutic effects. In this study, we found that DG can activate the SIRT1/PGC-1α pathway and upregulate the expression of its downstream targets nuclear respiratory factor 1 (NRF1), complex IV (COX IV), mitofusin-2 (MFN2), and PPARα (perox-isome proliferator-activated receptor α) in SD rats induced by high-fat diet (HFD) and HepG2 cells caused by free fatty acids (FFAs, sodium oleate: sodium palmitate = 2:1). Conversely, the levels of dynamin-related protein 1 (DRP1) and inflammatory factors, including NF-κB p65, IL6, and TNFα, were downregulated both in vitro and in vivo. This improved mitochondrial dysfunction, fatty acid oxidation (FAO), lipid accumulation, steatosis, oxidative stress, and hepatocyte inflammation. Subsequently, we applied SIRT1 inhibitor EX527 and SIRT1 agonist SRT1720 to confirm further the necessity of activating SIRT1 for DG to exert therapeutic effects on NAFLD. In summary, these results further demonstrate the potential therapeutic role of DG as a SIRT1 natural agonist for NAFLD. (Graphical Abstracts).
Assuntos
Diosgenina , Fígado , Hepatopatia Gordurosa não Alcoólica , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Transdução de Sinais , Sirtuína 1 , Animais , Humanos , Masculino , Ratos , Dieta Hiperlipídica/efeitos adversos , Diosgenina/farmacologia , Diosgenina/uso terapêutico , Diosgenina/análogos & derivados , Células Hep G2 , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismoRESUMO
Metabolic-associated fatty liver disease (MAFLD) is one of the most common liver diseases worldwide; however, its pathogenesis and treatment methods have not been perfected. NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) is a promising therapeutic target for MAFLD. Diosgenin (DG) is a natural compound that was identified in a traditional Chinese herbal medicine, which has pharmacological effects, such as anti-inflammatory, antioxidant, hepatoprotective, and hypolipidemic activities. In this study, we examined the effects and molecular mechanisms of DG on MAFLD in vitro and in vivo. We established a rat model by administering a high-fat diet (HFD). We also generated an in vitro MAFLD model by treating HepG2 cells with free fatty acids (FFAs). The results indicated that DG attenuated lipid accumulation and liver injury in both in vitro and in vivo models. DG downregulated the expression of NLRP3, apoptosis-associated speckle-like protein (ASC), cysteinyl aspartate specific proteinase-1 (caspase-1), gasdermin D (GSDMD), GSDMD-n, and interleukin-1ß (IL-1ß). In addition, we silenced and overexpressed NLRP3 in vitro to determine the effects of DG on antiMAFLD. Silencing NLRP3 enhanced the effect of DG on the treatment of MAFLD, whereas NLRP3 overexpression reversed its beneficial effects. Taken together, the results show that DG has a favorable effect on attenuating MAFLD through the hepatic NLRP3 inflammasome-dependent signaling pathway. DG represents a natural NLRP3 inhibitor for the MAFLD treatment.
Assuntos
Diosgenina , Inflamassomos , Fígado , Proteína 3 que Contém Domínio de Pirina da Família NLR , Hepatopatia Gordurosa não Alcoólica , Ratos Sprague-Dawley , Transdução de Sinais , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Inflamassomos/metabolismo , Humanos , Transdução de Sinais/efeitos dos fármacos , Masculino , Células Hep G2 , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Ratos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/imunologia , Diosgenina/farmacologia , Diosgenina/uso terapêutico , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêuticoRESUMO
Purpose: Ovarian cancer is a fatal gynecologic malignancy with a high rate of abdominal metastasis. Chemotherapy still has a poor clinical prognosis for ovarian cancer patients, with cell proliferation and angiogenesis leading to invasion, migration, and recurrence. To overcome these obstacles, we constructed a novel HA-modified paclitaxel and diosgenin liposome (PEG-TK-HA-PDLPs) using two novel functional materials, DSPE-PEG2000-HA and DSPE-PEG2000-TK-PEG5000, to specifically deliver the drugs to the tumor site in order to reduce OC cell proliferation and anti-angiogenic generation, thereby inhibiting invasion and migration. Methods and Results: PEG-TK-HA-PDLPs were prepared by film dispersion, with ideal physicochemical properties and exhibits active targeting for enhanced cellular uptake. The ZIP synergy score for PTX and Dios was calculated using the online SynergyFinder software to be 3.15, indicating synergy. In vitro results showed that PEG-TK-HA-PDLPs were highly cytotoxic to ID8 cells, induced ID8 cell apoptosis, and inhibited ID8 cell migration and invasion. In vivo studies showed that PEG-TK-HA-PDLPs could prolong the circulation time in the blood, accumulate significantly in the tumor site, and effectively fight against angiogenesis with significant anti-tumor effects. Conclusion: The production of PEG-TK-HA-PDLPs is an effective strategy for the treatment of OC.
