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Healthy plasma lipidomic signatures depend on sex, age, body mass index, and contraceptives but not perceived stress. 健康血浆脂质体特征取决于性别、年龄、体重指数和避孕药具,但与感知到的压力无关。
IF 5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-22 DOI: 10.1152/ajpcell.00630.2024
Lisa Hahnefeld, Juliane Hackel, Sandra Trautmann, Carlo Angioni, Yannick Schreiber, Robert Gurke, Dominique Thomas, Sabine Wicker, Gerd Geisslinger, Irmgard Tegeder

Perceived stress is thought to contribute to the pathogenesis of metabolic, vascular, mental, and immune diseases, with different susceptibilities in women and men. The present study investigated if and how perceived stress and/or demographic variables including sex, age, body mass index, regular prescription drugs, occasional analgesics, or dietary supplements manifested in plasma lipidomic profiles, obtained by targeted and untargeted mass spectrometry analyses. The study included 217 healthy women and 108 healthy men, aged 18-68 years, who were recruited in a 2:1 female:male ratio to account for women with/without contraceptives. As expected, dehydroepiandrosterone sulfate (DHEAS) and ceramides were higher in men than women, and DHEAS decreased with age, while ceramides increased. Contrary to expectations, neither DHEAS nor ceramides were associated with perceived stress (PSQ30 questionnaire), which was however, associated with BMI in men, but not in women. None of the lipid species or classes showed a similar "age X sex X BMI" interaction, but the endocannabinoid palmitoylethanolamide (PEA) correlated with BMI and hypertension. Independent of perceived stress, lysophosphatidylcholines (LPCs) were lower in women than men, whereas LPC metabolites, lysophosphatidic acids (LPAs), were higher in women. The LPA:LPC ratio was particularly high in women using oral contraceptives suggesting a strong hormone-induced extracellular conversion of LPCs to LPAs, which is catalyzed by the phospholipase D, autotaxin. The results reveal complex sex differences in perceived stress and lipidomic profiles, the latter being exacerbated by contraceptive use, but perceived stress and lipids were not directly correlated.

感知压力被认为是代谢、血管、精神和免疫疾病的发病机制之一,而女性和男性的易感性有所不同。本研究调查了感知到的压力和/或人口统计学变量(包括性别、年龄、体重指数、经常服用的处方药、偶尔服用的镇痛药或膳食补充剂)是否以及如何体现在通过靶向和非靶向质谱分析获得的血浆脂质体图谱中。研究对象包括 217 名健康女性和 108 名健康男性,年龄在 18-68 岁之间,男女比例为 2:1,以考虑到使用/未使用避孕药具的女性。不出所料,男性的硫酸脱氢表雄酮(DHEAS)和神经酰胺含量均高于女性,而且随着年龄的增长,DHEAS有所下降,而神经酰胺则有所增加。与预期相反,DHEAS 和神经酰胺均与压力感知(PSQ30 问卷)无关,但男性的压力感知与体重指数有关,而女性则与之无关。没有一种脂质或脂质类别显示出类似的 "年龄 X 性别 X BMI "相互作用,但内源性大麻素棕榈酰乙醇酰胺(PEA)与 BMI 和高血压相关。与感知压力无关,女性的溶血磷脂酰胆碱(LPCs)低于男性,而女性的 LPC 代谢物溶血磷脂酸(LPAs)高于男性。使用口服避孕药的女性体内 LPA 与 LPC 的比率特别高,这表明 LPCs 在细胞外转化为 LPAs 的过程中受到了激素的强烈诱导,而这种转化是由磷脂酶 D 和自体脂酶催化的。研究结果表明,在感知压力和脂质组学特征方面存在复杂的性别差异,使用避孕药会加剧后者,但感知压力和脂质并不直接相关。
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引用次数: 0
TFEB signaling promotes autophagic degradation of NLRP3 to attenuate neuroinflammation in diabetic encephalopathy. TFEB 信号促进 NLRP3 的自噬降解,从而减轻糖尿病脑病的神经炎症。
IF 5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-22 DOI: 10.1152/ajpcell.00322.2024
Yijia Lin, Lizhen Cheng, Yixin Chen, Wei Li, Qihao Guo, Ya Miao

Diabetic encephalopathy (DE), a neurological complication of diabetes mellitus, has an unclear etiology. Shreds of evidence show that the Nucleotide-binding oligomerization domain-like receptor family protein 3 (NLRP3) inflammasome-induced neuroinflammation and transcription factor EB (TFEB)-mediated autophagy impairment may take part in DE development. The crosstalk between these two pathways and their contribution to DE remains to be explored. A mouse model of type 2 diabetes mellitus (T2DM) exhibiting cognitive dysfunction was created, along with high glucose (HG) cultured BV2 cells. Following, 3-methyladenine (3-MA) and rapamycin were utilized to modulate autophagy. To evaluate the potential therapeutic benefits of TFEB in DE, we overexpressed and knocked down TFEB in both mice and cells. Autophagy impairment and NLRP3 inflammasome activation were noticed in T2DM mice and HG-cultured BV2 cells. The inflammatory response caused by NLRP3 inflammasome activation was decreased by rapamycin-induced autophagy enhancement, while 3-MA treatment further deteriorated it. Nuclear translocation and expression of TFEB were hampered in HG-cultured BV2 cells and T2DM mice. Exogenous TFEB overexpression boosted NLRP3 degradation via autophagy, which in turn alleviated microglial activation as well as ameliorated cognitive deficits and neuronal damage. Additionally, TFEB knockdown exacerbated neuroinflammation by decreasing autophagy-mediated NLRP3 degradation. Our findings have unraveled the pathogenesis of a previously underappreciated disease, implying that the activation of NLRP3 inflammasome and impairment of autophagy in microglia are significant etiological factors in the DE. The TFEB-mediated autophagy pathway can reduce neuroinflammation by enhancing NLRP3 degradation. This could potentially serve as a viable and innovative treatment approach for DE.

