Objective To investigate whether 2,3,5,4'-tetrahydroxystilbene-2-O-β-glucoside(TSG)ameliorated polycystic ovary syndrome(PCOS)-like characteristics by inhibiting inflammation.Methods PCOS models were established ...Objective To investigate whether 2,3,5,4'-tetrahydroxystilbene-2-O-β-glucoside(TSG)ameliorated polycystic ovary syndrome(PCOS)-like characteristics by inhibiting inflammation.Methods PCOS models were established by injecting subcutaneously with dehydroepiandrosterone into female Sprague-Dawley rats,followed by receiving intraperitoneal injection of TSG.The granular cells(GCs)KGN were transfected with small interfering RNAs(si-NC and si-CYP19A1).The cells were preincubated with lipopolysaccharide(LPS)and then treated with or without TSG.The estrous cycle was monitored using vaginal exfoliated cells.The morphology of ovarian follicles was analyzed by H&E staining.ELISA was used to analyze estradiol(E2),testosterone(T),follicle stimulating hormone(FSH),luteinizing hormone(LH),IL-6,TNF-α,AGEs,CRP and Omentin-1 levels in serum.Immunohistochemistry was performed to analyze PCNA and CYP19A1 expressions in the GCs of ovaries.Tunel staining was executed to detect the apoptosis of GCs.Quantitative polymerase chain reaction(qPCR)and Western blot were implemented to measure the expression of CYP19A1 in the ovaries and transfected cells.qPCR was used to analyze the expression of IL-6 and TNF-αin the transfected cells treated with LPS and TSG.Results The estrous cycles were restored in TSG group.Compared with model group,the sinus follicles were reduced and corpus luteums were increased in TSG group.TSG group showed increased E2,and decreased T and LH,compared with model group.Pro-inflammatory factors(IL-6,TNF-α,CRP and AGEs)were decreased,and anti-inflammatory factor(Omentin-1)was increased in TSG group compared with those in model group.TSG could partially inhibit decrease of PNCA-positive GCs and increase of Tunel-positive GCs caused by PCOS.The CYP19A1 expression of GCs in TSG group was upregulated compared with model group.The expressions of IL-6 and TNFαin si-CYP19A1 cells were increased compared with si-NC cells.Compared with cells(si-NC and si-CYP19A1)treated without LPS,the expressions of IL-6 and TNF-αcells were increased,and the expression of CYP19A1 was downregulated in LPS-preincubated cells.Compared with cells treated with LPS,the expression of IL-6 and TNF-αwere decreased,and the expression of CYP19A1 was increased in cells treated with LPS and TSG.Compared with si-NC cells treated with LPS and TSG,the expressions of IL-6 and TNF-αcells were increased in the si-CYP19A1 cells treated with LPS and TSG.Conclusion TSG could alleviate PCOS-like characteristics by increasing the expression of CYP19A1 in GCs to inhibit inflammatory response.展开更多
Background:As a major histopathological subtype of gastric cancer(GC),stomach adenocarcinoma(STAD)is an important malignant tumor in the digestive system.Increasing evidence also indicates that endoplasmic reticulum(E...Background:As a major histopathological subtype of gastric cancer(GC),stomach adenocarcinoma(STAD)is an important malignant tumor in the digestive system.Increasing evidence also indicates that endoplasmic reticulum(ER)stress plays a pivotal role in the pathogenesis and progression of GC.Therefore,this study aims to screen and identify vital ER stress-related genes that could contribute to the malignant development and poor prognosis for STAD.Methods:A novel ER stress-related risk score signature was developed employingmachine learning techniques.Then,a prognostic prediction nomogram was also built based on the clinicopathological characteristics and the risk score signature.The tumor immune microenvironment characteristics and pathway enrichment analysis in different risk groups were also explored.Furthermore,through the single-cell RNA sequencing(scRNA-seq)analysis,the study highlightedCytochrome P450 