首页 > 最新文献

Journal of Cellular and Molecular Medicine最新文献

英文 中文
27-Hydroxycholesterol represses G9a expression via oestrogen receptor alpha in breast cancer 羟基胆固醇通过雌激素受体α抑制乳腺癌中G9a的表达
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-08-23 DOI: 10.1111/jcmm.17882
Ravindran Vini, Asha Lekshmi, Swathy Ravindran, Jissa Vinoda Thulaseedharan, Kunjuraman Sujathan, Arumugam Rajavelu, Sreeharshan Sreeja

27-hydroxycholesterol (27-HC) is a cholesterol metabolite and the first discovered endogenous selective estrogen receptor modulator (SERM) that has been shown to have proliferative and metastatic activity in breast cancer. However, whether 27-HC metabolite modulates the epigenetic signatures in breast cancer and its progression remains unclear. The current study, reports that 27-HC represses the expression of euchromatic histone lysine methyltransferase G9a, further reducing di-methylation at H3K9 in a subset of genes. We also observed reduced occupancy of ERα at the G9a promoter, indicating that 27-HC negatively regulates the ERα occupancy on the G9a promoter and functions as a transcriptional repressor. Further, ChIP-sequencing for the H3K9me2 mark has demonstrated that 27-HC treatment reduces the H3K9me2 mark on subset of genes linked to cancer progression, proliferation, and metastasis. We observed upregulation of these genes following 27-HC treatment which further confirms the loss of methylation at these genes. Immunohistochemical analysis with breast cancer patient tissues indicated a positive correlation between G9a expression and CYP7B1, a key enzyme of 27-HC catabolism. Overall, this study reports that 27-HC represses G9a expression via ERα and reduces the levels of H3K9me2 on a subset of genes, including the genes that aid in breast tumorigenesis and invasion further, increasing its expression in the breast cancer cells.

27-羟基胆固醇(27-HC)是一种胆固醇代谢物,是第一个发现的内源性选择性雌激素受体调节剂(SERM),已被证明在乳腺癌中具有增殖和转移活性。然而,27-HC代谢物是否调节乳腺癌及其进展的表观遗传特征仍不清楚。目前的研究报道,27-HC抑制了常染色质组蛋白赖氨酸甲基转移酶G9a的表达,进一步减少了一部分基因中H3K9的二甲基化。我们还观察到G9a启动子上ERα的占用减少,这表明27-HC负调控G9a启动子上ERα的占用,并作为转录抑制因子发挥作用。此外,H3K9me2标记的chip测序表明,27-HC治疗降低了与癌症进展、增殖和转移相关的基因子集上的H3K9me2标记。我们观察到27-HC处理后这些基因的上调,进一步证实了这些基因甲基化的缺失。乳腺癌患者组织免疫组化分析显示G9a表达与27-HC分解代谢关键酶CYP7B1呈正相关。总之,本研究报道27-HC通过ERα抑制G9a的表达,并降低一部分基因上的H3K9me2水平,包括有助于乳腺肿瘤发生和侵袭的基因,增加其在乳腺癌细胞中的表达。
{"title":"27-Hydroxycholesterol represses G9a expression via oestrogen receptor alpha in breast cancer","authors":"Ravindran Vini,&nbsp;Asha Lekshmi,&nbsp;Swathy Ravindran,&nbsp;Jissa Vinoda Thulaseedharan,&nbsp;Kunjuraman Sujathan,&nbsp;Arumugam Rajavelu,&nbsp;Sreeharshan Sreeja","doi":"10.1111/jcmm.17882","DOIUrl":"10.1111/jcmm.17882","url":null,"abstract":"<p>27-hydroxycholesterol (27-HC) is a cholesterol metabolite and the first discovered endogenous selective estrogen receptor modulator (SERM) that has been shown to have proliferative and metastatic activity in breast cancer. However, whether 27-HC metabolite modulates the epigenetic signatures in breast cancer and its progression remains unclear. The current study, reports that 27-HC represses the expression of euchromatic histone lysine methyltransferase G9a, further reducing di-methylation at H3K9 in a subset of genes. We also observed reduced occupancy of ERα at the G9a promoter, indicating that 27-HC negatively regulates the ERα occupancy on the <i>G9a</i> promoter and functions as a transcriptional repressor. Further, ChIP-sequencing for the H3K9me2 mark has demonstrated that 27-HC treatment reduces the H3K9me2 mark on subset of genes linked to cancer progression, proliferation, and metastasis. We observed upregulation of these genes following 27-HC treatment which further confirms the loss of methylation at these genes. Immunohistochemical analysis with breast cancer patient tissues indicated a positive correlation between G9a expression and CYP7B1, a key enzyme of 27-HC catabolism. Overall, this study reports that 27-HC represses G9a expression via ERα and reduces the levels of H3K9me2 on a subset of genes, including the genes that aid in breast tumorigenesis and invasion further, increasing its expression in the breast cancer cells.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":"27 18","pages":"2744-2755"},"PeriodicalIF":5.3,"publicationDate":"2023-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.17882","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10232251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Bazi Bushen alleviates skin senescence by orchestrating skin homeostasis in SAMP6 mice 八子补肾通过调节SAMP6小鼠的皮肤稳态来缓解皮肤衰老
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-08-23 DOI: 10.1111/jcmm.17833
Zhe Xu, Boyang Gong, Zhaodong Li, Ying Wang, Zeyu Zhao, Lulu Xie, Yanfei Peng, Shuwu Zhao, Huifang Zhou, Yuhong Bian

Bazi Bushen, a Chinese-patented drug with the function of relieving fatigue and delaying ageing, has been proven effective for extenuating skin senescence. To investigate the potential mechanism, senescence-accelerated mouse prone 6 (SAMP6) was intragastrically administered with Bazi Bushen for 9 weeks to induce skin homeostasis. Skin homeostasis is important in mitigating skin senescence, and it is related to many factors such as oxidative stress, SASP, apoptosis, autophagy and stem cell. In our study, skin damage in SAMP6 mice was observed using HE, Masson and SA-β-gal staining. The content of hydroxyproline and the activities of SOD, MDA, GSH-PX and T-AOC in the skin were measured using commercial assay kits. The level of SASP factors (IL-6, IL-1β, TNF-α, MMP2 and MMP9) in skin were measured using ELISA kits. The protein expressions of p16, p21, p53, Bax, Bcl-2, Cleaved caspase-3, LC3, p62, Beclin1, OCT4, SOX2 and NANOG were measured by western blotting. The expression of ITGA6 and COL17A1 was measured by immunofluorescence staining and western blotting. Our findings demonstrated that Bazi Bushen alleviated skin senescence by orchestrating skin homeostasis, reducing the level of oxidative stress and the expression of SASP, regulating the balance of apoptosis and autophagy and enhancing the protein expressions of ITGA6 and COL17A1 to improve skin structure in SAMP6 mice. This study indicated that Bazi Bushen could serve as a potential therapy for alleviating skin senescence.