Assuntos
Apoptose , Diosgenina , Ácido Hialurônico , Lipossomos , Neoplasias Ovarianas , Paclitaxel , Polietilenoglicóis , Espécies Reativas de Oxigênio , Feminino , Lipossomos/química , Lipossomos/farmacocinética , Paclitaxel/farmacologia , Paclitaxel/química , Paclitaxel/farmacocinética , Paclitaxel/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Diosgenina/farmacologia , Diosgenina/química , Diosgenina/farmacocinética , Diosgenina/administração & dosagem , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Linhagem Celular Tumoral , Polietilenoglicóis/química , Animais , Espécies Reativas de Oxigênio/metabolismo , Humanos , Apoptose/efeitos dos fármacos , Sinergismo Farmacológico , Proliferação de Células/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , FosfatidiletanolaminasRESUMO
BACKGROUND: Diosgenin is an important steroidal precursor renowned for its diverse medicinal uses. It is predominantly sourced from Dioscorea species, particularly Dioscorea zingiberensis. Dioscorea zingiberensis has an ability to accumulate 2-16% diosgenin in its rhizomes. In this study, a diverse population of 180 D. zingiberensis accessions was used to evaluate the genomic regions associated with diosgenin biosynthesis by the genome wide association study approach (GWAS). RESULTS: The whole population was characterized for diosgenin contents from tubers by gas chromatography mass spectrometry. The individuals were genotyped by the genotyping-by-sequencing approach and 10,000 high-quality SNP markers were extracted for the GWAS. The highest significant marker-trait-association was observed as an SNP transversion (G to T) on chromosome 10, with 64% phenotypic variance explained. The SNP was located in the promoter region of CYP94D144 which is a member of P450 gene family involved in the independent biosynthesis of diosgenin from cholesterol. The transcription factor (TF) binding site enrichment analysis of the promoter region of CYP94D144 revealed NAC TF as a potential regulator. The results were further validated through expression profiling by qRT-PCR, and the comparison of high and low diosgenin producing hybrids obtained from a bi-parental population. CONCLUSIONS: This study not only enhanced the understanding of the genetic basis of diosgenin biosynthesis but also serves as a valuable reference for future genomic investigations on CYP94D144, with the aim of augmenting diosgenin production in yam tubers.
Assuntos
Dioscorea , Diosgenina , Estudo de Associação Genômica Ampla , Tubérculos , Polimorfismo de Nucleotídeo Único , Diosgenina/metabolismo , Dioscorea/genética , Dioscorea/metabolismo , Tubérculos/genética , Tubérculos/metabolismo , Variação GenéticaRESUMO
BACKGROUND AND AIM: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with two core behavioral symptoms restricted/repetitive behavior and social-communication deficit. The unknown etiology of ASD makes it difficult to identify potential treatments. Valproic acid (VPA) is an anticonvulsant drug with teratogenic effects during pregnancy in humans and rodents. Prenatal exposure to VPA induces autism-like behavior in both humans and rodents. This study aimed to investigate the protective effects of Diosgenin in prenatal Valproic acid-induced autism in rats. METHOD: pregnant Wister female rats were given a single intraperitoneal injection of VPA (600 mg/kg, i.p.) on gestational day 12.5. The male offspring were given oral Dios (40 mg/kg, p.o.) or Carboxymethyl cellulose (5 mg/kg, p.o.) for 30 days starting from postnatal day 23. On postnatal day 52, behavioral tests were done. Additionally, biochemical assessments for oxidative stress markers were carried out on postnatal day 60. Further, histological evaluations were performed on the prefrontal tissue by Nissl staining and Immunohistofluorescence. RESULTS: The VPA-exposed rats showed increased anxiety-like behavior in the elevated plus maze (EPM). They also demonstrated repetitive and grooming behaviors in the marble burying test (MBT) and self-grooming test. Social interaction was reduced, and they had difficulty detecting the novel object in the novel object recognition (NOR) test. Also, VPA-treated rats have shown higher levels of oxidative stress malondialdehyde (MDA) and lower GPX, TAC, and superoxide dismutase (SOD) levels. Furthermore, the number of neurons decreased and the ERK signaling pathway upregulated in the prefrontal cortex (PFC). On the other hand, treatment with Dios restored the behavioral consequences, lowered oxidative stress, and death of neurons, and rescued the overly activated ERK1/2 signaling in the prefrontal cortex. CONCLUSION: Chronic treatment with Dios restored the behavioral, biochemical, and histological abnormalities caused by prenatal VPA exposure.