糖尿病脑病(DE)是糖尿病的一种神经系统并发症,其病因尚不清楚。一些证据表明,核苷酸结合寡聚化结构域样受体家族蛋白 3(NLRP3)炎性体诱导的神经炎症和转录因子 EB(TFEB)介导的自噬损伤可能参与了糖尿病脑病的发病。这两种途径之间的相互影响及其对 DE 的贡献仍有待探索。研究人员创建了一个表现出认知功能障碍的2型糖尿病(T2DM)小鼠模型,同时还创建了高糖(HG)培养的BV2细胞。随后,3-甲基腺嘌呤(3-MA)和雷帕霉素被用来调节自噬。为了评估 TFEB 在 DE 中的潜在治疗效果,我们在小鼠和细胞中过表达和敲除了 TFEB。在T2DM小鼠和HG培养的BV2细胞中,自噬功能受损,NLRP3炎性体活化。雷帕霉素诱导的自噬增强可降低 NLRP3 炎症小体激活引起的炎症反应,而 3-MA 处理则进一步恶化了这种反应。在 HG 培养的 BV2 细胞和 T2DM 小鼠中,TFEB 的核转位和表达受到阻碍。外源性 TFEB 的过表达通过自噬促进了 NLRP3 的降解,从而缓解了小胶质细胞的激活,并改善了认知障碍和神经元损伤。此外,敲除 TFEB 会减少自噬介导的 NLRP3 降解,从而加剧神经炎症。我们的研究结果揭示了一种以前未被重视的疾病的发病机制,暗示小胶质细胞中NLRP3炎性体的激活和自噬功能的受损是导致神经元损伤的重要病因。TFEB 介导的自噬途径可以通过增强 NLRP3 降解来减轻神经炎症。这有可能成为治疗 DE 的一种可行的创新方法。
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引用次数: 0
IQGAP-2: A novel interacting partner for the Human Colonic Thiamin Pyrophosphate Transporter (hcTPPT). IQGAP-2:人类结肠硫胺素焦磷酸转运体(hcTPPT)的新型相互作用伙伴。
IF 5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-14 DOI: 10.1152/ajpcell.00484.2024
Kalidas Ramamoorthy, Subrata Sabui, George Kim, James M Fleckenstein, Alaullah Sheikh, Hamid M Said

The human colonic thiamin pyrophosphate transporter (hcTPPT) mediates the uptake of the microbiota-generated and phosphorylated form of vitamin B1 (i. e., thiamin pyrophosphate) in the large intestine. Expression of hcTPPT along the absorptive tract is restricted to the large intestine and the transporter is exclusively localized at the apical membrane domain of the polarized epithelial cells/colonocytes. Previous studies have characterized different physiological/pathophysiological aspects of the hcTPPT system, but nothing is currently known on whether the transporter has interacting partner(s) that affects its physiology/biology. We addressed this issue using a Y2H to screen a human colonic cDNA library, and have identified 3 putative interactors, namely IQGAP-2, SNX-6 and DMXL-1. Focusing on IQGAP-2 (whose expression in human colonocytes is the highest), we found (using fluorescent microscopy imaging and co-immunoprecipitation approaches) the putative interactor to co-localize with hcTPPT, and to directly interact with the transporter. Also, over-expressing IQGAP-2 in NCM460 cells and in human primary differentiated colonoid monolayers was found to lead to significant (P < 0.01) induction in TPP uptake, while it's knocking down (using gene-specific siRNAs) caused significant (P < 0.01 & < 0.05) decrease in uptake. Furthermore, over-expressing IQGAP-2 in NCM460 cells was found to lead to a significant enhancement in hcTPPT protein stability. Finally, we found the expression of IQGAP-2 to be markedly suppressed in conditions/factors that negatively impact colonic TPP uptake. These results identify the IQGAP-2 as an interacting partner with the hcTPPT in human colonocytes and show that this interaction has physiological and biological consequences.

