RESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) remains a significant global medical challenge. Formononetin, an isoflavone derived from Astragalus membranaceus, has been shown to have various regulatory effects on HCC. However, the exact molecular mechanism by which formononetin acts against HCC is still unclear. PURPOSE: To elucidate the molecular mechanism of formononetin in treating HCC. METHODS: The potential targets of formononetin were retrieved from Swisstargets and SEA databases, while targets associated with HCC were sourced from GeneCards, NCBI and DisGeNET databases. The overlapping targets were visualized using protein-protein interaction (PPI) network analysis via String database, and subsequently subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Molecular docking was employed to confirm the interaction between formononetin and key targets. Ultimately, the effectiveness of formononetin on HCC and the signalling pathway with the highest enrichment were confirmed in the HCC tumour-bearing mice. Histopathological changes in tumour tissues were observed using haematoxylin and eosin (HE) staining, while apoptosis of tumour cells in mice was assessed through TdT-mediated dUTP nick end labelling (TUNEL) and immunofluorescence staining. The most enriched signalling pathway was verified using Western blotting and immunohistochemical (IHC) staining. RESULTS: One hundred and ninety-three potential targets related to formononetin, 6980 targets associated with HCC and 156 overlapping targets were obtained from the online public databases. Molecular docking studies demonstrated formononetin's robust interaction with core targets. KEGG enrichment analysis identified 111 signalling pathways, including PI3K/AKT and apoptosis signalling pathways. In vivo experiments demonstrated that formononetin significantly promoted apoptosis of tumour cell in mice, as confirmed by HE, TUNEL and immunofluorescence staining (p < .05). Formononetin was found to decrease the phosphorylation levels of PI3K and AKT, reduce the expression of Bcl-2, and increase the expression of cleaved-Caspase-3 and Bax (p < .05). CONCLUSIONS: Formononetin demonstrates dose-dependent regulatory effects on multiple targets, biological processes and signalling pathways in HCC. The compound can mitigate HCC by enhancing PI3K/AKT-mediated apoptosis of tumour cells.
Assuntos
Apoptose , Carcinoma Hepatocelular , Isoflavonas , Neoplasias Hepáticas , Simulação de Acoplamento Molecular , Transdução de Sinais , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/metabolismo , Animais , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Camundongos , Humanos , Apoptose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Mapas de Interação de Proteínas , Masculino , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Endogâmicos BALB C , Simulação por Computador , Proteínas Proto-Oncogênicas c-akt/metabolismo , Camundongos NusRESUMO
8-Prenylgenistein (8PG), a genistein derivative, is present in fermented soybeans (Glycine max), including cheonggukjang (CGJ), and exhibits osteoprotective, osteogenic, and antiadipogenic properties. However, the hepatoprotective effects of 8PG and its underlying molecular mechanisms remain largely unexplored. Here, we identified the high binding affinity of 8PG with AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1), which acts as a potent AMPK activator that counteracts hepatic steatosis. Notably, 8PG exhibited better pharmacokinetics with greater absorption and higher plasma binding than the positive controls for the target proteins. Moreover, 8PG exerted non-carcinogenic activity in rats and significantly increased AMPK phosphorylation. Compound C, an AMPK inhibitor, did not antagonize 8PG-activated AMPK in HepG2 cells. 8PG significantly attenuated palmitate-induced lipid accumulation and enhanced phosphorylated AMPK and its downstream target, acetyl-CoA carboxylase. Further, 8PG activated nuclear SIRT1 at the protein level, which promoted fatty acid oxidation in palmitate-treated HepG2 cells. Overall, 8PG acts as a potent AMPK activator, further attenuating hepatic steatosis via the SIRT1-mediated pathway and providing new avenues for dietary interventions to treat metabolic dysfunction-associated steatotic liver disease (MASLD).
