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Genetics, epigenetics and autoimmunity constitute a Bermuda triangle for the pathogenesis of rheumatoid arthritis 遗传学、表观遗传学和自身免疫学构成了类风湿关节炎发病机制的百慕大三角。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2024-09-26 DOI: 10.1016/j.lfs.2024.123075

Rheumatoid arthritis (RA), a multigene disorder with a heritability rate of 60 %, is characterized by persistent pain, synovial hyperplasia, and cartilage and bone destruction, ultimately causing irreversible joint deformity. The etiology and pathogenesis of rheumatoid arthritis (RA) are primarily influenced by specific genetic variants, particularly HLA alleles such as HLA-DRB1*01 and DRB1*04. However, other HLA alleles such as HLA-DRB1*10 and DPB*1 have also been found to contribute to increased susceptibility to RA. However, non-HLA genes also confer a comparatively high risk of RA disease manifestation. The most relevant single nucleotide polymorphisms (SNPs) associated with non-HLA genes are PTPN22, TRAF1, CXCL-12, TBX-5, STAT4, FCGR, PADI4, and MTHFR. In conjunction with genetic susceptibility, epigenetic alterations orchestrate paramount involvement in regulating RA pathogenesis. Increasing evidence implicates DNA methylation and histone protein modifications, including acetylation and methylation, as the primary epigenetic mechanisms that drive the pathogenesis and clinical progression of the disease. In addition to genetic and epigenetic changes, autoimmune inflammation also determines the pathological progression of the synovial membrane in joints with RA. Glycosylation changes, such as sialylation and fucosylation, in immune cells have been shown to be relevant to disease progression. Genetic heterogeneity, epigenetic factors, and changes in glycosylation do not fully explain the features of RA. Therefore, investigating the interplay between genetics, epigenetics, and autoimmunity is crucial. This review highlights the significance and interaction of these elements in RA pathophysiology, suggesting their diagnostic potential and opening new avenues for novel therapeutic approaches.

类风湿性关节炎（RA）是一种多基因疾病，遗传率高达 60%，以持续疼痛、滑膜增生、软骨和骨破坏为特征，最终导致不可逆转的关节畸形。类风湿性关节炎（RA）的病因和发病机制主要受特定遗传变异的影响，尤其是 HLA 等位基因，如 HLA-DRB1*01 和 DRB1*04。不过，也发现其他 HLA 等位基因，如 HLA-DRB1*10 和 DPB*1 也会导致 RA 易感性增加。然而，非 HLA 基因也会导致相对较高的 RA 发病风险。与非 HLA 基因最相关的单核苷酸多态性（SNPs）包括 PTPN22、TRAF1、CXCL-12、TBX-5、STAT4、FCGR、PADI4 和 MTHFR。除遗传易感性外，表观遗传学改变也是调节 RA 发病机制的重要因素。越来越多的证据表明，DNA甲基化和组蛋白修饰（包括乙酰化和甲基化）是驱动疾病发病和临床进展的主要表观遗传机制。除了遗传和表观遗传学变化外，自身免疫性炎症也决定了 RA 关节滑膜的病理进展。免疫细胞中的糖基化变化，如糖基化和岩藻糖基化，已被证明与疾病进展有关。遗传异质性、表观遗传因素和糖基化变化并不能完全解释 RA 的特征。因此，研究遗传学、表观遗传学和自身免疫学之间的相互作用至关重要。本综述强调了这些因素在RA病理生理学中的重要性和相互作用，提示了它们的诊断潜力，并为新型治疗方法开辟了新途径。

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引用次数: 0

Out-of-phase treatment with the synthetic glucocorticoid betamethasone disturbs glucose metabolism in mice 合成糖皮质激素倍他米松的非阶段性治疗会扰乱小鼠的糖代谢。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2024-09-25 DOI: 10.1016/j.lfs.2024.123080

Objective

Endogenous glucocorticoid levels display a strong circadian rhythm, which is often not considered when synthetic glucocorticoids are prescribed as anti-inflammatory drugs. In this study we evaluated the effect timing of glucocorticoid administration, i.e. in-phase (administered when endogenous glucocorticoid levels are high) versus out-of-phase (administered when endogenous glucocorticoid levels are low). We investigated the synthetic glucocorticoid betamethasone – which is extensively used in the clinic - and monitored the development of common metabolic side effects in mice upon prolonged treatment, with a particular focus on glucose metabolism.

