Background:The development and prognosis of breast cancer are intricately linked to psychological stress.In addition,depression is the most common psychological comorbidity among breast cancer survivors,and reportedly...Background:The development and prognosis of breast cancer are intricately linked to psychological stress.In addition,depression is the most common psychological comorbidity among breast cancer survivors,and reportedly,Fang-Xia-Dihuang decoction(FXDH)can effectively manage depression in such patients.However,its pharmacological and molecular mechanisms remain obscure.Methods:Public databases were used for obtaining active components and related targets.Main active components were further verified by ultra-high-performance liquid chromatography-high-resolution mass spectrometry(UPLC-HRMS).Protein–protein interaction and enrichment analyses were taken to predict potential hub targets and related pathways.Molecule docking was used to understand the interactions between main compounds and hub targets.In addition,an animal model of breast cancer combined with depression was established to evaluate the intervention effect of FXDH and verify the pathways screened by network pharmacology.Results:174 active components of FXDH and 163 intersection targets of FXDH,breast cancer,and depression were identified.Quercetin,methyl ferulate,luteolin,ferulaldehyde,wogonin,and diincarvilone were identified as the principal active components of FXDH.Protein–protein interaction and KEGG enrichment analyses revealed that the phosphoinositide-3-kinase–protein kinase B(PI3K/AKT)and Janus kinase/signal transducer and activator of transcription(JAK2/STAT3)signaling pathways played a crucial role in mediating the efficacy of FXDH for inhibiting breast cancer progression induced by depression.In addition,in vivo experiments revealed that FXDH ameliorated depression-like behavior in mice and inhibited excessive tumor growth in mice with breast cancer and depression.FXDH treatment downregulated the expression of epinephrine,PI3K,AKT,STAT3,and JAK2 compared with the control treatment(p<0.05).Molecular docking verified the relationship between the six primary components of FXDH and the three most important targets,including phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha(PIK3CA),AKT,and STAT3.Conclusion:This study provides a scientific basis to support the clinical application of FXDH for improving depression-like behavior and inhibiting breast cancer progression promoted by chronic stress.The therapeutic effects FXDH may be closely related to the PI3K/AKT and JAK2/STAT3 pathways.This finding helps better understand the regulatory mechanisms underlying the efficacy of FXDH.展开更多
Yu Gan Long(YGL)is a Chinese traditional herbal formula which has been reported to attenuate liver fibrosis for many years and we have explored its anti-fibrotic mechanism through blocking transforming growth factor(T...Yu Gan Long(YGL)is a Chinese traditional herbal formula which has been reported to attenuate liver fibrosis for many years and we have explored its anti-fibrotic mechanism through blocking transforming growth factor(TGF-β)in the previous study.But the mechanisms associated with platelet-derived growth factor(PDGF)-BB remain obscure.In this study,we further investigated the mechanism of YGL reducing carbon tetrachloride(CCl4)-induced liver fibrosis in rats.Our results showed that YGL suppressed CCl4-induced upregulation of collagen IV(Col IV),type HI precollagen(PCHI),hyaluronuc acid(HA)and laminin(LN),which are implicated in liver fibrosis.Also,YGL reduced theα-smooth muscle actin(α-SMA)expression,which acts as the indicator of liver fibrosis.Furthermore,YGL decreased the serum levels of hepatic stellate cell(HSC)mitogen PDGF-BB and inflammation cytokines,including TNF-α,IL-1β,IL-6.Markers involved in liver fibrosis,such as Ras,p-Raf-1,p-ERK1/2,p-JNK,p-P38,p-PI3K,p-AKT,p-JAKl,p-STAT3 were downregulated significantly after treatment with YGL.Our results indicated that YGL ameliorated CCl4-induced liver fibrosis by reducing inflammation cytokines production,and suppressing Ras/ERK,PI3K/AKT,and JAK1/STAT3 signaling pathways,which provided further evidence towards elucidation of the anti-fibrotic mechanism of YGL.展开更多