Assuntos
Proteínas Quinases Ativadas por AMP , Isoflavonas , Sirtuína 1 , Sirtuína 1/metabolismo , Animais , Humanos , Proteínas Quinases Ativadas por AMP/metabolismo , Células Hep G2 , Ratos , Masculino , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Transdução de Sinais/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ratos Sprague-Dawley , Glycine max/química , Genisteína/farmacologiaRESUMO
Excessive activity of osteoclasts(OCs) lead to bone resorption in chronic inflammatory conditions. The use of natural compounds to target OCs offers significant promise in the treatment or prevention of OC-associated diseases. Irilin D (IRD), a natural isoflavone derived from Belamcanda chinensis (L.) DC., has potential effects on OC differentiation both in vitro and in vivo that have yet to be thoroughly explored. In our study, we found that IRD inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced OC differentiation, actin ring formation, and bone resorption in vitro without compromising cell viability. However, IRD did not exhibit anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated macrophages. Furthermore, IRD reduced LPS-induced inflammatory bone loss by blocking osteoclastogenesis in a mouse model. Mechanistically, IRD disrupted RANKL-induced activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB), leading to the inhibition of c-Fos and nuclear factor of activated T cells cytoplasmic 1 (NFATc1) activation. We also demonstrated that IRD inhibited RANKL-induced osteoclastic NFATc1 target genes, including DC-STAMP, ACP5, and CtsK. Our results indicate that IRD mitigates LPS-induced inflammatory bone resorption in mice by inhibiting RANKL-activated MAPKs and NF-κB signaling pathways, suggesting its potential as a natural isoflavone for preventing or treating OC-associated diseases.
Assuntos
Reabsorção Óssea , Inflamação , Isoflavonas , Sistema de Sinalização das MAP Quinases , NF-kappa B , Osteoclastos , Osteogênese , Ligante RANK , Animais , Masculino , Camundongos , Reabsorção Óssea/prevenção & controle , Reabsorção Óssea/induzido quimicamente , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/patologia , Reabsorção Óssea/metabolismo , Diferenciação Celular/efeitos dos fármacos , Inflamação/patologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Lipopolissacarídeos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Ligante RANK/metabolismo , Células RAW 264.7RESUMO
Hyperactive osteoclasts and hypoactive osteoblasts usually result in osteolytic conditions such as estrogen-deficiency bone loss. Few natural compounds that both attenuating bone resorption and enhancing bone formation could exert effects on this imbalance. 5-Deoxycajanin (5-D), an isoflavonoid extracted from Cajan leaf with estrogen-like properties, were found to have beneficial pharmacological effects on rebalancing the activities of osteoclasts and osteoblasts. This study revealed that 5-D at the same concentration could inhibit osteoclastogenesis of BMMs and promoted osteoblast differentiation of BMSCs. 5-D not only attenuated the fluorescent formation of RANKL-induced F-actin belts and NFATc1, but also activated ALP and RUNX2 expressions. As to downstream factor expressions, 5-D could block osteoclast-specific genes and proteins including NFATc1 and CTSK, while increased osteogenic genes and proteins including OPG and OCN, as confirmed by Real-time PCR and Western Blotting. Additionally, the network pharmacology and molecular docking identified the involvement of 5-D in the MIF and MAPK signaling pathways and the stable binding between 5-D and MAPK2K1. Further Western blot studies showed that 5-D decreased the phosphorylation of p38 and ERK in osteoclasts, but promoted these phosphorylations in osteoblasts. In a female C57BL/6J mouse model of estrogen deficiency-induced bone loss, 5-D demonstrated efficacy in enhancing BMD through attenuating osteoclast activities and promoting osteogenesis. These results underscore the potential application of 5-D on treating osteolysis resulting from hyperactive osteoclasts and hypoactive osteoblasts, shedding light on modulating osteoclast-osteoblast homeostasis.
Assuntos
Reabsorção Óssea , Estrogênios , Osteoblastos , Osteoclastos , Animais , Osteoclastos/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Camundongos , Feminino , Estrogênios/deficiência , Estrogênios/metabolismo , Reabsorção Óssea/tratamento farmacológico , Osteogênese/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Células Cultivadas , Diferenciação Celular/efeitos dos fármacos , Ovariectomia , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Ligante RANK/metabolismo , Humanos , Simulação de Acoplamento Molecular , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismoRESUMO
Oxaliplatin (OXA) as the platinum-based agent induces the cumulative neuropathy including functional impairment and neuropathic pain. OXA treatment triggered oxidative stress and inflammatory reaction in the spinal cord. Puerarin as a natural product has the neuroprotective effect on neuropathic pain. Hence, the roles and mechanisms of Pue on OXA induced neuropathic pain were studied. In this study, OXA-induced neuropathic pain mouse model was constructed by oxaliplatin injection for 5 consecutive days and two cycles. Pue (10 mg/kg) was administered intraperitoneally for seven consecutive days. The changes of behavior, morphology and levels of related proteins were detected. As a result, OXA-induced mice exhibited as the increased pain hypersensitivity, the impaired motor coordination, the activated NLRP3 inflammasome mediated inflammation and the suppressed nuclear factor erythroid 2-related factor 2 (Nrf2) mediated antioxidative reaction in the spinal cord (P<0.05 vs Control). After Pue administration, the mechanical pain threshold, thermal pain latency, spontaneous pain number and motor latency were improved (P<0.05 vs OXA). In the spinal cord, Pue administration reduced the levels of inflammatory elements, increased the levels of antioxidative elements and decreased the levels of oxidative factors (P<0.05 vs OXA). Furthermore, Pue also bind with Nrf2 and increased the association of Nrf2 to glutathione peroxidase 4 (GPX4). In summary, Pue alleviates oxaliplatin induced neuropathic pain by enhancing Nrf2/GPX4-mediated antioxidant response and suppressing inflammatory reaction in the spinal cord.