Methods

Male and female C57BL/6J mice were treated with the synthetic glucocorticoid betamethasone in-phase and out-of-phase, and the development of metabolic side effects was monitored.

Results

We observed that, compared with in-phase treatment, out-of-phase treatment with betamethasone results in hyperinsulinemia in both male and female C57BL/6J mice. We additionally found that out-of-phase betamethasone treatment strongly reduced insulin sensitivity as compared to in-phase administration during morning measurements. Our study shows that the adverse effects of betamethasone are dependent on the time of treatment with generally less side effects on glucose metabolism with in-phase treatment.

Conclusions

This study highlights differences in glucocorticoid outcome based on the time of measurement, advocating that potential circadian variation should be taken into account when studying glucocorticoid biology.

目的：内源性糖皮质激素水平具有很强的昼夜节律性，但在使用合成糖皮质激素作为抗炎药物时往往没有考虑到这一点。在本研究中，我们评估了糖皮质激素给药时机的影响，即同相（内源性糖皮质激素水平高时给药）和非同相（内源性糖皮质激素水平低时给药）。我们研究了临床上广泛使用的合成糖皮质激素倍他米松，并监测了小鼠在长期治疗后常见代谢副作用的发展，尤其关注葡萄糖代谢：方法：用合成糖皮质激素倍他米松对雌雄C57BL/6J小鼠进行阶段性和非阶段性治疗，并监测代谢副作用的发生：结果：我们观察到，与同阶段治疗相比，倍他米松非同阶段治疗会导致雄性和雌性 C57BL/6J 小鼠出现高胰岛素血症。此外，我们还发现，在早晨测量时，与同阶段给药相比，非同阶段倍他米松治疗会大大降低胰岛素敏感性。我们的研究表明，倍他米松的不良反应与治疗时间有关，一般来说，相位治疗对糖代谢的副作用较小：本研究强调了糖皮质激素的结果因测量时间而异，主张在研究糖皮质激素生物学时应考虑潜在的昼夜节律变化。

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引用次数: 0

Phage display screening in breast cancer: From peptide discovery to clinical applications 乳腺癌的噬菌体展示筛选：从多肽发现到临床应用。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2024-09-25 DOI: 10.1016/j.lfs.2024.123077

Breast cancer is known as the most common type of cancer found in women and a leading cause of cancer death in women, with the global incidence only increasing. Breast cancer in Malaysia is also unfortunately the most prevalent in Malaysian women. Many treatment options are available for breast cancer, but there is increasing resistance developed against treatment and increased recurrence risk, emphasizing the need for new treatment options. This review will focus on the applications of phage display screening in the context of breast cancer. Phage display screening can facilitate the drug discovery process by providing rapid screening and isolation of peptides that bind to targets of interest with high specificity. Peptides derived from phage display target various types of proteins involved in breast cancer, including HER2, C5AR1, p53 and PRDM14, either for therapeutic or diagnostic purposes. Different approaches were employed as well to produce potential peptides using radiolabelling and conjugation techniques. Promising results were reported for in vitro and in vivo studies utilizing peptides derived from phage display screening. Further optimization of the protocols and factors to consider are required to mitigate the challenges involved with phage display screening of peptides for breast cancer diagnosis and treatment.