人类结肠硫胺素焦磷酸转运体(hcTPPT)在大肠中介导微生物群生成的磷酸化形式的维生素 B1(即硫胺素焦磷酸)的吸收。hcTPPT 沿着吸收道的表达仅限于大肠,而且该转运体只定位在极化上皮细胞/结肠细胞的顶端膜域。以前的研究已经描述了 hcTPPT 系统的不同生理/病理生理学特征,但目前还不知道该转运体是否有影响其生理/生物学的相互作用伙伴。我们利用 Y2H 筛选人类结肠 cDNA 文库来解决这个问题,并确定了 3 个推定的相互作用者,即 IQGAP-2、SNX-6 和 DMXL-1。以 IQGAP-2(其在人类结肠细胞中的表达量最高)为重点,我们发现(使用荧光显微镜成像和共沉淀免疫方法)该推定相互作用因子与 hcTPPT 共定位,并与该转运体直接相互作用。研究还发现,在 NCM460 细胞和人类原代分化结肠单层中过度表达 IQGAP-2 会显著(P 0.01)诱导 TPP 的吸收,而敲除 IQGAP-2(使用基因特异性 siRNAs)则会显著(P < 0.01 和 0.05)降低 TPP 的吸收。此外,我们还发现在 NCM460 细胞中过度表达 IQGAP-2 会显著增强 hcTPPT 蛋白的稳定性。最后,我们发现在对结肠 TPP 吸收有负面影响的条件/因素下,IQGAP-2 的表达受到明显抑制。这些结果确定了 IQGAP-2 是人结肠细胞中 hcTPPT 的相互作用伙伴,并表明这种相互作用具有生理和生物学后果。
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引用次数: 0
Emerging Roles of Ketone Bodies in Cardiac Fibrosis. 酮体在心脏纤维化中的新作用
IF 5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-14 DOI: 10.1152/ajpcell.00241.2024
Kellina Maduray, Jingquan Zhong

Cardiac fibrosis, characterized by excessive extracellular matrix (ECM) deposition within the myocardium, poses a significant challenge in cardiovascular health, contributing to various cardiac pathologies. Ketone bodies (KBs), particularly β-hydroxybutyrate (β-OHB), have emerged as subjects of interest due to their potential cardioprotective effects. However, their specific influence on cardiac fibrosis remains underexplored. This literature review comprehensively examines the relationship between KBs and cardiac fibrosis, elucidating potential mechanisms through which KBs modulate fibrotic pathways. A multifaceted interplay exists between KBs and key mediators of cardiac fibrosis. While some studies indicate a pro-fibrotic role for KBs, others highlight their potential to attenuate fibrosis and cardiac remodeling. Mechanistically, KBs may regulate fibrotic pathways through modulation of cellular components such as cardiac fibroblasts, macrophages, and lymphocytes, as well as extracellular matrix proteins. Furthermore, the impact of KBs on cellular processes implicated in fibrosis, including oxidative stress, chemokine and cytokine expression, caspase activation, and inflammasome signaling are explored. While conflicting findings exist regarding the effects of KBs on these processes, emerging evidence suggests a predominantly beneficial role in mitigating inflammation and oxidative stress associated with fibrotic remodeling. Overall, this review underscores the importance of elucidating the complex interplay between KB metabolism and cardiac fibrosis. Insights gained have the potential to inform novel therapeutic strategies for managing cardiac fibrosis and associated cardiovascular disorders, highlighting the need for further research in this area.

心肌纤维化的特点是细胞外基质(ECM)在心肌内过度沉积,它对心血管健康构成了重大挑战,并导致各种心脏病变。酮体(KBs),尤其是β-羟基丁酸(β-OHB),因其潜在的心脏保护作用而成为人们关注的对象。然而,它们对心脏纤维化的具体影响仍未得到充分探讨。这篇文献综述全面研究了KBs与心脏纤维化之间的关系,阐明了KBs调节纤维化途径的潜在机制。KBs与心脏纤维化的关键介质之间存在着多方面的相互作用。一些研究表明,KBs 具有促进纤维化的作用,而另一些研究则强调了其减轻纤维化和心脏重塑的潜力。从机理上讲,KBs 可通过调节心脏成纤维细胞、巨噬细胞和淋巴细胞等细胞成分以及细胞外基质蛋白来调节纤维化途径。此外,还探讨了 KBs 对与纤维化有关的细胞过程的影响,包括氧化应激、趋化因子和细胞因子表达、Caspase 激活和炎性体信号转导。虽然关于 KBs 对这些过程的影响存在相互矛盾的研究结果,但新出现的证据表明,KBs 在减轻与纤维化重塑相关的炎症和氧化应激方面起着主要的有益作用。总之,本综述强调了阐明 KB 代谢与心脏纤维化之间复杂的相互作用的重要性。所获得的见解有可能为管理心肌纤维化和相关心血管疾病的新型治疗策略提供依据,并强调了在这一领域开展进一步研究的必要性。
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引用次数: 0
Effects of age on human skeletal muscle: A systematic review and meta-analysis of myosin heavy chain isoform protein expression, fiber size and distribution. 年龄对人体骨骼肌的影响:肌球蛋白重链同工酶蛋白表达、纤维大小和分布的系统回顾和荟萃分析。
IF 5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-07 DOI: 10.1152/ajpcell.00347.2024
Christopher Lee, Philip C Woods, Amanda E Paluch, Mark S Miller

Human studies examining the cellular mechanisms behind sarcopenia, or age-related loss of skeletal muscle mass and function, have produced inconsistent results. A systematic review and meta-analysis were performed to determine the aging effects on protein expression, size and distribution of fibers with various myosin heavy chain (MyHC) isoforms. Study eligibility included MyHC comparisons between young (18-49 years) and older (≥ 60 years) adults, with 27 studies identified. Relative protein expression was higher with age for the slow-contracting MyHC I fibers, with correspondingly lower fast-contracting MyHC II and IIA values. Fiber sizes were similar with age for MyHC I, while smaller for MyHC II and IIA. Fiber distributions were similar with age. When separated by sex, the few studies that examined females showed atrophy of MyHC II and IIA fibers with age, but no change in MyHC protein expression. Additional analyses by measurement technique, physical activity, and muscle biopsied provided important insights. In summary, age-related atrophy in fast-contracting fibers lead to more of the slow-contracting, lower force-producing isoform in older male muscles, which helps explain their age-related loss in whole muscle force, velocity, and power. Exercise or pharmacological interventions that shift MyHC expression towards faster isoforms and/or increase fast-contracting fiber size should decrease the prevalence of sarcopenia. Our findings also indicate that future studies need to include or focus solely on females, measure MyHC IIA and IIX isoforms separately, examine fiber type distribution, sample additional muscles to the vastus lateralis, and incorporate an objective measurement of physical activity.