背景与目的:蛋白酪氨酸磷酸酶基因(phosphatase and tensin homolog deleted on chromosome ten,PTEN)与表皮生长因子受体(epidermal growth factor receptor,EGFR)信号途径的下游因子丝-苏氨酸激酶AKT、核因子-кB(nuclear factor-kapp...背景与目的:蛋白酪氨酸磷酸酶基因(phosphatase and tensin homolog deleted on chromosome ten,PTEN)与表皮生长因子受体(epidermal growth factor receptor,EGFR)信号途径的下游因子丝-苏氨酸激酶AKT、核因子-кB(nuclear factor-kappa B,NF-кB)以及信号转导子和转录激活子-3(signal transducer and activator of transcription-3,STAT3)与恶性肿瘤的发生、增殖与凋亡过程关系密切。本研究探讨AKT、NF-кB及STAT3在有淋巴结转移及雌激素受体阳性的乳腺癌组织中的活化情况及其与患者预后的关系。方法:免疫组化法检测130例雌激素受体阳性和有腋窝淋巴结转移的乳腺癌患者肿瘤组织中磷酸化AKT、NF-кB及STAT3的表达,以反映三者在肿瘤组织中的活化状态。同时检测这些组织中EGFR、PTEN、Ki67及HER-2的表达。结果:高活化状态的AKT(p-AKT)和NF-кB(p-NF-кB)与HER-2过度表达显著相关(分别P=0.023和P=0.017),并随着肿瘤组织学级别的升高表达显著增强(分别P=0.035和P=0.004)。而p-AKT、p-NF-кB和p-STAT3与肿瘤大小、EGFR的过度表达以及Ki67所反映的增殖状况无关,但p-AKT和p-NF-кB的表达呈显著正相关(r=0.43,P<0.001)而与PENT的表达呈显著负相关(r=-0.20,P=0.002)。单因素生存分析显示p-AKT和p-NF-кB在肿瘤组织中过度表达的患者生存期显著缩短(分别P=0.005和P=0.003),而且p-NF-кB表达增加也预示患者较高的复发或转移的可能性(P=0.006)。Cox分析发现,p-AKT和p-NF-кB的过度表达与患者总生存期(OS)(分别P=0.017和P=0.008)及患者无病生存期(DFS)(分别P=0.005和P=0.012)缩短显著相关,但p-STAT3的表达与OS和DFS无相关性(分别P=0.332和P=0.237)。结论:AKT和NF-кB在乳腺癌组织中的活化与肿瘤的发展显著相关,在有腋窝淋巴结转移及ER阳性的癌组织中p-AKT和p-NF-кB过度表达是乳腺癌患者预后不良的判断因子之一。展开更多
基金supported by the Xiamen High-Level Health Talents Introduction and Training Project(Xiaweidang 2021-124)the National Natural Science Foundation of China(No.81774319).
文摘Background:The development and prognosis of breast cancer are intricately linked to psychological stress.In addition,depression is the most common psychological comorbidity among breast cancer survivors,and reportedly,Fang-Xia-Dihuang decoction(FXDH)can effectively manage depression in such patients.However,its pharmacological and molecular mechanisms remain obscure.Methods:Public databases were used for obtaining active components and related targets.Main active components were further verified by ultra-high-performance liquid chromatography-high-resolution mass spectrometry(UPLC-HRMS).Protein–protein interaction and enrichment analyses were taken to predict potential hub targets and related pathways.Molecule docking was used to understand the interactions between main compounds and hub targets.In addition,an animal model of breast cancer combined with depression was established to evaluate the intervention effect of FXDH and verify the pathways screened by network pharmacology.Results:174 active components of FXDH and 163 intersection targets of FXDH,breast cancer,and depression were identified.Quercetin,methyl ferulate,luteolin,ferulaldehyde,wogonin,and diincarvilone were identified as the principal active components of FXDH.Protein–protein interaction and KEGG enrichment analyses revealed that the phosphoinositide-3-kinase–protein kinase B(PI3K/AKT)and Janus kinase/signal transducer and activator of transcription(JAK2/STAT3)signaling pathways played a crucial role in mediating the efficacy of FXDH for inhibiting breast cancer progression induced by depression.In addition,in vivo experiments revealed that FXDH ameliorated depression-like behavior in mice and inhibited excessive tumor growth in mice with breast cancer and depression.FXDH treatment downregulated the expression of epinephrine,PI3K,AKT,STAT3,and JAK2 compared with the control treatment(p<0.05).Molecular docking verified the relationship between the six primary components of FXDH and the three most important targets,including phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha(PIK3CA),AKT,and STAT3.Conclusion:This study provides a scientific basis to support the clinical application of FXDH for improving depression-like behavior and inhibiting breast cancer progression promoted by chronic stress.The therapeutic effects FXDH may be closely related to the PI3K/AKT and JAK2/STAT3 pathways.This finding helps better understand the regulatory mechanisms underlying the efficacy of FXDH.