众所周知，乳腺癌是女性最常见的癌症类型，也是女性癌症死亡的主要原因，全球发病率只增不减。不幸的是，乳腺癌也是马来西亚妇女最常见的癌症。目前有许多治疗乳腺癌的方法，但抗药性越来越强，复发风险越来越高，因此需要新的治疗方法。本综述将重点介绍噬菌体展示筛选在乳腺癌方面的应用。噬菌体展示筛选可以快速筛选和分离出与感兴趣的靶点结合的高特异性多肽，从而促进药物发现过程。通过噬菌体展示筛选得到的多肽靶标涉及乳腺癌的各类蛋白质，包括 HER2、C5AR1、p53 和 PRDM14，可用于治疗或诊断。此外，还采用了不同的方法，利用放射性标记和共轭技术生产潜在的多肽。利用噬菌体展示筛选出的肽进行体外和体内研究的结果令人鼓舞。要减轻噬菌体展示筛选用于乳腺癌诊断和治疗的多肽所带来的挑战，还需要进一步优化方案和考虑因素。

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引用次数: 0

Unveiling the intricate dance: Obesity and TNBC connection examined 揭开复杂舞蹈的面纱研究肥胖与 TNBC 的关系

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2024-09-25 DOI: 10.1016/j.lfs.2024.123082

Amid the dynamic field of cancer research, various targeted therapies have proven crucial in combating breast cancer, the most prevalent cancer among women globally. Triple Negative Breast Cancer (TNBC) stands out from other types of breast cancer due to the absence of three key receptors on the cell surface (progesterone, estrogen, and HER2). Researchers are working on finding ways to address TNBC's elusive biomarkers and minimize the damage caused by the disease through treatments like chemotherapies and targeted pathway receptors. One connection that should receive more attention is the link between TNBC and obesity. Obesity is defined as consuming significantly more energy than is expended, resulting in a high BMI. Moreover, obesity fosters a cancer-friendly environment characterized by inflammation, elevated levels of hormones, proteins, and signaling that activate pathways promoting cancer. Non-Hispanic black women have experienced notable disparities in TNBC rates. Various factors have led to the higher incidence and poorer outcomes of TNBC in non-Hispanic black women. This detailed review explores the complex relationship between obesity and TNBC, examining how the two disorders are connected in terms of disparities and offering a glimpse into future research and interventions.

在充满活力的癌症研究领域中，各种靶向疗法已被证明在抗击全球女性发病率最高的癌症--乳腺癌方面至关重要。三阴性乳腺癌（TNBC）由于细胞表面缺乏三种关键受体（孕激素、雌激素和 HER2）而与其他类型的乳腺癌截然不同。研究人员正在努力寻找解决 TNBC 难以捉摸的生物标志物的方法，并通过化疗和靶向通路受体等治疗手段将该疾病造成的伤害降到最低。TNBC与肥胖之间的联系应该得到更多关注。肥胖的定义是消耗的能量明显多于消耗的能量，从而导致高体重指数。此外，肥胖还助长了一种有利于癌症的环境，其特点是炎症、激素水平升高、蛋白质和信号传导激活了促进癌症的通路。非西班牙裔黑人妇女的 TNBC 患病率存在明显差异。各种因素导致了非西班牙裔黑人妇女 TNBC 的高发病率和较差的治疗效果。这篇详细的综述探讨了肥胖与 TNBC 之间的复杂关系，研究了这两种疾病在差异方面的联系，并为未来的研究和干预措施提供了一瞥。

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引用次数: 0

DNA-PKcs modulates mouse lung homeostasis via the regulation of mitochondrial fission DNA-PKcs通过调控线粒体分裂调节小鼠肺稳态

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2024-09-25 DOI: 10.1016/j.lfs.2024.123078

Background

The role of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is multifaceted, paradoxically promoting both cell survival and cell death across multiple organs. However, its impact on lung homeostasis remains elusive. Here, we investigate the function of DNA-PKcs in mouse lungs, aiming to elucidate its role for lung abnormalities associated with DNA-PKcs deficiency.

Materials and methods

Histological assessment and immunohistochemistry were used to reveal the pathological changes of the lungs in DNA-PKcs-deficient mice. Transcriptomic analysis identified differentially expressed genes and pathways in DNA-PKcs-deficient lungs. Furthermore, mitochondrial dysfunction induced by DNA-PKcs deficiency was investigated by qPCR and immunoblotting. Mouse primary lung fibroblasts were used to evaluate the potential therapeutic effect of inhibiting mitochondrial fission with Mdivi-1.

