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Author Correction: Insulin signaling is critical for sinoatrial node maintenance and function 作者更正:胰岛素信号对中房节点的维持和功能至关重要
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-24 DOI: 10.1038/s12276-024-01278-z
Sangmi Ock, Seong Woo Choi, Seung Hee Choi, Hyun Kang, Sung Joon Kim, Wang-Soo Lee, Jaetaek Kim
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引用次数: 0
Publisher Correction: Alleviation of preeclampsia-like symptoms through PlGF and eNOS regulation by hypoxia- and NF-κB-responsive miR-214-3p deletion 出版商更正:缺氧和 NF-κB 响应型 miR-214-3p 基因缺失可通过 PlGF 和 eNOS 调节缓解先兆子痫样症状。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-18 DOI: 10.1038/s12276-024-01275-2
Suji Kim, Sungbo Shim, Jisoo Kwon, Sungwoo Ryoo, Junyoung Byeon, Jungwoo Hong, Jeong-Hyung Lee, Young-Guen Kwon, Ji-Yoon Kim, Young-Myeong Kim
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引用次数: 0
Accelerated aging of skeletal muscle and the immune system in patients with chronic liver disease 加速慢性肝病患者骨骼肌和免疫系统的衰老。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-18 DOI: 10.1038/s12276-024-01287-y
Thomas Nicholson, Amritpal Dhaliwal, Jonathan I. Quinlan, Sophie L. Allen, Felicity R. Williams, Jon Hazeldine, Kirsty C. McGee, Jack Sullivan, Leigh Breen, Ahmed M. Elsharkawy, Matthew J. Armstrong, Simon W. Jones, Carolyn A. Greig, Janet M. Lord
Patients with chronic liver disease (CLD) often present with significant frailty, sarcopenia, and impaired immune function. However, the mechanisms driving the development of these age-related phenotypes are not fully understood. To determine whether accelerated biological aging may play a role in CLD, epigenetic, transcriptomic, and phenotypic assessments were performed on the skeletal muscle tissue and immune cells of CLD patients and age-matched healthy controls. Accelerated biological aging of the skeletal muscle tissue of CLD patients was detected, as evidenced by an increase in epigenetic age compared with chronological age (mean +2.2 ± 4.8 years compared with healthy controls at −3.0 ± 3.2 years, p = 0.0001). Considering disease etiology, age acceleration was significantly greater in both the alcohol-related (ArLD) (p = 0.01) and nonalcoholic fatty liver disease (NAFLD) (p = 0.0026) subgroups than in the healthy control subgroup, with no age acceleration observed in the immune-mediated subgroup or healthy control subgroup (p = 0.3). The skeletal muscle transcriptome was also enriched for genes associated with cellular senescence. Similarly, blood cell epigenetic age was significantly greater than that in control individuals, as calculated using the PhenoAge (p < 0.0001), DunedinPACE (p < 0.0001), or Hannum (p = 0.01) epigenetic clocks, with no difference using the Horvath clock. Analysis of the IMM-Age score indicated a prematurely aged immune phenotype in CLD patients that was 2-fold greater than that observed in age-matched healthy controls (p < 0.0001). These findings suggested that accelerated cellular aging may contribute to a phenotype associated with advanced age in CLD patients. Therefore, therapeutic interventions to reduce biological aging in CLD patients may improve health outcomes. Chronic liver disease, a long-term condition damaging the liver, is causing more deaths worldwide. Patients often develop immune dysfunction and sarcopenia. This study aimed to see if CLD patients show signs of fast biological ageing, particularly in muscles and the immune system. The research compared CLD patients to healthy people, looking at muscle samples, blood samples, and immune cells to check for ageing signs. Results showed that CLD patients have faster biological ageing in muscles and immune cells, with increased epigenetic age and more senescence-associated genes. This suggests that CLD speeds up the ageing process, which could explain the common occurrence of sarcopenia and immune dysfunction in these patients. Future implications include the possibility of developing treatments targeting the ageing process in CLD patients, offering hope for better health and quality of life This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