Assuntos
Antioxidantes , Isoflavonas , Fator 2 Relacionado a NF-E2 , Neuralgia , Oxaliplatina , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Animais , Oxaliplatina/efeitos adversos , Neuralgia/tratamento farmacológico , Neuralgia/induzido quimicamente , Neuralgia/metabolismo , Camundongos , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Medula Espinal/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Estresse Oxidativo/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Modelos Animais de Doenças , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Formononetin (FNT) is an isoflavone known for its anti-inflammatory properties and has been shown to reduce insulin resistance in Type 2 Diabetes Mellitus (T2DM). However, its effects and the underlying mechanisms in diabetic liver injury remain largely unexplored. METHODS: We established a T2DM-induced liver injury mouse model by feeding high-fat diet, followed by injecting streptozotocin. The mice were then treated with FNT and the liver function in these mice was assessed. Macrophage markers in FNT-treated T2DM mice or human THP-1 cells were evaluated using flow cytometry, RT-qPCR, and Western blotting. The expression of PTP1B and STAT6 in mouse liver tissues and THP-1 cells was analyzed. Molecular docking predicted the interaction between PTP1B and STAT6, which was validated via co-immunoprecipitation (Co-IP) and phos-tag analysis. Microscale thermophoresis (MST) assessed the binding affinity of FNT to PTP1B. RESULTS: FNT treatment significantly ameliorated blood glucose levels, hepatocyte apoptosis, inflammatory response, and liver dysfunction in T2DM mice. Moreover, FNT facilitated M2 macrophage polarization in both T2DM mice and high glucose (HG)-induced THP-1-derived macrophages. The PTP1B/STAT6 axis, deregulated in T2DM mice, was normalized by FNT treatment, which counteracted the T2DM-induced upregulation of PTP1B and downregulation of phosphorylated STAT6. Molecular docking and subsequent analyses revealed that PTP1B binds to and dephosphorylates STAT6 at the S325A site. In contrast, FNT strongly binds to PTP1B and influences its expression at the K116A site, promoting M2 polarization of THP-1 cells via downregulation of PTP1B. CONCLUSION: Formononetin mitigates diabetic hepatic injury by fostering M2 macrophage polarization via the PTP1B/STAT6 axis.
Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Isoflavonas , Macrófagos , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Animais , Humanos , Masculino , Camundongos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição STAT6/metabolismo , Estreptozocina , Células THP-1RESUMO
Metabolic diseases (MetD) such as diabetes mellitus, obesity, and hyperlipidemia have become global health challenges. As a naturally occurring plant component, puerarin has been verified to possess a wide range of pharmacological effects including lowering blood glucose, improving insulin resistance, and regulating lipid metabolism, which has attracted extensive attention in recent years, and its potential in the treatment of MetD has been highly acclaimed. In addition, puerarin has exhibited antioxidant, anti-inflammatory, and cardiovascular protective effects, which are of great significance in the prevention and treatment of MetD. This article comprehensively summarizes the research progress of puerarin in the treatment of MetD and explores its pharmacological mechanisms, clinical applications, and future perspectives. More importantly, this review provided a list of the involved molecular mechanims in treating MetD of puerarin. Taking into account these conclusions, it may provide a strong foundation for the optimized use of puerarin in the treatment of patients suffering from MetD.
