Life sciences最新文献

Biochanin A-mediated anti-ferroptosis is associated with reduction of septic kidney injury 生物钱币素 A 介导的抗铁细胞生成与减轻脓毒性肾损伤有关

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2024-10-11 DOI: 10.1016/j.lfs.2024.123124

Aims

This study aimed to investigate the therapeutic potential of biochanin A in a sepsis associated- acute kidney injury (SA-AKI) mouse model induced by lipopolysaccharide (LPS).

Main methods

Male BALB/C mice (n = 7 per group) were injected with biochanin A (40 mg/kg, i.p.) or ferrostatin-1 (5 mg/kg, i.p.) in the presence or absence of LPS (10 mg/kg, i.p.). Survival rates were monitored twice a day for up to 2 weeks. Morphologic and functional changes in kidney tissue were assessed by H&E staining and by analyzing of levels of blood-urea nitrogen (BUN) and creatinine (CR) in serum, respectively. Kidney epithelial cell death was analyzed by TUNEL staining, Prussian blue staining, iron quantification, lipid peroxide quantification, and glutathione quantification. Anti-ferroptosis mechanism of biochanin A was analyzed by RNA sequencing in mouse embryonic fibroblast cells.

Key findings

Biochanin A increased the survival rate of septic mice and inhibited the secretion of high mobility group box 1, an important inflammatory mediator in sepsis. Biochanin A inhibited LPS-induced kidney damage by suppressing dilatation and kidney tubular epithelial cell death. Furthermore, serum levels of BUN and CR were reduced in biochanin A-treated endotoxemic mice. Biochanin A inhibited the accumulation of iron and lipid peroxide and prevented glutathione depletion in the kidney tissue. Also, nine genes associated with the anti-ferroptosis effects of biochanin A were identified by RNA sequencing analysis.

Significance

The present study suggests that biochanin A is an effective inhibitor of ferroptosis, representing a potential treatment or prophylactic for sepsis-related disorders such as SA-AKI.

主要方法雄性 BALB/C 小鼠（每组 7 只）在有或没有 LPS（10 毫克/千克，静注）的情况下注射生物茶碱 A（40 毫克/千克，静注）或铁前列素-1（5 毫克/千克，静注）。在长达两周的时间里，每天监测两次存活率。通过H&E染色和分析血清中的血尿素氮（BUN）和肌酐（CR）水平，分别评估肾组织的形态和功能变化。通过 TUNEL 染色、普鲁士蓝染色、铁定量、过氧化脂质定量和谷胱甘肽定量分析肾上皮细胞的死亡。通过对小鼠胚胎成纤维细胞进行 RNA 测序，分析了生物黄芩素 A 的抗败血病机制。主要发现生物黄芩素 A 提高了败血病小鼠的存活率，并抑制了败血病中重要的炎症介质高迁移率基团框 1 的分泌。生物黄酮素 A 能抑制肾小管扩张和肾小管上皮细胞死亡，从而抑制 LPS 引起的肾损伤。此外，经生物变色素 A 处理的内毒素血症小鼠血清中的 BUN 和 CR 水平降低。生物黄铜素 A 可抑制过氧化铁和过氧化脂质的积累，防止肾组织中谷胱甘肽的耗竭。本研究表明，生物黄铜素 A 是一种有效的铁氧化酶抑制剂，是治疗或预防脓毒症相关疾病（如 SA-AKI）的潜在药物。

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引用次数: 0

Schwann cell autotransplantation for the treatment of peripheral nerve injury 用于治疗周围神经损伤的许旺细胞自体移植。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2024-10-10 DOI: 10.1016/j.lfs.2024.123129

Peripheral nerve injury occurs in a relatively large proportion of trauma patients, in whom it generally results in severe functional impairment and permanent disability. At present, however, there are no effective treatments available. Studies have shown that Schwann cells play an indispensable role in removing myelin debris and guiding axonal regeneration, and transplantation using autologous Schwann cells has shown good efficacy for patients with peripheral nerve injury. In recent years, Schwann cell autologous transplantation therapy has become an area of intensive research and is anticipated to provide a new strategy for the clinical treatment of peripheral nerve injury. In this article, we review the rationale for selecting Schwann cell autotransplantation therapy and the latest progress in key aspects of cell transplantation and clinical efficacy, and also summarize the future directions of research on this therapy. All of the above provide a strong basis for the further improvement and clinical promotion of this therapy.

