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LncRNA MCM3AP-AS1 promotes chemoresistance in triple-negative breast cancer through the miR-524-5p/RBM39 axis. LncRNA MCM3AP-AS1通过miR-524-5p/RBM39轴促进三阴性乳腺癌的化疗耐药性
IF 3.5 2区 生物学 Q3 CELL BIOLOGY Pub Date : 2025-01-01 Epub Date: 2024-03-12 DOI: 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.

三阴性乳腺癌(TNBC)是乳腺癌中最致命的亚型,治疗效果不佳。有证据表明,lncRNA MCM3AP-AS1参与了BC的发展。本研究调查了MCM3AP-AS1在TNBC细胞化疗耐药性中的作用。通过增加多柔比星/多西他赛(DOX/DXL)的浓度,构建了耐药 TNBC 细胞系 SUM159PTR 和 MDA-MB-231R。通过 RT-qPCR 测定 MCM3AP-AS1 和 miR-524-5p 的表达水平。采用 Western 印迹法测定 RNA 结合基序 39 (RBM39) 的水平。细胞活力和细胞凋亡通过 CCK-8 检测法和流式细胞术进行评估。通过 ECORI 数据库预测了 miR-524-5p 与 MCM3AP-AS1 或 RBM39 的靶向结合,并通过双荧光素酶试验进行了验证。为了研究 MCM3AP-AS1、miR-524-5p 和 RBM39 之间的相互作用,我们在细胞中进行了功能增益和丧失试验。通过皮下注射MCM3AP-AS1沉默的MDA-MB-231R细胞并腹腔注射DOX/DXL,建立了TNBC异种移植小鼠模型,以验证MCM3AP-AS1在体内的作用。MCM3AP-AS1在耐药TNBC细胞中上调,沉默MCM3AP-AS1可通过促进细胞凋亡使耐药TNBC细胞对化疗药物敏感。MCM3AP-AS1靶向miR-524-5p。经 DOX/DXL 处理后,抑制 miR-524-5p 可部分逆转沉默 MCM3AP-AS1 在抑制耐药 TNBC 细胞化疗耐药性和促进其凋亡方面的作用。沉默MCM3AP-AS1可通过miR-524-5p/RBM39轴促进细胞凋亡,从而增强耐药TNBC细胞的化疗敏感性。敲除MCM3AP-AS1可上调miR-524-5p,下调RBM39,抑制体内肿瘤的发展。沉默MCM3AP-AS1可通过上调miR-524-5p和下调RBM39促进耐药TNBC细胞的凋亡,从而抑制TNBC的化疗耐药性。
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引用次数: 0
STK32C modulates doxorubicin resistance in triple-negative breast cancer cells via glycolysis regulation. STK32C 通过糖酵解调节三阴性乳腺癌细胞的多柔比星耐药性
IF 3.5 2区 生物学 Q3 CELL BIOLOGY Pub Date : 2025-01-01 Epub Date: 2024-03-20 DOI: 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.

了解三阴性乳腺癌(TNBC)产生多柔比星耐药性的机制具有重要的临床意义。在我们的研究中,我们调查了 STK32C(一种鲜为人知的激酶)对 TNBC 细胞中多柔比星敏感性的潜在影响。我们的研究结果表明,STK32C 在 TNBC 标本中的表达升高与接受多柔比星治疗的 TNBC 患者的不良预后有关。随后的实验表明,STK32C 的缺失显著提高了对多柔比星耐药的 TNBC 细胞对多柔比星的敏感性。从机理上讲,我们揭示了 STK32C 的细胞质亚群在介导多柔比星敏感性方面起着关键作用,主要是通过调节糖酵解。此外,STK32C 的激酶活性被证明是其介导多柔比星敏感性的必要条件,从而强调了其作为激酶的作用。我们的研究表明,靶向 STK32C 可能是一种新的治疗方法,有可能提高多柔比星在 TNBC 治疗中的疗效。
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引用次数: 0
PCSK5 downregulation promotes the inhibitory effect of andrographolide on glioblastoma through regulating STAT3. PCSK5下调通过调节STAT3促进穿心莲内酯对胶质母细胞瘤的抑制作用
IF 3.5 2区 生物学 Q3 CELL BIOLOGY Pub Date : 2025-01-01 Epub Date: 2024-03-29 DOI: 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.

