Pub Date : 2025-01-01Epub Date: 2024-03-12DOI: 10.1007/s11010-023-04908-8
Yueping Wang, Xuedong Wang, Haiyi Sun, Ziyun Zhang, Juan Gu
Triple-negative breast cancer (TNBC) is the most lethal subtype of BC, with unfavorable treatment outcomes. Evidence suggests the engagement of lncRNA MCM3AP-AS1 in BC development. This study investigated the action of MCM3AP-AS1 in chemoresistance of TNBC cells. Drug-resistant TNBC cell lines SUM159PTR and MDA-MB-231R were constructed by exposure to increasing concentrations of doxorubicin/docetaxel (DOX/DXL). MCM3AP-AS1 and miR-524-5p expression levels were determined by RT-qPCR. RNA binding motif 39 (RBM39) level was measured using Western blot. Cell viability and apoptosis were assessed by CCK-8 assay and flow cytometry. The targeted binding of miR-524-5p with MCM3AP-AS1 or RBM39 was predicted by ECORI database and validated by dual-luciferase assays. The gain-and-loss of function assays were conducted in cells to investigate the interactions among MCM3AP-AS1, miR-524-5p, and RBM39. TNBC xenograft mouse models were established through subcutaneous injection of MCM3AP-AS1-silencing MDA-MB-231R cells and intraperitoneally administrated with DOX/DXL to verify the role of MCM3AP-AS1 in vivo. MCM3AP-AS1 was upregulated in drug-resistant TNBC cells, and MCM3AP-AS1 silencing could sensitize drug-resistant TNBC cells to chemotherapeutic drugs by promoting apoptosis. MCM3AP-AS1 targeted miR-524-5p. After DOX/DXL treatment, miR-524-5p inhibition partially reversed the effect of MCM3AP-AS1 silencing on inhibiting chemoresistance and promoting apoptosis of drug-resistant TNBC cells. miR-524-5p targeted RBM39. Silencing MCM3AP-AS1 promoted apoptosis via the miR-524-5p/RBM39 axis, thereby enhancing chemosensitivity of drug-resistant TNBC cells. MCM3AP-AS1 knockdown upregulated miR-524-5p, downregulated RBM39, and restrained tumor development in vivo. MCM3AP-AS1 silencing potentiates apoptosis of drug-resistant TNBC cells by upregulating miR-524-5p and downregulating RBM39, thereby suppressing chemoresistance in TNBC.
{"title":"LncRNA MCM3AP-AS1 promotes chemoresistance in triple-negative breast cancer through the miR-524-5p/RBM39 axis.","authors":"Yueping Wang, Xuedong Wang, Haiyi Sun, Ziyun Zhang, Juan Gu","doi":"10.1007/s11010-023-04908-8","DOIUrl":"10.1007/s11010-023-04908-8","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is the most lethal subtype of BC, with unfavorable treatment outcomes. Evidence suggests the engagement of lncRNA MCM3AP-AS1 in BC development. This study investigated the action of MCM3AP-AS1 in chemoresistance of TNBC cells. Drug-resistant TNBC cell lines SUM159PT<sup>R</sup> and MDA-MB-231<sup>R</sup> were constructed by exposure to increasing concentrations of doxorubicin/docetaxel (DOX/DXL). MCM3AP-AS1 and miR-524-5p expression levels were determined by RT-qPCR. RNA binding motif 39 (RBM39) level was measured using Western blot. Cell viability and apoptosis were assessed by CCK-8 assay and flow cytometry. The targeted binding of miR-524-5p with MCM3AP-AS1 or RBM39 was predicted by ECORI database and validated by dual-luciferase assays. The gain-and-loss of function assays were conducted in cells to investigate the interactions among MCM3AP-AS1, miR-524-5p, and RBM39. TNBC xenograft mouse models were established through subcutaneous injection of MCM3AP-AS1-silencing MDA-MB-231<sup>R</sup> cells and intraperitoneally administrated with DOX/DXL to verify the role of MCM3AP-AS1 in vivo. MCM3AP-AS1 was upregulated in drug-resistant TNBC cells, and MCM3AP-AS1 silencing could sensitize drug-resistant TNBC cells to chemotherapeutic drugs by promoting apoptosis. MCM3AP-AS1 targeted miR-524-5p. After DOX/DXL treatment, miR-524-5p inhibition partially reversed the effect of MCM3AP-AS1 silencing on inhibiting chemoresistance and promoting apoptosis of drug-resistant TNBC cells. miR-524-5p targeted RBM39. Silencing MCM3AP-AS1 promoted apoptosis via the miR-524-5p/RBM39 axis, thereby enhancing chemosensitivity of drug-resistant TNBC cells. MCM3AP-AS1 knockdown upregulated miR-524-5p, downregulated RBM39, and restrained tumor development in vivo. MCM3AP-AS1 silencing potentiates apoptosis of drug-resistant TNBC cells by upregulating miR-524-5p and downregulating RBM39, thereby suppressing chemoresistance in TNBC.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":"371-384"},"PeriodicalIF":3.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140110641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-03-20DOI: 10.1007/s11010-024-04989-z
Huawei Xiao, Lei Liu, Shaoyan Huang
Understanding the mechanisms underlying doxorubicin resistance in triple-negative breast cancer (TNBC) holds paramount clinical significance. In our study, we investigate the potential of STK32C, a little-explored kinase, to impact doxorubicin sensitivity in TNBC cells. Our findings reveal elevated STK32C expression in TNBC specimens, associated with unfavorable prognosis in doxorubicin-treated TNBC patients. Subsequent experiments highlighted that STK32C depletion significantly augmented the sensitivity of doxorubicin-resistant TNBC cells to doxorubicin. Mechanistically, we unveiled that the cytoplasmic subset of STK32C plays a pivotal role in mediating doxorubicin sensitivity, primarily through the regulation of glycolysis. Furthermore, the kinase activity of STK32C proved to be essential for its mediation of doxorubicin sensitivity, emphasizing its role as a kinase. Our study suggests that targeting STK32C may represent a novel therapeutic approach with the potential to improve doxorubicin's efficacy in TNBC treatment.