外周神经损伤发生在相对较大比例的外伤患者身上，通常会导致严重的功能障碍和永久性残疾。然而，目前还没有有效的治疗方法。研究表明，许旺细胞在清除髓鞘碎片和引导轴突再生方面发挥着不可或缺的作用，利用自体许旺细胞进行移植对周围神经损伤患者有良好的疗效。近年来，许旺细胞自体移植疗法已成为一个深入研究的领域，有望为周围神经损伤的临床治疗提供一种新策略。本文回顾了选择许旺细胞自体移植疗法的理论依据，以及细胞移植关键环节和临床疗效的最新进展，并总结了该疗法未来的研究方向。所有这些都为该疗法的进一步完善和临床推广奠定了坚实的基础。

引用次数: 0

Sodium selenite inhibits cervical cancer progression via ROS-mediated suppression of glucose metabolic reprogramming 亚硒酸钠通过 ROS 介导的葡萄糖代谢重编程抑制宫颈癌的进展。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2024-10-09 DOI: 10.1016/j.lfs.2024.123109

Aims

This study aims to explore the inhibitory effect of selenium on cervical cancer through suppression of glucose metabolic reprogramming and its underlying mechanisms.

Methods

Sodium selenite (SS) treated HeLa and SiHa cells were assessed for proliferation using the CCK-8 assay and immunofluorescence. DNA synthesis was measured with the EdU assay. A nude mouse xenograft model evaluated SS's anti-cervical cancer effects. Reactive oxygen species (ROS) and mitochondrial membrane potential were measured using flow cytometry, DCFH-DA, and JC-1 probes, respectively. Apoptosis was detected via Annexin V/PI staining and Western blot. Glucose uptake, lactate production, and ATP generation were determined using 2-NBDG probes and assay kits. The mRNA and protein levels of glycolysis-related genes HK2, GLUT1, and PDK1 were measured using RT-qPCR and Western blot.

Key findings

SS inhibited HeLa and SiHa cells viability in a dose- and time-dependent manner. Intraperitoneal injection of SS in nude mice significantly inhibited HeLa cell xenograft growth without evident hepatotoxicity or nephrotoxicity. SS inhibited glucose metabolic reprogramming in cancer cells primarily via ROS-mediated AKT/mTOR/HIF-1α pathway inhibition. Pretreatment with N-acetylcysteine (NAC) or MHY1485 (an mTOR activator) partially reversed the inhibitory effects of SS on glucose metabolic reprogramming, cell proliferation, and migration, as well as its pro-apoptotic effects.

Significance

SS exhibited anti-cervical cancer effects, likely through the induction of ROS generation and inhibition of glucose metabolic reprogramming in cervical cancer cells, thereby inhibiting cell proliferation and promoting apoptosis. These findings provide new insights into understanding the molecular mechanisms underlying SS for potential new drug development for cervical cancer.

目的：本研究旨在探讨硒通过抑制葡萄糖代谢重编程对宫颈癌的抑制作用及其内在机制：方法：亚硒酸钠（SS）处理过的 HeLa 和 SiHa 细胞用 CCK-8 检测法和免疫荧光法进行增殖评估。DNA 合成用 EdU 试验进行测定。裸鼠异种移植模型评估了 SS 的抗宫颈癌效果。使用流式细胞仪、DCFH-DA 和 JC-1 探针分别测量了活性氧（ROS）和线粒体膜电位。通过 Annexin V/PI 染色和 Western 印迹检测细胞凋亡。使用 2-NBDG 探针和检测试剂盒测定葡萄糖摄取、乳酸生成和 ATP 生成。使用 RT-qPCR 和 Western 印迹法测定了糖酵解相关基因 HK2、GLUT1 和 PDK1 的 mRNA 和蛋白质水平：主要发现：SS对HeLa和SiHa细胞活力的抑制呈剂量和时间依赖性。裸鼠腹腔注射 SS 能显著抑制 HeLa 细胞异种移植的生长，且无明显的肝毒性或肾毒性。SS 主要通过抑制 ROS 介导的 AKT/mTOR/HIF-1α 通路抑制癌细胞的葡萄糖代谢重编程。用 N-乙酰半胱氨酸（NAC）或 MHY1485（一种 mTOR 激活剂）进行预处理可部分逆转 SS 对葡萄糖代谢重编程、细胞增殖和迁移的抑制作用及其促凋亡作用：SS具有抗宫颈癌的作用，可能是通过诱导ROS生成和抑制宫颈癌细胞的葡萄糖代谢重编程，从而抑制细胞增殖和促进细胞凋亡。这些发现为了解 SS 的分子机制提供了新的视角，有助于开发治疗宫颈癌的新药。

