Preliminary studies on emerging herbal ingredients have highlighted alternative pathways that inflammation and modulate perturbed immunity as valuable strategies for treating depression.Previous studies have shown tha...Preliminary studies on emerging herbal ingredients have highlighted alternative pathways that inflammation and modulate perturbed immunity as valuable strategies for treating depression.Previous studies have shown that 5-O-methylvisammioside,a bioactive compound derived from Saposhnikoviae Radix,possesses excellent anti-inflammatory and antioxidant biological functions,exhibits a neuroprotective effect.The purpose of this study was to explore the targets and signaling pathways of 5-O-methylvisammioside in the potential treatment of major depressive disorder using a combination of network pharmacology analysis and biological experiments.The network pharmacological analysis results indicated that the proto-oncogene tyrosine-protein kinase Src and the nuclear factor kappa B signaling pathway were highly correlated with the treatment of major depressive disorder with 5-O-methylvisammioside.Further experiments indicated that 5-O-methylvisammioside significantly improved lipopolysaccharide-induced depression-like behaviors in mice,ameliorated microglial polarization in the hippocampal CA1 and CA3 regions,and inhibited Src phosphorylation and nuclear factor kappa B pathway activation.The effects of 5-O-methylvisammioside were similar to those of the Src inhibitor PP2.When 5-O-methylvisammioside was administered with PP2,no effects were observed on lipopolysaccharide-induced depression-like behaviors in mice,nuclear factor kappa B pathway proteins,and microglial polarization.These findings indicate that 5-O-methylvisammioside may exert its antidepressant potential by inhibiting Src-mediated activation of the nuclear factor kappa B signaling pathway.Therefore,5-O-methylvisammioside might serve as a promising Chinese herbal medicine for the prevention and treatment of depression.展开更多
微管类药物在转移、耐药的癌症治疗中发挥重要的作用。然而,临床上出现微管类药物耐药现象,需要研究者研发具有新作用模式、新机制的分子来克服耐药问题。多靶点药物分子策略是近年来针对复杂性疾病及耐药问题发展起来的一种药物分子设...微管类药物在转移、耐药的癌症治疗中发挥重要的作用。然而,临床上出现微管类药物耐药现象,需要研究者研发具有新作用模式、新机制的分子来克服耐药问题。多靶点药物分子策略是近年来针对复杂性疾病及耐药问题发展起来的一种药物分子设计策略。本文在替巴尼布林基础上,结合课题组前期研究,开展微管蛋白(tubulin)及原癌基因酪氨酸蛋白激酶Src(proto-oncogene tyrosine protein kinase Src,c-Src)双靶点抑制剂研究。从增加饱和碳原子比率(fraction of sp^(3)-hybridized carbon atoms,Fsp^(3))角度出发,合成16个目标化合物,并通过核磁共振氢谱、碳谱和质谱对其结构进行表征;采用噻唑蓝(MTT)法评价了化合物对宫颈癌细胞(HeLa)和肝癌细胞(HepG2)两种细胞株的生长抑制活性,并通过免疫荧光和流式细胞术评价化合物22对微管和细胞周期的影响。结果显示2-咪唑啉酮不适合替代替巴尼布林中的吡啶结构,化合物22对HeLa和HepG2的半数生长抑制浓度分别为45和51 nmol·L^(-1),并且能够破坏微管结构,将细胞周期阻滞于G2/M期。化合物22可作为先导物开展进一步深入研究。展开更多
Pancreatic adenocarcinoma(PAAD)is notorious for its limited treatment options and dismal prognosis,un-derscoring an urgent need for innovative therapeutic strategies.This study leverages advanced bioinformatics and a ...Pancreatic adenocarcinoma(PAAD)is notorious for its limited treatment options and dismal prognosis,un-derscoring an urgent need for innovative therapeutic strategies.This study leverages advanced bioinformatics and a novel ChatGPT-4o evaluation framework to identify and validate SRC kinase as a significant drug target for PAAD.Initial bioinformatics screening illustrated SRC’s critical involvement in essential signaling pathways associated with the disease.Subsequently,the ChatGPT-4o framework provided an unbiased,efficient evalua-tion,emphasizing SRC’s role in disease mechanisms.Our findings reveal substantial overexpression of SRC in PAAD compared to normal pancreatic tissue,with expression levels escalating in line with tumor grade and stage.Protein expression analysis using the Human Protein Atlas dataset showed a statistically significant dif-ference between PAAD samples and normal samples for SRC(P<1×10^(-15)).Survival analysis using the Kaplan-Meier Plotter dataset further demonstrates a strong association between high SRC expression and reduced survival,with hazard ratios of 1.45(P<7.69×10^(-3))for overall survival and 2.15(P<9.19×10^(-5))for disease free survival in advanced disease stages.SRC's involvement in key oncogenic pathways suggests its potential as part of combination therapies,enhancing the efficacy of existing treatments by targeting complementary me-chanisms.This study shows the therapeutic relevance of SRC and demonstrates the effectiveness of combining innovative AI technologies with traditional bioinformatics to accelerate the discovery and validation of critical drug targets in oncology.展开更多
基金supported by a grant from Department of Science and Technology of Jilin Province,No.20230204039YY(to RC)the Construction Project for Antidepressant Screening Engineering Laboratory of Jilin Province,No.2023C010(to BL).