{"title":"STK32C modulates doxorubicin resistance in triple-negative breast cancer cells via glycolysis regulation.","authors":"Huawei Xiao, Lei Liu, Shaoyan Huang","doi":"10.1007/s11010-024-04989-z","DOIUrl":"10.1007/s11010-024-04989-z","url":null,"abstract":"<p><p>Understanding the mechanisms underlying doxorubicin resistance in triple-negative breast cancer (TNBC) holds paramount clinical significance. In our study, we investigate the potential of STK32C, a little-explored kinase, to impact doxorubicin sensitivity in TNBC cells. Our findings reveal elevated STK32C expression in TNBC specimens, associated with unfavorable prognosis in doxorubicin-treated TNBC patients. Subsequent experiments highlighted that STK32C depletion significantly augmented the sensitivity of doxorubicin-resistant TNBC cells to doxorubicin. Mechanistically, we unveiled that the cytoplasmic subset of STK32C plays a pivotal role in mediating doxorubicin sensitivity, primarily through the regulation of glycolysis. Furthermore, the kinase activity of STK32C proved to be essential for its mediation of doxorubicin sensitivity, emphasizing its role as a kinase. Our study suggests that targeting STK32C may represent a novel therapeutic approach with the potential to improve doxorubicin's efficacy in TNBC treatment.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":"459-471"},"PeriodicalIF":3.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140175557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2024-03-29DOI: 10.1007/s11010-024-04977-3
Huiyuan Gong, Xiaomin Yang, Lijun An, Wangming Zhang, Xiaohua Liu, Liping Shu, Liuqi Yang
Proprotein convertase subtilisin/kexin type 5 (PCSK5) is a member of the proprotein convertase (PC) family, which processes immature proteins into functional proteins and plays an important role in the process of cell migration and transformation. Andrographolide is a non-peptide compound with PC inhibition and antitumor activity. Our research aimed to investigate the functional role of PCSK5 downregulation combined with Andro on GBM progression. Results from the cancer genome atlas (TCGA) and clinical samples revealed a significant upregulation of PCSK5 in GBM tissues than in non-tumor brain tissues. Higher expression of PCSK5 was correlated with advanced GBM stages and worse patient prognosis. PCSK5 knockdown attenuated the epithelial-mesenchymal transition (EMT)-like properties of GBM cells induced by IL-6. PCSK5 knockdown in combination with Andro treatment significantly inhibited the proliferation and invasion of GBM cells in vitro, as well as tumor growth in vivo. Mechanistically, PCSK5 downregulation reduced the expression of p-STAT3 and Matrix metalloproteinases (MMPs), which could be rescued by the p-STAT3 agonist. STAT3 silencing downregulated the expression of MMPs without affecting PCSK5. Furthermore, Andro in combination with PCSK5 silencing significantly inhibited STAT3/MMPs axis. These observations provided evidence that PCSK5 functioned as a potential tumor promoter by regulating p-STAT3/MMPs and the combination of Andro with PCSK5 silencing might be a good strategy to prevent GBM progression.