人类对肌肉疏松症(与年龄有关的骨骼肌质量和功能丧失)背后的细胞机制进行了研究,但结果并不一致。为了确定衰老对各种肌球蛋白重链(MyHC)异构体的蛋白质表达、大小和纤维分布的影响,我们进行了系统回顾和荟萃分析。研究资格包括对年轻人(18-49 岁)和老年人(≥ 60 岁)的 MyHC 进行比较,共确定了 27 项研究。随着年龄的增长,慢收缩 MyHC I 纤维的相对蛋白表达量较高,相应地,快收缩 MyHC II 和 IIA 值较低。随着年龄的增长,MyHC I 纤维的大小相似,而 MyHC II 和 IIA 纤维的大小较小。纤维分布与年龄相似。如果按性别区分,少数研究显示女性的肌强直素 II 和 IIA 纤维随着年龄的增长而萎缩,但肌强直素蛋白的表达没有变化。按测量技术、体力活动和肌肉活检进行的其他分析提供了重要的见解。总之,在老年男性肌肉中,与年龄相关的快速收缩纤维萎缩导致了更多的慢速收缩、低力异构体,这有助于解释与年龄相关的整块肌肉力、速度和力量的损失。通过运动或药物干预,将 MyHC 的表达转向较快的同工酶和/或增加快速收缩纤维的大小,应能降低肌肉疏松症的发病率。我们的研究结果还表明,未来的研究需要包括女性或仅关注女性,分别测量 MyHC IIA 和 IIX 同工酶,检查纤维类型分布,对阔筋膜外的其他肌肉进行抽样调查,并纳入体育锻炼的客观测量方法。
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引用次数: 0
5-Aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase promotes pulmonary arterial smooth muscle cell proliferation via the Ras signaling pathway. --------ATIC 通过 Ras 信号通路促进肺动脉平滑肌细胞增殖。
IF 5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-12 DOI: 10.1152/ajpcell.00262.2024
Xiaofan Shi, Qian Ma, Yuqing Huo, Yunchao Su

Pulmonary arterial hypertension (PAH) is a debilitating vascular disorder characterized by abnormal pulmonary artery smooth muscle cell (PASMC) proliferation and collagen synthesis, contributing to vascular remodeling and elevated pulmonary vascular resistance. This study investigated the critical role of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC) in cell proliferation and collagen synthesis in PASMCs in PAH. Here we show that ATIC levels are significantly increased in the lungs of monocrotaline (MCT)-induced PAH rat model, hypoxia-induced PAH mouse model, and platelet-derived growth factor (PDGF)-stimulated PASMCs. Inhibition of ATIC attenuated PDGF-induced cell proliferation and collagen I synthesis in PASMCs. Conversely, overexpression or knockdown of ATIC causes a significant promotion or inhibition of Ras and ERK activation, cell proliferation, and collagen synthesis in PASMCs. Moreover, ATIC deficiency attenuated Ras activation in the lungs of hypoxia-induced PAH mice. Furthermore, Ras inhibition attenuates ATIC overexpression- and PDGF-induced collagen synthesis and PASMC proliferation. Notably, we identified that transcription factors MYC, early growth response protein 1 (EGR1), and specificity protein 1 (SP1) directly binds to promoters of Atic gene and regulate ATIC expression. These results provide the first evidence that ATIC promotes PASMC proliferation in pulmonary vascular remodeling through the Ras signaling pathway.NEW & NOTEWORTHY Our findings highlight the important role of ATIC in the PASMC proliferation of pulmonary vascular remodeling through its modulation of the Ras signaling pathway and its regulation by transcription factors MYC, EGR1, and SP1. ATIC's modulation of Ras signal pathway represents a novel mechanism contributing to PAH development.