八子补肾是一种具有缓解疲劳和延缓衰老功能的中成药,已被证明对缓解皮肤衰老有效。为了探讨其潜在的机制,我们将衰老加速小鼠易感6 (SAMP6)灌胃八子补肾9周,以诱导皮肤稳态。皮肤稳态在缓解皮肤衰老中起着重要作用,它与氧化应激、SASP、细胞凋亡、自噬、干细胞等多种因素有关。在我们的研究中,使用HE、Masson和SA-β-gal染色观察SAMP6小鼠的皮肤损伤。采用商品化检测试剂盒检测皮肤中羟脯氨酸含量及SOD、MDA、GSH-PX、T-AOC活性。采用ELISA试剂盒检测皮肤中SASP因子(IL-6、IL-1β、TNF-α、MMP2、MMP9)水平。western blotting检测p16、p21、p53、Bax、Bcl-2、Cleaved caspase-3、LC3、p62、Beclin1、OCT4、SOX2、NANOG蛋白的表达。免疫荧光染色和western blotting检测ITGA6和COL17A1的表达。我们的研究结果表明,八子补肾通过调节皮肤稳态,降低氧化应激水平和SASP的表达,调节细胞凋亡和自噬的平衡,提高ITGA6和COL17A1的蛋白表达,改善SAMP6小鼠的皮肤结构,从而缓解皮肤衰老。本研究提示八字补肾具有缓解皮肤衰老的潜在疗效。
{"title":"Bazi Bushen alleviates skin senescence by orchestrating skin homeostasis in SAMP6 mice","authors":"Zhe Xu,&nbsp;Boyang Gong,&nbsp;Zhaodong Li,&nbsp;Ying Wang,&nbsp;Zeyu Zhao,&nbsp;Lulu Xie,&nbsp;Yanfei Peng,&nbsp;Shuwu Zhao,&nbsp;Huifang Zhou,&nbsp;Yuhong Bian","doi":"10.1111/jcmm.17833","DOIUrl":"10.1111/jcmm.17833","url":null,"abstract":"<p>Bazi Bushen, a Chinese-patented drug with the function of relieving fatigue and delaying ageing, has been proven effective for extenuating skin senescence. To investigate the potential mechanism, senescence-accelerated mouse prone 6 (SAMP6) was intragastrically administered with Bazi Bushen for 9 weeks to induce skin homeostasis. Skin homeostasis is important in mitigating skin senescence, and it is related to many factors such as oxidative stress, SASP, apoptosis, autophagy and stem cell. In our study, skin damage in SAMP6 mice was observed using HE, Masson and SA-β-gal staining. The content of hydroxyproline and the activities of SOD, MDA, GSH-PX and T-AOC in the skin were measured using commercial assay kits. The level of SASP factors (IL-6, IL-1β, TNF-α, MMP2 and MMP9) in skin were measured using ELISA kits. The protein expressions of p16, p21, p53, Bax, Bcl-2, Cleaved caspase-3, LC3, p62, Beclin1, OCT4, SOX2 and NANOG were measured by western blotting. The expression of ITGA6 and COL17A1 was measured by immunofluorescence staining and western blotting. Our findings demonstrated that Bazi Bushen alleviated skin senescence by orchestrating skin homeostasis, reducing the level of oxidative stress and the expression of SASP, regulating the balance of apoptosis and autophagy and enhancing the protein expressions of ITGA6 and COL17A1 to improve skin structure in SAMP6 mice. This study indicated that Bazi Bushen could serve as a potential therapy for alleviating skin senescence.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":"27 18","pages":"2651-2660"},"PeriodicalIF":5.3,"publicationDate":"2023-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.17833","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10226719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The rejuvenating influence of young plasma on aged intestine 青年血浆对衰老肠道的恢复作用
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-08-23 DOI: 10.1111/jcmm.17926
Taha Ceylani, Hikmet Taner Teker, Seda Keskin, Gizem Samgane, Eda Acikgoz, Rafig Gurbanov

This study aims to investigate the effects of plasma exchange on the biomolecular profiles and histology of ileum and colon tissues in young and aged Sprague–Dawley male rats. Fourier transform infrared (FTIR) spectroscopy, linear discriminant analysis and support vector machine (SVM) techniques were employed to analyse the lipid, protein, and nucleic acid indices in young and aged rats. Following the application of young plasma, aged rats demonstrated biomolecular profiles similar to those of their younger counterparts. Histopathological and immunohistochemical assessments showed that young plasma had a protective effect on the intestinal tissues of aged rats, increasing cell density and reducing inflammation. Additionally, the expression levels of key inflammatory mediators tumour necrosis factor-alpha and cyclooxygenase-2 significantly decreased after young plasma administration. These findings underscore the therapeutic potential of young plasma for mitigating age-related changes and inflammation in the intestinal tract. They highlight the critical role of plasma composition in the ageing process and suggest the need for further research to explore how different regions of the intestines respond to plasma exchange. Such understanding could facilitate the development of innovative therapies targeting the gastrointestinal system, enhancing overall health during ageing.