{"title":"PCSK5 downregulation promotes the inhibitory effect of andrographolide on glioblastoma through regulating STAT3.","authors":"Huiyuan Gong, Xiaomin Yang, Lijun An, Wangming Zhang, Xiaohua Liu, Liping Shu, Liuqi Yang","doi":"10.1007/s11010-024-04977-3","DOIUrl":"10.1007/s11010-024-04977-3","url":null,"abstract":"<p><p>Proprotein convertase subtilisin/kexin type 5 (PCSK5) is a member of the proprotein convertase (PC) family, which processes immature proteins into functional proteins and plays an important role in the process of cell migration and transformation. Andrographolide is a non-peptide compound with PC inhibition and antitumor activity. Our research aimed to investigate the functional role of PCSK5 downregulation combined with Andro on GBM progression. Results from the cancer genome atlas (TCGA) and clinical samples revealed a significant upregulation of PCSK5 in GBM tissues than in non-tumor brain tissues. Higher expression of PCSK5 was correlated with advanced GBM stages and worse patient prognosis. PCSK5 knockdown attenuated the epithelial-mesenchymal transition (EMT)-like properties of GBM cells induced by IL-6. PCSK5 knockdown in combination with Andro treatment significantly inhibited the proliferation and invasion of GBM cells in vitro, as well as tumor growth in vivo. Mechanistically, PCSK5 downregulation reduced the expression of p-STAT3 and Matrix metalloproteinases (MMPs), which could be rescued by the p-STAT3 agonist. STAT3 silencing downregulated the expression of MMPs without affecting PCSK5. Furthermore, Andro in combination with PCSK5 silencing significantly inhibited STAT3/MMPs axis. These observations provided evidence that PCSK5 functioned as a potential tumor promoter by regulating p-STAT3/MMPs and the combination of Andro with PCSK5 silencing might be a good strategy to prevent GBM progression.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":"521-533"},"PeriodicalIF":3.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140326861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-31DOI: 10.1007/s11010-024-05194-8
Minshan Tang, Kai Song, Danning Xie, Xinyu Yuan, Yaxuan Wang, Zhiyang Li, Xiansheng Lu, Liang Guo, Xiaotong Zhu, Le Xiong, Wenqian Zhou, Jie Lin
Colorectal cancer (CRC) ranks third for morbidity and second for mortality among all digestive malignant tumors worldwide, but its pathogenesis remains not entirely clear. Bioinformatic analyses were performed to find out important biomarkers for CRC. For validation, reverse transcription-quantitative PCR, western blotting, and immunohistochemistry were performed. Then, cell transfection, gain- and loss-of-function assays, immunofluorescence, cell line RNA-sequencing and analyses, and in vivo tumorigenesis assay were also performed to further explore the mechanism. We prioritized phosphoserine aminotransferase 1 (PSAT1) as an important biomarker in CRC. PSAT1 expression was gradually up-regulated as the CRC disease progresses and may relate to poor prognosis. PSAT1 promoted the malignant behaviors of CRC cells. Although PSAT1 is an enzyme essential to serine biosynthesis, an exogenous supplement of serine did not completely rescue the malignant behaviors in PSAT1-knockdown CRC cells. Interestingly, PSAT1 inhibited the Hippo tumor-suppressor pathway by promoting the nucleus-localization of YAP/TAZ and increasing the expression of ID1 in CRC cells. Furthermore, AMOT, a vascular-related molecule that molecularly interacts with YAP/TAZ, was up-regulated upon PSAT1 knockdown in CRC cells. Knocking down AMOT partially rescued the inhibition of proliferation and the reduced nuclear localization of YAP/TAZ caused by PSAT1 knockdown in CRC cells. Moreover, PSAT1 was closely related to vascular-related pathways, in which AMOT might act as a mediator. Finally, PSAT1 promoted CRC proliferation by negatively regulating AMOT in vivo. PSAT1 could enhance the progression of colorectal cancer by regulating Hippo-YAP/TAZ-ID1 axis via AMOT, which is independent of the metabolic function of PSAT1.
{"title":"PSAT1 promotes the progression of colorectal cancer by regulating Hippo-YAP/TAZ-ID1 axis via AMOT.","authors":"Minshan Tang, Kai Song, Danning Xie, Xinyu Yuan, Yaxuan Wang, Zhiyang Li, Xiansheng Lu, Liang Guo, Xiaotong Zhu, Le Xiong, Wenqian Zhou, Jie Lin","doi":"10.1007/s11010-024-05194-8","DOIUrl":"https://doi.org/10.1007/s11010-024-05194-8","url":null,"abstract":"<p><p>Colorectal cancer (CRC) ranks third for morbidity and second for mortality among all digestive malignant tumors worldwide, but its pathogenesis remains not entirely clear. Bioinformatic analyses were performed to find out important biomarkers for CRC. For validation, reverse transcription-quantitative PCR, western blotting, and immunohistochemistry were performed. Then, cell transfection, gain- and loss-of-function assays, immunofluorescence, cell line RNA-sequencing and analyses, and in vivo tumorigenesis assay were also performed to further explore the mechanism. We prioritized phosphoserine aminotransferase 1 (PSAT1) as an important biomarker in CRC. PSAT1 expression was gradually up-regulated as the CRC disease progresses and may relate to poor prognosis. PSAT1 promoted the malignant