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关键词： CD4+CD10+ lymphocytes   Exhausted CD8+ lymphocytes   Major depressive episode   Th1   Th17  

摘要： Depression is a highly prevalent psychiatric condition referred to as a major depressive episode (MDE). The underlying causes and mechanisms of depression remain poorly elucidated and, in consequence, the efficacy of the current therapies. Inflammation has been proposed to contribute to the pathophysiology of MDE with altered innate and adaptive immune responses. The present work aimed to shed light on the effector CD4⁺ T helper (Th) cell subsets response and the activation and exhaustion condition of CD8⁺ lymphocytes in the peripheral blood of patients with MDE. Patients with MDE (n = 57) and healthy controls (HCs) (n = 34) were recruited. The intracellular production of interferon (IFN) γ (Th1), interleukin (IL)-17 (Th17), and IL-10 (CD4⁺ IL-10⁺) as the activation and exhausted status of CD8⁺ lymphocytes were evaluated by flow cytometry. The frequencies of Th1 and Th17 cells did not show statistical differences, but a lower percentage of CD4⁺IL-10⁺ cells (P < 0.05) and CD4⁺IFNγ⁺IL-10⁺ cells (P < .01) were found in patients with MDE compared with HCs. The reduction in the CD4⁺IL-10⁺ and CD4⁺IFNγ⁺IL-10⁺ population negatively correlated with the number of depressive episodes (P < .05 and P < .01) and duration of illness (P < .01). A higher proportion of activated CD8⁺CD69⁺ (P < .0001) with potentially exhausted phenotype CD8⁺PD1⁺LAG3⁺ (P < .0001) were observed, which positively correlated with the severity, number of episodes, and duration of illness in MDE compared with HCs. Altogether, patients with MDE are characterized by unbalanced Th1/Th17/CD4⁺IL-10⁺ cells and increased activation and exhaustion of cytotoxic CD8⁺ T cells. Therapeutic strategies restoring this balance and effective control of inflammatory response

关键词： 富血小板血浆   软骨细胞   细胞凋亡   细胞自噬   骨关节炎   细胞因子   信号通路  

摘要： 背景:富血小板血浆通过调节自噬和凋亡细胞因子、信号转导通路等方面在干预骨关节炎发展过程中发挥了重要作用。目的:总结近年来富血小板血浆在骨关节炎中发挥作用的细胞因子与信号通路,以及与软骨细胞自噬和凋亡的相关性,为未来治疗骨关节炎提供有效的靶点。方法:在中国知网、万方数据库、维普、PubMed、Web of Science和Medline数据库进行文献检索,以“富血小板血浆,软骨细胞,细胞凋亡,细胞自噬,骨关节炎,细胞因子,信号通路”作为中文检索词,以“platelet-rich plasma,chondrocyte,apoptosis,autophagy,osteoarthritis,cytokines,signaling pathway”作为英文检索词,对最终纳入的66篇文献进行了系统性的总结和归纳。结果与结论:现有研究显示富血小板血浆能够通过多种途径促进软骨修复,助力骨组织愈合,其主要分为3个方面:①富血小板血浆参与调控了微自噬小体的延伸、闭合与成熟,并在特定条件下促进软骨细胞巨自噬和分子伴侣介导的细胞自噬,促进LC3Ⅱ/Ⅰ、Beclin1等自噬相关因子的表达,抑制P62/SQSTM1的表达,目前尚未有明确的研究直接探讨富血小板血浆对热休克蛋白的具体作用,未来在这一领域值得进一步研究;②富血小板血浆释放的各类生长因子抑制促凋亡因子Caspase、白细胞介素1β、肿瘤坏死因子α的表达,促进抗凋亡因子Bcl-2的表达,阻止软骨细胞凋亡和变性;③富血小板血浆通过激活PI3K/AKT/mTOR信号通路、NF-κB信号转导通路、死亡受体通路、线粒体应激通路等途径,抑制Bax和Caspase的表达,阻止细胞色素c的释放,从而抑制软骨细胞死亡和坏死性凋亡。综合而言,富血小板血浆促进软骨修复、支持软骨再生及发挥抗炎作用,其在软骨细胞中实现生物效应通常依赖于细胞自噬和凋亡相关细胞因子及信号通路的调控。

摘要： Highlights•There is no standard treatment in NSCLC and acquired resistance to immunotherapy. •OSE2101, a therapeutic cancer vaccine, demonstrated survival benefit in this setting. •We present the design of the phase 3 trial to confirm initial positive results.