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引用次数: 0

Enhanced oxidative stress aggravates BLM-induced pulmonary fibrosis by promoting cellular senescence through enhancing NLRP3 activation. 氧化应激的增强通过加强 NLRP3 的激活促进细胞衰老，从而加重 BLM 诱导的肺纤维化。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2024-10-09 DOI: 10.1016/j.lfs.2024.123128

Jiukang Feng, Hui Liu, Kewei Jiang, Xinyu Gong, Rong Huang, Chao Zhou, Jiali Mao, Yuanli Chen, Hongmei Xu, Xiaoming Zhang, Xiaoxiao Yang, Dahai Zhao

Aims: Idiopathic pulmonary fibrosis (IPF) is a disease associated with aging, where increased oxidative stress accelerates the progression of pulmonary fibrosis (PF). The specific mechanisms through which oxidative stress intensifies PF are still not fully understood.

Materials and methods: In this study, we used bleomycin (BLM)-induced PF mouse model and TGF-β-induced collagen deposition cells for in vivo and in vitro experiments, respectively. Additionally, we employed BSO, a glutathione synthesis inhibitor, to induce excess ROS.

Key findings: Our findings revealed that heightened ROS production significantly exacerbated PF development in mice and increased collagen deposition in A549 cells. We also showed that cellular senescence was further intensified by the combined treatment of BSO with BLM or TGF-β, as indicated by the increased levels of p53 and p21, along with an increase in β-galactosidase-positive cells. Moreover, inflammatory responses, including inflammatory cells, inflammatory cytokines, and ROS levels were dramatically increased with the BSO and BLM or TGF-β combination. Mechanistically, we found that NLRP3 inflammasome was activated more significantly by the combined treatments of BSO with BLM or TGF-β. Inhibition of NLRP3 ameliorated the aging-related phenotype and reduced p53 and p21 expression. Furthermore, we showed that N-acetylcysteine (NAC) treatment significantly attenuated BLM or BLM plus BSO-enhanced PF in vivo.

Significance: Our study demonstrates that elevated ROS levels contribute to the development of PF via NLRP3-mediated cellular senescence. We also provide that targeting oxidative stress might be an effective strategy for treating PF.

目的：特发性肺纤维化（IPF）是一种与衰老相关的疾病，氧化应激的增加会加速肺纤维化（PF）的进展。氧化应激加剧肺纤维化的具体机制尚未完全明了：在本研究中，我们使用博莱霉素（BLM）诱导的肺纤维化小鼠模型和 TGF-β 诱导的胶原沉积细胞分别进行体内和体外实验。此外，我们还使用了谷胱甘肽合成抑制剂 BSO 来诱导过量的 ROS：我们的研究结果表明，ROS 生成的增加显著加剧了小鼠 PF 的发展，并增加了 A549 细胞中胶原蛋白的沉积。我们还发现，细胞衰老在 BSO 与 BLM 或 TGF-β 联合处理后进一步加剧，表现为 p53 和 p21 水平升高，β-半乳糖苷酶阳性细胞增加。此外，炎症反应，包括炎症细胞、炎症细胞因子和 ROS 水平在 BSO 和 BLM 或 TGF-β 联合作用下显著增加。从机理上讲，我们发现 BSO 与 BLM 或 TGF-β 联合处理后，NLRP3 炎性体的激活更为显著。抑制 NLRP3 可改善衰老相关表型，减少 p53 和 p21 的表达。此外，我们还发现，N-乙酰半胱氨酸（NAC）治疗可显著减轻体内BLM或BLM加BSO增强的PF：我们的研究表明，ROS 水平升高会通过 NLRP3 介导的细胞衰老导致 PF 的发生。我们还发现，针对氧化应激可能是治疗 PF 的有效策略。

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引用次数: 0

Zinc pyrithione ameliorates colitis in mice by interacting on intestinal epithelial TRPA1 and TRPV4 channels 吡啶硫酮锌通过与肠上皮 TRPA1 和 TRPV4 通道相互作用，缓解小鼠结肠炎。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2024-10-09 DOI: 10.1016/j.lfs.2024.123090

Aims

Although zinc pyrithione (ZPT) has been studied as topical antimicrobial and cosmetic consumer products, little is known about its pharmacological actions in gastrointestinal (GI) health and inflammation. Our aims were to investigate the effects of ZPT on transient receptor potential (TRP) channels and Ca²⁺ signaling in intestinal epithelial cells (IECs) and its therapeutic potential for colitis.