慢性肝病(CLD)患者通常表现出明显的虚弱、肌肉疏松和免疫功能受损。然而,这些与年龄有关的表型的形成机制尚未完全明了。为了确定加速生物衰老是否可能在 CLD 中起作用,研究人员对 CLD 患者和年龄匹配的健康对照组的骨骼肌组织和免疫细胞进行了表观遗传学、转录组学和表型评估。结果发现,CLD 患者骨骼肌组织的生物衰老速度加快,表现为表观遗传年龄比实际年龄增加(平均+2.2 ± 4.8岁,而健康对照组为-3.0 ± 3.2岁,P = 0.0001)。考虑到疾病病因,与酒精相关(ArLD)(p = 0.01)和非酒精性脂肪肝(NAFLD)(p = 0.0026)亚组的年龄加速明显大于健康对照亚组,免疫介导亚组或健康对照亚组未观察到年龄加速(p = 0.3)。骨骼肌转录组也富集了与细胞衰老相关的基因。同样,使用 PhenoAge 计算得出的血细胞表观遗传年龄也明显大于对照组(p = 0.3)。
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引用次数: 0
The role of BCAA metabolism in metabolic health and disease BCAA 代谢在代谢健康和疾病中的作用。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-02 DOI: 10.1038/s12276-024-01263-6
Byeong Hun Choi, Seunghoon Hyun, Seung-Hoi Koo
It has long been postulated that dietary restriction is beneficial for ensuring longevity and extending the health span of mammals, including humans. In particular, a reduction in protein consumption has been shown to be specifically linked to the beneficial effect of dietary restriction on metabolic disorders, presumably by reducing the activity of the mechanistic target of rapamycin complex (mTORC) 1 and the reciprocal activation of AMP-activated protein kinase (AMPK) and sirtuin pathways. Although it is widely used as a dietary supplement to delay the aging process in humans, recent evidence suggests that branched-chain amino acids (BCAAs) might be a major cause of the deteriorating effect of a protein diet on aging and related disorders. In this review, we delineate the regulation of metabolic pathways for BCAAs at the tissue-specific level and summarize recent findings regarding the role of BCAAs in the control of metabolic health and disease in mammals. This review article illustrates the function of branched-chain amino acids (BCAAs - essential nutrients we get from food) and how they’re processed in our bodies, in relation to health and illness. BCAAs are connected to aging processes and metabolic health - the body’s way of converting food into energy. Recent studies found that reducing BCAA intake can improve the health and lifespan of rodents. Similar studies were also conducted by using different animal models, like yeast, flies, rodents, and primates. It also emphasized the potential influence of BCAAs on human disease and aging metabolic processes. The review article concluded that BCAAs and their processing are vital for metabolic health and lifespan, and more research is needed to understand their effect on human health. Further studies on BCAAs could be important for creating diet plans and treatments for metabolic issues and aging-related diseases. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
长期以来,人们一直认为限制饮食有利于确保哺乳动物(包括人类)长寿并延长其健康寿命。特别是,蛋白质摄入量的减少已被证明与饮食限制对代谢紊乱的有益影响有特别联系,这可能是通过降低雷帕霉素机理靶点复合体(mTORC)1的活性以及AMP激活蛋白激酶(AMPK)和sirtuin通路的相互激活来实现的。尽管支链氨基酸被广泛用作延缓人类衰老的膳食补充剂,但最近的证据表明,支链氨基酸可能是导致蛋白质膳食对衰老和相关疾病产生不良影响的主要原因。在这篇综述中,我们将从组织特异性水平上描述支链氨基酸代谢途径的调控,并总结有关支链氨基酸在控制哺乳动物代谢健康和疾病方面作用的最新发现。
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引用次数: 0
Circadian disruption reduces MUC4 expression via the clock molecule BMAL1 during dry eye development 在干眼发育过程中,昼夜节律紊乱会通过时钟分子 BMAL1 减少 MUC4 的表达。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-02 DOI: 10.1038/s12276-024-01269-0
Hao Zeng, Xue Yang, Kai Liao, Xin Zuo, Lihong Liang, Dalian He, Rong Ju, Bowen Wang, Jin Yuan
Circadian disruption, as a result of shiftwork, jet lag, and other lifestyle factors, is a common public health problem associated with a wide range of diseases, such as metabolic disorders, neurodegenerative diseases, and cancer. In the present study, we established a chronic jet lag model using a time shift method every 3 days and assessed the effects of circadian disruption on ocular surface homeostasis. Our results indicated that jet lag increased corneal epithelial defects, cell apoptosis, and proinflammatory cytokine expression. However, the volume of tear secretion and the number of conjunctival goblet cells did not significantly change after 30 days of jet lag. Moreover, further analysis of the pathogenic mechanism using RNA sequencing revealed that jet lag caused corneal transmembrane mucin deficiency, specifically MUC4 deficiency. The crucial role of MUC4 in pathogenic progression was demonstrated by