关键词： Cadmium   Leydig cell   Necroptosis   Reactive oxygen species (ROS)   TNF- α  

摘要： Cadmium, a ubiquitous environmental pollutant, has been linked to testicular damage, primarily through mechanisms such as oxidative stress and various forms of programmed cell death. Despite extensive studies on its toxic effects, the specific role of necroptosis in cadmium-induced reproductive toxicity remains unclear. In this study, we provide critical insights into how cadmium triggers necroptosis in Leydig cells, leading to testicular dysfunction. Using both in vitro and in vivo models, we demonstrated that cadmium exposure induces necroptotic cell death in Leydig cells, with significant involvement of the TNF-α/TNFR1 signaling pathway and reactive oxygen species (ROS) generation. Co-treatment with Nec-1, a specific necroptosis inhibitor, significantly reduced elevated ROS levels and suppressed TNF-α/TNFR1-induced necroptotic cell death, suggesting that ROS and the TNF-α/TNFR1 signaling pathway contribute to necroptosis activation in cadmium-induced Leydig cell injury. In conclusion, we demonstrate that necroptosis is a key driver of cadmium-induced testicular damage, suggesting that targeting necroptosis could offer novel therapeutic strategies for mitigating reproductive toxicity caused by heavy metals. © 2025

关键词： IL-17A   Inflammation   Kallikrein-related peptidases   Keratinization   Psoriasis   RNA sequencing   Sakuranetin   Skin barrier function  

摘要： Sakuranetin, a methoxylated flavanone with known anti-inflammatory and antioxidant properties, has yet to be explored for its therapeutic potential in psoriasis treatment. This study evaluates its efficacy in an imiquimod-induced psoriasis-like murine model, focusing on both immune modulation and skin barrier restoration. Topical administration of sakuranetin significantly attenuated psoriatic inflammation, with high-dose treatment achieving comparable efficacy to desoximetasone. RNA sequencing and qPCR validation revealed that sakuranetin modulates keratinization, cornified envelope formation, and kallikrein-related peptidase activity, suggesting its role in epidermal homeostasis. Notably, sakuranetin selectively downregulated IL-17A while maintaining IL-17F expression, supporting a targeted immunomodulatory effect. Additionally, sakuranetin upregulated KRT1, KRT16, KLK7, Sprr2f, and Wfdc18 while downregulating Sprr2k and Sprr3, indicating a refined regulation of skin barrier proteins. The observed upregulation of Tslp suggests a potential role in epidermal repair mechanisms. These findings highlight sakuranetin as a novel, plant-derived therapeutic candidate with dual anti-inflammatory and skin barrier-enhancing properties, providing a potential corticosteroid-sparing approach for long-term psoriasis management. © 2025 The Authors

关键词： Osteoarthritis   Benzophenone-3   IL-6   STAT3   Exposure  

摘要： Currently, limited research exists on the relationship between osteoarthritis (OA) and Benzophenone-3 (BP-3). This study aims to explore the potential molecular pathways involved, using both in vivo and in vitro biological experiments. In vivo experiments revealed that exposure to BP-3 leads to cartilage damage in the knee joints of rats, suggesting that BP-3 may be a significant risk factor in the development and progression of osteoarthritis. Proteomic sequencing of knee cartilage tissue revealed alterations in multiple inflammatory pathways in the BP-3 group. In vitro cellular experiments further demonstrated the toxic effects of BP-3 on chondrocytes, including inflammatory changes and increased transcriptional levels of IL-6. Cellular transcriptomics sequencing revealed significant changes in multiple intracellular inflammatory pathways, particularly the JAK-STAT pathway. Additional experiments demonstrated that BP-3 enhances STAT3 phosphorylation, promoting the degradation of extracellular matrix (ECM) proteins. Silence of STAT3 alleviated the impaired effects of BP-3 on chondrocytes. Overall, our data suggest that BP-3 exposure may be a significant risk factor for OA development. This study provides substantial evidence and a comprehensive understanding of the impact of BP-3 on OA development.

关键词： Autophagy   Heme   Interleukin 33   Progesterone receptor   Uterine endometrial cancer  

摘要： Progesterone is an important drug for hormone therapy in uterine endometrial cancer (UEC). However, the therapeutic efficacy of progestogen is often limited by resistance, and the underlying mechanism remains unknown. In this study, we observed heme metabolism is more active in progesterone-insensitive patients. Heme induced macrophages (Mφs) bias towards M2-like phenotype and downregulated the expression of IL-33, resulting in increased levels of Paired box gene 8 (PAX8). Further study showed PAX8 inhibited the transcriptional activity of PGR by binding to the PGR promoter region. In addition, PGR can also act as a transcriptional factor to regulate the transcription of autophagy-related gene 7 (ATG). Low expression of PGR decreases the transcriptional activity of ATG7 promoter, which decreases cell autophagy and promotes the progression of UEC. Overall, this study reveals the important interaction between heme metabolism, IL-33 and PGR in progesterone-insensitive UEC, and is promising to provide new therapeutic targets for overcoming progesterone resistance. © 2025 The Authors