肺动脉高压(PAH)是一种使人衰弱的血管疾病,其特点是肺动脉平滑肌细胞(PASMC)增殖和胶原合成异常,导致血管重塑和肺血管阻力升高。本研究调查了 5-氨基咪唑-4-甲酰胺核糖核苷酸甲酰转移酶/肌苷酸单磷酸环醇酶(ATIC)在 PAH 患者 PASMC 细胞增殖和胶原合成中的关键作用。我们在这里发现,在 MCT 诱导的 PAH 大鼠模型和缺氧诱导的 PAH 小鼠模型肺中,以及 PDGF 刺激的 PASMCs 中,ATIC 水平明显升高。抑制 ATIC 可减少血小板衍生生长因子(PDGF)诱导的 PASMCs 细胞增殖和胶原 I 合成。相反,过表达或敲除 ATIC 会显著促进或抑制 PASMCs 中 Ras 和 ERK 的活化、细胞增殖和胶原合成。此外,ATIC 的缺失可减轻缺氧诱导的 PAH 小鼠肺部的 Ras 激活。此外,抑制 Ras 可减轻 ATIC 过表达和 PDGF 诱导的胶原合成和 PASMC 增殖。值得注意的是,我们发现转录因子 MYC、EGR1 和 SP1 直接与 ATIC 基因启动子结合并调控 ATIC 的表达。这些结果首次证明 ATIC 通过 Ras 信号通路促进肺血管重塑过程中 PASMC 的增殖。
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引用次数: 0
Time of day affects MrgD-dependent modulation of cardiomyocyte contractility. 时间对心肌细胞收缩力的调节具有依赖性。
IF 5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-19 DOI: 10.1152/ajpcell.00049.2024
André L L Monteiro, Marcos Eliezeck, Sérgio R A Scalzo, Mário Morais Silva, Bruno Sanches, Katyana K S Ferreira, Maristela O Poletini, Rodrigo A Peliciari-Garcia, Stêfany B A Cau, Robson A Souza Santos, Silvia Guatimosim

The renin-angiotensin system (RAS) is composed of a series of peptides, receptors, and enzymes that play a pivotal role in maintaining cardiovascular homeostasis. Among the most important players in this system are the angiotensin-II and angiotensin-(1-7) peptides. Our group has recently demonstrated that alamandine (ALA), a peptide with structural and functional similarities to angiotensin-(1-7), interacts with cardiomyocytes, enhancing contractility via the Mas-related G protein-coupled receptor member D (MrgD). It is currently unknown whether this modulation varies along the distinct phases of the day. To address this issue, we assessed the ALA-induced contractility response of cardiomyocytes from mice at four Zeitgeber times (ZTs). At ZT2 (light phase), ALA enhanced cardiomyocyte shortening in an MrgD receptor-dependent manner, which was associated with nitric oxide (NO) production. At ZT14 (dark phase), ALA induced a negative modulation on the cardiomyocyte contraction. β-Alanine, an MrgD agonist, reproduced the time-of-day effects of ALA on myocyte shortening. NG-nitro-l-arginine methyl ester, an NO synthase inhibitor, blocked the increase in fractional shortening induced by ALA at ZT2. No effect of ALA on myocyte shortening was observed at ZT8 and ZT20. Our results show that ALA/MrgD signaling in cardiomyocytes is subject to temporal modulation. This finding has significant implications for pharmacological approaches that combine chronotherapy for cardiac conditions triggered by disruption of circadian rhythms and hormonal signaling.NEW & NOTEWORTHY Alamandine, a member of the renin-angiotensin system, serves critical roles in cardioprotection, including the modulation of cardiomyocyte contractility. Whether this effect varies along the day is unknown. Our results provide evidence that alamandine via receptor MrgD exerts opposing actions on cardiomyocyte shortening, enhancing, or reducing contraction depending on the time of day. These findings may have significant implications for the development and effectiveness of future cardiac therapies.

肾素-血管紧张素系统(RAS)由一系列肽、受体和酶组成,在维持心血管平衡方面发挥着关键作用。该系统中最重要的角色是血管紧张素-II 和血管紧张素-(1-7)肽。我们的研究小组最近证明,阿拉曼丁(ALA)是一种在结构和功能上与血管紧张素-(1-7)相似的多肽,它能与心肌细胞相互作用,通过与 Mas 相关的 G 蛋白偶联受体成员 D(MrgD)增强收缩力。目前还不清楚这种调节作用是否会随着一天中不同阶段的变化而变化。为了解决这个问题,我们评估了 ALA 诱导的小鼠心肌细胞在四个 Zeitgeber 时间(ZTs)的收缩力反应。在 ZT2(光照阶段),ALA 以依赖于 MrgD 受体的方式增强了心肌细胞的缩短,这与 NO 的产生有关。在 ZT14(暗期),ALA 对心肌细胞收缩产生负向调节。MrgD激动剂β-丙氨酸再现了ALA对心肌细胞缩短的时间效应。氮氧化物合成酶抑制剂 L-NG-硝基精氨酸甲酯(L-NAME)阻断了 ALA 在 ZT2 诱导的缩短率增加。在 ZT 8 和 20 时,未观察到 ALA 对肌细胞缩短的影响。我们的研究结果表明,心肌细胞中的 ALA/MrgD 信号传导受时间调节。这一发现对结合时间疗法的药理方法具有重要意义,可治疗昼夜节律紊乱和激素信号转导引发的心脏疾病。
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引用次数: 0
Renoprotective effects of empagliflozin in high-fat diet-induced obesity-related glomerulopathy by regulation of gut-kidney axis. Empagliflozin 通过调节肠道-肾脏轴对高脂饮食诱发肥胖相关性肾小球病变的雷诺保护作用
IF 5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-26 DOI: 10.1152/ajpcell.00367.2024
Lei Lei, Ting Zhu, Tian-Jiao Cui, Yvonne Liu, Johann-Georg Hocher, Xin Chen, Xue-Mei Zhang, Kai-Wen Cai, Zi-Yan Deng, Xiao-Hua Wang, Chun Tang, Lian Lin, Christoph Reichetzeder, Zhi-Hua Zheng, Berthold Hocher, Yong-Ping Lu