Family 19 SubfamilyAMember 1(CYP19A1)as the pivotal research target and detected its effect on cell proliferation by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazoliumbromide(MTT)and the expression of ER stress-related genes by RT-qPCR in STAD.Results:Based on the evaluation of five screened key ER stressrelated genes(AKR1B1,SERPINE1,ADCYAP1,MATN3,CYP19A1),our ER stress-related risk score signature offers a novel approach for assessing STAD prognosis hazards.The novel prognostic prediction nomogram based on the signature also accurately predicted the survival outcomes of patients with STAD.Furthermore,the expression of CYP19A1 is significantly higher in STAD tissues than in normal tissues.High expression of CYP19A1 was related to a poor survival outcome for patients with STAD.Besides,compared to normal gastric epithelial cells,the expression of CYP19A1 was significantly higher in STAD cell lines.Silencing the expression of CYP19A1 significantly inhibited the cell proliferation ability and decreased the expression of ER stress-related genes,including ATF4,DDIT3 and XBP1 in STAD.Conclusions:In conclusion,our study developed a novel prognosis prediction signature and identified the novel diagnostic and therapeutic target CYP19A1 for patients with STAD.展开更多
消化道肿瘤是我国最常见的恶性肿瘤,发病率和死亡率均居高位,严重威胁人们的身体健康,亟需寻找有效的诊断方法和治疗靶点。CYP19A1属于细胞色素P450家族的成员,定位于内质网,是将雄激素构化为雌激素的关键限速酶,在不同组织中发挥不同...消化道肿瘤是我国最常见的恶性肿瘤,发病率和死亡率均居高位,严重威胁人们的身体健康,亟需寻找有效的诊断方法和治疗靶点。CYP19A1属于细胞色素P450家族的成员,定位于内质网,是将雄激素构化为雌激素的关键限速酶,在不同组织中发挥不同的作用以维持重要的组织特异性功能。近年来的研究发现,CYP19A1在胃癌、结直肠癌等恶性消化道肿瘤中异常表达并促进肿瘤的进展。然而,CYP19A1在消化道肿瘤中的具体调控机制尚不明确。因此,本文对近年相关研究进行综述,以表明CYP19A1在消化道肿瘤生长过程中存在潜在的研究价值,对于靶向CYP19A1诠释消化道肿瘤的生长机制、预后预测以及靶向治疗等方面具有重要意义。Gastrointestinal tumors are the most prevalent malignant tumors in China, featuring high morbidity and mortality rates, seriously threatening people’s physical health. There is an urgent need to discover effective diagnostic approaches and therapeutic targets. Aromatase (CYP19A1), a member of the cytochrome P450 family, is located in the endoplasmic reticulum and serves as the key rate-limiting enzyme that converts androgens into estrogens, exerting diverse functions in different tissues to maintain crucial tissue-specific functions. Recent studies have revealed that CYP19A1 is aberrantly expressed in malignant gastrointestinal tumors such as gastric cancer and colorectal cancer and promotes tumor progression. Nevertheless, the specific mechanism underlying CYP19A1 in gastrointestinal tumors remains unclear. Thus, this article conducts a review of the relevant research in recent years to indicate the potential research value of CYP19A1 in the growth process of gastrointestinal tumors, which is of significant importance for interpreting the growth mechanism, prognosis prediction, and targeted therapy of gastrointestinal tumors by targeting CYP19A1.展开更多
Myocardial fibrosis is a major pathogenic factor contributing to cardiac remodeling and heart failure. Recent research has indicated that micro RNAs play a crucial role in the progression of cardiac fibrosis. Bone mor...Myocardial fibrosis is a major pathogenic factor contributing to cardiac remodeling and heart failure. Recent research has indicated that micro RNAs play a crucial role in the progression of cardiac fibrosis. Bone morphogenetic protein and activin membrane-bound inhibitor(BAMBI) have been shown to alleviate myocardial fibrosis by inhibiting the transforming growth factor β1(TGF-β1) signaling pathway. Therefore, the current study aimed to elucidate the post-transcriptional regulation of BAMBI by miR-19a-3p and its role in TGF-β1-induced cardiac fibroblast activation. We found that transverse aortic constriction induced both myocardial interstitial and perivascular collagen deposition. Quantitative reverse transcription-PCR(q RT-PCR) analysis showed that the expression level of miR-19a-3p was increased in the myocardial tissues of