Key findings

In DNA-PKcs-deficient mouse lungs, we observed pathological changes including alveolar septal thickening, capillary congestion and hemorrhage, along with lung cell proliferation. Transcriptome analysis revealed an upregulation of the reactive oxygen species (ROS) biosynthesis process and the apoptotic signaling pathway caused by DNA-PKcs deficiency. Further investigations demonstrated that DNA-PKcs deficiency led to mitochondrial dysfunction and increased oxidative stress, along with increased cell apoptosis in the mouse lungs. Notably, we detected enhanced phosphorylation of the mitochondrial fission protein DRP1 in DNA-PKcs-deficient mouse lungs. Intriguingly, inhibiting mitochondrial fission using Mdivi-1 suppressed cell death in primary mouse lung fibroblasts with siRNA-mediated DNA-PKcs knockdown.

Significance

Our study provides insights into the crucial role of DNA-PKcs in sustaining lung homeostasis via the maintenance of mitochondrial functionality and provides a therapeutic strategy targeting mitochondrial fission against DNA-PKcs deficiency-associated lung diseases.

背景：DNA 依赖性蛋白激酶催化亚基（DNA-PKcs）的作用是多方面的，在多个器官中同时促进细胞存活和死亡。然而，它对肺稳态的影响仍然难以捉摸。在此，我们研究了DNA-PKcs在小鼠肺部的功能，旨在阐明其在DNA-PKcs缺乏症相关肺部异常中的作用。材料与方法：组织学评估和免疫组化被用于揭示DNA-PKcs缺乏症小鼠肺部的病理变化。转录组分析确定了DNA-PKcs缺陷小鼠肺部不同表达的基因和通路。此外，还通过 qPCR 和免疫印迹研究了 DNA-PKcs 缺陷诱导的线粒体功能障碍。小鼠原代肺成纤维细胞被用来评估用Mdivi-1抑制线粒体分裂的潜在治疗效果：在DNA-PKcs缺陷的小鼠肺中，我们观察到病理变化，包括肺泡间隔增厚、毛细血管充血和出血，以及肺细胞增殖。转录组分析显示，DNA-PKcs缺陷导致活性氧（ROS）生物合成过程和细胞凋亡信号通路上调。进一步的研究表明，DNA-PKcs缺乏会导致线粒体功能障碍、氧化应激增加以及小鼠肺部细胞凋亡增加。值得注意的是，我们在 DNA-PKcs 缺乏的小鼠肺中检测到线粒体裂变蛋白 DRP1 的磷酸化增强。有趣的是，使用Mdivi-1抑制线粒体裂变可抑制siRNA介导的DNA-PKcs基因敲除的原代小鼠肺成纤维细胞的细胞死亡：我们的研究深入揭示了DNA-PKcs通过维持线粒体功能在维持肺稳态中的关键作用，并提供了针对线粒体裂变的治疗策略，以防治DNA-PKcs缺乏相关的肺部疾病。

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引用次数: 0

Tubulin interaction at tubulin-binding sequence 1 (TBS1) is required for proper surface expression and TRPV1 channel activity 正常的表面表达和 TRPV1 通道活性需要管蛋白结合序列 1 (TBS1) 上的管蛋白相互作用。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2024-09-25 DOI: 10.1016/j.lfs.2024.123070

TRPV1, a polymodal and nonselective cation channel has unique gating mechanisms which is regulated by supramolecular complexes at the plasma membrane formed with membrane proteins, lipids and kinase pathways. Crosstalk between microtubule cytoskeleton with TRPV1 at various level has been established. Previously we demonstrated that the positively-charged residues present at specific tubulin-binding stretch sequences (i.e. TBS1 and TBS2, AA 710–730 and 770–797 respectively) located at the C-terminus of TRPV1 are crucial for tubulin interaction and such sequences have evolutionary origin. The nature of TRPV1-tubulin complex and its functional importance remain poorly understood. Here, we made several mutations in the TBS1 and TBS2 regions and characterized such mutants. Though these mutations reduce tubulin interaction drastically, a low and basal-level of tubulin interaction remains with these mutants. Substitution of positively-charged residues (Lys and Arg) to Ala in the TBS1, but not in TBS2 region results in reduced ligand-sensitivity. Such ligand-sensitivity is altered in response to Taxol or Nocodazole. We suggest that tubulin interaction at the TBS1 region favours channel opening while interaction in TBS2 favours channel closure. We demonstrate for the first time the functional significance of TRPV1-tubulin complex and endorse microtubule dynamics as a parameter that can alter TRPV1 channel functions. These findings can be relevant for several physiological functions and also in the context of chemotherapy-induced neuropathic pain caused by various microtubule stabilizing chemotherapeutic drugs. Thus, this characterization may indicate TRPV1 as a potential therapeutic target relevant for chemotherapeutic drug-induced peripheral neuropathies, neurodegeneration and other neurological disorders.