The increasing prevalence of obesity-related glomerulopathy (ORG) poses a significant threat to public health. Sodium-glucose cotransporter-2 (SGLT2) inhibitors effectively reduce body weight and total fat mass in individuals with obesity and halt the progression of ORG. However, the underlying mechanisms of their reno-protective effects in ORG remain unclear. We established a high-fat diet-induced ORG model using C57BL/6J mice, which were divided into three groups: normal chow diet (NCD group), high-fat diet (HFD) mice treated with placebo (ORG group), and HFD mice treated with empagliflozin (EMPA group). We conducted 16S ribosomal RNA gene sequencing of feces and analyzed metabolites from kidney, feces, liver, and serum samples. ORG mice showed increased urinary albumin creatinine ratio, cholesterol, triglyceride levels, and glomerular diameter compared with NCD mice (all P < 0.05). EMPA treatment significantly alleviated these parameters (all P < 0.05). Multitissue metabolomics analysis revealed lipid metabolic reprogramming in ORG mice, which was significantly altered by EMPA treatment. MetOrigin analysis showed a close association between EMPA-related lipid metabolic pathways and gut microbiota alterations, characterized by reduced abundances of Firmicutes and Desulfovibrio and increased abundance of Akkermansia (all P < 0.05). The metabolic homeostasis of ORG mice, especially in lipid metabolism, was disrupted and closely associated with gut microbiota alterations, contributing to the progression of ORG. EMPA treatment improved kidney function and morphology by regulating lipid metabolism through the gut-kidney axis, highlighting a novel therapeutic approach for ORG. NEW & NOTEWORTHY Our study uncovered that empagliflozin (EMPA) potentially protects renal function and morphology in obesity-related glomerulopathy (ORG) mice by regulating the gut-kidney axis. EMPA's reno-protective effects in ORG mice are associated with the lipid metabolism, especially in glycerophospholipid metabolism and the pantothenate/CoA synthesis pathways. EMPA's modulation of gut microbiota appears to be pivotal in suppressing glycerol 3-phosphate and CoA synthesis. The insights into gut microbiota-host metabolic interactions offer a novel therapeutic approach for ORG.

背景:肥胖相关肾小球病(ORG)的发病率不断上升,对公众健康构成了严重威胁。钠-葡萄糖共转运体-2(SGLT2)抑制剂能有效降低肥胖者的体重和总脂肪量,并阻止肥胖相关性肾小球肾病的发展。然而,它们对 ORG 起保护作用的内在机制仍不清楚:我们利用 C57BL/6J 小鼠建立了高脂饮食诱导的 ORG 模型,并将其分为三组:正常饲料组(NCD 组)、使用安慰剂治疗的高脂饮食组(ORG 组)和使用恩格列净治疗的高脂饮食组(EMPA 组)。我们对粪便进行了 16S 核糖体 RNA 基因测序,并分析了肾脏、粪便、肝脏和血清样本中的代谢物:结果:与 NCD 小鼠相比,ORG 小鼠的尿白蛋白肌酐比值、胆固醇、甘油三酯水平和肾小球直径均有所增加(所有 P < 0.05)。EMPA治疗可明显缓解这些参数(所有P < 0.05)。多组织代谢组学分析显示,ORG小鼠的脂质代谢重编程在EMPA治疗后发生了明显改变。MetOrigin分析表明,EMPA相关的脂质代谢途径与肠道微生物群的改变密切相关,其特征是固氮菌和脱硫弧菌的丰度降低,而Akkermansia的丰度增加(所有P < 0.05):结论:ORG小鼠的代谢平衡,尤其是脂质代谢平衡受到破坏,并与肠道微生物群的改变密切相关,从而导致了ORG的进展。EMPA治疗通过肠道-肾脏轴调节脂质代谢,改善了肾脏功能和形态,是治疗ORG的一种新方法。
{"title":"Renoprotective effects of empagliflozin in high-fat diet-induced obesity-related glomerulopathy by regulation of gut-kidney axis.","authors":"Lei Lei, Ting Zhu, Tian-Jiao Cui, Yvonne Liu, Johann-Georg Hocher, Xin Chen, Xue-Mei Zhang, Kai-Wen Cai, Zi-Yan Deng, Xiao-Hua Wang, Chun Tang, Lian Lin, Christoph Reichetzeder, Zhi-Hua Zheng, Berthold Hocher, Yong-Ping Lu","doi":"10.1152/ajpcell.00367.2024","DOIUrl":"10.1152/ajpcell.00367.2024","url":null,"abstract":"<p><p>The increasing prevalence of obesity-related glomerulopathy (ORG) poses a significant threat to public health. Sodium-glucose cotransporter-2 (SGLT2) inhibitors effectively reduce body weight and total fat mass in individuals with obesity and halt the progression of ORG. However, the underlying mechanisms of their reno-protective effects in ORG remain unclear. We established a high-fat diet-induced ORG model using C57BL/6J mice, which were divided into three groups: normal chow diet (NCD group), high-fat diet (HFD) mice treated with placebo (ORG group), and HFD mice treated with empagliflozin (EMPA group). We conducted 16S ribosomal RNA gene sequencing of feces and analyzed metabolites from kidney, feces, liver, and serum samples. ORG mice showed increased urinary albumin creatinine ratio, cholesterol, triglyceride levels, and glomerular diameter compared with NCD mice (all <i>P</i> < 0.05). EMPA treatment significantly alleviated these parameters (all <i>P</i> < 0.05). Multitissue metabolomics analysis revealed lipid metabolic reprogramming in ORG mice, which was significantly altered by EMPA treatment. MetOrigin analysis showed a close association between EMPA-related lipid metabolic pathways and gut microbiota alterations, characterized by reduced abundances of <i>Firmicutes</i> and <i>Desulfovibrio</i> and increased abundance of <i>Akkermansia</i> (all <i>P</i> < 0.05). The metabolic homeostasis of ORG mice, especially in lipid metabolism, was disrupted and closely associated with gut microbiota alterations, contributing to the progression of ORG. EMPA treatment improved kidney function and morphology by regulating lipid metabolism through the gut-kidney axis, highlighting a novel therapeutic approach for ORG. <b>NEW & NOTEWORTHY</b> Our study uncovered that empagliflozin (EMPA) potentially protects renal function and morphology in obesity-related glomerulopathy (ORG) mice by regulating the gut-kidney axis. EMPA's reno-protective effects in ORG mice are associated with the lipid metabolism, especially in glycerophospholipid metabolism and the pantothenate/CoA synthesis pathways. EMPA's modulation of gut microbiota appears to be pivotal in suppressing glycerol 3-phosphate and CoA synthesis. The insights into gut microbiota-host metabolic interactions offer a novel therapeutic approach for ORG.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11481992/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142054662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Tumor microenvironment-like conditions alter pancreatic cancer cell metabolism and behavior. 类似肿瘤微环境的条件会改变胰腺癌细胞的新陈代谢和行为
IF 5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-26 DOI: 10.1152/ajpcell.00452.2024
Georgina Louise Gardner, Jeffrey Alan Stuart