Main methods

Digital Ca²⁺ imaging and patch-clamp electrophysiology were performed on human colonic epithelial cells (HCoEpiC) and rat small intestinal epithelial cells (IEC-6). The transcription levels of proinflammatory cytokines such as IL-1β were detected by RTq-PCR. Dextran sulfate sodium (DSS) was used to induce colitis in mice.

Key findings

ZPT dose-dependently induced Ca²⁺ signaling and membrane currents in IECs, which were attenuated by selective blockers of transient receptor potential ankyrin 1 (TRPA1) and transient receptor potential vanilloid 4 (TRPV4) channels, respectively. Interestingly, Ca²⁺ entry via TRPA1 channels inhibited the activity of TRPV4 channels in HCoEpiC, but not vice versa. ZPT significantly promoted migration of IECs by activating TRPA1 and TRPV4 channels. ZPT reversed lipopolysaccharides (LPS)-induced changes in mRNA expression of TRPA1 and TRPV4. Moreover, ZPT decreased mRNA levels of pro-inflammatory factors promoted by LPS in HCoEpiC, which were restored by selective TRPA1 blocker. In whole animal studies in vivo, ZPT significantly ameliorated DSS-induced body weight loss, colon shortening and increases in stool score, serum calprotectin and lactic acid (LD) in mouse model of colitis.

Significance

ZPT exerts anti-colitic action likely by anti-inflammation and pro-mucosal healing through TRP channels in IECs. The present study not only expands pharmacology spectrum of ZPT in GI tract, but also repurposes it to a potential drug for colitis therapy.

目的：尽管吡啶硫酮锌（ZPT）已被研究用作局部抗菌剂和化妆品，但人们对其在胃肠道（GI）健康和炎症方面的药理作用知之甚少。我们的目的是研究 ZPT 对肠上皮细胞（IECs）中瞬时受体电位（TRP）通道和 Ca2+ 信号转导的影响及其治疗结肠炎的潜力：主要方法：对人结肠上皮细胞（HCoEpiC）和大鼠小肠上皮细胞（IEC-6）进行了数字 Ca2+ 成像和膜片钳电生理学研究。通过 RTq-PCR 检测了 IL-1β 等促炎细胞因子的转录水平。用葡聚糖硫酸钠（DSS）诱导小鼠结肠炎：ZPT剂量依赖性地诱导IECs中的Ca2+信号传导和膜电流，而瞬时受体电位ankyrin 1（TRPA1）和瞬时受体电位vanilloid 4（TRPV4）通道的选择性阻断剂可分别减弱这些信号传导和膜电流。有趣的是，通过 TRPA1 通道进入的 Ca2+ 可抑制 HCoEpiC 中 TRPV4 通道的活性，反之亦然。ZPT 通过激活 TRPA1 和 TRPV4 通道明显促进了 IECs 的迁移。ZPT 逆转了脂多糖（LPS）诱导的 TRPA1 和 TRPV4 mRNA 表达变化。此外，ZPT 还能降低 LPS 促成的 HCoEpiC 中促炎因子的 mRNA 水平，而选择性 TRPA1 阻断剂则能恢复这些水平。在整个动物体内研究中，ZPT 能显著改善 DSS 诱导的小鼠结肠炎模型的体重减轻、结肠缩短以及粪便评分、血清钙蛋白和乳酸（LD）的增加：ZPT可能通过IECs中的TRP通道抗炎和促进黏膜愈合，从而发挥抗结肠炎作用。本研究不仅拓展了 ZPT 在消化道中的药理作用范围，还将其重新定位为治疗结肠炎的潜在药物。