文摘Preliminary studies on emerging herbal ingredients have highlighted alternative pathways that inflammation and modulate perturbed immunity as valuable strategies for treating depression.Previous studies have shown that 5-O-methylvisammioside,a bioactive compound derived from Saposhnikoviae Radix,possesses excellent anti-inflammatory and antioxidant biological functions,exhibits a neuroprotective effect.The purpose of this study was to explore the targets and signaling pathways of 5-O-methylvisammioside in the potential treatment of major depressive disorder using a combination of network pharmacology analysis and biological experiments.The network pharmacological analysis results indicated that the proto-oncogene tyrosine-protein kinase Src and the nuclear factor kappa B signaling pathway were highly correlated with the treatment of major depressive disorder with 5-O-methylvisammioside.Further experiments indicated that 5-O-methylvisammioside significantly improved lipopolysaccharide-induced depression-like behaviors in mice,ameliorated microglial polarization in the hippocampal CA1 and CA3 regions,and inhibited Src phosphorylation and nuclear factor kappa B pathway activation.The effects of 5-O-methylvisammioside were similar to those of the Src inhibitor PP2.When 5-O-methylvisammioside was administered with PP2,no effects were observed on lipopolysaccharide-induced depression-like behaviors in mice,nuclear factor kappa B pathway proteins,and microglial polarization.These findings indicate that 5-O-methylvisammioside may exert its antidepressant potential by inhibiting Src-mediated activation of the nuclear factor kappa B signaling pathway.Therefore,5-O-methylvisammioside might serve as a promising Chinese herbal medicine for the prevention and treatment of depression.
文摘微管类药物在转移、耐药的癌症治疗中发挥重要的作用。然而,临床上出现微管类药物耐药现象,需要研究者研发具有新作用模式、新机制的分子来克服耐药问题。多靶点药物分子策略是近年来针对复杂性疾病及耐药问题发展起来的一种药物分子设计策略。本文在替巴尼布林基础上,结合课题组前期研究,开展微管蛋白(tubulin)及原癌基因酪氨酸蛋白激酶Src(proto-oncogene tyrosine protein kinase Src,c-Src)双靶点抑制剂研究。从增加饱和碳原子比率(fraction of sp^(3)-hybridized carbon atoms,Fsp^(3))角度出发,合成16个目标化合物,并通过核磁共振氢谱、碳谱和质谱对其结构进行表征;采用噻唑蓝(MTT)法评价了化合物对宫颈癌细胞(HeLa)和肝癌细胞(HepG2)两种细胞株的生长抑制活性,并通过免疫荧光和流式细胞术评价化合物22对微管和细胞周期的影响。结果显示2-咪唑啉酮不适合替代替巴尼布林中的吡啶结构,化合物22对HeLa和HepG2的半数生长抑制浓度分别为45和51 nmol·L^(-1),并且能够破坏微管结构,将细胞周期阻滞于G2/M期。化合物22可作为先导物开展进一步深入研究。
基金supported by the National Institute of Health Center grant awards(U54TR001005)to Dr.Jake Y.Chen,in which he serves as a co-investigator,a research start-up fund provided by the University of Alabama at Birmingham(UAB)to Dr.Chen and the UAB Systems Pharmacology AI Research Center grant to Dr.Chen.
文摘Pancreatic adenocarcinoma(PAAD)is notorious for its limited treatment options and dismal prognosis,un-derscoring an urgent need for innovative therapeutic strategies.This study leverages advanced bioinformatics and a novel ChatGPT-4o evaluation framework to identify and validate SRC kinase as a significant drug target for PAAD.Initial bioinformatics screening illustrated SRC’s critical involvement in essential signaling pathways associated with the disease.Subsequently,the ChatGPT-4o framework provided an unbiased,efficient evalua-tion,emphasizing SRC’s role in disease mechanisms.Our findings reveal substantial overexpression of SRC in PAAD compared to normal pancreatic tissue,with expression levels escalating in line with tumor grade and stage.Protein expression analysis using the Human Protein Atlas dataset showed a statistically significant dif-ference between PAAD samples and normal samples for SRC(P<1×10^(-15)).Survival analysis using the Kaplan-Meier Plotter dataset further demonstrates a strong association between high SRC expression and reduced survival,with hazard ratios of 1.45(P<7.69×10^(-3))for overall survival and 2.15(P<9.19×10^(-5))for disease free survival in advanced disease stages.SRC's involvement in key oncogenic pathways suggests its potential as part of combination therapies,enhancing the efficacy of existing treatments by targeting complementary me-chanisms.This study shows the therapeutic relevance of SRC and demonstrates the effectiveness of combining innovative AI technologies with traditional bioinformatics to accelerate the discovery and validation of critical drug targets in oncology.