TRPV1 是一种多模式、非选择性阳离子离子通道，具有独特的门控机制，由质膜上的膜蛋白、脂质和激酶途径形成的超分子复合物调控。微管细胞骨架与 TRPV1 之间在不同水平上的串扰已被证实。以前我们曾证明，位于 TRPV1 C 端的特定小管蛋白结合伸展序列（即 TBS1 和 TBS2，分别为 AA 710-730 和 770-797）上的正电荷残基对于小管蛋白的相互作用至关重要，而且这些序列具有进化起源。人们对 TRPV1-微管蛋白复合物的性质及其功能重要性仍然知之甚少。在这里，我们对 TBS1 和 TBS2 区域进行了若干突变，并对这些突变体进行了表征。虽然这些突变极大地降低了管蛋白的相互作用，但这些突变体中的管蛋白相互作用仍处于较低的基础水平。将 TBS1 区带正电荷的残基（Lys 和 Arg）替换为 Ala，但不替换 TBS2 区带正电荷的残基，会导致配体敏感性降低。这种配体敏感性会改变对 Taxol 或 Nocodazole 的反应。我们认为，TBS1 区域的微管蛋白相互作用有利于通道开放，而 TBS2 区域的相互作用则有利于通道关闭。我们首次证明了 TRPV1-微管蛋白复合物的功能意义，并认可微管动力学是一个可以改变 TRPV1 通道功能的参数。这些发现可能与多种生理功能有关，也与各种微管稳定化疗药物引起的化疗诱发的神经病理性疼痛有关。

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引用次数: 0

Hypoxia impairs male reproductive functions via inducing rat Leydig cell ferroptosis under simulated environment at altitude of 5000 m 在海拔 5000 米的模拟环境下，缺氧通过诱导大鼠睾丸髓质细胞铁蛋白沉积损害雄性生殖功能。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2024-09-25 DOI: 10.1016/j.lfs.2024.123076

Aims

Many studies demonstrated reproductive damage in men residing in plains who are exposed to hypoxia at high altitudes. However, little is known about mechanisms between male reproductive impairment and hypobaric hypoxia. Hypoxia is one of the reasons for the imbalance of cellular redox system. Ferroptosis, involved in many pathophysiological progresses, is an oxidative damage-related, iron-dependent regulated cell death, which needs exogenous inducer. In our study, we explored the mechanism between hypoxia and male reproductive dysfunction.

Materials and methods

Here, we established animal model simulating hypobaric hypoxia at an altitude of 5000 m and used ELISA, WB, qPCR, flow cytometry and etc. to obtain different results.

Key findings

The results demonstrated decrease of plasma testosterone (T) and free testosterone (FT) levels under hypoxia, meanwhile there's decline in sperm counts and sperm motility, coupled with increase in sperm malformation rates. Flow cytometry confirmed significant reduction in Leydig cell numbers. Prussian blue staining showed iron depositions in interstitial testis. Features of ferroptosis such as increased MDA (malondialdehyde) levels, reduced solute carrier family 7 member 11 (SLC7A11, xCT) and glutathione peroxidase 4 (GPX4) expression were observed in testis after hypoxic exposure. Further in vitro experiments, we observed that hypoxia suppressed xCT-GPX4 pathway and enhanced cellular ROS accumulation to lead Leydig cell proliferation activity decline.

Significance

Our findings firstly indicated that hypoxia leads to male reproductive dysfunction via inducing Leydig cell ferroptosis. This discovery may offer a potential intervention target for addressing male reproductive injuries under hypoxic conditions.