cardiac fibrosis, and TGF-β1 induced an upregulation in miR-19a-3p expression in cardiac fibroblasts. The dual-luciferase reporter assay and q RT-PCR verified that miR-19a-3p directly bound to the 3 ′ untranslated regions of BAMBI m RNA, thereby reducing BAMBI expression and diminishing its ability to inhibit the TGF-β1 signaling pathway. Furthermore,overexpression of miR-19a-3p mimic increased the activation of TGF-β1/SMAD2/3 pathway signaling,promoting cardiac fibroblast activation. However, this activation was blocked by BAMBI overexpression. These findings imply that miR-19a-3p enhances the activation of TGF-β1/SMAD2/3 by inhibiting BAMBI, further boosting the activation of cardiac fibroblasts and contributing to myocardial fibrosis.展开更多
目的系统性探究传统中草药钩吻(Gelsemium elegans)的主要活性成分钩吻素子(KM)在胃癌的作用机制和抗肿瘤功效。方法综合运用靶点预测、癌症基因组图谱(TCGA)数据生物信息学分析及分子对接等计算机模拟方法,筛选KM的潜在靶点并构建胃癌...目的系统性探究传统中草药钩吻(Gelsemium elegans)的主要活性成分钩吻素子(KM)在胃癌的作用机制和抗肿瘤功效。方法综合运用靶点预测、癌症基因组图谱(TCGA)数据生物信息学分析及分子对接等计算机模拟方法,筛选KM的潜在靶点并构建胃癌预后风险模型。通过体外细胞功能实验,在胃癌细胞系(MKN28和AGS)中进行活力、增殖和凋亡评估,以验证KM的抗肿瘤效果。利用表面等离子共振(SPR)、qRT-PCR和Western-blot分析,深入探究其与关键靶点CYP 19 A 1相互作用和调控的分子机制。结果生物信息学分析和预后模型鉴定出CYP 19 A 1是胃癌中与不良预后相关的关键潜在靶点和高风险因子。体外实验表明,KM能显著抑制胃癌细胞MKN28和AGS的增殖和活力,并诱导其凋亡,即使在CYP 19 A 1过表达的情况下,这些效应依然存在。机制上,研究证实KM能直接与CYP19A1蛋白结合,并在转录后水平下调其蛋白表达。结论本研究为KM抗胃癌的治疗潜力提供依据,CYP 19 A 1可能是KM发挥抗胃癌作用的关键靶点。展开更多
文摘Objective To investigate whether 2,3,5,4'-tetrahydroxystilbene-2-O-β-glucoside(TSG)ameliorated polycystic ovary syndrome(PCOS)-like characteristics by inhibiting inflammation.Methods PCOS models were established by injecting subcutaneously with dehydroepiandrosterone into female Sprague-Dawley rats,followed by receiving intraperitoneal injection of TSG.The granular cells(GCs)KGN were transfected with small interfering RNAs(si-NC and si-CYP19A1).The cells were preincubated with lipopolysaccharide(LPS)and then treated with or without TSG.The estrous cycle was monitored using vaginal exfoliated cells.The morphology of ovarian follicles was analyzed by H&E staining.ELISA was used to analyze estradiol(E2),testosterone(T),follicle stimulating hormone(FSH),luteinizing hormone(LH),IL-6,TNF-α,AGEs,CRP and Omentin-1 levels in serum.Immunohistochemistry was performed to analyze PCNA and CYP19A1 expressions in the GCs of ovaries.Tunel staining was executed to detect the apoptosis of GCs.Quantitative polymerase chain reaction(qPCR)and Western blot were implemented to measure the expression of CYP19A1 in the ovaries and transfected cells.qPCR was used to analyze the expression of IL-6 and TNF-αin the transfected cells treated with LPS and TSG.Results The estrous cycles were restored in TSG group.Compared with model group,the sinus follicles were reduced and corpus luteums were increased in TSG group.TSG group showed increased E2,and decreased T and LH,compared with model group.Pro-inflammatory factors(IL-6,TNF-α,CRP and AGEs)were decreased,and anti-inflammatory factor(Omentin-1)was increased in TSG group compared with those in model group.TSG could partially inhibit decrease of PNCA-positive GCs and increase of Tunel-positive GCs caused by PCOS.The CYP19A1 expression of GCs in TSG group was upregulated compared with model group.The expressions of IL-6 and TNFαin si-CYP19A1 cells were increased compared with si-NC cells.Compared with cells(si-NC and si-CYP19A1)treated without LPS,the expressions of IL-6 and TNF-αcells were increased,and the expression of CYP19A1 was downregulated in LPS-preincubated cells.Compared with cells treated with LPS,the expression of IL-6 and TNF-αwere decreased,and the expression of CYP19A1 was increased in cells treated with LPS and TSG.Compared with si-NC cells treated with LPS and TSG,the expressions of IL-6 and TNF-αcells were increased in the si-CYP19A1 cells treated with LPS and TSG.Conclusion TSG could alleviate PCOS-like characteristics by increasing the expression of CYP19A1 in GCs to inhibit inflammatory response.