behaviors of CRC cells. Although PSAT1 is an enzyme essential to serine biosynthesis, an exogenous supplement of serine did not completely rescue the malignant behaviors in PSAT1-knockdown CRC cells. Interestingly, PSAT1 inhibited the Hippo tumor-suppressor pathway by promoting the nucleus-localization of YAP/TAZ and increasing the expression of ID1 in CRC cells. Furthermore, AMOT, a vascular-related molecule that molecularly interacts with YAP/TAZ, was up-regulated upon PSAT1 knockdown in CRC cells. Knocking down AMOT partially rescued the inhibition of proliferation and the reduced nuclear localization of YAP/TAZ caused by PSAT1 knockdown in CRC cells. Moreover, PSAT1 was closely related to vascular-related pathways, in which AMOT might act as a mediator. Finally, PSAT1 promoted CRC proliferation by negatively regulating AMOT in vivo. PSAT1 could enhance the progression of colorectal cancer by regulating Hippo-YAP/TAZ-ID1 axis via AMOT, which is independent of the metabolic function of PSAT1.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142910046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-26DOI: 10.1007/s11010-024-05189-5
Shweta Madiwale, Vaishali Kasture, Deepali Sundrani, G V Krishnaveni, Sanjay Gupte, Sadhana Joshi
GDM is an increasing global concern, with its etiology not fully understood, though altered placental function is likely to play a role. Placental angiogenesis, essential for sufficient blood flow and nutrient exchange between mother and fetus, may be affected by GDM. However, the role of angiogenic markers in GDM remains unclear. This study aims to investigate angiogenic markers from early pregnancy till delivery and their relationship with placental dimensions. This study is a part of a longitudinal study, where a total of 1154 women were recruited, out of which 167 women developed GDM (15.2%). The current study includes a total of 130 women randomly selected (65 GDM and 65 Non-GDM women). Plasma and placental levels of angiogenic markers such as VEGF, PLGF and sFlt-1/Flt-1 were estimated. Placental dimensions and birth outcomes were recorded, and associations between angiogenic markers and these parameters were examined. sFlt-1 (p < 0.05) levels were higher at V1 (11-14 weeks) in GDM women as compared to Non-GDM women. Placental PLGF (p < 0.01) and Flt-1 (p < 0.05) levels were lower in the GDM group. PLGF and Flt-1 were negatively associated with placental dimensions such as major axis, minor axis and breadth of the placenta. This study reveals altered expression of placental angiogenic markers in women with GDM, potentially affecting placental development and function. Negative correlations between these markers and placental dimensions suggest their influence on pregnancy outcomes in GDM.
{"title":"Angiogenic Markers in Gestational Diabetes and their Association with Placental Dimensions.","authors":"Shweta Madiwale, Vaishali Kasture, Deepali Sundrani, G V Krishnaveni, Sanjay Gupte, Sadhana Joshi","doi":"10.1007/s11010-024-05189-5","DOIUrl":"https://doi.org/10.1007/s11010-024-05189-5","url":null,"abstract":"<p><p>GDM is an increasing global concern, with its etiology not fully understood, though altered placental function is likely to play a role. Placental angiogenesis, essential for sufficient blood flow and nutrient exchange between mother and fetus, may be affected by GDM. However, the role of angiogenic markers in GDM remains unclear. This study aims to investigate angiogenic markers from early pregnancy till delivery and their relationship with placental dimensions. This study is a part of a longitudinal study, where a total of 1154 women were recruited, out of which 167 women developed GDM (15.2%). The current study includes a total of 130 women randomly selected (65 GDM and 65 Non-GDM women). Plasma and placental levels of angiogenic markers such as VEGF, PLGF and sFlt-1/Flt-1 were estimated. Placental dimensions and birth outcomes were recorded, and associations between angiogenic markers and these parameters were examined. sFlt-1 (p < 0.05) levels were higher at V1 (11-14 weeks) in GDM women as compared to Non-GDM women. Placental PLGF (p < 0.01) and Flt-1 (p < 0.05) levels were lower in the GDM group. PLGF and Flt-1 were negatively associated with placental dimensions such as major axis, minor axis and breadth of the placenta. This study reveals altered expression of placental angiogenic markers in women with GDM, potentially affecting placental development and function. Negative correlations between these markers and placental dimensions suggest their influence on pregnancy outcomes in GDM.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142896167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-24DOI: 10.1007/s11010-024-05184-w
Yao Yao, Yuexin Yu, Yaping Xu, Yingtian Liu, Zhikun Guo