目的：许多研究表明，居住在平原地区的男性在暴露于高海拔缺氧环境中时，生殖系统会受到损害。然而，人们对男性生殖损伤与低压缺氧之间的机制知之甚少。缺氧是导致细胞氧化还原系统失衡的原因之一。铁凋亡参与了许多病理生理过程，是一种与氧化损伤相关的、依赖铁的调节性细胞死亡，需要外源诱导剂。材料与方法：我们建立了模拟海拔 5000 米低压缺氧的动物模型，并使用 ELISA、WB、qPCR、流式细胞术等方法得出了不同的结果：结果表明，在缺氧条件下，血浆睾酮（T）和游离睾酮（FT）水平下降，同时精子数量和精子活力下降，精子畸形率增加。流式细胞术证实，精原细胞数量明显减少。普鲁士蓝染色显示睾丸间质有铁沉积。缺氧暴露后，我们在睾丸中观察到了铁中毒的特征，如 MDA（丙二醛）水平升高、溶质运载家族 7 成员 11（SLC7A11，xCT）和谷胱甘肽过氧化物酶 4（GPX4）表达减少。在进一步的体外实验中，我们观察到缺氧抑制了 xCT-GPX4 通路，并增强了细胞 ROS 的积累，从而导致 Leydig 细胞增殖活性下降：我们的研究结果首次表明，缺氧会通过诱导亮德细胞铁变态反应导致男性生殖功能障碍。这一发现为解决缺氧条件下男性生殖损伤提供了潜在的干预靶点。

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引用次数: 0

Skeletal muscle-derived exosomes prevent osteoporosis by promoting osteogenesis 骨骼肌源性外泌体通过促进骨生成预防骨质疏松症

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2024-09-24 DOI: 10.1016/j.lfs.2024.123079

Skeletal muscle and bone are the major organs for physical activity, in which there is a parallel correlation between muscle mass and bone density throughout a lifetime. Osteoporosis is a systemic bone metabolic disorder caused by reduced bone formation and increased bone resorption. Based on the metabolic symbiosis relationship between skeletal muscle and bone, we hypothesis that skeletal muscle secretory factors could play constructive roles in osteoporosis. Exosomes have been verified to transfer bioactive factors among cells. However, the role of skeletal muscle derived-exosomes (SM-Exos) in osteoporosis is still unclear. In this study, we performed neuromuscular electrical stimulation (NMES) intervention on denervated skeletal muscles and subsequently extracted exosomes (DN + ES-Exo) from the skeletal muscles, and then injected these DN + ES-Exo into sarco-osteoporotic rats through tail vein. In vitro studies, we cocultured SM-Exos from different states with differentiated MC3T3-E1 osteoblasts. In brief, our research findings demonstrate that SM-Exos could partially promote osteogenesis both in vivo and in vitro. Further, our findings indicate that skeletal muscle contraction induced by NMES can reverse the incidence of sarco-osteoporosis to a certain degree, and DN + ES-Exo contributes to the improvement in osteoporosis by facilitating osteoblast differentiation. Then, we revealed that NMES might regulate several miRNAs in skeletal muscle, the miRNAs that are encapsulated by SM-Exos might be involved in osteogenic differentiation in a network manner. All in all, this study confirmed the effect of NMES on sarco-osteoporosis and explored the role of SM-Exos in the improvement of osteoporosis, which provide an effective theoretical support for the physical therapy of clinical sarco-osteoporosis.