the protection of corneal epithelial cells and the inhibition of inflammatory activation following MUC4 replenishment. Unexpectedly, genetic ablation of BMAL1 in mice caused MUC4 deficiency and dry eye disease. The underlying mechanism was revealed in cultured human corneal epithelial cells in vitro, where BMAL1 silencing reduced MUC4 expression, and BMAL1 overexpression increased MUC4 expression. Furthermore, melatonin, a circadian rhythm restorer, had a therapeutic effect on jet lag-induced dry eye by restoring the expression of BMAL1, which upregulated MUC4. Thus, we generated a novel dry eye mouse model induced by circadian disruption, elucidated the underlying mechanism, and identified a potential clinical treatment. Dry eye disease, a long-term issue causing discomfort and vision problems, impacts millions globally. In this research, scientists studied how disturbances in our internal clock contribute to DED. Researchers made the mice experience an 8-hour shift in their day-night cycle every 3 days, imitating chronic jet lag. The findings showed that chronic jet lag resulted in a significant decrease in MUC4 expression in the cornea, leading to DED symptoms. Supplementing with MUC4 or treating the mice with melatonin, eased these symptoms. This indicates that disruptions to our internal clock can directly affect eye health by impacting key protective proteins in the eye. Researchers conclude that maintaining a healthy internal clock is vital for eye health and that treatments targeting internal clock disruptions could help DED patients. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
由于轮班工作、时差和其他生活方式因素造成的昼夜节律紊乱是一个常见的公共健康问题,与代谢紊乱、神经退行性疾病和癌症等多种疾病相关。在本研究中,我们使用每 3 天一次的时间转换方法建立了一个慢性时差模型,并评估了昼夜节律紊乱对眼表平衡的影响。结果表明,时差增加了角膜上皮缺陷、细胞凋亡和促炎细胞因子的表达。然而,时差 30 天后,泪液分泌量和结膜上皮细胞的数量并无明显变化。此外,利用 RNA 测序对致病机制的进一步分析表明,时差导致角膜跨膜粘蛋白缺乏,特别是 MUC4 缺乏。补充 MUC4 后,角膜上皮细胞得到保护,炎症激活也受到抑制,这证明了 MUC4 在致病过程中的关键作用。意想不到的是,小鼠BMAL1基因消减会导致MUC4缺乏和干眼症。在体外培养的人类角膜上皮细胞中,BMAL1沉默会减少MUC4的表达,而BMAL1过表达则会增加MUC4的表达。此外,褪黑激素是一种昼夜节律恢复剂,它能恢复 BMAL1 的表达,从而上调 MUC4,对时差引起的干眼症有治疗作用。因此,我们建立了一种由昼夜节律紊乱诱发的新型干眼症小鼠模型,阐明了其潜在机制,并确定了一种潜在的临床治疗方法。
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引用次数: 0
Patient-derived tumor organoids: a new avenue for preclinical research and precision medicine in oncology 源自患者的肿瘤器官组织:肿瘤学临床前研究和精准医疗的新途径。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-01 DOI: 10.1038/s12276-024-01272-5
Lucie Thorel, Marion Perréard, Romane Florent, Jordane Divoux, Sophia Coffy, Audrey Vincent, Cédric Gaggioli, Géraldine Guasch, Xavier Gidrol, Louis-Bastien Weiswald, Laurent Poulain
Over the past decade, the emergence of patient-derived tumor organoids (PDTOs) has broadened the repertoire of preclinical models and progressively revolutionized three-dimensional cell culture in oncology. PDTO can be grown from patient tumor samples with high efficiency and faithfully recapitulates the histological and molecular characteristics of the original tumor. Therefore, PDTOs can serve as invaluable tools in oncology research, and their translation to clinical practice is exciting for the future of precision medicine in oncology. In this review, we provide an overview of methods for establishing PDTOs and their various applications in cancer research, starting with basic research and ending with the identification of new targets and preclinical validation of new anticancer compounds and precision medicine. Finally, we highlight the challenges associated with the clinical implementation of PDTO, such as its representativeness, success rate, assay speed, and lack of a tumor microenvironment. Technological developments and autologous cocultures of PDTOs and stromal cells are currently ongoing to meet these challenges and optimally exploit the full potential of these models. The use of PDTOs as standard tools in clinical oncology could lead to a new era of precision oncology in the coming decade. The shift from 2D to 3D cell cultures has greatly improved cancer research, providing a more realistic model of tumors. Patient-Derived Tumor Organoids (PDTOs) have become a key tool in cancer research, allowing scientists to grow efficiently tumor cells from patient samples in a 3D environment that closely mirrors the original tumor. PDTOs are a major step forward in cancer research, bridging the gap between traditional cell cultures and clinical realities, with the potential for successful clinical applications despite some challenges that could be overcome by technological developments. Thus, they offer a promising platform for understanding cancer, testing drug responses, and developing personalized treatments, with the potential to greatly impact future patient care. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