{"title":"Zinc pyrithione ameliorates colitis in mice by interacting on intestinal epithelial TRPA1 and TRPV4 channels","authors":"","doi":"10.1016/j.lfs.2024.123090","DOIUrl":"10.1016/j.lfs.2024.123090","url":null,"abstract":"<div><h3>Aims</h3><div>Although zinc pyrithione (ZPT) has been studied as topical antimicrobial and cosmetic consumer products, little is known about its pharmacological actions in gastrointestinal (GI) health and inflammation. Our aims were to investigate the effects of ZPT on transient receptor potential (TRP) channels and Ca<sup>2+</sup> signaling in intestinal epithelial cells (IECs) and its therapeutic potential for colitis.</div></div><div><h3>Main methods</h3><div>Digital Ca<sup>2+</sup> imaging and patch-clamp electrophysiology were performed on human colonic epithelial cells (HCoEpiC) and rat small intestinal epithelial cells (IEC-6). The transcription levels of proinflammatory cytokines such as IL-1β were detected by RTq-PCR. Dextran sulfate sodium (DSS) was used to induce colitis in mice.</div></div><div><h3>Key findings</h3><div>ZPT dose-dependently induced Ca<sup>2+</sup> signaling and membrane currents in IECs, which were attenuated by selective blockers of transient receptor potential ankyrin 1 (TRPA1) and transient receptor potential vanilloid 4 (TRPV4) channels, respectively. Interestingly, Ca<sup>2+</sup> entry via TRPA1 channels inhibited the activity of TRPV4 channels in HCoEpiC, but not vice versa. ZPT significantly promoted migration of IECs by activating TRPA1 and TRPV4 channels. ZPT reversed lipopolysaccharides (LPS)-induced changes in mRNA expression of TRPA1 and TRPV4. Moreover, ZPT decreased mRNA levels of pro-inflammatory factors promoted by LPS in HCoEpiC, which were restored by selective TRPA1 blocker. In whole animal studies in vivo, ZPT significantly ameliorated DSS-induced body weight loss, colon shortening and increases in stool score, serum calprotectin and lactic acid (LD) in mouse model of colitis.</div></div><div><h3>Significance</h3><div>ZPT exerts anti-colitic action likely by anti-inflammation and pro-mucosal healing through TRP channels in IECs. The present study not only expands pharmacology spectrum of ZPT in GI tract, but also repurposes it to a potential drug for colitis therapy.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391650","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}

引用次数: 0

Navigating therapeutic prospects by modulating autophagy in colorectal cancer 通过调节结直肠癌中的自噬作用探索治疗前景。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2024-10-09 DOI: 10.1016/j.lfs.2024.123121

Colorectal cancer (CRC) remains a leading cause of death globally despite the improvements in cancer treatment. Autophagy is an evolutionarily conserved lysosomal-dependent degradation pathway that is critical in maintaining cellular homeostasis. However, in cancer, autophagy may have conflicting functions in preventing early tumour formation versus the maintenance of advanced-stage tumours. Defective autophagy has a broad and dynamic effect not just on cancer cells, but also on the tumour microenvironment which influences tumour progression and response to treatment. To add to the layer of complexity, somatic mutations in CRC including tumour protein p53 (TP53), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), Kirsten rat sarcoma viral oncogene homolog (KRAS), and phosphatase and tensin homolog (PTEN) can render chemoresistance by promoting a pro-survival advantage through autophagy. Recent studies have also reported autophagy-related cell deaths that are distinct from classical autophagy by employing parts of the autophagic machinery, which impacts strategies for autophagy regulation in cancer therapy. This review discusses the molecular processes of autophagy in the evolution of CRC and its role in the tumour microenvironment, as well as prospective therapeutic methods based on autophagy suppression or promotion. It also highlights clinical trials using autophagy modulators for treating CRC, underscoring the importance of autophagy regulation in CRC therapy.

尽管癌症治疗有所改善，但结直肠癌（CRC）仍然是全球死亡的主要原因。自噬是一种进化保守的依赖溶酶体的降解途径，对维持细胞平衡至关重要。然而，在癌症中，自噬在防止早期肿瘤形成和维持晚期肿瘤方面可能具有相互冲突的功能。自噬缺陷不仅对癌细胞有广泛而动态的影响，而且对肿瘤微环境也有影响，而肿瘤微环境会影响肿瘤的进展和对治疗的反应。更为复杂的是，CRC 中的体细胞突变，包括肿瘤蛋白 p53（TP53）、v-raf 小鼠肉瘤病毒癌基因同源物 B1（BRAF）、Kirsten 大鼠肉瘤病毒癌基因同源物（KRAS）以及磷酸酶和天丝同源物（PTEN），可通过自噬促进有利于生存的优势，从而产生化疗抗药性。最近的研究还报道了与自噬相关的细胞死亡，这些细胞死亡与经典的自噬不同，采用了部分自噬机制，这影响了癌症治疗中的自噬调控策略。本综述讨论了自噬在 CRC 演变中的分子过程及其在肿瘤微环境中的作用，以及基于抑制或促进自噬的前瞻性治疗方法。它还重点介绍了使用自噬调节剂治疗 CRC 的临床试验，强调了自噬调节在 CRC 治疗中的重要性。