<p><p>To investigate the promoting effect of extracellular vesicles derived from myocardial cells (CM-EVs) on the reprogramming of cardiac fibroblasts (CFs) into cardiomyocyte-like cells (iCMs) and their therapeutic effect on myocardial infarction (MI) in rats. Cell experiments: The differential adhesion method was used to obtain Sprague Dawley (SD) suckling rat CFs and cardiomyocytes (CMs), while the ultracentrifugation method was used to obtain CM-EVs. Transmission electron microscopy and nanoparticle tracking technology were used to analyze and determine the morphology and particle size of CM-EVs. Western blotting was used to identify the expression of EV markers CD9, CD63, and Alix proteins. Small molecule combination of CHIR99021, Forskolin, Dorsomorphin, SB431542, and Valproic acid (CFDSV) and CFDSV + CM-EVs combination were used to induce CFs to differentiate into cardiomyocytes. The expression of cellular morphological changes, myocardial-specific protein cardiac troponin T (cTnT), and α-actinin were detected on the 3rd, 6th, 9th, and 15th day of reprogramming, respectively. After transfection and inhibition of miRNA-133, immunofluorescence, RT-qPCR, and Western blotting techniques were used to detect the expression of cTnT and α-actinin of induced CFs in the CMs group (CM-EVs), miRNA-133 high expression group (133H), and miRNA-133 inhibition group (133I). Animal experiment: CM-EVs were injected into the margin of myocardial infarction in rats. Cardiac function was detected by echocardiography before and 4 weeks after infarction, and the pathological changes were detected by HE and Masson staining, while Tunel and CD31 fluorescence staining were used to detect myocardial cell apoptosis and angiogenesis. CFs in the CM-EVs group expressed cTnT and α-actinin after induction, and the expression intensity gradually increased with the extension of induction time. On the 15th day after induction, cTnT-positive cells accounted for 85.6% of the total cell count, while the CFDSV group accounted for 48.8%. The majority of cells expressed GATA-binding protein 4 (GATA4), NK2 homeobox 5 (Nkx-2.5), and connexin 43 (Cx43). The RT-qPCR analysis showed the induced CFs expressed mature cardiomyocyte markers, including cTnT, Ryr2, Nkx-2.5, and GATA, which were similar to those of CMs (P < 0.05). Upon induction of CFs into iCMs, iCMs expressed cardiac precursor cell markers, such as source domain transcription factor-1 (Isl-1), mesodermal posterior spiral transcription factor-1 (Mesp-1), GATA4, and fetal liver kinase-1 (Flk-1). RT-qPCR, Western blotting, and immunofluorescence results showed that cTnT and α-actinin were highly expressed in CFs induced by CM-EVs group and 133H group until the 15th day, while the expression levels were low in cont group and 133I group. In animal in vivo experiments, injection of CM-EVs was found to alleviate myocardial fibrosis and reduce apoptosis of myocardial cells in the infarcted area compared to the MI group (P < 0.001).
{"title":"Enhancing cardiac regeneration: direct reprogramming of fibroblasts into myocardial-like cells using extracellular vesicles secreted by cardiomyocytes.","authors":"Yao Yao, Yuexin Yu, Yaping Xu, Yingtian Liu, Zhikun Guo","doi":"10.1007/s11010-024-05184-w","DOIUrl":"https://doi.org/10.1007/s11010-024-05184-w","url":null,"abstract":"<p><p>To investigate the promoting effect of extracellular vesicles derived from myocardial cells (CM-EVs) on the reprogramming of cardiac fibroblasts (CFs) into cardiomyocyte-like cells (iCMs) and their therapeutic effect on myocardial infarction (MI) in rats. Cell experiments: The differential adhesion method was used to obtain Sprague Dawley (SD) suckling rat CFs and cardiomyocytes (CMs), while the ultracentrifugation method was used to obtain CM-EVs. Transmission electron microscopy and nanoparticle tracking technology were used to analyze and determine the morphology and particle size of CM-EVs. Western blotting was used to identify the expression of EV markers CD9, CD63, and Alix proteins. Small molecule combination of CHIR99021, Forskolin, Dorsomorphin, SB431542, and Valproic acid (CFDSV) and CFDSV + CM-EVs combination were used to induce CFs to differentiate into cardiomyocytes. The expression of cellular morphological changes, myocardial-specific protein cardiac troponin T (cTnT), and α-actinin were detected on the 3rd, 6th, 9th, and 15th day of reprogramming, respectively. After transfection and inhibition of miRNA-133, immunofluorescence, RT-qPCR, and Western blotting techniques were used to detect the expression of cTnT and α-actinin of induced CFs in the CMs group (CM-EVs), miRNA-133 high expression group (133H), and miRNA-133 inhibition group (133I). Animal experiment: CM-EVs were injected into the margin of myocardial infarction in rats. Cardiac function was detected by echocardiography before and 4 weeks after infarction, and the pathological changes were detected by HE and Masson staining, while Tunel and CD31 fluorescence staining were used to detect myocardial cell apoptosis and angiogenesis. CFs in the CM-EVs group expressed cTnT and α-actinin after induction, and the expression intensity gradually increased with the extension of induction time. On the 15th day after induction, cTnT-positive cells accounted for 85.6% of the total cell count, while the CFDSV group accounted for 48.8%. The majority of cells expressed GATA-binding protein 4 (GATA4), NK2 homeobox 5 (Nkx-2.5), and connexin 43 (Cx43). The RT-qPCR analysis showed the induced CFs expressed mature cardiomyocyte markers, including cTnT, Ryr2, Nkx-2.5, and GATA, which were similar to those