Assuntos
Isoflavonas , Doenças Metabólicas , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Humanos , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Doenças Metabólicas/prevenção & controle , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Resistência à InsulinaRESUMO
Puerarin, a monomer of traditional Chinese medicine, is a key component of Pueraria radix. Both clinical and experimental researches demonstrated that puerarin has therapeutic effects on Parkinson's disease (PD). Puerarin's pharmacological mechanisms include: 1) Anti-apoptosis. Puerarin inhibits cell apoptosis through the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (Akt) and c-Jun N-terminal kinase (JNK) signaling pathways. Puerarin also exerts a hormone-like effect against cell apoptosis; 2) Anti-oxidative stress injury. Puerarin inhibits the Nrf2 nuclear exclusion through the GSK-3ß/Fyn pathway to promote the Nrf2 accumulation in the nucleus, and then promotes the antioxidant synthesis through the Nrf2/ARE signaling pathway to protect against oxidative stress; 3) Neuroprotective effects by intervening in the ubiquitin-proteasome system (UPS) and autophagy-lysosomal pathway (ALP). Puerarin significantly enhances the activity of chaperone-mediated autophagy (CMA), which downregulates the expression of α-synuclein, reduces its accumulation, and thus improves the function of damaged neurons. Additionally, puerarin increases proteasome activity and decreases ubiquitin-binding proteins, thereby preventing toxic accumulation of intracellular proteins; 4) Alleviating inflammatory response. Puerarin inhibits the conversion of microglia to the M1 phenotype while inducing the transition of microglia to the M2 phenotype. Furthermore, puerarin promotes the secretion of anti-inflammatory factor and inhibits the expression of pro-inflammatory factors; 5) Increasing the levels of dopamine and its metabolites. Puerarin could increase the levels of dopamine, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum; 6) Promoting neurotrophic factor expression and neuronal repair. Puerarin increases the expression of glial cell-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), thereby exerting a neuroprotective effect. Moreover, the regulation of the gut microbiota by puerarin may be a potential mechanism for the treatment of PD. The current review discusses the molecular mechanisms of puerarin, which may provide insight into the active components of traditional Chinese medicine in the treatment of PD.
Assuntos
Isoflavonas , Fármacos Neuroprotetores , Doença de Parkinson , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Humanos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Animais , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacosRESUMO
Despite efforts to find effective drugs for sepsis-associated acute kidney injury (SA-AKI), mortality rates in patients with SA-AKI have not decreased. Our study evaluated the protective effects of isoflavone osajin (OSJ) on SA-AKI in rats by targeting inflammation, oxidative stress, and apoptosis, which represent the cornerstones in the pathophysiological mechanism of SA-AKI. Polymicrobial sepsis was induced in rats via the cecal ligation and puncture (CLP) technique. Markers of oxidative stress were evaluated in kidney tissues using biochemical methods. The expression of interleukin-33 (IL-33), 8-hydroxydeoxyguanosine (8-OHdG), caspase-3, and kidney injury molecule-1 (KIM-1) was evaluated as indicators of inflammation, DNA damage, apoptosis, and SA-AKI respectively in the kidney tissues using immunohistochemical and immunofluorescent detection methods. The CLP technique significantly (p < 0.001) increased lipid peroxidation (LPO) levels and significantly (p < 0.001) decreased the activities of superoxide dismutase and catalase in kidney tissues. In the renal tissues, strong expression of IL-33, 8-OHdG, caspase-3, and KIM-1 was observed with severe degeneration and necrosis in the tubular epithelium and intense interstitial nephritis. In contrast, the administration of OSJ significantly (p < 0.001) reduced the level of LPO, markedly improved biomarkers of antioxidant status, decreased the levels of serum creatinine and urea, lowered the expression of IL-33, 8-OHdG, caspase-3, and KIM-1 and alleviated changes in renal histopathology. A promising binding score was found via a molecular docking investigation of the OSJ-binding mode with mouse IL-33 (PDB Code: 5VI4). Therefore, OSJ protects against SA-AKI by suppressing the IL-33/LPO/8-OHdG/caspase-3 pathway and improving the antioxidant system.