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引用次数: 0

The effect of m6A methyltransferase METTL3 mediated TMEM30A regulation on tumor energy metabolism and cisplatin anti-tumor activity in oral squamous cell carcinoma. m6A甲基转移酶METTL3介导的TMEM30A调控对口腔鳞状细胞癌肿瘤能量代谢和顺铂抗肿瘤活性的影响

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2024-10-08 DOI: 10.1016/j.lfs.2024.123122

Wei Yuan, Shaobo Ouyang, Qiaoli Lv, Lan Liao

Aims: Cisplatin (CDDP) is still one of the most commonly used first-line treatments for advanced and recurrent oral squamous cell carcinoma patients in clinical practice. However, the decrease in tumor sensitivity to CDDP weakens its therapeutic effect. There is still limited research on the effect of METTL3-mediated methylation of m6A on CDDP sensitivity in oral squamous cell carcinoma (OSCC). TMEM30A widely exists in biomembranes and regulates the lipid asymmetry of the membrane, but there is no report on its function in OSCC. This study aims to explore the specific mechanism by which METTL3 regulates m6A methylation of TMEM30A and affects the occurrence and development of OSCC, and further investigate the effects of METTL3 and TMEM30A on the anti-tumor activity of CDDP.

Key findings: In oral squamous cell carcinoma, METTL3 plays a pro cancer role and weakens the anti-tumor efficacy of CDDP; METTL3 positively regulates the expression of TMEM30A by m6A methylation modification and binding to TMEM30A; The abnormally high expression of TMEM30A in tumors not only weakens CDDP sensitivity, but also enhances the malignant evolution of cancer cells, regulates the metabolic balance of ATP and lactate in cells, and is a potential oncogenic gene.

Significance: TMEM30A promotes malignant progression of tumors through METTL3 mediated m6A methylation modification, participates in maintaining the balance of tumor ATP and lactate metabolism, and thus reduces the anti-tumor activity of CDDP. TMEM30A is a potential gene target for CDDP anti-tumor activity in OSCC.

目的：顺铂（CDDP）仍是临床上治疗晚期和复发性口腔鳞状细胞癌患者最常用的一线疗法之一。然而，肿瘤对 CDDP 的敏感性降低削弱了其治疗效果。关于METTL3介导的m6A甲基化对口腔鳞状细胞癌（OSCC）CDDP敏感性的影响，目前的研究还很有限。TMEM30A广泛存在于生物膜中，调节膜的脂质不对称性，但目前还没有关于其在OSCC中功能的报道。本研究旨在探讨METTL3调控TMEM30A的m6A甲基化并影响OSCC发生和发展的具体机制，并进一步研究METTL3和TMEM30A对CDDP抗肿瘤活性的影响：METTL3通过m6A甲基化修饰与TMEM30A结合，正向调节TMEM30A的表达；TMEM30A在肿瘤中的异常高表达不仅会削弱CDDP的敏感性，还会增强癌细胞的恶性进化，调节细胞中ATP和乳酸的代谢平衡，是潜在的致癌基因：TMEM30A通过METTL3介导的m6A甲基化修饰促进肿瘤恶性进展，参与维持肿瘤ATP和乳酸代谢平衡，从而降低CDDP的抗肿瘤活性。TMEM30A是CDDP在OSCC中抗肿瘤活性的潜在基因靶点。

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引用次数: 0

Tyrosine hydroxylase-positive neurons in the rostral ventrolateral medulla mediate sympathetic activation in sepsis. 酪氨酸羟化酶阳性神经元在脓毒症中介导交感神经的激活。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2024-10-07 DOI: 10.1016/j.lfs.2024.123118

Yuan Mi, Hao Yu, PingWang, Yuxin Miao, Xu Teng, Sheng Jin, Lin Xiao, Hongmei Xue, Danyang Tian, Qi Guo, Yuming Wu

Aim: Sepsis results in high mortality and is associated with organ dysfunction caused by infection. The present study aimed to elucidate whether early-stage sympathetic activation is associated with the prognosis of sepsis and its possible mechanisms.