骨骼肌和骨骼是身体活动的主要器官，在人的一生中，肌肉质量和骨密度之间存在着平行关系。骨质疏松症是一种全身性骨代谢疾病，由骨形成减少和骨吸收增加引起。基于骨骼肌与骨骼之间的代谢共生关系，我们假设骨骼肌分泌因子可能在骨质疏松症中发挥建设性作用。外泌体已被证实能在细胞间传递生物活性因子。然而，骨骼肌外泌体（SM-Exos）在骨质疏松症中的作用仍不清楚。在这项研究中，我们对去神经支配的骨骼肌进行了神经肌肉电刺激（NMES）干预，随后从骨骼肌中提取了外泌体（DN + ES-Exo），然后通过尾静脉将这些DN + ES-Exo注射到肉瘤骨质疏松症大鼠体内。在体外研究中，我们将不同状态的SM-Exos与分化的MC3T3-E1成骨细胞进行了共培养。简而言之，我们的研究结果表明，SM-Exos 在体内和体外都能部分促进成骨。此外，我们的研究结果表明，NMES诱导的骨骼肌收缩可在一定程度上逆转肉芽肿性骨质疏松症的发病率，而DN + ES-Exo可通过促进成骨细胞分化来改善骨质疏松症。此外，我们还发现NMES可调控骨骼肌中的多种miRNA，被SM-Exos包裹的miRNA可能以网络方式参与成骨分化。总之，本研究证实了NMES对肉芽肿性骨质疏松症的作用，并探讨了SM-Exos在改善骨质疏松症中的作用，为临床肉芽肿性骨质疏松症的物理治疗提供了有效的理论支持。

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引用次数: 0

Gamma-aminobutyric acid-mediated neuro-immune interactions in glioblastoma: Implications for prognosis and immunotherapy response 胶质母细胞瘤中γ-氨基丁酸介导的神经-免疫相互作用：对预后和免疫疗法反应的影响。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2024-09-23 DOI: 10.1016/j.lfs.2024.123067

Aims

This study aimed to investigate the role of gamma-aminobutyric acid (GABA) in the glioblastoma (GBM) tumor immune microenvironment (TIME) and its impact on prognosis and response to immunotherapy.

Main methods

This study employed single-cell RNA sequencing (scRNA-seq) to delineate the TIME of GBM, utilized non-negative matrix factorization (NMF) for GABA-associated cell clustering, and performed pseudotime analysis for cellular trajectories. Additionally, we integrated immunohistochemistry (IHC), immunofluorescence (IF), and protein-protein interaction (PPI) analysis to explore the regulatory mechanisms within the tumor microenvironment.

Key findings

The study identified distinct GABA-associated immune cell subtypes, particularly macrophages and T-cells, with unique gene expression and developmental trajectories. The development of the GABA-associated scoring model (GABAAS), introduced novel prognostic indicators, enhancing our ability to predict patient outcomes. This study also suggests that GABA-related genes, including NDRG2 and TIMP1, play a crucial role in immune modulation, with potential implications for immunotherapy responsiveness.

Significance

The findings underscore the potential of targeting GABA-related genes (NDRG2 and TIMP1) and M2 macrophage to reshape the glioblastoma immune landscape, offering a new frontier in personalized neuro-immunotherapy. This approach holds promise to counter individual tumor immunosuppressive mechanisms, enhancing patient outcomes.

目的：本研究旨在探讨γ-氨基丁酸（GABA）在胶质母细胞瘤（GBM）肿瘤免疫微环境（TIME）中的作用及其对预后和免疫治疗反应的影响：本研究采用单细胞RNA测序（scRNA-seq）来划分GBM的TIME，利用非负矩阵因式分解（NMF）对GABA相关细胞进行聚类，并对细胞轨迹进行伪时间分析。此外，我们还整合了免疫组化（IHC）、免疫荧光（IF）和蛋白-蛋白相互作用（PPI）分析，以探索肿瘤微环境的调控机制：研究发现了不同的GABA相关免疫细胞亚型，尤其是巨噬细胞和T细胞，它们具有独特的基因表达和发育轨迹。GABA相关评分模型（GABAAS）的开发引入了新的预后指标，提高了我们预测患者预后的能力。这项研究还表明，GABA相关基因（包括NDRG2和TIMP1）在免疫调节中发挥着关键作用，对免疫疗法的反应性具有潜在影响：研究结果强调了靶向GABA相关基因（NDRG2和TIMP1）和M2巨噬细胞重塑胶质母细胞瘤免疫格局的潜力，为个性化神经免疫疗法开辟了新领域。这种方法有望对抗个别肿瘤的免疫抑制机制，改善患者的预后。

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引用次数: 0

Effect of senolytic drugs in young female mice chemically induced to estropause 化学诱导雌性小鼠衰老药物的效果

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2024-09-21 DOI: 10.1016/j.lfs.2024.123073

Aims

This study aimed to assess metabolic responses and senescent cell burden in young female mice induced to estropause and treated with senolytic drugs.