在过去十年中,患者来源肿瘤器官组织(PDTO)的出现拓宽了临床前模型的范围,并逐步革新了肿瘤学中的三维细胞培养。PDTO 可以从患者肿瘤样本中高效培养出来,并忠实再现原始肿瘤的组织学和分子特征。因此,PDTO 可作为肿瘤学研究的宝贵工具,将其应用于临床实践对肿瘤学精准医学的未来发展具有重要意义。在这篇综述中,我们概述了建立 PDTO 的方法及其在癌症研究中的各种应用,从基础研究开始,到新靶点的鉴定、新抗癌化合物的临床前验证和精准医疗。最后,我们强调了与 PDTO 临床应用相关的挑战,如其代表性、成功率、检测速度和缺乏肿瘤微环境等。为应对这些挑战并以最佳方式充分挖掘这些模型的潜力,目前正在进行技术开发以及 PDTO 和基质细胞的自体共培养。将 PDTOs 作为临床肿瘤学的标准工具可在未来十年开创精准肿瘤学的新纪元。
{"title":"Patient-derived tumor organoids: a new avenue for preclinical research and precision medicine in oncology","authors":"Lucie Thorel,&nbsp;Marion Perréard,&nbsp;Romane Florent,&nbsp;Jordane Divoux,&nbsp;Sophia Coffy,&nbsp;Audrey Vincent,&nbsp;Cédric Gaggioli,&nbsp;Géraldine Guasch,&nbsp;Xavier Gidrol,&nbsp;Louis-Bastien Weiswald,&nbsp;Laurent Poulain","doi":"10.1038/s12276-024-01272-5","DOIUrl":"10.1038/s12276-024-01272-5","url":null,"abstract":"Over the past decade, the emergence of patient-derived tumor organoids (PDTOs) has broadened the repertoire of preclinical models and progressively revolutionized three-dimensional cell culture in oncology. PDTO can be grown from patient tumor samples with high efficiency and faithfully recapitulates the histological and molecular characteristics of the original tumor. Therefore, PDTOs can serve as invaluable tools in oncology research, and their translation to clinical practice is exciting for the future of precision medicine in oncology. In this review, we provide an overview of methods for establishing PDTOs and their various applications in cancer research, starting with basic research and ending with the identification of new targets and preclinical validation of new anticancer compounds and precision medicine. Finally, we highlight the challenges associated with the clinical implementation of PDTO, such as its representativeness, success rate, assay speed, and lack of a tumor microenvironment. Technological developments and autologous cocultures of PDTOs and stromal cells are currently ongoing to meet these challenges and optimally exploit the full potential of these models. The use of PDTOs as standard tools in clinical oncology could lead to a new era of precision oncology in the coming decade. The shift from 2D to 3D cell cultures has greatly improved cancer research, providing a more realistic model of tumors. Patient-Derived Tumor Organoids (PDTOs) have become a key tool in cancer research, allowing scientists to grow efficiently tumor cells from patient samples in a 3D environment that closely mirrors the original tumor. PDTOs are a major step forward in cancer research, bridging the gap between traditional cell cultures and clinical realities, with the potential for successful clinical applications despite some challenges that could be overcome by technological developments. Thus, they offer a promising platform for understanding cancer, testing drug responses, and developing personalized treatments, with the potential to greatly impact future patient care. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 7","pages":"1531-1551"},"PeriodicalIF":9.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141472203","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
Phospholipase C-β3 is dispensable for vascular constriction but indispensable for vascular hyperplasia 磷脂酶 C-β3 对于血管收缩是不可或缺的,但对于血管增生却是不可或缺的。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-01 DOI: 10.1038/s12276-024-01271-6
Seo Yeon Jin, Jung Min Ha, Hye Jin Kum, Ji Soo Ma, Hong Koo Ha, Sang Heon Song, Yong Ryoul Yang, Ho Lee, Yoon Soo Bae, Masahiro Yamamoto, Pann-Ghill Suh, Sun Sik Bae