本研究旨在探讨血浆交换对青年和老年雄性大鼠回肠和结肠组织的生物分子特征和组织学的影响。采用傅里叶变换红外光谱(FTIR)、线性判别分析和支持向量机(SVM)技术对幼龄和老年大鼠的脂质、蛋白质和核酸指标进行分析。在应用年轻血浆后,老年大鼠表现出与年轻大鼠相似的生物分子特征。组织病理学和免疫组化评价表明,年轻血浆对老年大鼠肠道组织具有保护作用,增加细胞密度,减少炎症。此外,关键炎症介质肿瘤坏死因子- α和环氧化酶-2的表达水平在年轻血浆给药后显著降低。这些发现强调了年轻血浆在缓解肠道年龄相关变化和炎症方面的治疗潜力。他们强调了血浆成分在衰老过程中的关键作用,并建议需要进一步研究,以探索肠道不同区域对血浆交换的反应。这样的理解可以促进针对胃肠道系统的创新疗法的发展,增强衰老过程中的整体健康。
{"title":"The rejuvenating influence of young plasma on aged intestine","authors":"Taha Ceylani,&nbsp;Hikmet Taner Teker,&nbsp;Seda Keskin,&nbsp;Gizem Samgane,&nbsp;Eda Acikgoz,&nbsp;Rafig Gurbanov","doi":"10.1111/jcmm.17926","DOIUrl":"10.1111/jcmm.17926","url":null,"abstract":"<p>This study aims to investigate the effects of plasma exchange on the biomolecular profiles and histology of ileum and colon tissues in young and aged Sprague–Dawley male rats. Fourier transform infrared (FTIR) spectroscopy, linear discriminant analysis and support vector machine (SVM) techniques were employed to analyse the lipid, protein, and nucleic acid indices in young and aged rats. Following the application of young plasma, aged rats demonstrated biomolecular profiles similar to those of their younger counterparts. Histopathological and immunohistochemical assessments showed that young plasma had a protective effect on the intestinal tissues of aged rats, increasing cell density and reducing inflammation. Additionally, the expression levels of key inflammatory mediators tumour necrosis factor-alpha and cyclooxygenase-2 significantly decreased after young plasma administration. These findings underscore the therapeutic potential of young plasma for mitigating age-related changes and inflammation in the intestinal tract. They highlight the critical role of plasma composition in the ageing process and suggest the need for further research to explore how different regions of the intestines respond to plasma exchange. Such understanding could facilitate the development of innovative therapies targeting the gastrointestinal system, enhancing overall health during ageing.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":"27 18","pages":"2804-2816"},"PeriodicalIF":5.3,"publicationDate":"2023-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.17926","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10283165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 2
Challenges in anti-aging medicine–trends in biomarker discovery and therapeutic interventions for a healthy lifespan 抗衰老医学的挑战——生物标志物发现的趋势和健康寿命的治疗干预
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-08-23 DOI: 10.1111/jcmm.17912
Iuliana Popescu, Joris Deelen, Maddalena Illario, Jan Adams

We are facing a growing aging population, along with increasing pressure on health systems, caused by the impact of chronic co-morbidities (i.e. cancer, cardiovascular and neurodegenerative diseases) and functional disabilities as people age. Relatively simple preventive lifestyle interventions, such as dietary restriction and physical exercise, are important contributors to active and healthy aging in the general population. However, as shown in model organisms or in 'in vitro' conditions, lifestyle-independent interventions may have additional health benefits and can even be conceived as possible reversers of the aging process. Thus, pharmaceutical laboratories, research institutes, and universities are putting more and more effort into finding new molecular pathways and druggable targets to develop gerotherapeutics. One approach is to target the driving mechanisms of aging, some of which, like cellular senescence and impaired autophagy, we discussed in an update on the biology of aging at AgingFit 2023 in Lille, France. We underline the importance of carefully and extensively testing senotherapeutics, given the pleiotropism and heterogeneity of targeted senescent cells within different organs, at different time frames. Other druggable targets emerging from new putative mechanisms, like those based on transcriptome imbalance, nucleophagy, protein phosphatase depletion, glutamine metabolism, or seno-antigenicity, have been evidenced by recent preclinical studies in classical models of aging but need to be validated in humans. Finally, we highlight several approaches in the discovery of biomarkers of healthy aging, as well as for the prediction of neurodegenerative diseases and the evaluation of rejuvenation strategies.

随着年龄的增长,慢性并发症(如癌症、心血管和神经退行性疾病)和功能性残疾的影响导致我们面临着日益增长的人口老龄化,以及卫生系统面临的压力越来越大。相对简单的预防性生活方式干预措施,如饮食限制和体育锻炼,是促进普通人群积极健康老龄化的重要因素。然而,正如在模式生物或“体外”条件下所显示的那样,独立于生活方式的干预措施可能对健康有额外的好处,甚至可以被认为是衰老过程的可能逆转者。因此,制药实验室、研究机构和大学正越来越多地致力于寻找新的分子途径和药物靶点来开发Gertherapeutics。一种方法是针对衰老的驱动机制,其中一些机制,如细胞衰老和自噬受损,我们在法国里尔AgingFit 2023的衰老生物学更新中进行了讨论。鉴于不同器官、不同时间段内靶向衰老细胞的多效性和异质性,我们强调了仔细和广泛测试感觉疗法的重要性。从新的假定机制中出现的其他可药用靶点,如基于转录组失衡、自噬、蛋白质磷酸酶耗竭、谷氨酰胺代谢或seno抗原性的靶点,已被最近在经典衰老模型中的临床前研究所证明,但需要在人类中进行验证。最后,我们强调了在发现健康衰老的生物标志物、预测神经退行性疾病和评估恢复策略方面的几种方法。
{"title":"Challenges in anti-aging medicine–trends in biomarker discovery and therapeutic interventions for a healthy lifespan","authors":"Iuliana Popescu,&nbsp;Joris Deelen,&nbsp;Maddalena Illario,&nbsp;Jan Adams","doi":"10.1111/jcmm.17912","DOIUrl":"10.1111/jcmm.17912","url":null,"abstract":"<p>We are facing a growing aging population, along with increasing pressure on health systems, caused by the impact of chronic co-morbidities (i.e. cancer, cardiovascular and neurodegenerative diseases) and functional disabilities as people age. Relatively simple preventive lifestyle interventions, such as dietary restriction and physical exercise, are important contributors to active and healthy aging in the general population. However, as shown in model organisms or in 'in vitro' conditions, lifestyle-independent interventions may have additional health benefits and can even be conceived as possible reversers of the aging process. Thus, pharmaceutical laboratories, research institutes, and universities are putting more and more effort into finding new molecular pathways and druggable targets to develop gerotherapeutics. One approach is to target the driving mechanisms of aging, some of which, like cellular senescence and impaired autophagy, we discussed in an update on the biology of aging at AgingFit 2023 in Lille, France. We underline the importance of carefully and extensively testing senotherapeutics, given the pleiotropism and heterogeneity of targeted senescent cells within different organs, at different time frames. Other druggable targets emerging from new putative mechanisms, like those based on transcriptome imbalance, nucleophagy, protein phosphatase depletion, glutamine metabolism, or seno-antigenicity, have been evidenced by recent preclinical studies in classical models of aging but need to be validated in humans. Finally, we highlight several approaches in the discovery of biomarkers of healthy aging, as well as for the prediction of neurodegenerative diseases and the evaluation of rejuvenation strategies.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":"27 18","pages":"2643-2650"},"PeriodicalIF":5.3,"publicationDate":"2023-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.17912","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10595298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Programmed cell death pathways as targets for developing antifilarial drugs: Lessons from the recent findings 程序化细胞死亡途径作为开发抗丝虫药物的靶点:从最近的发现中吸取的教训。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-08-22 DOI: 10.1111/jcmm.17913
Nabarun Chandra Das, Pritha Chakraborty, Samapika Nandy, Abhijit Dey, Tabarak Malik, Suprabhat Mukherjee