Main methods

Estropause was induced by 4-vinylcyclohexene diepoxide (VCD) injection in two-month-old mice. The senolytics dasatinib and quercetin (D + Q) or fisetin were given by oral gavage once a month from five to 11 months of age.

Key findings

VCD-induced estropause led to increased body mass and reduced albumin concentrations compared to untreated cyclic mice, without affecting insulin sensitivity, lipid profile, liver enzymes, or total proteins. Estropause decreased catalase activity in adipose tissue but had no significant effect on other redox parameters in adipose and hepatic tissues. Fisetin treatment reduced ROS levels in the hepatic tissue of estropause mice. Estropause did not influence senescence-associated beta-galactosidase activity in adipose and hepatic tissues but increased senescent cell markers and fibrosis in ovaries. Senolytic treatment did not decrease ovarian cellular senescence induced by estropause.

Significance

Overall, the findings suggest that estropause leads to minor metabolic changes in young females, and the senolytics D + Q and fisetin had no protective effects despite increased ovarian senescence.

目的：本研究旨在评估年轻雌性小鼠在诱导雌激素减少并接受衰老药物治疗后的代谢反应和衰老细胞负担：主要方法：在两个月大的小鼠体内注射 4-乙烯基环己烯二环氧化物（VCD）诱导雌激素减少。主要研究结果：VCD诱导的雌激素减少会导致小鼠雌激素减少：与未经处理的周期性小鼠相比，VCD诱导的雌激素导致体重增加和白蛋白浓度降低，但不影响胰岛素敏感性、血脂、肝酶或总蛋白。雌激素减少了脂肪组织中过氧化氢酶的活性，但对脂肪组织和肝组织中的其他氧化还原参数没有显著影响。菲赛汀能降低雌激素过多小鼠肝组织中的 ROS 水平。雌激素停滞不会影响脂肪组织和肝组织中与衰老相关的 beta-半乳糖苷酶活性，但会增加衰老细胞标志物和卵巢纤维化。溶酶治疗并不能降低雌激素停经诱导的卵巢细胞衰老：总体而言，研究结果表明，雌激素减少会导致年轻女性发生轻微的新陈代谢变化，尽管卵巢衰老增加，但解老剂 D + Q 和鱼腥草素没有保护作用。

{"title":"Effect of senolytic drugs in young female mice chemically induced to estropause","authors":"","doi":"10.1016/j.lfs.2024.123073","DOIUrl":"10.1016/j.lfs.2024.123073","url":null,"abstract":"<div><h3>Aims</h3><div>This study aimed to assess metabolic responses and senescent cell burden in young female mice induced to estropause and treated with senolytic drugs.</div></div><div><h3>Main methods</h3><div>Estropause was induced by 4-vinylcyclohexene diepoxide (VCD) injection in two-month-old mice. The senolytics dasatinib and quercetin (D + Q) or fisetin were given by oral gavage once a month from five to 11 months of age.</div></div><div><h3>Key findings</h3><div>VCD-induced estropause led to increased body mass and reduced albumin concentrations compared to untreated cyclic mice, without affecting insulin sensitivity, lipid profile, liver enzymes, or total proteins. Estropause decreased catalase activity in adipose tissue but had no significant effect on other redox parameters in adipose and hepatic tissues. Fisetin treatment reduced ROS levels in the hepatic tissue of estropause mice. Estropause did not influence senescence-associated beta-galactosidase activity in adipose and hepatic tissues but increased senescent cell markers and fibrosis in ovaries. Senolytic treatment did not decrease ovarian cellular senescence induced by estropause.</div></div><div><h3>Significance</h3><div>Overall, the findings suggest that estropause leads to minor metabolic changes in young females, and the senolytics D + Q and fisetin had no protective effects despite increased ovarian senescence.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142290422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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