关键词： Autoimmune hepatitis   Concanavalin A   Dapansutrile   JNK/p38 MAPK   NLRP3  

摘要： Aim: Dapansutrile (Dapan) is a newly developed anti-inflammatory molecule that supresses the production of NLRP3 inflammasome-dependent IL-1β. Its hepatoprotective effects against autoimmune hepatitis (AIH) have not yet been explored. Hence, this study was conducted to examine the possible protective effects of Dapan against concanavalin A (Con A)-induced hepatitis in mice. Main methods: Mice were randomly divided into five groups (n = 6): control, Con A (15 mg/kg), Dapan (60 mg/kg), Dapan (6 mg/kg) + Con A, and Dapan (60 mg/kg) + Con A. Mice were euthanised at the end of the study, and blood and hepatic tissues were collected. Key findings: Hepatic function testing using lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase levels, in addition to hepatic tissue histological examination, revealed that intraperitoneal administration of Dapan noticeably ameliorated Con A-induced hepatic enzyme impairment and histopathological disruption. Moreover, Dapan-treated mice had significantly lower malondialdehyde hepatic content and elevated reduced glutathione, superoxide dismutase, and total antioxidant capacity levels than non-treated mice in a dose-dependent manner. The Dapan-treated groups showed significantly lower levels of the inflammatory mediators, NLRP3, TNF-α, IL-6, and IL-1β, in addition to the immunomodulators CD8, CD4, INF-γ, and NFκB and inhibition of JNK and p38 MAPK levels compared to the Con A-treated group. Significance: Our results showed that intraperitoneal administration of Dapan could be a therapeutic opportunity to inhibit the development of AIH via inhibition of inflammatory pathways. © 2025 The Authors

关键词： Interferon lambda   MERS-CoV   SARS-CoV-2   Therapeutics   Variants of concern  

摘要： Therapeutic options against pathogenic human coronaviruses remain limited. In a recent clinical trial, we demonstrated the therapeutic efficacy of pegylated-IFN-λ in COVID-19 outpatients. However, the emergence of variants that have the potential to evade IFN-mediated antiviral responses raises concerns regarding the continued efficacy of this approach. In this work, we compared the sensitivity of SARS-CoV-2 variants and MERS-CoV to IFN-λ treatment in vitro and explored the potential of combination therapy with other FDA-authorized or approved antiviral agents. We observed that in contrast to the ancestral strain, all other SARS-CoV-2 lineages showed varying, but increased resistance to IFN-λ treatment, from a 5.7-fold increase in EC₅₀ value for the P.1 strain to a 32.7-fold increase for the B.1.1.7 variant. We further show that combination treatment with remdesivir or nirmatrelvir enhanced the antiviral effect of IFN-λ against both SARS-CoV-2 and MERS-CoV. These findings justify the initiation of further in vivo testing that ultimately can help inform the development of more effective therapeutic guidelines against pathogenic coronaviruses. © 2025

关键词： 山羊   乳房炎   乳腺组织   白细胞介素6   生物学标志  

摘要： 随着山羊养殖业不断集约化发展,乳房炎的发病率逐年升高,给山羊养殖业造成巨大的经济损失。为了确定乳房炎乳腺病理变化程度与乳腺组织白细胞介素-6(interlukin-6,IL-6)表达水平之间的联系,采用加利福尼亚乳房炎检测法(CMT)和病原菌分离鉴定法检测山羊乳房炎,使用real-time PCR检测健康山羊和乳房炎患病山羊乳汁体细胞趋化因子的相对表达水平,对健康和乳房炎乳腺组织进行苏木素-伊红(HE)染色,根据乳腺组织病理变化程度将其划分为轻度乳房炎乳腺、中度乳房炎乳腺、重度乳房炎乳腺,使用免疫荧光染色法确定不同病理变化程度乳房炎乳腺组织的IL-6表达水平。最后,对乳腺组织进行双重免疫荧光染色确定IL-6的来源。结果表明,乳房炎患病山羊乳汁体细胞的趋化因子表达水平显著上调;患病山羊乳腺组织腺泡排列紊乱,结构完整性被破坏,乳腺上皮细胞脱落并伴有大量的炎性细胞浸润;随着乳腺组织病理损伤程度的加重,IL-6表达水平也随之上调;IL-6可由乳腺组织的Ly6G+细胞和CD68+细胞分泌。研究结果提示IL-6可作为监测乳房炎的病理变化程度的生物学标志。