基金Natural Science Foundation of Liaoning Province(2022-MS-083)Application Basic Research Plan of Liaoning Province(2023JH2/101300084).
文摘Background:As a major histopathological subtype of gastric cancer(GC),stomach adenocarcinoma(STAD)is an important malignant tumor in the digestive system.Increasing evidence also indicates that endoplasmic reticulum(ER)stress plays a pivotal role in the pathogenesis and progression of GC.Therefore,this study aims to screen and identify vital ER stress-related genes that could contribute to the malignant development and poor prognosis for STAD.Methods:A novel ER stress-related risk score signature was developed employingmachine learning techniques.Then,a prognostic prediction nomogram was also built based on the clinicopathological characteristics and the risk score signature.The tumor immune microenvironment characteristics and pathway enrichment analysis in different risk groups were also explored.Furthermore,through the single-cell RNA sequencing(scRNA-seq)analysis,the study highlightedCytochrome P450 Family 19 SubfamilyAMember 1(CYP19A1)as the pivotal research target and detected its effect on cell proliferation by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazoliumbromide(MTT)and the expression of ER stress-related genes by RT-qPCR in STAD.Results:Based on the evaluation of five screened key ER stressrelated genes(AKR1B1,SERPINE1,ADCYAP1,MATN3,CYP19A1),our ER stress-related risk score signature offers a novel approach for assessing STAD prognosis hazards.The novel prognostic prediction nomogram based on the signature also accurately predicted the survival outcomes of patients with STAD.Furthermore,the expression of CYP19A1 is significantly higher in STAD tissues than in normal tissues.High expression of CYP19A1 was related to a poor survival outcome for patients with STAD.Besides,compared to normal gastric epithelial cells,the expression of CYP19A1 was significantly higher in STAD cell lines.Silencing the expression of CYP19A1 significantly inhibited the cell proliferation ability and decreased the expression of ER stress-related genes,including ATF4,DDIT3 and XBP1 in STAD.Conclusions:In conclusion,our study developed a novel prognosis prediction signature and identified the novel diagnostic and therapeutic target CYP19A1 for patients with STAD.