Angiotensin II (AngII) induces the contraction and proliferation of vascular smooth muscle cells (VSMCs). AngII activates phospholipase C-β (PLC-β), thereby inducing Ca2+ mobilization as well as the production of reactive oxygen species (ROS). Since contraction is a unique property of contractile VSMCs, signaling cascades related to the proliferation of VSMCs may differ. However, the specific molecular mechanism that controls the contraction or proliferation of VSMCs remains unclear. AngII-induced ROS production, migration, and proliferation were suppressed by inhibiting PLC-β3, inositol trisphosphate (IP3) receptor, and NOX or by silencing PLC-β3 or NOX1 but not by NOX4. However, pharmacological inhibition or silencing of PLC-β3 or NOX did not affect AngII-induced VSMC contraction. Furthermore, the AngII-dependent constriction of mesenteric arteries isolated from PLC-β3∆SMC, NOX1−/−, NOX4−/− and normal control mice was similar. AngII-induced VSMC contraction and mesenteric artery constriction were blocked by inhibiting the L-type calcium channel Rho-associated kinase 2 (ROCK2) or myosin light chain kinase (MLCK). The activation of ROCK2 and MLCK was significantly induced in PLC-β3∆SMC mice, whereas the depletion of Ca2+ in the extracellular medium suppressed the AngII-induced activation of ROCK2, MLCK, and vasoconstriction. AngII-induced hypertension was significantly induced in NOX1−/− and PLC-β3∆SMC mice, whereas LCCA ligation-induced neointima formation was significantly suppressed in NOX1−/− and PLC-β3∆SMC mice. These results suggest that PLC-β3 is essential for vascular hyperplasia through NOX1-mediated ROS production but is nonessential for vascular constriction or blood pressure regulation. Angiotensin II is important in heart health. It makes blood vessels tighten and grow. This study looked at how AngII affects the creation of reactive oxygen species (ROS, molecules that change cell function) in vascular smooth muscle cells (VSMCs, cells in blood vessel walls). The researchers tested how stopping certain cell signals changes ROS creation and cell behaviors like growth and movement. They found that a specific protein, PLC-β3, and an enzyme, NOX1, are key in this process. Stopping these molecules could lower ROS levels and change cell growth and movement, important for blood vessel health. Interestingly, these molecules didn’t affect blood vessel tightening, also controlled by AngII. This study could help develop new treatments for blood vessel diseases, potentially helping manage conditions like high blood pressure and heart disease. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
血管紧张素 II(AngII)可诱导血管平滑肌细胞(VSMC)收缩和增殖。血管紧张素 II 会激活磷脂酶 C-β(PLC-β),从而诱导 Ca2+ 迁移并产生活性氧(ROS)。由于收缩是收缩性血管内皮细胞的独特特性,与血管内皮细胞增殖相关的信号级联可能有所不同。然而,控制 VSMC 收缩或增殖的具体分子机制仍不清楚。抑制 PLC-β3、三磷酸肌醇(IP3)受体和 NOX 或沉默 PLC-β3 或 NOX1 均可抑制 AngII 诱导的 ROS 生成、迁移和增殖,但 NOX4 却不能抑制。然而,药物抑制或沉默 PLC-β3 或 NOX 并不影响 AngII 诱导的 VSMC 收缩。此外,从 PLC-β3∆SMC、NOX1-/-、NOX4-/- 和正常对照小鼠分离的肠系膜动脉受 AngII 依赖性收缩的情况相似。抑制 L 型钙通道罗-相关激酶 2(ROCK2)或肌球蛋白轻链激酶(MLCK)可阻断 AngII 诱导的 VSMC 收缩和肠系膜动脉收缩。在 PLC-β3∆SMC 小鼠中,ROCK2 和 MLCK 的活化被显著诱导,而细胞外培养基中 Ca2+ 的耗竭抑制了 AngII 诱导的 ROCK2、MLCK 活化和血管收缩。NOX1-/-和 PLC-β3∆SMC 小鼠明显诱发了 AngII 诱导的高血压,而 NOX1-/- 和 PLC-β3∆SMC 小鼠则明显抑制了 LCCA 结扎诱导的新内膜形成。这些结果表明,PLC-β3 通过 NOX1 介导的 ROS 生成对血管增生是必不可少的,但对血管收缩或血压调节则是非必需的。
{"title":"Phospholipase C-β3 is dispensable for vascular constriction but indispensable for vascular hyperplasia","authors":"Seo Yeon Jin,&nbsp;Jung Min Ha,&nbsp;Hye Jin Kum,&nbsp;Ji Soo Ma,&nbsp;Hong Koo Ha,&nbsp;Sang Heon Song,&nbsp;Yong Ryoul Yang,&nbsp;Ho Lee,&nbsp;Yoon Soo Bae,&nbsp;Masahiro Yamamoto,&nbsp;Pann-Ghill Suh,&nbsp;Sun Sik Bae","doi":"10.1038/s12276-024-01271-6","DOIUrl":"10.1038/s12276-024-01271-6","url":null,"abstract":"Angiotensin II (AngII) induces the contraction and proliferation of vascular smooth muscle cells (VSMCs). AngII activates phospholipase C-β (PLC-β), thereby inducing Ca2+ mobilization as well as the production of reactive oxygen species (ROS). Since contraction is a unique property of contractile VSMCs, signaling cascades related to the proliferation of VSMCs may differ. However, the specific molecular mechanism that controls the contraction or proliferation of VSMCs remains unclear. AngII-induced ROS production, migration, and proliferation were