Assuntos
Injúria Renal Aguda , Antioxidantes , Apoptose , Rim , Simulação de Acoplamento Molecular , Estresse Oxidativo , Sepse , Animais , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/prevenção & controle , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Sepse/complicações , Sepse/tratamento farmacológico , Ratos , Estresse Oxidativo/efeitos dos fármacos , Masculino , Apoptose/efeitos dos fármacos , Rim/patologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Modelos Animais de Doenças , Interleucina-33/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Caspase 3/metabolismo , Ratos Sprague-Dawley , Moléculas de Adesão CelularRESUMO
OBJECTIVE: To explore the mechanism by which soybean isoflavone (SI) reduces calcium overload induced by cerebral ischemia-reperfusion (I/R). METHODS: Forty-eight SD rats were randomized into 4 groups to receive sham operation, cerebral middle artery occlusion for 2 h followed by 24 h of reperfusion (I/R model group), or injection of adeno-associated virus carrying Frizzled-2 siRNA or empty viral vector into the lateral cerebral ventricle after modeling.Western blotting was used to examine Frizzled-2 knockdown efficiency and changes in protein expressions in the Wnt/Ca2+ signaling pathway.Calcium levels and pathological changes in the ischemic penumbra (IP) were measured using calcium chromogenic assay and HE staining, respectively.Another 72 SD randomly allocated for sham operation, I/R modeling, or soy isoflavones pretreatment before modeling were examined for regional cerebral blood flow using a Doppler flowmeter, and the cerebral infarct volume was assessed using TTC staining.Pathologies in the IP area were evaluated using HE and Nissl staining, and ROS level, Ca2+ level, cell apoptosis, and intracellular calcium concentration were analyzed using immunofluorescence assay or flow cytometry; the protein expressions of Wnt5a, Frizzled-2, and P-CaMK â ¡ in the IP were detected with Western blotting and immunohistochemistry. RESULTS: In rats with cerebral I/R, Frizzled-2 knockdown significantly lowered calcium concentration (P < 0.001) and the expression levels of Wnt5a, Frizzled-2, and P-CaMK â ¡ in the IP area.In soy isoflavones-pretreated rats, calcium concentration, ROS and MDA levels, cell apoptosis rate, cerebral infarct volume, and expression levels of Wnt/Ca2+ signaling pathway-related proteins were all significantly lower while SOD level was higher than those in rats in I/R model group. CONCLUSION: Soy isoflavones can mitigate calcium overload in rats with cerebral I/R by inhibiting the Wnt/Ca2+ signaling pathway.
Assuntos
Isquemia Encefálica , Cálcio , Glycine max , Isoflavonas , Ratos Sprague-Dawley , Traumatismo por Reperfusão , Via de Sinalização Wnt , Animais , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Ratos , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Via de Sinalização Wnt/efeitos dos fármacos , Isquemia Encefálica/metabolismo , Cálcio/metabolismo , Glycine max/química , Apoptose/efeitos dos fármacos , Masculino , Proteína Wnt-5a/metabolismo , RNA Interferente Pequeno/genéticaRESUMO
Endometritis is one of the important causes of infertility. Puerarin (PU) can inhibit oxidative stress and reduce inflammation; however, it is unclear whether PU has a protective effect on the endometritis. In our study, we used Staphylococcus aureus to induce mouse endometritis. The PU group (100 mg/kg PU) and the S. aureus + PU group received daily intraperitoneal injection of PU (25, 50 or 100 mg/kg PU). The results showed that S. aureus significantly increased the levels of MPO, TNF-α, IL-1ß and IL-6 in uterine tissue, and increased the expression of p-p65 and p-IκBα proteins in uterine tissue to induce endometritis in mice (p < 0.05). Furthermore, it has been found that S. aureus promotes the occurrence of ferroptosis by reducing GSH and ATP content, increasing MDA and iron content and reducing GPX4 and SLC7A11 protein expression levels (p < 0.05). S. aureus significantly increase the expression of NLRP3, ASC, caspase-1 and P2X7 proteins in uterine tissue (p < 0.05). However, PU obviously reduced the inflammatory response and reversed the changes of ferroptosis and the expression of P2X7 receptor/NLRP3 pathway associated proteins of the uterus induced by S. aureus (p < 0.05). Taken together, these findings emphasize the protective effect of PU on endometritis by regulating the P2X7 receptor/NLRP3 signalling pathway and inhibiting ferroptosis.