Methods: Patients with sepsis and healthy controls were included. Sepsis in rats was induced by lipopolysaccharide. Dexmedetomidine, a α2-adrenergic receptor agonist, was used in patients and rats with sepsis to evaluate the role of the sympathetic nervous system in sepsis. Holter monitoring was used to detect heart rate variability, while plasma samples were obtained to measure levels of norepinephrine and inflammatory markers. Mean arterial pressure, heart rate, and renal sympathetic nerve activity were recorded. Immunofluorescence was used to detect the activation of neurons in the rostral ventrolateral medulla (RVLM).

Results: In patients with sepsis, plasma levels of norepinephrine and interleukin-1β were higher compared with those in controls and positively correlated with acute physiology and chronic health evaluation (APACHEII). SDNN and SDANN were significantly reduced as well as negatively correlated with APACHEII. Meanwhile, rats with sepsis showed increased of sympathetic outflow and plasma levels of norepinephrine, with increased c-fos levels in the RVLM. Treatment with dexmedetomidine could improve prognosis. Lesion of tyrosine hydroxylase-positive neurons in the RVLM attenuated sympathetic activation and target organs damage in septic rats as well as improved survival.

Conclusion: The results suggest that tyrosine hydroxylase-positive neurons in the RVLM might contribute to the prognosis of sepsis via activation of the sympathetic nervous system, while dexmedetomidine could ameliorate sepsis via inhibiting sympathetic activation.

目的：败血症死亡率高，与感染导致的器官功能障碍有关。本研究旨在阐明早期交感神经激活是否与败血症的预后有关及其可能的机制：方法：纳入败血症患者和健康对照组。方法：纳入败血症患者和健康对照组。在败血症患者和大鼠中使用α2-肾上腺素能受体激动剂右美托咪定，以评估交感神经系统在败血症中的作用。Holter 监测用于检测心率变异性，同时采集血浆样本以测量去甲肾上腺素和炎症标志物的水平。同时还记录了平均动脉压、心率和肾交感神经活动。免疫荧光用于检测喙腹外侧延髓（RVLM）神经元的激活情况：结果：与对照组相比，脓毒症患者血浆中去甲肾上腺素和白细胞介素-1β的水平较高，并与急性生理学和慢性健康评估（APACHEII）呈正相关。SDNN和SDANN明显降低，并与APACHEII呈负相关。同时，脓毒症大鼠的交感神经外流和血浆去甲肾上腺素水平增加，RVLM 中的 c-fos 水平升高。使用右美托咪定治疗可改善预后。对RVLM中酪氨酸羟化酶阳性神经元的切除可减轻脓毒症大鼠交感神经的激活和靶器官的损伤，并提高存活率：结果表明，RVLM 中的酪氨酸羟化酶阳性神经元可能通过激活交感神经系统导致败血症的预后，而右美托咪定可通过抑制交感神经激活改善败血症。

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引用次数: 0

Unravelling the interplay between ER stress, UPR and the cGAS-STING pathway: Implications for osteoarthritis pathogenesis and treatment strategy 揭示 ER 应激、UPR 和 cGAS-STING 通路之间的相互作用：对骨关节炎发病机制和治疗策略的影响。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2024-10-06 DOI: 10.1016/j.lfs.2024.123112

Osteoarthritis (OA) is a debilitating chronic degenerative disease affecting the whole joint organ leading to pain and disability. Cellular stress and injuries trigger inflammation and the onset of pathophysiological changes ensue after irreparable damage and inability to resolve inflammation, impeding the completion of the healing process. Extracellular matrix (ECM) degradation leads to dysregulated joint tissue metabolism. The reparative effort induces the proliferation of hypertrophic chondrocytes and matrix protein synthesis. Aberrant protein synthesis leads to endoplasmic reticulum (ER) stress and chondrocyte apoptosis with consequent cartilage matrix loss. These events in a vicious cycle perpetuate inflammation, hindering the restoration of normal tissue homeostasis. Recent evidence suggests that inflammatory responses and chondrocyte apoptosis could be caused by the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signalling axis in response to DNA damage. It has been reported that there is a crosstalk between ER stress and cGAS-STING signalling in cellular senescence and other diseases. Based on recent evidence, this review discusses the role of ER stress, Unfolded Protein Response (UPR) and cGAS-STING pathway in mediating inflammatory responses in OA.