suppressed by inhibiting PLC-β3, inositol trisphosphate (IP3) receptor, and NOX or by silencing PLC-β3 or NOX1 but not by NOX4. However, pharmacological inhibition or silencing of PLC-β3 or NOX did not affect AngII-induced VSMC contraction. Furthermore, the AngII-dependent constriction of mesenteric arteries isolated from PLC-β3∆SMC, NOX1−/−, NOX4−/− and normal control mice was similar. AngII-induced VSMC contraction and mesenteric artery constriction were blocked by inhibiting the L-type calcium channel Rho-associated kinase 2 (ROCK2) or myosin light chain kinase (MLCK). The activation of ROCK2 and MLCK was significantly induced in PLC-β3∆SMC mice, whereas the depletion of Ca2+ in the extracellular medium suppressed the AngII-induced activation of ROCK2, MLCK, and vasoconstriction. AngII-induced hypertension was significantly induced in NOX1−/− and PLC-β3∆SMC mice, whereas LCCA ligation-induced neointima formation was significantly suppressed in NOX1−/− and PLC-β3∆SMC mice. These results suggest that PLC-β3 is essential for vascular hyperplasia through NOX1-mediated ROS production but is nonessential for vascular constriction or blood pressure regulation. Angiotensin II is important in heart health. It makes blood vessels tighten and grow. This study looked at how AngII affects the creation of reactive oxygen species (ROS, molecules that change cell function) in vascular smooth muscle cells (VSMCs, cells in blood vessel walls). The researchers tested how stopping certain cell signals changes ROS creation and cell behaviors like growth and movement. They found that a specific protein, PLC-β3, and an enzyme, NOX1, are key in this process. Stopping these molecules could lower ROS levels and change cell growth and movement, important for blood vessel health. Interestingly, these molecules didn’t affect blood vessel tightening, also controlled by AngII. This study could help develop new treatments for blood vessel diseases, potentially helping manage conditions like high blood pressure and heart disease. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 7","pages":"1620-1630"},"PeriodicalIF":9.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297146/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141472205","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
Activation of the osteoblastic HIF-1α pathway partially alleviates the symptoms of STZ-induced type 1 diabetes mellitus via RegIIIγ 通过 RegIIIγ 激活成骨细胞 HIF-1α 通路可部分缓解 STZ 诱导的 1 型糖尿病的症状。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-01 DOI: 10.1038/s12276-024-01257-4
Minglong Qiu, Leilei Chang, Guoqing Tang, Wenkai Ye, Yiming Xu, Nijiati Tulufu, Zhou Dan, Jin Qi, Lianfu Deng, Changwei Li
The hypoxia-inducible factor-1α (HIF-1α) pathway coordinates skeletal bone homeostasis and endocrine functions. Activation of the HIF-1α pathway increases glucose uptake by osteoblasts, which reduces blood glucose levels. However, it is unclear whether activating the HIF-1α pathway in osteoblasts can help normalize glucose metabolism under diabetic conditions through its endocrine function. In addition to increasing bone mass and reducing blood glucose levels, activating the HIF-1α pathway by specifically knocking out Von Hippel‒Lindau (Vhl) in osteoblasts partially alleviated the symptoms of streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM), including increased glucose clearance in the diabetic state, protection of pancreatic β cell from STZ-induced apoptosis, promotion of pancreatic β cell proliferation, and stimulation of insulin secretion. Further screening of bone-derived factors revealed that islet regeneration-derived protein III gamma (RegIIIγ) is an osteoblast-derived hypoxia-sensing factor critical for protection against STZ-induced T1DM. In addition, we found that iminodiacetic acid deferoxamine (SF-DFO), a compound that mimics hypoxia and targets bone tissue, can alleviate symptoms of STZ-induced T1DM by activating the HIF-1α-RegIIIγ pathway in the skeleton. These data suggest that the osteoblastic HIF-1α-RegIIIγ pathway is a potential target for treating T1DM. The skeleton isn’t just for support, it also helps control body functions. This research looked at how a specific process in bone-forming cells, called the hypoxia-inducible factor-1 alpha (HIF-1α) pathway, affects sugar breakdown and diabetes. The scientists discovered that triggering this process in these cells can help manage sugar levels in diabetes through a protein named RegIIIγ. They also found that a substance named SF-DFO, which imitates low oxygen conditions and focuses on bone tissue, can somewhat ease type 1 diabetes symptoms by triggering the HIF-1α-RegIIIγ process in the skeleton. This implies that this specific process in bone-forming cells could be a possible treatment for type 1 diabetes. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
缺氧诱导因子-1α(HIF-1α)通路协调着骨骼的骨稳态和内分泌功能。激活 HIF-1α 通路可增加成骨细胞对葡萄糖的吸收,从而降低血糖水平。然而,激活成骨细胞中的 HIF-1α 通路是否能通过其内分泌功能帮助糖尿病患者实现葡萄糖代谢正常化,目前尚不清楚。通过特异性敲除成骨细胞中的Von Hippel-Lindau(Vhl)来激活HIF-1α通路,除了能增加骨量和降低血糖水平外,还能部分缓解链脲佐菌素(STZ)诱导的1型糖尿病(T1DM)的症状,包括增加糖尿病状态下的葡萄糖清除率、保护胰腺β细胞免受STZ诱导的凋亡、促进胰腺β细胞增殖以及刺激胰岛素分泌。对骨源性因子的进一步筛选发现,胰岛再生衍生蛋白Ⅲγ(RegⅢγ)是一种成骨细胞衍生的低氧传感因子,对保护STZ诱导的T1DM至关重要。此外,我们还发现亚氨基二乙酸去氧胺(SF-DFO)是一种模拟缺氧并靶向骨组织的化合物,它能通过激活骨骼中的 HIF-1α-RegIIIγ 通路来缓解 STZ 诱导的 T1DM 症状。这些数据表明,成骨细胞的 HIF-1α-RegIIIγ 通路是治疗 T1DM 的潜在靶点。
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引用次数: 0
Development of a novel testis-on-a-chip that demonstrates reciprocal crosstalk between Sertoli and Leydig cells in testicular tissue 开发新型睾丸芯片,展示睾丸组织中 Sertoli 细胞和 Leydig 细胞之间的相互串扰。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-01 DOI: 10.1038/s12276-024-01258-3
Se-Ra Park, Myung Geun Kook, Soo-Rim Kim, Choon-Mi Lee, Jin Woo Lee, Jung-Kyu Park, Chan Hum Park, Byung-Chul Oh, YunJae Jung, In-Sun Hong
The reciprocal crosstalk between testicular Sertoli and Leydig cells plays a vital role in supporting germ cell development and maintaining testicular characteristics and spermatogenesis. Conventional 2D and the recent 3D assay systems fail to accurately replicate the dynamic interactions between these essential endocrine cells. Furthermore, most in vitro testicular tissue models lack the ability to capture the complex multicellular nature of the testis. To address these limitations, we developed a 3D multicellular testis-on-a-chip platform that effectively demonstrates the reciprocal crosstalk between Sertoli cells and the adjacent Leydig cells while incorporating various human testicular tissue constituent cells and various natural polymers infused with blood coagulation factors. Additionally, we identified SERPINB2 as a biomarker of male reproductive toxicity that is activated in both Sertoli and Leydig cells upon exposure to various toxicants. Leveraging this finding, we designed a fluorescent reporter-conjugated toxic biomarker detection system that enables both an intuitive and quantitative assessment of material toxicity by measuring the converted fluorescence intensity. By integrating this fluorescent reporter system into the Sertoli and Leydig cells within our 3D multicellular chip platform, we successfully developed a testis-on-chip model that can be utilized to evaluate the male reproductive toxicity of potential drug candidates. This innovative approach holds promise for advancing toxicity screening and reproductive research. Spermatogenesis, or sperm creation, happens in the testis and involves various cells, including Sertoli and Leydig cells. However, traditional single-cell-based 2D assay models (tests that measure the presence of a substance) don’t accurately show the complex interactions between these cells. To solve this, scientists created a ‘human testis-on-a-chip’ platform that imitates the complex cell interactions and hormone communication of seminiferous tubules (small tubes) in the testis. The chip was made using polydimethylsiloxane (a type of silicone) and included multiple testicular tissue cells. The scientists found that the chip could keep the cells alive and active for up to 28 days. Also, the chip was able to produce hormones and respond to hormonal stimulation. This study provides a useful tool for studying male reproductive biology and testing potential drugs. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