文摘消化道肿瘤是我国最常见的恶性肿瘤,发病率和死亡率均居高位,严重威胁人们的身体健康,亟需寻找有效的诊断方法和治疗靶点。CYP19A1属于细胞色素P450家族的成员,定位于内质网,是将雄激素构化为雌激素的关键限速酶,在不同组织中发挥不同的作用以维持重要的组织特异性功能。近年来的研究发现,CYP19A1在胃癌、结直肠癌等恶性消化道肿瘤中异常表达并促进肿瘤的进展。然而,CYP19A1在消化道肿瘤中的具体调控机制尚不明确。因此,本文对近年相关研究进行综述,以表明CYP19A1在消化道肿瘤生长过程中存在潜在的研究价值,对于靶向CYP19A1诠释消化道肿瘤的生长机制、预后预测以及靶向治疗等方面具有重要意义。Gastrointestinal tumors are the most prevalent malignant tumors in China, featuring high morbidity and mortality rates, seriously threatening people’s physical health. There is an urgent need to discover effective diagnostic approaches and therapeutic targets. Aromatase (CYP19A1), a member of the cytochrome P450 family, is located in the endoplasmic reticulum and serves as the key rate-limiting enzyme that converts androgens into estrogens, exerting diverse functions in different tissues to maintain crucial tissue-specific functions. Recent studies have revealed that CYP19A1 is aberrantly expressed in malignant gastrointestinal tumors such as gastric cancer and colorectal cancer and promotes tumor progression. Nevertheless, the specific mechanism underlying CYP19A1 in gastrointestinal tumors remains unclear. Thus, this article conducts a review of the relevant research in recent years to indicate the potential research value of CYP19A1 in the growth process of gastrointestinal tumors, which is of significant importance for interpreting the growth mechanism, prognosis prediction, and targeted therapy of gastrointestinal tumors by targeting CYP19A1.
基金National Natural Science Foundation of China (Grant Nos. 82070234 and 82100254)。
文摘Myocardial fibrosis is a major pathogenic factor contributing to cardiac remodeling and heart failure. Recent research has indicated that micro RNAs play a crucial role in the progression of cardiac fibrosis. Bone morphogenetic protein and activin membrane-bound inhibitor(BAMBI) have been shown to alleviate myocardial fibrosis by inhibiting the transforming growth factor β1(TGF-β1) signaling pathway. Therefore, the current study aimed to elucidate the post-transcriptional regulation of BAMBI by miR-19a-3p and its role in TGF-β1-induced cardiac fibroblast activation. We found that transverse aortic constriction induced both myocardial interstitial and perivascular collagen deposition. Quantitative reverse transcription-PCR(q RT-PCR) analysis showed that the expression level of miR-19a-3p was increased in the myocardial tissues of cardiac fibrosis, and TGF-β1 induced an upregulation in miR-19a-3p expression in cardiac fibroblasts. The dual-luciferase reporter assay and q RT-PCR verified that miR-19a-3p directly bound to the 3 ′ untranslated regions of BAMBI m RNA, thereby reducing BAMBI expression and diminishing its ability to inhibit the TGF-β1 signaling pathway. Furthermore,overexpression of miR-19a-3p mimic increased the activation of TGF-β1/SMAD2/3 pathway signaling,promoting cardiac fibroblast activation. However, this activation was blocked by BAMBI overexpression. These findings imply that miR-19a-3p enhances the activation of TGF-β1/SMAD2/3 by inhibiting BAMBI, further boosting the activation of cardiac fibroblasts and contributing to myocardial fibrosis.
文摘目的系统性探究传统中草药钩吻(Gelsemium elegans)的主要活性成分钩吻素子(KM)在胃癌的作用机制和抗肿瘤功效。方法综合运用靶点预测、癌症基因组图谱(TCGA)数据生物信息学分析及分子对接等计算机模拟方法,筛选KM的潜在靶点并构建胃癌预后风险模型。通过体外细胞功能实验,在胃癌细胞系(MKN28和AGS)中进行活力、增殖和凋亡评估,以验证KM的抗肿瘤效果。利用表面等离子共振(SPR)、qRT-PCR和Western-blot分析,深入探究其与关键靶点CYP 19 A 1相互作用和调控的分子机制。结果生物信息学分析和预后模型鉴定出CYP 19 A 1是胃癌中与不良预后相关的关键潜在靶点和高风险因子。体外实验表明,KM能显著抑制胃癌细胞MKN28和AGS的增殖和活力,并诱导其凋亡,即使在CYP 19 A 1过表达的情况下,这些效应依然存在。机制上,研究证实KM能直接与CYP19A1蛋白结合,并在转录后水平下调其蛋白表达。结论本研究为KM抗胃癌的治疗潜力提供依据,CYP 19 A 1可能是KM发挥抗胃癌作用的关键靶点。