The tumor microenvironment is complex and dynamic, characterized by poor vascularization, limited nutrient availability, hypoxia, and an acidic pH. This environment plays a critical role in driving cancer progression. However, standard cell culture conditions used to study cancer cell biology in vitro fail to replicate the in vivo environment of tumors. Recently, "physiological" cell culture media that closely resemble human plasma have been developed (e.g., Plasmax, HPLM), along with more frequent adoption of physiological oxygen conditions (1%-8% O2). Nonetheless, further refinement of tumor-specific culture conditions may be needed. In this study, we describe the development of a tumor microenvironment medium (TMEM) based on murine pancreatic ductal adenocarcinoma (PDAC) tumor interstitial fluid. Using RNA-sequencing, we show that murine PDAC cells (KPCY) cultured in tumor-like conditions (TMEM, pH 7.0, 1.5% O2) exhibit profound differences in gene expression compared with plasma-like conditions (mouse plasma medium, pH 7.4, 5% O2). Specifically, the expression of genes and pathways associated with cell migration, biosynthesis, angiogenesis, and epithelial-to-mesenchymal transition were altered, suggesting tumor-like conditions promote metastatic phenotypes and metabolic remodeling. Using functional assays to validate RNA-seq data, we confirmed increased motility at 1.5% O2/TMEM, despite reduced cell proliferation. Moreover, a hallmark shift to glycolytic metabolism was identified via measurement of glucose uptake/lactate production and mitochondrial respiration. Taken together, these findings demonstrate that growth in 1.5% O2/TMEM alters several biological responses in ways relevant to cancer biology, and more closely models hallmark cancerous phenotypes in culture. This highlights the importance of establishing tumor microenvironment-like conditions in standard cancer research. NEW & NOTEWORTHY Standard cell culture conditions do not replicate the complex tumor microenvironment experienced by cells in vivo. Although currently available plasma-like media are superior to traditional supraphysiological media, they fail to model tumor-like conditions. Using RNA-seq analysis and functional metabolic and migratory assays, we show that tumor microenvironment medium (TMEM), used with representative tumor hypoxia, better models cancerous phenotypes in culture. This emphasizes the critical importance of accurately modeling the tumor microenvironment in cancer research.

肿瘤微环境复杂多变,其特点是血管不畅、营养供应有限、缺氧和酸性 pH 值。这种环境在推动癌症进展方面起着至关重要的作用。然而,用于体外研究癌细胞生物学的标准细胞培养条件无法复制肿瘤的体内环境。最近,与人体血浆非常相似的 "生理性 "细胞培养基(如 Plasmax、HPLM)被开发出来,同时更频繁地采用生理性氧气条件(1-8% O2)。尽管如此,肿瘤特异性培养条件仍需进一步完善。在本研究中,我们介绍了基于小鼠胰腺导管腺癌(PDAC)肿瘤间质开发的肿瘤微环境培养基(TMEM)。我们利用 RNA 序列分析表明,与血浆样条件(小鼠血浆培养基,pH 7.4,5% O2)相比,在肿瘤样条件(TMEM,pH 7.0,1.5% O2)下培养的小鼠 PDAC 细胞(KPCY)在基因表达方面表现出很大差异。具体来说,与细胞迁移、生物合成、血管生成和上皮到间质转化相关的基因和通路的表达发生了改变,这表明类肿瘤条件促进了转移表型和代谢重塑。利用功能测试来验证 RNA-seq 数据,我们证实了在 1.5%O2/TMEM 条件下,尽管细胞增殖减少,但细胞的运动性却增加了。此外,通过测量葡萄糖摄取/乳酸生成和线粒体呼吸,我们还发现了向糖酵解代谢转变的特征。总之,这些研究结果表明,在 1.5%O2/TMEM 中生长会以与癌症生物学相关的方式改变几种生物反应,并更接近于在培养物中模拟标志性癌症表型。这凸显了在标准癌症研究中建立类似肿瘤微环境条件的重要性。
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引用次数: 0
Junctions at the crossroads: the impact of mechanical cues on endothelial cell-cell junction conformations and vascular permeability. 十字路口的连接:机械线索对内皮细胞-细胞连接构型和血管通透性的影响》(The Impact of Mechanical Cues on Endothelial Cell-Cell Junction Conformations and Vascular Permeability.
IF 5 2区 生物学 Q2 CELL BIOLOGY Pub Date : 2024-10-01 Epub Date: 2024-08-12 DOI: 10.1152/ajpcell.00605.2023
Ken D Brandon, William E Frank, Kimberly M Stroka