of CMs (P < 0.05). Upon induction of CFs into iCMs, iCMs expressed cardiac precursor cell markers, such as source domain transcription factor-1 (Isl-1), mesodermal posterior spiral transcription factor-1 (Mesp-1), GATA4, and fetal liver kinase-1 (Flk-1). RT-qPCR, Western blotting, and immunofluorescence results showed that cTnT and α-actinin were highly expressed in CFs induced by CM-EVs group and 133H group until the 15th day, while the expression levels were low in cont group and 133I group. In animal in vivo experiments, injection of CM-EVs was found to alleviate myocardial fibrosis and reduce apoptosis of myocardial cells in the infarcted area compared to the MI group (P < 0.001). ","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dysregulated expression of microtubule-associated protein tau (MAPT) has been reported in a variety of human cancers. However, whether and how Tau influences hepatocellular carcinogenesis remains elusive. This study was aimed to investigate the role and the underlying mechanism of Tau in the proliferation, invasion, migration and sorafenib sensitivity of hepatocellular carcinoma (HCC) cells. An increased level of Tau was found in the primary tumor samples of HCC compared with the adjacent normal liver tissues, and the increase of Tau was positively correlated with p62 evidenced by the data obtained from The Cancer Genome Atlas (TCGA), Gene Expression Profiling Interactive Analysis (GEPIA), and human samples from HCC patients. The high Tau expression was also correlated with a poorer survival in HCC patients demonstrated by using the GEPIA survival analysis and OncoLnc database. Further studies showed that Tau overexpression promoted the growth, invasion and migration and decreased sorafenib sensitivity in HepG2 and Huh7 cells; Tau also accelerated growth of xenograft tumors with blockage of autophagosome-lysosome fusion. Finally, overexpressing Tau inhibited AMPK, which contributed to Tau-induced promotion of hepatocellular carcinogenesis. In conclusion, our study provides the proof-of-concept evidence validating Tau as an attractive HCC target.
{"title":"Accumulation of microtubule-associated protein tau promotes hepatocellular carcinogenesis through inhibiting autophagosome-lysosome fusion.","authors":"Xuemin Liu, Zhiwei Hao, Huanhuan He, Xuan Wang, Wenqi Wang, Xiji Shu, Binlian Sun, Zhiyong Hu, Shaobo Hu, Xiaoying Hou, Yue Xiao, Hongyan Zhou, Yuchen Liu, Jianzhi Wang, Zhengqi Fu","doi":"10.1007/s11010-024-05193-9","DOIUrl":"https://doi.org/10.1007/s11010-024-05193-9","url":null,"abstract":"<p><p>Dysregulated expression of microtubule-associated protein tau (MAPT) has been reported in a variety of human cancers. However, whether and how Tau influences hepatocellular carcinogenesis remains elusive. This study was aimed to investigate the role and the underlying mechanism of Tau in the proliferation, invasion, migration and sorafenib sensitivity of hepatocellular carcinoma (HCC) cells. An increased level of Tau was found in the primary tumor samples of HCC compared with the adjacent normal liver tissues, and the increase of Tau was positively correlated with p62 evidenced by the data obtained from The Cancer Genome Atlas (TCGA), Gene Expression Profiling Interactive Analysis (GEPIA), and human samples from HCC patients. The high Tau expression was also correlated with a poorer survival in HCC patients demonstrated by using the GEPIA survival analysis and OncoLnc database. Further studies showed that Tau overexpression promoted the growth, invasion and migration and decreased sorafenib sensitivity in HepG2 and Huh7 cells; Tau also accelerated growth of xenograft tumors with blockage of autophagosome-lysosome fusion. Finally, overexpressing Tau inhibited AMPK, which contributed to Tau-induced promotion of hepatocellular carcinogenesis. In conclusion, our study provides the proof-of-concept evidence validating Tau as an attractive HCC target.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-23DOI: 10.1007/s11010-024-05192-w
Iasmina M Hâncu, Silvia Giuchici, Adina V Furdui-Lința, Bogdan Lolescu, Adrian Sturza, Danina M Muntean, Maria D Dănilă, Rodica Lighezan
The global burden of cancer as a major cause of death and invalidity has been constantly increasing in the past decades. Monoamine oxidases (MAO) with two isoforms, MAO-A and MAO-B, are mammalian mitochondrial enzymes responsible for the oxidative deamination of neurotransmitters and amines in the central nervous system and peripheral tissues with the constant generation of hydrogen peroxide as the main deleterious ancillary product. However, given the complexity of cancer biology, MAO involvement in tumorigenesis is multifaceted with different tumors displaying either an increased or decreased MAO profile. MAO inhibitors are currently approved for the treatment of neurodegenerative diseases (mainly, Parkinson's disease) and as secondary/adjunctive therapeutic options for the treatment of major depression. Herein, we review the literature characterizing MAO's involvement and the putative role of MAO inhibitors in several malignancies, and also provide perspectives regarding the potential biomarker role that MAO could play in the future in oncology.