More than half a century has passed since the introduction of the National Filariasis Control Program; however, as of 2023, lymphatic filariasis (LF) still prevails globally, particularly in the tropical and subtropical regions, posing a substantial challenge to the objective of worldwide elimination. LF is affecting human beings and its economically important livestock leading to a crucial contributor to morbidities and disabilities. The current scenario has been blowing up alarms of attention to develop potent therapeutics and strategies having efficiency against the adult stage of filarial nematodes. In this context, the exploration of a suitable drug target that ensures lethality to macro and microfilariae is now our first goal to achieve. Apoptosis has been the potential target across all three stages of filarial nematodes viz. oocytes, microfilariae (mf) and adults resulting in filarial death after receiving the signal from the reactive oxygen species (ROS) and executed through intrinsic and extrinsic pathways. Hence, it is considered a leading target for developing antifilarial drugs. Herein, we have shown the efficacy of several natural and synthetic compounds/nanoformulations in triggering the apoptotic death of filarial parasites with little or no toxicity to the host body system.

自从国家丝虫病防治计划出台以来,半个多世纪过去了;然而,截至2023年,淋巴丝虫病仍在全球流行,特别是在热带和亚热带地区,这对在全球范围内消除淋巴丝虫病的目标构成了重大挑战。LF正在影响人类及其经济上重要的牲畜,导致疾病和残疾的关键因素。目前的情况已经引起了人们的注意,以开发有效的治疗方法和策略来对抗成年阶段的丝虫线虫。在这种情况下,探索一种合适的药物靶点,确保对宏微丝蚴和微丝蚴的致命性,现在是我们要实现的第一个目标。细胞凋亡一直是丝虫线虫所有三个阶段的潜在靶点,即卵母细胞、微丝蚴(mf)和成虫,在接受活性氧(ROS)的信号并通过内在和外在途径执行后导致丝虫死亡。因此,它被认为是开发抗丝虫药物的主要目标。在此,我们已经证明了几种天然和合成化合物/纳米制剂在引发丝虫寄生虫的细胞凋亡方面的功效,对宿主身体系统几乎没有毒性。
{"title":"Programmed cell death pathways as targets for developing antifilarial drugs: Lessons from the recent findings","authors":"Nabarun Chandra Das,&nbsp;Pritha Chakraborty,&nbsp;Samapika Nandy,&nbsp;Abhijit Dey,&nbsp;Tabarak Malik,&nbsp;Suprabhat Mukherjee","doi":"10.1111/jcmm.17913","DOIUrl":"10.1111/jcmm.17913","url":null,"abstract":"<p>More than half a century has passed since the introduction of the National Filariasis Control Program; however, as of 2023, lymphatic filariasis (LF) still prevails globally, particularly in the tropical and subtropical regions, posing a substantial challenge to the objective of worldwide elimination. LF is affecting human beings and its economically important livestock leading to a crucial contributor to morbidities and disabilities. The current scenario has been blowing up alarms of attention to develop potent therapeutics and strategies having efficiency against the adult stage of filarial nematodes. In this context, the exploration of a suitable drug target that ensures lethality to macro and microfilariae is now our first goal to achieve. Apoptosis has been the potential target across all three stages of filarial nematodes viz. oocytes, microfilariae (mf) and adults resulting in filarial death after receiving the signal from the reactive oxygen species (ROS) and executed through intrinsic and extrinsic pathways. Hence, it is considered a leading target for developing antifilarial drugs. Herein, we have shown the efficacy of several natural and synthetic compounds/nanoformulations in triggering the apoptotic death of filarial parasites with little or no toxicity to the host body system.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":"27 19","pages":"2819-2840"},"PeriodicalIF":5.3,"publicationDate":"2023-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.17913","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10396086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 1
OPA1, a molecular regulator of dilated cardiomyopathy OPA1,扩张型心肌病的分子调节因子。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-08-21 DOI: 10.1111/jcmm.17918
Jiaqi Chen, Jianan Shao, Yaoyao Wang, Kangxiang Wu, Mingyuan Huang

Dilated cardiomyopathy (DCM) is a disease with no specific treatment, poor prognosis and high mortality. During DCM development, there is apoptosis, mitochondrial dynamics imbalance and changes in cristae structure. Optic atrophy 1 (OPA1) appears at high frequency in these three aspects. DCM LMNA (LaminA/C) gene mutation can activate TP53, and the study of P53 shows that P53 affects OPA1 through Bak/Bax and OMA1 (a metalloprotease). OPA1 can be considered the missing link between DCMp53 and DCM apoptosis, mitochondrial dynamics imbalance and changes in cristae structure. OPA1 regulates apoptosis by regulating the release of cytochrome c from the mitochondrial matrix through CJs (crisp linkages, located in the inner mitochondrial membrane) and unbalances mitochondrial fusion and fission by affecting mitochondrial inner membrane (IM) fusion. OPA1 is also associated with the formation and maintenance of mitochondrial cristae. OPA1 is not the root cause of DCM, but it is an essential mediator in P53 mediating the occurrence and development of DCM, so OPA1 also becomes a molecular regulator of DCM. This review discusses the implication of OPA1 for DCM from three aspects: apoptosis, mitochondrial dynamics and ridge structure.