Assuntos
Endometrite , Ferroptose , Isoflavonas , Proteína 3 que Contém Domínio de Pirina da Família NLR , Receptores Purinérgicos P2X7 , Transdução de Sinais , Infecções Estafilocócicas , Staphylococcus aureus , Animais , Feminino , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Ferroptose/efeitos dos fármacos , Staphylococcus aureus/patogenicidade , Endometrite/metabolismo , Endometrite/microbiologia , Endometrite/tratamento farmacológico , Endometrite/patologia , Transdução de Sinais/efeitos dos fármacos , Camundongos , Receptores Purinérgicos P2X7/metabolismo , Infecções Estafilocócicas/metabolismo , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Útero/metabolismo , Útero/patologia , Útero/efeitos dos fármacos , Útero/microbiologia , Estresse Oxidativo/efeitos dos fármacosRESUMO
OBJECTIVE: Atherosclerosis (AS) is a common pathogenesis of cardiovascular diseases. Puerarin (Pue) is a Chinese herbal remedy used to prevent and treat AS. Here, this research investigated the effect of Pue on AS progression. METHODS: ApoE-/- mice were induced with acrolein. Body weight, blood lipid index, inflammatory factors, mitochondrial oxidative stress, and lipid deposition were detected. IL-6 and TNF-α were detected by ELISA. Oil red staining and H&E staining were used to observe the aortic sinus plaque lesions. Serum expressions of inflammatory factors IL-6, TNF-a, SOD, GSH and MDA were detected by ELISA, the mRNA expression levels of HDAC1 in the aorta were detected by RT-qPCR, and IL-6 and TNF-α in the aorta were detected by immunohistochemistry. JNK, p-JNK, OPA-1, and HDAC1 were detected by Western blotting. RESULTS: Pue administration can effectively reduce lipid accumulation in AS mice induced by acrolein. Pue promoted the activity of SOD, GSH and MDA, and inhibited the formation of atherosclerotic plaques and the process of aortic histological changes. Pue reduced IL-6 and TNF-α. HDAC1 expression was down-regulated and p-JNK-1 and JNK protein expression was up-regulated. CONCLUSION: Pue reduces inflammation and alleviates AS induced by acrolein by mediating the JNK pathway to inhibit HDAC1-mediated oxidative stress disorder.
Assuntos
Acroleína , Aterosclerose , Histona Desacetilase 1 , Isoflavonas , Estresse Oxidativo , Animais , Aterosclerose/induzido quimicamente , Aterosclerose/metabolismo , Aterosclerose/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Histona Desacetilase 1/metabolismo , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Acroleína/farmacologia , Masculino , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Western Blotting , Aorta/efeitos dos fármacos , Aorta/patologiaRESUMO
The spreading of cancer cells from the primary tumor site to other parts of the body, known as metastasis, is the leading cause of cancer recurrence and mortality in patients with triple-negative breast cancer (TNBC). Overexpression of epidermal growth factor receptor (EGFR) is observed in approximately 70% of TNBC patients. EGFR is crucial for promoting tumor metastasis and associated with poor prognosis. Therefore, it is vital to identify effective therapeutic strategies targeting EGFR inhibition. Ononin, an isoflavonoid found in various plants, such as clover and soybeans, has been shown to have anticancer properties in several cancers. In the present study, we aimed to investigate the effects of ononin on TNBC lung metastasis and the associated molecular pathways. We used various assays, including cell viability, colony formation, Transwell, wound healing, ELISA, Western blotting, and staining techniques, to achieve this objective. The results demonstrated that ononin effectively suppressed cellular proliferation and induced apoptosis, as evidenced by the cell viability assay, colony formation assay, and expression of apoptosis markers, and reduced the metastatic capabilities of TNBC cells. These effects were achieved through the direct suppression of cell adhesion, invasiveness and motility. Furthermore, in TNBC xenograft lung metastatic models, ononin treatment significantly reduced tumor growth and lung metastasis. Additionally, ononin reversed the epithelial-mesenchymal transition (EMT) by downregulating the expression of EMT markers and matrix metalloproteinases, as confirmed by Western blot analysis. Furthermore, ononin treatment reduced EGFR phosphorylation and suppressed the PI3K, Akt, and mTOR signaling pathways, which was further confirmed using EGFR agonists or inhibitors. Importantly, ononin treatment did not exert any toxic effects on liver or kidney function. In conclusion, our findings suggest that ononin is a safe and potentially therapeutic treatment for TNBC metastasis that targets the EGFR-mediated PI3K/Akt/mTOR pathway. Further studies are warranted to validate its efficacy and explore its potential clinical applications.