骨关节炎（OA）是一种使人衰弱的慢性退行性疾病，影响整个关节器官，导致疼痛和残疾。细胞应激和损伤引发炎症，在不可修复的损伤和无法消除炎症之后，病理生理学变化随之发生，阻碍了愈合过程的完成。细胞外基质（ECM）降解导致关节组织新陈代谢失调。修复努力会诱导肥大软骨细胞增殖和基质蛋白合成。异常的蛋白质合成导致内质网（ER）应激和软骨细胞凋亡，从而造成软骨基质流失。这些事件形成恶性循环，使炎症长期存在，阻碍了正常组织平衡的恢复。最近的证据表明，炎症反应和软骨细胞凋亡可能是由于 DNA 损伤激活了环 GMP-AMP 合成酶（cGAS）-干扰素基因刺激器（STING）信号轴。有报道称，在细胞衰老和其他疾病中，ER 压力和 cGAS-STING 信号之间存在串扰。基于最新证据，本综述讨论了ER应激、折叠蛋白反应（UPR）和cGAS-STING通路在介导OA炎症反应中的作用。

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引用次数: 0

Metformin's cardioprotective role in isoprenaline-induced myocardial infarction: Unveiling insights into the AMPK, NF-κB, JAK2/STAT3 pathways, and cholinergic regulation 二甲双胍在异丙肾上腺素诱发的心肌梗死中的心脏保护作用：揭示 AMPK、NF-κB、JAK2/STAT3 通路和胆碱能调节的奥秘。

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2024-10-05 DOI: 10.1016/j.lfs.2024.123115

Aim

Despite advancements in treatment modalities, myocardial infarction (MI) remains a significant global cause of mortality and morbidity. Metformin (MET), a commonly used antidiabetic medication, has demonstrated potential in various cardioprotective mechanisms. This study investigated whether MET could alleviate the histopathological, electrocardiographic, and molecular consequences of MI in rats.

Materials and methods

The study hypothesis was tested using an isoprenaline (ISOP)-induced MI model, where male Wistar rats were injected with ISOP (85 mg/kg/day, s.c., for 2 days) and treated with MET at the doses of 500 and 1000 mg/kg/day for 18 days or left untreated.

Key findings

ISOP-treated rats exhibited several indicators of MI, including significant ST-segment depression and prolonged QT-intervals on ECGs, worsened left ventricular histopathology with increased inflammatory cell infiltration, reduced expression of cardiac CHRM2, a cardioprotective cholinergic receptor, adaptive increases in AMPK and α7nAchR levels, and elevated levels of iNOS, NO, STAT3, JAK2, IL-6, TNF-α, and NF-κB. These effects were attenuated in rats treated with either low or high doses of MET. MET administration restored normal ECG recordings, diminished oxidative stress and inflammatory mediators, and downregulated NF-κB expression. Moreover, MET improved CHRM2 expression and normalized α7nAchR levels. Additionally, MET influenced the expression of key signaling molecules such as Akt, STAT3, and JAK2.

Significance

These findings might suggest that MET exerts cardioprotective effects in ISOP-induced MI in rats by mitigating critical inflammatory signaling pathways and regulating protective cholinergic mechanisms in the heart.

目的：尽管治疗方法不断进步，心肌梗死（MI）仍然是全球死亡率和发病率的重要原因。二甲双胍（MET）是一种常用的抗糖尿病药物，已被证明具有多种心脏保护机制的潜力。本研究探讨了二甲双胍是否能减轻大鼠心肌梗死的组织病理学、心电图和分子后果：给雄性 Wistar 大鼠注射异丙肾上腺素（ISOP）（85 毫克/千克/天，静脉注射，2 天），然后用 MET 按 500 和 1000 毫克/千克/天的剂量治疗 18 天或不治疗：主要研究结果：经 ISOP 处理的大鼠表现出多种心肌梗死指标，包括心电图上 ST 段明显压低和 QT 间期延长，左心室组织病理学恶化，炎性细胞浸润增加，心脏保护胆碱能受体 CHRM2 表达减少，AMPK 和 α7nAchR 水平适应性增加，iNOS、NO、STAT3、JAK2、IL-6、TNF-α 和 NF-κB 水平升高。使用低剂量或高剂量 MET 治疗大鼠后，这些影响均有所减弱。服用 MET 后，心电图记录恢复正常，氧化应激和炎症介质减少，NF-κB 表达下调。此外，MET 还改善了 CHRM2 的表达，并使α7nAchR 水平正常化。此外，MET还影响了Akt、STAT3和JAK2等关键信号分子的表达：这些发现可能表明，MET通过减轻关键的炎症信号通路和调节心脏的保护性胆碱能机制，在ISOP诱导的大鼠心肌梗死中发挥心脏保护作用。

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引用次数: 0