Assuntos
Transtorno Autístico , Diosgenina , Modelos Animais de Doenças , Fármacos Neuroprotetores , Estresse Oxidativo , Efeitos Tardios da Exposição Pré-Natal , Ratos Wistar , Ácido Valproico , Animais , Ácido Valproico/farmacologia , Feminino , Gravidez , Fármacos Neuroprotetores/farmacologia , Ratos , Estresse Oxidativo/efeitos dos fármacos , Masculino , Diosgenina/farmacologia , Transtorno Autístico/induzido quimicamente , Transtorno Autístico/metabolismo , Transtorno Autístico/tratamento farmacológico , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Comportamento Animal/efeitos dos fármacos , Anticonvulsivantes/farmacologia , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/tratamento farmacológico , Ansiedade/tratamento farmacológico , Ansiedade/induzido quimicamente , Comportamento SocialRESUMO
Cervical cancer (CC) is a common gynecological malignancy, and improving cisplatin sensitivity has become a hot topic in CC chemotherapy research. Polyphyllin I (PPI), a potent bioactive compound found in Rhizoma Paridis, known for its anticancer properties, remains underexplored in CC resistance. In this study, we evaluated PPI's impact on cisplatin-resistant CC cells and elucidated its underlying mechanism. Our findings reveal that PPI enhances the sensitivity of cisplatin-resistant CC cells to the drug, promotes apoptosis, and inhibits cell migration. Mechanistically, PPI was found to regulate p53 expression and its target genes, and suppressing p53 expression reverses PPI's sensitizing effect in drug-resistant CC cells. In conclusion, PPI showed promise in sensitizing cisplatin-resistant human CC cells to cisplatin treatment, suggesting that it could serve as a potent adjunct therapy for cervical cancer, particularly for cases that have developed resistance to cisplatin, thereby providing a promising basis for further clinical investigation into PPI for enhancing the efficacy of existing chemotherapy regimens in resistant cervical cancer.
Assuntos
Apoptose , Cisplatino , Diosgenina , Resistencia a Medicamentos Antineoplásicos , Neoplasias do Colo do Útero , Humanos , Cisplatino/farmacologia , Feminino , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia , Diosgenina/farmacologia , Diosgenina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Antineoplásicos/farmacologia , Movimento Celular/efeitos dos fármacos , Sinergismo FarmacológicoRESUMO
BACKGROUND: Lung adenocarcinoma (LUAD) is the most common pathological type of lung cancer. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been administered as the first-line therapy for patients with EGFR mutations in LUAD, but it is almost inevitable that resistance to EGFR-TKIs therapy eventually arises. Polyphyllin I (PPI), derived from Paris polyphylla rhizomes, has been shown to have potent anti-cancer properties in a range of human cancer types including LUAD. However, the role of PPI in gefitinib resistance and the underlying mechanism remain elusive. PURPOSE: To evaluate the antitumor impacts of PPI on gefitinib resistance cells and investigate its molecular mechanism. METHODS: CCK-8, wound healing, transwell assay, and xenograft model were performed to determine the anti-cancer effects of PPI as well as its ability to overcome gefitinib resistance. Immunoblotting, co-immunoprecipitation, phospho-RTK antibody array, qRT-PCR, and immunofluorescence were utilized to explore the mechanism by which PPI overrides gefitinib resistance. RESULTS: PPI inhibited cell survival, growth, and migration/invasion in both gefitinib-sensitive (PC9) and -resistant (PC9/GR) LUAD cells (IC50 at 2.0 µM). Significantly, treatment with PPI at 1.0 µM resensitized the resistant cells to gefitinib. Moreover, cell-derived xenograft experiments revealed that the combination of PPI and gefitinib overcame gefitinib resistance. The phospho-RTK array and immunoblotting analyses showed PPI significant inhibition of the VEGFR2/p38 pathway. In addition, molecular docking suggested the interaction between PPI and HIF-1α. Mechanistically, PPI reduced the protein expression of HIF-1α in both normoxia and hypoxia conditions by triggering HIF-1α degradation. Moreover, HIF-1α protein but not mRNA level was elevated in gefitinib-resistant LUAD. We further demonstrated that PPI considerably facilitated the binding of HIF-1α to VHL. CONCLUSIONS: We present a novel discovery demonstrating that PPI effectively counteracts gefitinib resistance in LUAD by modulating the VEGF/VEGFR2/p38 pathway. Mechanistic investigations unveil that PPI facilitates the formation of the HIF-1α /VHL complex, leading to the degradation of HIF-1α and subsequent inhibition of angiogenesis. These findings uncover a previously unidentified mechanism governing HIF-1α expression in reaction to PPI, providing a promising method for therapeutic interventions targeting EGFR-TKI resistance in LUAD.