扩张型心肌病(DCM)是一种无特异性治疗、预后差、死亡率高的疾病。DCM发展过程中,细胞凋亡、线粒体动力学失衡和嵴结构变化。视神经萎缩1型(OPA1)在这三个方面出现频率较高。DCM LMNA(LaminA/C)基因突变可以激活TP53,对P53的研究表明,P53通过Bak/Bax和OMA1(一种金属蛋白酶)影响OPA1。OPA1可被认为是DCMp53与DCM细胞凋亡、线粒体动力学失衡和嵴结构变化之间的缺失环节。OPA1通过CJs(位于线粒体内膜的脆键)调节线粒体基质中细胞色素c的释放来调节细胞凋亡,并通过影响线粒体内膜(IM)融合来平衡线粒体融合和分裂。OPA1也与线粒体嵴的形成和维持有关。OPA1不是DCM的根本原因,但它是P53中介导DCM发生和发展的重要介质,因此OPA1也成为DCM的分子调节因子。本文从细胞凋亡、线粒体动力学和嵴结构三个方面论述了OPA1对DCM的影响。
{"title":"OPA1, a molecular regulator of dilated cardiomyopathy","authors":"Jiaqi Chen,&nbsp;Jianan Shao,&nbsp;Yaoyao Wang,&nbsp;Kangxiang Wu,&nbsp;Mingyuan Huang","doi":"10.1111/jcmm.17918","DOIUrl":"10.1111/jcmm.17918","url":null,"abstract":"<p>Dilated cardiomyopathy (DCM) is a disease with no specific treatment, poor prognosis and high mortality. During DCM development, there is apoptosis, mitochondrial dynamics imbalance and changes in cristae structure. Optic atrophy 1 (OPA1) appears at high frequency in these three aspects. DCM LMNA (LaminA/C) gene mutation can activate TP53, and the study of P53 shows that P53 affects OPA1 through Bak/Bax and OMA1 (a metalloprotease). OPA1 can be considered the missing link between DCMp53 and DCM apoptosis, mitochondrial dynamics imbalance and changes in cristae structure. OPA1 regulates apoptosis by regulating the release of cytochrome c from the mitochondrial matrix through CJs (crisp linkages, located in the inner mitochondrial membrane) and unbalances mitochondrial fusion and fission by affecting mitochondrial inner membrane (IM) fusion. OPA1 is also associated with the formation and maintenance of mitochondrial cristae. OPA1 is not the root cause of DCM, but it is an essential mediator in P53 mediating the occurrence and development of DCM, so OPA1 also becomes a molecular regulator of DCM. This review discusses the implication of OPA1 for DCM from three aspects: apoptosis, mitochondrial dynamics and ridge structure.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":"27 20","pages":"3017-3025"},"PeriodicalIF":5.3,"publicationDate":"2023-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.17918","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10035101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 1
Epigenetic histone modification by butyrate downregulates KIT and attenuates mast cell function 丁酸修饰表观遗传组蛋白下调KIT并减弱肥大细胞功能。
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-08-21 DOI: 10.1111/jcmm.17924
Ravindra Gudneppanavar, Emma Elizabeth Sabu Kattuman, Lakshminarayan Reddy Teegala, Erik Southard, Ramakumar Tummala, Bina Joe, Charles K. Thodeti, Sailaja Paruchuri

Short-chain fatty acid butyrate is produced from the bacterial fermentation of indigestible fiber in the intestinal lumen, and it has been shown to attenuate lung inflammation in murine asthma models. Mast cells (MCs) are initiators of inflammatory response to allergens, and they play an important role in asthma. MC survival and proliferation is regulated by its growth factor stem cell factor (SCF), which acts through the receptor, KIT. It has previously been shown that butyrate attenuates the activation of MCs by allergen stimulation. However, how butyrate mechanistically influences SCF signalling to impact MC function remains unknown. Here, we report that butyrate treatment triggered the modification of MC histones via butyrylation and acetylation, and inhibition of histone deacetylase (HDAC) activity. Further, butyrate treatment caused downregulation of SCF receptor KIT and associated phosphorylation, leading to significant attenuation of SCF-mediated MC proliferation, and pro-inflammatory cytokine secretion. Mechanistically, butyrate inhibited MC function by suppressing KIT and downstream p38 and Erk phosphorylation, and it mediated these effects via modification of histones, acting as an HDAC inhibitor and not via its traditional GPR41 (FFAR3) or GPR43 (FFAR2) butyrate receptors. In agreement, the pharmacological inhibition of Class I HDAC (HDAC1/3) mirrored butyrate's effects, suggesting that butyrate impacts MC function by HDAC1/3 inhibition. Taken together, butyrate epigenetically modifies histones and downregulates the SCF/KIT/p38/Erk signalling axis, leading to the attenuation of MC function, validating its ability to suppress MC-mediated inflammation. Therefore, butyrate supplementations could offer a potential treatment strategy for allergy and asthma via epigenetic alterations in MCs.