{"title":"The highs and lows of monoamine oxidase as molecular target in cancer: an updated review.","authors":"Iasmina M Hâncu, Silvia Giuchici, Adina V Furdui-Lința, Bogdan Lolescu, Adrian Sturza, Danina M Muntean, Maria D Dănilă, Rodica Lighezan","doi":"10.1007/s11010-024-05192-w","DOIUrl":"https://doi.org/10.1007/s11010-024-05192-w","url":null,"abstract":"<p><p>The global burden of cancer as a major cause of death and invalidity has been constantly increasing in the past decades. Monoamine oxidases (MAO) with two isoforms, MAO-A and MAO-B, are mammalian mitochondrial enzymes responsible for the oxidative deamination of neurotransmitters and amines in the central nervous system and peripheral tissues with the constant generation of hydrogen peroxide as the main deleterious ancillary product. However, given the complexity of cancer biology, MAO involvement in tumorigenesis is multifaceted with different tumors displaying either an increased or decreased MAO profile. MAO inhibitors are currently approved for the treatment of neurodegenerative diseases (mainly, Parkinson's disease) and as secondary/adjunctive therapeutic options for the treatment of major depression. Herein, we review the literature characterizing MAO's involvement and the putative role of MAO inhibitors in several malignancies, and also provide perspectives regarding the potential biomarker role that MAO could play in the future in oncology.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Metabolic syndrome (MetS) is driven by a complex interplay of genetic, lifestyle, and dietary factors, leading to weight gain, insulin resistance, dyslipidemia, and chronic inflammation. Gut microbiota dysbiosis has been recently recognized as a key contributor to MetS, leading to advancements in gut microbiome-based interventions to improve health outcomes. Considering the unique challenges associated with the use of pre/probiotics, short-chain fatty acids (SCFA), also known as postbiotics, have emerged as promising therapeutic agents due to their role in modulating host metabolism and physiology. Considering this, the aim of the current study was to explore the therapeutic potential of SCFA (butyrate, propionate, and acetate) supplementation against a high-fat diet (HFD)-induced experimental model of MetS in male Wistar rats. Alterations in body weight, lipid profile, histopathology, and adipose tissue accumulation were assessed to establish SCFA-mediated amelioration of experimental MetS. Further, the enzymatic (GPx, Catalase, GR, and GST) and non-enzymatic (LPO, total ROS, and Redox ratio were evaluated. The results indicated that SCFA supplementation could effectively mitigate key features of MetS. A significant reduction in body weight gain and fasting blood glucose levels, along with markedly lowered triglycerides, total cholesterol, and LDL levels, with partial restoration of HDL levels was observed following SCFA supplementation. SCFA administration also attenuated MetS-associated hepatic damage as studied by histopathological investigation and analysis of liver function marker enzyme activities. Such ameliorative effects of SCFA against HFD-induced MetS were owed to potential redox modulation studied using enzymatic and non-enzymatic oxidative stress markers. In conclusion, the study's outcomes show that SCFA supplementation could potentially be used against managing MetS. It underscores the therapeutic potential of SCFA by placing them as a novel gut microbiome-based dietary approach to improve metabolic health and reduce the risk of MetS-associated complications. However, more detailed mechanistic explorations are warranted in the future, leading to their beneficial role in MetS contributing to holistic health outcomes.
{"title":"Short-chain fatty acids as a novel intervention for high-fat diet-induced metabolic syndrome.","authors":"Tanvi Sharma, Pavitra Ranawat, Ayushi Garg, Pulkit Rastogi, Naveen Kaushal","doi":"10.1007/s11010-024-05185-9","DOIUrl":"https://doi.org/10.1007/s11010-024-05185-9","url":null,"abstract":"<p><p>Metabolic syndrome (MetS) is driven by a complex interplay of genetic, lifestyle, and dietary factors, leading to weight gain, insulin resistance, dyslipidemia, and chronic inflammation. Gut microbiota dysbiosis has been recently recognized as a key contributor to MetS, leading to advancements in gut microbiome-based interventions to improve health outcomes. Considering the unique challenges associated with the use of pre/probiotics, short-chain fatty acids (SCFA), also known as postbiotics, have emerged as promising therapeutic agents due to their role in modulating host metabolism and physiology. Considering this, the aim of the current study was to explore the therapeutic potential of SCFA (butyrate, propionate, and acetate) supplementation against a high-fat diet (HFD)-induced experimental model of MetS in male Wistar rats. Alterations in body weight, lipid profile, histopathology, and adipose tissue accumulation were assessed to establish SCFA-mediated amelioration of experimental MetS. Further, the enzymatic (GPx, Catalase, GR, and GST) and non-enzymatic (LPO, total ROS, and Redox ratio were evaluated. The results indicated that SCFA supplementation could effectively mitigate key features of MetS. A significant reduction in body weight gain and fasting blood glucose levels, along with markedly lowered triglycerides, total cholesterol, and LDL levels, with partial restoration of HDL levels was observed following SCFA supplementation. SCFA administration also attenuated MetS-associated hepatic damage as studied by histopathological investigation and analysis of liver function marker enzyme activities. Such ameliorative effects of SCFA against HFD-induced MetS were owed to potential redox modulation studied using enzymatic and non-enzymatic oxidative stress markers. In conclusion, the study's outcomes show that SCFA supplementation could potentially be used against managing MetS. It underscores the therapeutic potential of SCFA by placing them as a novel gut microbiome-based dietary approach to improve metabolic health and reduce the risk of MetS-associated complications. However, more detailed mechanistic explorations are warranted in the future, leading to their beneficial role in MetS contributing to holistic health outcomes.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-20DOI: 10.1007/s11010-024-05165-z