Assuntos
Adenocarcinoma de Pulmão , Diosgenina , Resistencia a Medicamentos Antineoplásicos , Gefitinibe , Subunidade alfa do Fator 1 Induzível por Hipóxia , Neoplasias Pulmonares , Camundongos Nus , Fator A de Crescimento do Endotélio Vascular , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Gefitinibe/farmacologia , Humanos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Diosgenina/farmacologia , Diosgenina/análogos & derivados , Neoplasias Pulmonares/tratamento farmacológico , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Animais , Linhagem Celular Tumoral , Adenocarcinoma de Pulmão/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , FemininoRESUMO
Oxidative stress and inflammation play a fundamental role in the beginning and advancement of silicosis. Hence, questing active phytocompounds (APCs) with anti-oxidative and anti-inflammatory properties such as diosgenin (DG) and emodin (ED) can be a therapeutic intervention targeting silica-induced pulmonary inflammation and fibrosis. Hydrophobicity and low bioavailability are the barriers that restrict the therapeutic efficacy of DG and ED against pulmonary defects. Encapsulating these APCs in polymeric nanoparticles can overcome this limitation. The present study has thus explored the anti-inflammatory and anti-fibrotic effects of polylactic-co-glycolic acid (PLGA) nanoparticles (NPs) individually loaded with DG (DGn) or ED (EDn) and in combine DG+ED [(DG+ED)n] in respirable silica dust (RSD)-induced pulmonary fibrosis silicosis rat model. Our study found that individual and combined NPs revealed physiochemical characteristics appropriate for IV administration with sustained-drug release purposes. Physiological evaluations of RSD-induced silicosis rats suggested that no treatment could improve the body weight. Still, they reduced the lung coefficient by maintaining lung moisture. Only (DG+ED)n significantly cleared free lung silica. All interventions were found to attribute the increased per cent cell viability in BALF, reduce cytotoxicity via minimizing LDH levels, and balance the oxidant-antioxidant status in silicotic rats. The expression of inflammatory cytokines (TNF-α, IL-1ß, IL-6, MCP-1, and TGF-ß1) were efficiently down-regulated with NPs interventions compared to pure (DG+ED) treatment. All drug treatments significantly declined, the 8-HdG and HYP productions indicate that RSD-induced oxidative DNA damage and collagen deposition were successfully repaired. Moreover, histopathological investigations proposed that individual or combined drugs NPs interventions could decrease the fibrosis and alveolitis grades in RSD-induced silicosis rats. However, (DG+ED)n intervention significantly inhibited pulmonary fibrosis and alveolitis compared to pure (DG+ED) treatment. In conclusion, the RSD can induce oxidative stress and inflammation in rats, producing reactive oxygen species (ROS)-mediated cytotoxicity to pulmonary cells and leading to silicosis development. The IV administration of combined NP suppressed lung inflammation and collagen formation by maintaining oxidant-antioxidant status and effectively interrupting the fibrosis-silicosis progression. These results may be attributed to the improved bioavailability of DG and ED through their combined nano-encapsulation-mediated targeted drug delivery.
Assuntos
Diosgenina , Emodina , Nanopartículas , Fibrose Pulmonar , Dióxido de Silício , Silicose , Animais , Diosgenina/farmacologia , Silicose/tratamento farmacológico , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/prevenção & controle , Ratos , Emodina/farmacologia , Masculino , Poeira , Estresse Oxidativo/efeitos dos fármacos , Anti-Inflamatórios , Ratos Wistar , Pulmão/efeitos dos fármacos , Pulmão/patologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/químicaRESUMO
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.