短链脂肪酸丁酸是由肠腔中不可消化纤维的细菌发酵产生的,在小鼠哮喘模型中,它已被证明可以减轻肺部炎症。肥大细胞是过敏原炎症反应的发起者,在哮喘中起着重要作用。MC的生存和增殖受其生长因子干细胞因子(SCF)的调节,SCF通过受体KIT发挥作用。先前已经表明丁酸盐通过过敏原刺激来减弱MCs的激活。然而,丁酸盐如何在机制上影响SCF信号传导以影响MC功能仍然未知。在此,我们报道了丁酸盐处理通过丁酰化和乙酰化触发MC组蛋白的修饰,并抑制组蛋白脱乙酰酶(HDAC)活性。此外,丁酸盐治疗导致SCF受体KIT和相关磷酸化的下调,导致SCF介导的MC增殖和促炎细胞因子分泌的显著减弱。从机制上讲,丁酸通过抑制KIT和下游p38和Erk磷酸化来抑制MC功能,并且它通过组蛋白的修饰介导这些作用,作为HDAC抑制剂,而不是通过其传统的GPR41(FFAR3)或GPR43(FFAR2)丁酸受体。一致认为,I类HDAC(HDAC1/3)的药理学抑制反映了丁酸的作用,表明丁酸通过HDAC1/3抑制影响MC功能。总之,丁酸盐表观遗传学修饰组蛋白并下调SCF/KIT/p38/Erk信号轴,导致MC功能减弱,验证了其抑制MC介导的炎症的能力。因此,补充丁酸盐可以通过MC的表观遗传学改变为过敏和哮喘提供一种潜在的治疗策略。
{"title":"Epigenetic histone modification by butyrate downregulates KIT and attenuates mast cell function","authors":"Ravindra Gudneppanavar,&nbsp;Emma Elizabeth Sabu Kattuman,&nbsp;Lakshminarayan Reddy Teegala,&nbsp;Erik Southard,&nbsp;Ramakumar Tummala,&nbsp;Bina Joe,&nbsp;Charles K. Thodeti,&nbsp;Sailaja Paruchuri","doi":"10.1111/jcmm.17924","DOIUrl":"10.1111/jcmm.17924","url":null,"abstract":"<p>Short-chain fatty acid butyrate is produced from the bacterial fermentation of indigestible fiber in the intestinal lumen, and it has been shown to attenuate lung inflammation in murine asthma models. Mast cells (MCs) are initiators of inflammatory response to allergens, and they play an important role in asthma. MC survival and proliferation is regulated by its growth factor stem cell factor (SCF), which acts through the receptor, KIT. It has previously been shown that butyrate attenuates the activation of MCs by allergen stimulation. However, how butyrate mechanistically influences SCF signalling to impact MC function remains unknown. Here, we report that butyrate treatment triggered the modification of MC histones via butyrylation and acetylation, and inhibition of histone deacetylase (HDAC) activity. Further, butyrate treatment caused downregulation of SCF receptor KIT and associated phosphorylation, leading to significant attenuation of SCF-mediated MC proliferation, and pro-inflammatory cytokine secretion. Mechanistically, butyrate inhibited MC function by suppressing KIT and downstream p38 and Erk phosphorylation, and it mediated these effects via modification of histones, acting as an HDAC inhibitor and not via its traditional GPR41 (FFAR3) or GPR43 (FFAR2) butyrate receptors. In agreement, the pharmacological inhibition of Class I HDAC (HDAC1/3) mirrored butyrate's effects, suggesting that butyrate impacts MC function by HDAC1/3 inhibition. Taken together, butyrate epigenetically modifies histones and downregulates the SCF/KIT/p38/Erk signalling axis, leading to the attenuation of MC function, validating its ability to suppress MC-mediated inflammation. Therefore, butyrate supplementations could offer a potential treatment strategy for allergy and asthma via epigenetic alterations in MCs.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":"27 19","pages":"2983-2994"},"PeriodicalIF":5.3,"publicationDate":"2023-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.17924","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10096355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
WKYMVm ameliorates obesity by improving lipid metabolism and leptin signalling WKYMVm通过改善脂质代谢和瘦素信号传导来改善肥胖
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-08-21 DOI: 10.1111/jcmm.17910
Ji Hyeon Kang, Hyung Sik Kim, Seon Hyang Park, Ye Seon Kim, Yoe-Sik Bae

Obesity is a metabolic disorder that results from an imbalance of energy intake and consumption. As low-grade chronic inflammation caused by obesity can lead to various complications, it is important to develop effective treatments against obesity. In this study, we investigate the effects of WKYMVm, a strong anti-inflammatory agent, against obesity. Administration of WKYMVm into high fat diet (HFD)-induced obese mice significantly attenuated body weight gain, food intake and increased insulin sensitivity. HFD-induced hepatic steatosis and adipose tissue hypertrophy were also markedly ameliorated by WKYMVm. During the maturation of adipocytes, WKYMVm improves lipid metabolism by increasing lipolysis, adipogenesis, mitochondrial biogenesis and fat browning. WKYMVm administration also elicited a decrease in leptin levels, but an increase in leptin sensitivity via regulation of hypothalamic endoplasmic reticulum stress and the leptin receptor cascade. Taken together, our results show that WKYMVm ameliorates obesity by improving lipid metabolism and leptin signalling, suggesting that WKYMVm can be a useful molecule for the development of anti-obesity agents.

肥胖是一种代谢紊乱,由能量摄入和消耗的不平衡引起。肥胖引起的低级别慢性炎症可导致各种并发症,因此开发有效的治疗方法非常重要。在这项研究中,我们研究了WKYMVm,一种强抗炎剂,对肥胖的影响。在高脂饮食(HFD)诱导的肥胖小鼠中给予WKYMVm可显著降低体重增加、食物摄入量和胰岛素敏感性。WKYMVm也能显著改善hfd诱导的肝脂肪变性和脂肪组织肥厚。在脂肪细胞成熟过程中,WKYMVm通过增加脂肪分解、脂肪生成、线粒体生物生成和脂肪褐变来改善脂质代谢。WKYMVm也引起了瘦素水平的降低,但通过调节下丘脑内质网应激和瘦素受体级联增加了瘦素敏感性。综上所述,我们的研究结果表明,WKYMVm通过改善脂质代谢和瘦素信号传导来改善肥胖,这表明WKYMVm可以成为开发抗肥胖药物的有用分子。
{"title":"WKYMVm ameliorates obesity by improving lipid metabolism and leptin signalling","authors":"Ji Hyeon Kang,&nbsp;Hyung Sik Kim,&nbsp;Seon Hyang Park,&nbsp;Ye Seon Kim,&nbsp;Yoe-Sik Bae","doi":"10.1111/jcmm.17910","DOIUrl":"10.1111/jcmm.17910","url":null,"abstract":"<p>Obesity is a metabolic disorder that results from an imbalance of energy intake and consumption. As low-grade chronic inflammation caused by obesity can lead to various complications, it is important to develop effective treatments against obesity. In this study, we investigate the effects of WKYMVm, a strong anti-inflammatory agent, against obesity. Administration of WKYMVm into high fat diet (HFD)-induced obese mice significantly attenuated body weight gain, food intake and increased insulin sensitivity. HFD-induced hepatic steatosis and adipose tissue hypertrophy were also markedly ameliorated by WKYMVm. During the maturation of adipocytes, WKYMVm improves lipid metabolism by increasing lipolysis, adipogenesis, mitochondrial biogenesis and fat browning. WKYMVm administration also elicited a decrease in leptin levels, but an increase in leptin sensitivity via regulation of hypothalamic endoplasmic reticulum stress and the leptin receptor cascade. Taken together, our results show that WKYMVm ameliorates obesity by improving lipid metabolism and leptin signalling, suggesting that WKYMVm can be a useful molecule for the development of anti-obesity agents.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":"27 18","pages":"2782-2791"},"PeriodicalIF":5.3,"publicationDate":"2023-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.17910","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10283150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Oestrogen treatment restores dentate gyrus development in premature newborns by IGF1 regulation 雌激素治疗通过IGF1调控恢复早产儿齿状回发育
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-08-18 DOI: 10.1111/jcmm.17816
Deep R. Sharma, Bokun Cheng, Rauhin Sahu, Xusheng Zhang, Rana Mehdizadeh, Divya Singh, Dumitru Iacobas, Praveen Ballabh