基金This study was supported by grants from China Postdoctoral Science Foundation(No.2016M592320,No.2016M600670)Hubei Provincial Natural Science Foundation of China(No.2018CFB657)the National Natural Science Foundation of China(No.81601605).
文摘Yu Gan Long(YGL)is a Chinese traditional herbal formula which has been reported to attenuate liver fibrosis for many years and we have explored its anti-fibrotic mechanism through blocking transforming growth factor(TGF-β)in the previous study.But the mechanisms associated with platelet-derived growth factor(PDGF)-BB remain obscure.In this study,we further investigated the mechanism of YGL reducing carbon tetrachloride(CCl4)-induced liver fibrosis in rats.Our results showed that YGL suppressed CCl4-induced upregulation of collagen IV(Col IV),type HI precollagen(PCHI),hyaluronuc acid(HA)and laminin(LN),which are implicated in liver fibrosis.Also,YGL reduced theα-smooth muscle actin(α-SMA)expression,which acts as the indicator of liver fibrosis.Furthermore,YGL decreased the serum levels of hepatic stellate cell(HSC)mitogen PDGF-BB and inflammation cytokines,including TNF-α,IL-1β,IL-6.Markers involved in liver fibrosis,such as Ras,p-Raf-1,p-ERK1/2,p-JNK,p-P38,p-PI3K,p-AKT,p-JAKl,p-STAT3 were downregulated significantly after treatment with YGL.Our results indicated that YGL ameliorated CCl4-induced liver fibrosis by reducing inflammation cytokines production,and suppressing Ras/ERK,PI3K/AKT,and JAK1/STAT3 signaling pathways,which provided further evidence towards elucidation of the anti-fibrotic mechanism of YGL.
文摘背景与目的:蛋白酪氨酸磷酸酶基因(phosphatase and tensin homolog deleted on chromosome ten,PTEN)与表皮生长因子受体(epidermal growth factor receptor,EGFR)信号途径的下游因子丝-苏氨酸激酶AKT、核因子-кB(nuclear factor-kappa B,NF-кB)以及信号转导子和转录激活子-3(signal transducer and activator of transcription-3,STAT3)与恶性肿瘤的发生、增殖与凋亡过程关系密切。本研究探讨AKT、NF-кB及STAT3在有淋巴结转移及雌激素受体阳性的乳腺癌组织中的活化情况及其与患者预后的关系。方法:免疫组化法检测130例雌激素受体阳性和有腋窝淋巴结转移的乳腺癌患者肿瘤组织中磷酸化AKT、NF-кB及STAT3的表达,以反映三者在肿瘤组织中的活化状态。同时检测这些组织中EGFR、PTEN、Ki67及HER-2的表达。结果:高活化状态的AKT(p-AKT)和NF-кB(p-NF-кB)与HER-2过度表达显著相关(分别P=0.023和P=0.017),并随着肿瘤组织学级别的升高表达显著增强(分别P=0.035和P=0.004)。而p-AKT、p-NF-кB和p-STAT3与肿瘤大小、EGFR的过度表达以及Ki67所反映的增殖状况无关,但p-AKT和p-NF-кB的表达呈显著正相关(r=0.43,P<0.001)而与PENT的表达呈显著负相关(r=-0.20,P=0.002)。单因素生存分析显示p-AKT和p-NF-кB在肿瘤组织中过度表达的患者生存期显著缩短(分别P=0.005和P=0.003),而且p-NF-кB表达增加也预示患者较高的复发或转移的可能性(P=0.006)。Cox分析发现,p-AKT和p-NF-кB的过度表达与患者总生存期(OS)(分别P=0.017和P=0.008)及患者无病生存期(DFS)(分别P=0.005和P=0.012)缩短显著相关,但p-STAT3的表达与OS和DFS无相关性(分别P=0.332和P=0.237)。结论:AKT和NF-кB在乳腺癌组织中的活化与肿瘤的发展显著相关,在有腋窝淋巴结转移及ER阳性的癌组织中p-AKT和p-NF-кB过度表达是乳腺癌患者预后不良的判断因子之一。