睾丸Sertoli细胞和Leydig细胞之间的相互交织在支持生殖细胞发育、维持睾丸特征和精子生成方面起着至关重要的作用。传统的二维和最新的三维检测系统无法准确复制这些重要内分泌细胞之间的动态相互作用。此外,大多数体外睾丸组织模型都无法捕捉睾丸复杂的多细胞特性。为了解决这些局限性,我们开发了一种三维多细胞睾丸芯片平台,它能有效地展示 Sertoli 细胞和邻近的 Leydig 细胞之间的相互串扰,同时结合了各种人类睾丸组织成分细胞和注入血液凝固因子的各种天然聚合物。此外,我们还发现 SERPINB2 是男性生殖毒性的生物标志物,当暴露于各种有毒物质时,Sertoli 和 Leydig 细胞中的 SERPINB2 都会被激活。利用这一发现,我们设计了一种荧光报告物共轭毒性生物标记物检测系统,通过测量转换后的荧光强度,对物质毒性进行直观和定量评估。通过将这种荧光报告系统集成到我们的三维多细胞芯片平台中的 Sertoli 细胞和 Leydig 细胞中,我们成功开发出了一种睾丸芯片模型,可用于评估潜在候选药物的男性生殖毒性。这种创新方法有望推动毒性筛选和生殖研究。
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引用次数: 0
Genome-resolved metagenomics: a game changer for microbiome medicine 基因组解析元基因组学:改变微生物组医学的游戏规则。
IF 9.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-01 DOI: 10.1038/s12276-024-01262-7
Nayeon Kim, Junyeong Ma, Wonjong Kim, Jungyeon Kim, Peter Belenky, Insuk Lee
Recent substantial evidence implicating commensal bacteria in human diseases has given rise to a new domain in biomedical research: microbiome medicine. This emerging field aims to understand and leverage the human microbiota and derivative molecules for disease prevention and treatment. Despite the complex and hierarchical organization of this ecosystem, most research over the years has relied on 16S amplicon sequencing, a legacy of bacterial phylogeny and taxonomy. Although advanced sequencing technologies have enabled cost-effective analysis of entire microbiota, translating the relatively short nucleotide information into the functional and taxonomic organization of the microbiome has posed challenges until recently. In the last decade, genome-resolved metagenomics, which aims to reconstruct microbial genomes directly from whole-metagenome sequencing data, has made significant strides and continues to unveil the mysteries of various human-associated microbial communities. There has been a rapid increase in the volume of whole metagenome sequencing data and in the compilation of novel metagenome-assembled genomes and protein sequences in public depositories. This review provides an overview of the capabilities and methods of genome-resolved metagenomics for studying the human microbiome, with a focus on investigating the prokaryotic microbiota of the human gut. Just as decoding the human genome and its variations marked the beginning of the genomic medicine era, unraveling the genomes of commensal microbes and their sequence variations is ushering us into the era of microbiome medicine. Genome-resolved metagenomics stands as a pivotal tool in this transition and can accelerate our journey toward achieving these scientific and medical milestones. The human body houses numerous microbes, tiny organisms, that are vital for our health. This research aims to overcome limitations using genome-resolved metagenomics, a method that assembles complete genomes from complex microbial communities without needing to grow the organisms in a lab. The study focuses on the gut microbiome, using advanced computer methods to build metagenome-assembled genomes from DNA sequencing data. The research successfully increased the genetic diversity of the human gut microbiome by adding many new genomes to the existing database. The main findings include identifying new microbial species and expanding the genetic repertoire of known species, providing deeper understanding of the microbial diversity within the human gut. Researchers conclude that genome-resolved metagenomics is a significant advancement in microbiome research, offering understanding of microbial communities and their functions. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
最近有大量证据表明,共生细菌与人类疾病有关联,这催生了生物医学研究的一个新领域:微生物组医学。这一新兴领域旨在了解和利用人体微生物群及其衍生分子来预防和治疗疾病。尽管这一生态系统的组织结构复杂且层次分明,但多年来大多数研究都依赖于 16S 扩增子测序,这是细菌系统发育和分类学的遗产。尽管先进的测序技术能够对整个微生物群进行经济有效的分析,但直到最近,将相对较短的核苷酸信息转化为微生物群的功能和分类组织仍是一项挑战。近十年来,旨在直接从全基因组测序数据重建微生物基因组的基因组解析元基因组学取得了长足的进步,并不断揭开各种人类相关微生物群落的神秘面纱。全元基因组测序数据的数量以及在公共储存库中汇编的新型元基因组组装基因组和蛋白质序列都在迅速增加。本综述概述了基因组分辨元基因组学研究人类微生物组的能力和方法,重点是研究人类肠道的原核微生物群。正如解码人类基因组及其变异标志着基因组医学时代的开始一样,揭示共生微生物的基因组及其序列变异正把我们带入微生物组医学时代。基因组解析元基因组学是这一转变过程中的关键工具,可以加快我们实现这些科学和医学里程碑的进程。
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引用次数: 0
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Experimental and Molecular Medicine
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