Assuntos
Apoptose , Proliferação de Células , Receptores ErbB , Neoplasias Pulmonares , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Serina-Treonina Quinases TOR , Neoplasias de Mama Triplo Negativas , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Serina-Treonina Quinases TOR/metabolismo , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores ErbB/metabolismo , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Feminino , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Fosfatidilinositol 3-Quinases/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Camundongos NusRESUMO
Continuing research is being conducted on novel preventive and therapeutic drugs for cardiovascular diseases (CVDs). Daidzein has shown potential beneficial effects regarding various CVDs and risk factors. However, data in this regard are inconsistent, and there is an urge to accumulate. Therefore, we reviewed the effects of daidzein and daidzin on CVDs. We conducted a search through Scopus, PubMed, Google Scholar, and Web of Science from inception up to October 2023 to find studies with the primary intention of assessing the impacts of daidzein and daidzin on cardiovascular disease in various in vitro, animal, and clinical settings. In vitro and animal studies showed that daidzein and daidzin are effective in terms of reducing inflammation, oxidative stress, hyperlipidemia, myocardial infarction, thromboembolism, hypertension, and aneurysms. However, clinical studies only confirmed a relatively small portion of the previous findings of the in vitro and animal investigations, including anti-hyperlipidemic effects. In conclusion, in vitro and animal studies have reported potential therapeutic effects for daidzein and daidzin regarding CVDs. However, most of the clinical studies were unable to exhibit the same results. Hence, further clinical studies are required to determine the outcomes of administering daidzein and its derivatives for an extended period and in various doses.
Assuntos
Doenças Cardiovasculares , Isoflavonas , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Humanos , Animais , Doenças Cardiovasculares/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacosRESUMO
Our former studies have identified the alleviating effect of Calycosin (CA) on spinal cord injury (SCI). In this study, our purpose is to explore the influence of CA on SCI from the perspective of promoting axon growth. The SCI animal model was constructed by spinal cord compression, wherein rat primary cortex neuronal isolation was performed, and the axonal growth restriction cell model was established via chondroitin sulfate proteoglycan (CSPG) treatment. The expressions of axon regeneration markers were measured via immunofluorescent staining and western blot, and the direct target of CA was examined using silver staining. Finally, the expression of the protein tyrosine phosphatase receptor type S (PTPRS) was assessed using western blot. CA treatment increased neuronal process outgrowth and the expressions of axon regeneration markers, such as neurofilament H (NF-H), vesicular glutamate transporter 1 (vGlut1), and synaptophysin (Syn) in both SCI model rats and CSPG-treated primary cortical neurons, and PTPRS levels were elevated after SCI induction. In addition, PTPRS was the direct target of CA, and according to in vivo findings, exposure to CA reduced the PTPRS content. Furthermore, PTPRS overexpression inhibited CA's enhancement of axon regeneration marker content and neuronal axon lengths. CA improves SCI by increasing axon development through regulating PTPRS expression.