Cells depend on precisely regulating barrier function within the vasculature to maintain physiological stability and facilitate essential substance transport. Endothelial cells achieve this through specialized adherens and tight junction protein complexes, which govern paracellular permeability across vascular beds. Adherens junctions, anchored by vascular endothelial (VE)-cadherin and associated catenins to the actin cytoskeleton, mediate homophilic adhesion crucial for barrier integrity. In contrast, tight junctions composed of occludin, claudin, and junctional adhesion molecule A interact with Zonula Occludens proteins, reinforcing intercellular connections essential for barrier selectivity. Endothelial cell-cell junctions exhibit dynamic conformations during development, maturation, and remodeling, regulated by local biochemical and mechanical cues. These structural adaptations play pivotal roles in disease contexts such as chronic inflammation, where junctional remodeling contributes to increased vascular permeability observed in conditions from cancer to cardiovascular diseases. Conversely, the brain microvasculature's specialized junctional arrangements pose challenges for therapeutic drug delivery due to their unique molecular compositions and tight organization. This commentary explores the molecular mechanisms underlying endothelial cell-cell junction conformations and their implications for vascular permeability. By highlighting recent advances in quantifying junctional changes and understanding mechanotransduction pathways, we elucidate how physical forces from cellular contacts and hemodynamic flow influence junctional dynamics.

细胞依靠精确调节血管内的屏障功能来维持生理稳定和促进重要物质的运输。内皮细胞通过特化的粘连蛋白和紧密连接蛋白复合物实现这一功能,这些复合物控制着血管床的细胞旁通透性。粘连接头由 VE-粘连蛋白和相关的 catenins 固定在肌动蛋白细胞骨架上,介导对屏障完整性至关重要的同亲粘附。与此相反,由闭塞素、凝集素和连接粘附分子 A 组成的紧密连接与闭塞斑块蛋白相互作用,加强了对屏障选择性至关重要的细胞间连接。内皮细胞-细胞连接在发育、成熟和重塑过程中表现出动态构象,并受局部生化和机械线索的调节。这些结构调整在慢性炎症等疾病中起着关键作用,从癌症到心血管疾病,连接重塑都会导致血管通透性增加。相反,脑微血管的特殊交界排列由于其独特的分子组成和严密的组织结构,给治疗药物的输送带来了挑战。这篇评论探讨了内皮细胞-细胞连接构象的分子机制及其对血管通透性的影响。通过重点介绍在量化连接变化和了解机械传导途径方面的最新进展,我们阐明了细胞接触和血液动力学流动所产生的物理力是如何影响连接动态的。
{"title":"Junctions at the crossroads: the impact of mechanical cues on endothelial cell-cell junction conformations and vascular permeability.","authors":"Ken D Brandon, William E Frank, Kimberly M Stroka","doi":"10.1152/ajpcell.00605.2023","DOIUrl":"10.1152/ajpcell.00605.2023","url":null,"abstract":"<p><p>Cells depend on precisely regulating barrier function within the vasculature to maintain physiological stability and facilitate essential substance transport. Endothelial cells achieve this through specialized adherens and tight junction protein complexes, which govern paracellular permeability across vascular beds. Adherens junctions, anchored by vascular endothelial (VE)-cadherin and associated catenins to the actin cytoskeleton, mediate homophilic adhesion crucial for barrier integrity. In contrast, tight junctions composed of occludin, claudin, and junctional adhesion molecule A interact with Zonula Occludens proteins, reinforcing intercellular connections essential for barrier selectivity. Endothelial cell-cell junctions exhibit dynamic conformations during development, maturation, and remodeling, regulated by local biochemical and mechanical cues. These structural adaptations play pivotal roles in disease contexts such as chronic inflammation, where junctional remodeling contributes to increased vascular permeability observed in conditions from cancer to cardiovascular diseases. Conversely, the brain microvasculature's specialized junctional arrangements pose challenges for therapeutic drug delivery due to their unique molecular compositions and tight organization. This commentary explores the molecular mechanisms underlying endothelial cell-cell junction conformations and their implications for vascular permeability. By highlighting recent advances in quantifying junctional changes and understanding mechanotransduction pathways, we elucidate how physical forces from cellular contacts and hemodynamic flow influence junctional dynamics.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11481987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141915846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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American journal of physiology. Cell physiology
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