Prematurely-born infants cared for in the neonatal units suffer from memory and learning deficits. Prematurity diminishes neurogenesis and synaptogenesis in the hippocampal dentate gyrus (DG). This dysmaturation of neurons is attributed to elevated PSD95, NMDR2A, and IGF1 levels. Since oestrogen treatment plays key roles in the development and plasticity of DG, we hypothesized that 17β-estradiol (E2) treatment would ameliorate neurogenesis and synaptogenesis in the DG, reversing cognitive deficits in premature newborns. Additionally, E2-induced recovery would be mediated by IGF1 signalling. These hypotheses were tested in a rabbit model of prematurity and nonmaternal care, in which premature kits were gavage-fed and reared by laboratory personnel. We compared E2- and vehicle-treated preterm kits for morphological, molecular, and behavioural parameters. We also treated kits with oestrogen degrader, RAD1901, and assessed IGF1 signalling. We found that E2 treatment increased the number of Tbr2+ and DCX+ neuronal progenitors and increased the density of glutamatergic synapses in the DG. E2 treatment restored PSD95 and NMDAR2A levels and cognitive function in preterm kits. Transcriptomic analyses showed that E2 treatment contributed to recovery by influencing interactions between IGF1R and neurodegenerative, as well as glutamatergic genes. ERα expression was reduced on completion of E2 treatment at D7, followed by D30 elevation. E2-induced fluctuation in ERα levels was associated with a reciprocal elevation in IGF1/2 expression at D7 and reduction at D30. ERα degradation by RAD1901 treatment enhanced IGF1 levels, suggesting ERα inhibits IGF1 expression. E2 treatment alleviates the prematurity-induced maldevelopment of DG and cognitive dysfunctions by regulating ERα and IGF1 levels.

在新生儿病房照顾的早产儿患有记忆和学习缺陷。早产减少海马齿状回(DG)的神经发生和突触发生。这种神经元的不成熟归因于PSD95、NMDR2A和IGF1水平的升高。由于雌激素治疗在DG的发育和可塑性中起着关键作用,我们假设17β-雌二醇(E2)治疗可以改善DG的神经发生和突触发生,逆转早产新生儿的认知缺陷。此外,e2诱导的恢复可能由IGF1信号介导。这些假设在兔的早产和非母性护理模型中进行了测试,其中早产的幼兔由实验室人员灌食和饲养。我们比较了E2和载体处理的早产儿试剂盒的形态、分子和行为参数。我们还用雌激素降解剂RAD1901处理试剂盒,并评估IGF1信号传导。我们发现E2处理增加了DG中Tbr2+和DCX+神经元祖细胞的数量,增加了谷氨酸突触的密度。E2治疗可恢复早产儿PSD95和NMDAR2A水平及认知功能。转录组学分析表明,E2治疗通过影响IGF1R与神经退行性和谷氨酸能基因之间的相互作用有助于恢复。E2治疗结束后,ERα表达在D7降低,随后D30升高。e2诱导的ERα水平波动与D7时IGF1/2表达升高和D30时表达降低相关。RAD1901处理的ERα降解提高了IGF1水平,表明ERα抑制IGF1的表达。E2治疗可通过调节ERα和IGF1水平减轻过早诱导的DG发育不良和认知功能障碍。
{"title":"Oestrogen treatment restores dentate gyrus development in premature newborns by IGF1 regulation","authors":"Deep R. Sharma,&nbsp;Bokun Cheng,&nbsp;Rauhin Sahu,&nbsp;Xusheng Zhang,&nbsp;Rana Mehdizadeh,&nbsp;Divya Singh,&nbsp;Dumitru Iacobas,&nbsp;Praveen Ballabh","doi":"10.1111/jcmm.17816","DOIUrl":"10.1111/jcmm.17816","url":null,"abstract":"<p>Prematurely-born infants cared for in the neonatal units suffer from memory and learning deficits. Prematurity diminishes neurogenesis and synaptogenesis in the hippocampal dentate gyrus (DG). This dysmaturation of neurons is attributed to elevated PSD95, NMDR2A, and IGF1 levels. Since oestrogen treatment plays key roles in the development and plasticity of DG, we hypothesized that 17β-estradiol (E2) treatment would ameliorate neurogenesis and synaptogenesis in the DG, reversing cognitive deficits in premature newborns. Additionally, E2-induced recovery would be mediated by IGF1 signalling. These hypotheses were tested in a rabbit model of prematurity and nonmaternal care, in which premature kits were gavage-fed and reared by laboratory personnel. We compared E2- and vehicle-treated preterm kits for morphological, molecular, and behavioural parameters. We also treated kits with oestrogen degrader, RAD1901, and assessed IGF1 signalling. We found that E2 treatment increased the number of Tbr2<sup>+</sup> and DCX<sup>+</sup> neuronal progenitors and increased the density of glutamatergic synapses in the DG. E2 treatment restored PSD95 and NMDAR2A levels and cognitive function in preterm kits. Transcriptomic analyses showed that E2 treatment contributed to recovery by influencing interactions between <i>IGF1R</i> and neurodegenerative, as well as glutamatergic genes. ERα expression was reduced on completion of E2 treatment at D7, followed by D30 elevation. E2-induced fluctuation in ERα levels was associated with a reciprocal elevation in IGF1/2 expression at D7 and reduction at D30. ERα degradation by RAD1901 treatment enhanced IGF1 levels, suggesting ERα inhibits IGF1 expression. E2 treatment alleviates the prematurity-induced maldevelopment of DG and cognitive dysfunctions by regulating ERα and IGF1 levels.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":"27 17","pages":"2467-2481"},"PeriodicalIF":5.3,"publicationDate":"2023-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.17816","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10180766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 1
Next-generation bromodomain inhibitors of the SWI/SNF complex enhance DNA damage and cell death in glioblastoma 下一代SWI/SNF复合物的溴结构域抑制剂可增强胶质母细胞瘤中的DNA损伤和细胞死亡
IF 5.3 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-08-18 DOI: 10.1111/jcmm.17907
Chuanhe Yang, Yali He, Yinan Wang, Peter J. McKinnon, Vijay Shahani, Duane D. Miller, Lawrence M. Pfeffer