Proprotein convertase subtilisin/kexin type 5(PCSK5)是 Proprotein convertase(PC)家族的成员,可将未成熟蛋白加工成功能蛋白,在细胞迁移和转化过程中发挥重要作用。穿心莲内酯是一种非肽化合物,具有抑制 PC 和抗肿瘤活性。我们的研究旨在探讨 PCSK5 下调联合穿心莲内酯对 GBM 进展的功能性作用。癌症基因组图谱(TCGA)和临床样本的结果显示,与非肿瘤脑组织相比,PCSK5在GBM组织中显著上调。PCSK5的高表达与GBM晚期和患者预后恶化相关。敲除 PCSK5 可减轻 IL-6 诱导的 GBM 细胞上皮-间质转化(EMT)样特性。PCSK5 基因敲除联合安络血治疗可显著抑制体外 GBM 细胞的增殖和侵袭,以及体内肿瘤的生长。从机理上讲,PCSK5的下调降低了p-STAT3和基质金属蛋白酶(MMPs)的表达,而p-STAT3激动剂可以挽救这一点。STAT3 沉默会降低 MMPs 的表达,但不会影响 PCSK5。此外,Andro与PCSK5沉默相结合可显著抑制STAT3/MMPs轴。这些观察结果提供了证据,证明PCSK5通过调节p-STAT3/MMPs发挥了潜在的肿瘤促进剂的作用,而将安多与PCSK5沉默联合使用可能是预防GBM进展的良好策略。
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引用次数: 0
PSAT1 promotes the progression of colorectal cancer by regulating Hippo-YAP/TAZ-ID1 axis via AMOT.
IF 3.5 2区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-12-31 DOI: 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}
引用次数: 0
Angiogenic Markers in Gestational Diabetes and their Association with Placental Dimensions.
IF 3.5 2区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-12-26 DOI: 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.

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引用次数: 0
Enhancing cardiac regeneration: direct reprogramming of fibroblasts into myocardial-like cells using extracellular vesicles secreted by cardiomyocytes.
IF 3.5 2区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-12-24 DOI: 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":"&lt;p&gt;&lt;p&gt;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 &lt; 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 &lt; 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}
引用次数: 0
Accumulation of microtubule-associated protein tau promotes hepatocellular carcinogenesis through inhibiting autophagosome-lysosome fusion.
IF 3.5 2区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-12-24 DOI: 10.1007/s11010-024-05193-9
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

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}
引用次数: 0
The highs and lows of monoamine oxidase as molecular target in cancer: an updated review.
IF 3.5 2区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-12-23 DOI: 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}
引用次数: 0
Short-chain fatty acids as a novel intervention for high-fat diet-induced metabolic syndrome.
IF 3.5 2区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-12-21 DOI: 10.1007/s11010-024-05185-9
Tanvi Sharma, Pavitra Ranawat, Ayushi Garg, Pulkit Rastogi, Naveen Kaushal

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}
引用次数: 0
Adipose tissue as target of environmental toxicants: focus on mitochondrial dysfunction and oxidative inflammation in metabolic dysfunction-associated steatotic liver disease. 作为环境毒物靶标的脂肪组织:关注代谢功能障碍相关脂肪肝中的线粒体功能障碍和氧化炎症。
IF 3.5 2区 生物学 Q3 CELL BIOLOGY Pub Date : 2024-12-20 DOI: 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.

肥胖症、糖尿病及其心血管和肝脏并发症是二十一世纪令人担忧的公共卫生问题,它们的共同病理生理机制是线粒体功能障碍、氧化应激和慢性炎症。越来越多的证据表明,多种环境毒物的综合暴露与代谢性疾病的发生和严重程度有关。内分泌干扰物(EDs)是一种无处不在的化学物质或混合物,除了对内分泌系统造成损害外,还对生物体产生持续的有害影响;尤其是那些被称为干扰新陈代谢的化学物质(MDCs),会增加成年生物体或其后代出现新陈代谢疾病的风险。由于主要是亲脂性的,MDCs 主要以脂肪组织为目标,通过干扰线粒体的生物能、生物生成、动力学和/或其他功能,引起线粒体功能障碍。塑料在分解成微塑料和纳米塑料(MNPs)后,已在包括肝脏在内的多个人体组织中被检测到。炎症过程和氧化还原过程之间存在有害的相互作用,两者相互影响,形成正反馈循环,因此被称为氧化性炎症("OxInflammation")。在肝脏和脂肪组织中,氧化性炎症都会导致代谢功能障碍相关性脂肪性肝病(MASLD)的恶化。此外,有报道称,患有代谢功能障碍相关性脂肪性肝病的人可能更容易受到毒物(主要是与线粒体有关的毒物)的有害影响,而长期暴露于 EDs/MDCs 或 MNPs 可能在该病的发展中起作用。肝脏作为环境化学物质的主要靶器官已得到系统研究,但令人惊讶的是,有关脂肪组织的文献资料却较少。在这篇叙事性综述中,我们深入研究了当前研究最多的环境毒物(双酚、多氯联苯、邻苯二甲酸盐、甲苯氟酰胺和三丁基锡、全氟烷基和多氟烷基物质、重金属和 MNPs),总结了它们对脂肪组织的有害影响,并探讨了线粒体失调和氧化炎症的作用,尤其是在 MASLD 的情况下。
{"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}
引用次数: 0
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Molecular and Cellular Biochemistry
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