Bogdan A Lolescu, Adina V Furdui-Lința, Cosmin A Ilie, Adrian Sturza, Flavia Zară, Danina M Muntean, Alexandru Blidișel, Octavian M Crețu
Obesity, diabetes, and their cardiovascular and hepatic comorbidities are alarming public health issues of the twenty-first century, which share mitochondrial dysfunction, oxidative stress, and chronic inflammation as common pathophysiological mechanisms. An increasing body of evidence links the combined exposure to multiple environmental toxicants with the occurrence and severity of metabolic diseases. Endocrine disruptors (EDs) are ubiquitous chemicals or mixtures with persistent deleterious effects on the living organisms beyond the endocrine system impairment; in particular, those known as metabolism-disrupting chemicals (MDCs), increase the risk of the metabolic pathologies in adult organism or its progeny. Being largely lipophilic, MDCs mainly target the adipose tissue and elicit mitochondrial dysfunction by interfering with mitochondrial bioenergetics, biogenesis, dynamics and/or other functions. Plastics, when broken down into micro- and nano-plastics (MNPs), have been detected in several human tissues, including the liver. The harmful interplay between inflammatory and redox processes, which mutually interact in a positive feed-back loop, hence the term oxidative inflammation ("OxInflammation"), occurs both at systemic and organ level. In both liver and adipose tissue, oxinflammation contributes to the progression of the metabolic dysfunction-associated steatotic liver disease (MASLD). Moreover, it has been reported that individuals with MASLD may be more susceptible to the harmful effects of toxicants (mainly, those related to mitochondria) and that chronic exposure to EDs/MDCs or MNPs may play a role in the development of the disease. While liver has been systematically investigated as major target organ for ambient chemicals, surprisingly, less information is available in the literature with respect to the adipose tissue. In this narrative review, we delve into the current literature on the most studied environmental toxicants (bisphenols, polychlorinated biphenyls, phthalates, tolylfluanid and tributyltin, per-fluoroalkyl and polyfluoroalkyl substances, heavy metals and MNPs), summarize their deleterious effects on adipose tissue, and address the role of dysregulated mitochondria and oxinflammation, particularly in the setting of MASLD.
{"title":"Adipose tissue as target of environmental toxicants: focus on mitochondrial dysfunction and oxidative inflammation in metabolic dysfunction-associated steatotic liver disease.","authors":"Bogdan A Lolescu, Adina V Furdui-Lința, Cosmin A Ilie, Adrian Sturza, Flavia Zară, Danina M Muntean, Alexandru Blidișel, Octavian M Crețu","doi":"10.1007/s11010-024-05165-z","DOIUrl":"https://doi.org/10.1007/s11010-024-05165-z","url":null,"abstract":"<p><p>Obesity, diabetes, and their cardiovascular and hepatic comorbidities are alarming public health issues of the twenty-first century, which share mitochondrial dysfunction, oxidative stress, and chronic inflammation as common pathophysiological mechanisms. An increasing body of evidence links the combined exposure to multiple environmental toxicants with the occurrence and severity of metabolic diseases. Endocrine disruptors (EDs) are ubiquitous chemicals or mixtures with persistent deleterious effects on the living organisms beyond the endocrine system impairment; in particular, those known as metabolism-disrupting chemicals (MDCs), increase the risk of the metabolic pathologies in adult organism or its progeny. Being largely lipophilic, MDCs mainly target the adipose tissue and elicit mitochondrial dysfunction by interfering with mitochondrial bioenergetics, biogenesis, dynamics and/or other functions. Plastics, when broken down into micro- and nano-plastics (MNPs), have been detected in several human tissues, including the liver. The harmful interplay between inflammatory and redox processes, which mutually interact in a positive feed-back loop, hence the term oxidative inflammation (\"OxInflammation\"), occurs both at systemic and organ level. In both liver and adipose tissue, oxinflammation contributes to the progression of the metabolic dysfunction-associated steatotic liver disease (MASLD). Moreover, it has been reported that individuals with MASLD may be more susceptible to the harmful effects of toxicants (mainly, those related to mitochondria) and that chronic exposure to EDs/MDCs or MNPs may play a role in the development of the disease. While liver has been systematically investigated as major target organ for ambient chemicals, surprisingly, less information is available in the literature with respect to the adipose tissue. In this narrative review, we delve into the current literature on the most studied environmental toxicants (bisphenols, polychlorinated biphenyls, phthalates, tolylfluanid and tributyltin, per-fluoroalkyl and polyfluoroalkyl substances, heavy metals and MNPs), summarize their deleterious effects on adipose tissue, and address the role of dysregulated mitochondria and oxinflammation, particularly in the setting of MASLD.</p>","PeriodicalId":18724,"journal":{"name":"Molecular and Cellular Biochemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}