Glioblastoma (GBM) is an aggressive brain cancer with a poor prognosis. While surgical resection is the primary treatment, adjuvant temozolomide (TMZ) chemotherapy and radiotherapy only provide slight improvement in disease course and outcome. Unfortunately, most treated patients experience recurrence of highly aggressive, therapy-resistant tumours and eventually succumb to the disease. To increase chemosensitivity and overcome therapy resistance, we have modified the chemical structure of the PFI-3 bromodomain inhibitor of the BRG1 and BRM catalytic subunits of the SWI/SNF chromatin remodelling complex. Our modifications resulted in compounds that sensitized GBM to the DNA alkylating agent TMZ and the radiomimetic bleomycin. We screened these chemical analogues using a cell death ELISA with GBM cell lines and a cellular thermal shift assay using epitope tagged BRG1 or BRM bromodomains expressed in GBM cells. An active analogue, IV-129, was then identified and further modified, resulting in new generation of bromodomain inhibitors with distinct properties. IV-255 and IV-275 had higher bioactivity than IV-129, with IV-255 selectively binding to the bromodomain of BRG1 and not BRM, while IV-275 bound well to both BRG1 and BRM bromodomains. In contrast, IV-191 did not bind to either bromodomain or alter GBM chemosensitivity. Importantly, both IV-255 and IV-275 markedly increased the extent of DNA damage induced by TMZ and bleomycin as determined by nuclear γH2AX staining. Our results demonstrate that these next-generation inhibitors selectively bind to the bromodomains of catalytic subunits of the SWI/SNF complex and sensitize GBM to the anticancer effects of TMZ and bleomycin. This approach holds promise for improving the treatment of GBM.

胶质母细胞瘤(GBM)是一种预后不良的侵袭性脑癌。虽然手术切除是主要治疗方法,但替莫唑胺(TMZ)辅助化疗和放疗仅对病程和预后有轻微改善。不幸的是,大多数接受治疗的患者都经历了高度侵袭性、治疗抵抗性肿瘤的复发,最终死于这种疾病。为了提高化疗敏感性和克服治疗耐药性,我们修改了SWI/SNF染色质重塑复合体BRG1和BRM催化亚基的PFI-3溴结构域抑制剂的化学结构。我们的修饰产生了使GBM对DNA烷基化剂TMZ和模拟辐射的博来霉素敏感的化合物。我们使用GBM细胞系的细胞死亡ELISA和在GBM细胞中表达的标记BRG1或BRM溴结构域的表位进行细胞热移试验筛选这些化学类似物。随后,一种活性类似物IV-129被鉴定并进一步修饰,从而产生具有不同性质的新一代溴结构域抑制剂。IV-255和IV-275比IV-129具有更高的生物活性,IV-255选择性结合BRG1的溴域而不结合BRM,而IV-275与BRG1和BRM的溴域结合良好。相比之下,IV-191不与溴结构域结合或改变GBM的化学敏感性。重要的是,通过核γ - h2ax染色,IV-255和IV-275均显著增加TMZ和博莱霉素诱导的DNA损伤程度。我们的研究结果表明,这些新一代抑制剂选择性地结合到SWI/SNF复合物的催化亚基的溴结构域,并使GBM对TMZ和博来霉素的抗癌作用敏感。这种方法有望改善GBM的治疗。
{"title":"Next-generation bromodomain inhibitors of the SWI/SNF complex enhance DNA damage and cell death in glioblastoma","authors":"Chuanhe Yang,&nbsp;Yali He,&nbsp;Yinan Wang,&nbsp;Peter J. McKinnon,&nbsp;Vijay Shahani,&nbsp;Duane D. Miller,&nbsp;Lawrence M. Pfeffer","doi":"10.1111/jcmm.17907","DOIUrl":"10.1111/jcmm.17907","url":null,"abstract":"<p>Glioblastoma (GBM) is an aggressive brain cancer with a poor prognosis. While surgical resection is the primary treatment, adjuvant temozolomide (TMZ) chemotherapy and radiotherapy only provide slight improvement in disease course and outcome. Unfortunately, most treated patients experience recurrence of highly aggressive, therapy-resistant tumours and eventually succumb to the disease. To increase chemosensitivity and overcome therapy resistance, we have modified the chemical structure of the PFI-3 bromodomain inhibitor of the BRG1 and BRM catalytic subunits of the SWI/SNF chromatin remodelling complex. Our modifications resulted in compounds that sensitized GBM to the DNA alkylating agent TMZ and the radiomimetic bleomycin. We screened these chemical analogues using a cell death ELISA with GBM cell lines and a cellular thermal shift assay using epitope tagged BRG1 or BRM bromodomains expressed in GBM cells. An active analogue, IV-129, was then identified and further modified, resulting in new generation of bromodomain inhibitors with distinct properties. IV-255 and IV-275 had higher bioactivity than IV-129, with IV-255 selectively binding to the bromodomain of BRG1 and not BRM, while IV-275 bound well to both BRG1 and BRM bromodomains. In contrast, IV-191 did not bind to either bromodomain or alter GBM chemosensitivity. Importantly, both IV-255 and IV-275 markedly increased the extent of DNA damage induced by TMZ and bleomycin as determined by nuclear γH2AX staining. Our results demonstrate that these next-generation inhibitors selectively bind to the bromodomains of catalytic subunits of the SWI/SNF complex and sensitize GBM to the anticancer effects of TMZ and bleomycin. This approach holds promise for improving the treatment of GBM.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":"27 18","pages":"2770-2781"},"PeriodicalIF":5.3,"publicationDate":"2023-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcmm.17907","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10231734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 2
期刊
Journal of Cellular and Molecular Medicine
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1