Assuntos
Axônios , Isoflavonas , Ratos Sprague-Dawley , Traumatismos da Medula Espinal , Sinaptofisina , Animais , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/tratamento farmacológico , Ratos , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Axônios/efeitos dos fármacos , Axônios/metabolismo , Células Cultivadas , Sinaptofisina/metabolismo , Sinaptofisina/genética , Proteínas de Neurofilamentos/metabolismo , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo , Proteína Vesicular 1 de Transporte de Glutamato/genética , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/citologia , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética , Masculino , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Crescimento Neuronal/efeitos dos fármacos , Feminino , Proteína Vesicular 2 de Transporte de GlutamatoRESUMO
BACKGROUND: Inflammatory macrophage infiltration plays a critical role in acute kidney disease induced by ischemia-reperfusion (IRI-AKI). Calycosin is a natural flavone with multiple bioactivities. This study aimed to investigate the therapeutic role of calycosin in IRI-AKI and its underlying mechanism. METHODS: The renoprotective and anti-inflammatory effects of calycosin were analyzed in C57BL/6 mice with IRI-AKI and lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. RNA-seq was used for mechanism investigation. The molecular target of calycosin was screened by in silico methods and validated by surface plasmon resonance (SPR). Macrophage chemotaxis was analyzed using Transwell and agarose gel spot assays. RESULTS: Calycosin treatment significantly reduced serum creatinine and urea nitrogen and attenuated tubular destruction in IRI-AKI mice. Additionally, calycosin markedly suppressed NF-κB signaling activation and the expression of inflammatory mediators IL-1ß and TNF-α in IRI-AKI kidneys and LPS-stimulated RAW 264.7 cells. Interestingly, RNA-seq revealed calycosin remarkably downregulated chemotaxis-related pathways in RAW 264.7 cells. Among the differentially expressed genes, Ccl2/MCP-1, a critical chemokine mediating macrophage inflammatory chemotaxis, was downregulated in both LPS-stimulated RAW 264.7 cells and IRI-AKI kidneys. Consistently, calycosin treatment attenuated macrophage infiltration in the IRI-AKI kidneys. Importantly, in silico target prediction, molecular docking, and SPR assay demonstrated that calycosin directly binds to macrophage migration inhibitory factor (MIF). Functionally, calycosin abrogated MIF-stimulated NF-κB signaling activation and Ccl2 expression and MIF-mediated chemotaxis in RAW 264.7 cells. CONCLUSIONS: In summary, calycosin attenuates IRI-AKI by inhibiting MIF-mediated macrophage inflammatory chemotaxis, suggesting it could be a promising therapeutic agent for the treatment of IRI-AKI.
Assuntos
Injúria Renal Aguda , Quimiotaxia , Isoflavonas , Fatores Inibidores da Migração de Macrófagos , Macrófagos , Traumatismo por Reperfusão , Animais , Masculino , Camundongos , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Quimiotaxia/efeitos dos fármacos , Oxirredutases Intramoleculares/metabolismo , Oxirredutases Intramoleculares/genética , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Rim/efeitos dos fármacos , Rim/patologia , Lipopolissacarídeos , Macrófagos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Células RAW 264.7 , Traumatismo por Reperfusão/tratamento farmacológicoRESUMO
Prostate cancer is one of the serious health problems of older male, about 13% of male was affected by prostate cancer. Prostate cancer is highly heterogeneity disease with complex molecular and genetic alterations. So, targeting the gene candidates in prostate cancer in single-cell level can be a promising approach for treating prostate cancer. In the present study, we analyzed the single cell sequencing data obtained from 2 previous reports to determine the differential gene expression of prostate cancer in single-cell level. By using the network pharmacology analysis, we identified the therapeutic targets of formononetin in immune cells and tissue cells of prostate cancer. We then applied molecular docking to determine the possible direct binding of formononetin to its target proteins. Our result identified a cluster of differential gene expression in prostate cancer which can serve as novel biomarkers such as immunoglobulin kappa C for prostate cancer prognosis. The result of network pharmacology delineated the roles of formononetin's targets such CD74 and THBS1 in immune cells' function of prostate cancer. Also, formononetin targeted insulin receptor and zinc-alpha-2-glycoprotein which play important roles in metabolisms of tissue cells of prostate cancer. The result of molecular docking suggested the direct binding of formononetin to its target proteins including INSR, TNF, and CXCR4. Finally, we validated our findings by using formononetin-treated human prostate cancer cell DU145. For the first time, our result suggested the use of formononetin for treating prostate cancer through targeting different cell types in a single-cell level.
Assuntos
Isoflavonas , Simulação de Acoplamento Molecular , Neoplasias da Próstata , Análise de Célula Única , Masculino , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Humanos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacosRESUMO
Cardiovascular diseases (CVDs) are the leading causes of death globally that seriously threaten human health. Although novel western medicines have continued to be discovered over the past few decades to inhibit the progression of CVDs, new drug research and development for treating CVDs with less side effects and adverse reactions are continuously being desired. Puerarin is a natural product found in a variety of medicinal plants belonging to the flavonoid family with potent biological and pharmacological activities. Abundant research findings in the literature have suggested that puerarin possesses a promising prospect in treating CVDs. In recent years, numerous new molecular mechanisms of puerarin have been explored in experimental and clinical studies, providing new evidence for this plant metabolite to protect against CVDs. This article systematically introduces the history of use, bioavailability, and various dosage forms of puerarin and further summarizes recently published data on the major research advances and their underlying therapeutic mechanisms in treating CVDs. It may provide references for researchers in the fields of pharmacology, natural products, and internal medicine.