Assuntos
Autofagia , Modelos Animais de Doenças , Microglia , Doenças Neuroinflamatórias , Traumatismo por Reperfusão , Animais , Microglia/efeitos dos fármacos , Microglia/metabolismo , Camundongos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/etiologia , Autofagia/efeitos dos fármacos , Masculino , Doenças Neuroinflamatórias/etiologia , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismo , Diosgenina/análogos & derivados , Diosgenina/farmacologia , Diosgenina/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Transdução de Sinais/efeitos dos fármacos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Serina-Treonina Quinases TOR/metabolismo , Camundongos Endogâmicos C57BL , Polaridade Celular/efeitos dos fármacosRESUMO
The emergence of Poly (ADP-ribose) polymerase inhibitors (PARPi) has marked the beginning of a precise targeted therapy era for ovarian cancer. However, an increasing number of patients are experiencing primary or acquired resistance to PARPi, severely limiting its clinical application. Deciphering the underlying mechanisms of PARPi resistance and discovering new therapeutic targets is an urgent and critical issue to address. In this study, we observed a close correlation between glycolysis, tumor angiogenesis, and PARPi resistance in ovarian cancer. Furthermore, we discovered that the natural compound Paris saponin VII (PS VII) partially reversed PARPi resistance in ovarian cancer and demonstrated synergistic therapeutic effects when combined with PARPi. Additionally, we found that PS VII potentially hindered glycolysis and angiogenesis in PARPi-resistant ovarian cancer cells by binding and stabilizing the expression of RORα, thus further inhibiting ECM1 and interfering with the VEGFR2/FAK/AKT/GSK3ß signaling pathway. Our research provides new targeted treatment for clinical ovarian cancer therapy and brings new hope to patients with PARPi-resistant ovarian cancer, effectively expanding the application of PARPi in clinical treatment.
Assuntos
Diosgenina/análogos & derivados , Glicólise , Neovascularização Patológica , Neoplasias Ovarianas , Saponinas , Transdução de Sinais , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Saponinas/farmacologia , Saponinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Linhagem Celular Tumoral , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Animais , Camundongos Nus , Camundongos , AngiogêneseRESUMO
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.
Assuntos
Cardiomiopatias , Diosgenina , Fator 88 de Diferenciação Mieloide , Sepse , Transdução de Sinais , Receptor 4 Toll-Like , Animais , Diosgenina/análogos & derivados , Diosgenina/farmacologia , Diosgenina/uso terapêutico , Receptor 4 Toll-Like/metabolismo , Ratos , Fator 88 de Diferenciação Mieloide/metabolismo , Sepse/complicações , Sepse/tratamento farmacológico , Sepse/metabolismo , Transdução de Sinais/efeitos dos fármacos , Masculino , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Cardiomiopatias/prevenção & controle , Linhagem Celular , Ratos Sprague-Dawley , Fator de Transcrição RelA/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Lipopolissacarídeos , Modelos Animais de Doenças , Apoptose/efeitos dos fármacosRESUMO
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.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos , Diosgenina , Camundongos Endogâmicos C57BL , Infarto do Miocárdio , Neovascularização Fisiológica , Animais , Humanos , Masculino , Camundongos , Angiogênese , Apoptose/efeitos dos fármacos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Diosgenina/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/fisiopatologia , Neovascularização Fisiológica/efeitos dos fármacosRESUMO
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.
Assuntos
Diosgenina , Ferroptose , Leucemia Mieloide Aguda , Peroxidação de Lipídeos , Fosfatidilinositol 3-Quinases , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Diosgenina/farmacologia , Diosgenina/análogos & derivados , Diosgenina/uso terapêutico , Ferroptose/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/metabolismoRESUMO
Fungal infections are a public health problem that mainly affects immunosuppressed people, Candida spp. have been responsible for most sources of contamination and invasive fungal infections described around the world. The need arises to find new therapeutic approaches to combat growing infections. Plants and natural products have been considered a valuable source for discovering new molecules with active ingredients. Diosgenin is a sapogenin found in the families of Leguminosae and Dioscoreaceae, it is obtained mainly from the dioscin saponin through the hydrolysis method, it is a phytochemical that has been highlighted in the treatment of various diseases, as well as in combating microbial resistance. The present study aimed to evaluate the susceptibility of fungal strains to diosgenin, as well as verify the association with the reference drug and evaluate the inhibition of the virulence factor through morphological changes in the yeast state to the filamentous form of hyphae and pseudohyphae in strains of Candida albicans, Candida tropicalis and Candida krusei using the broth microdilution method and microculture technique. Antifungal assays revealed that diosgenin was not able to inhibit the growth of the tested strains. However, it was able to inhibit the fungal dimorphism of the strains evaluated, however further studies are recommended to verify its effectiveness against other virulence factors.