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关键词： CP/CPPS   DHA   IL-17A   NF-κB   PPARγ   Th17  

摘要： INTRODUCTION:Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a prevalent urological disorder characterized by urinary symptoms, pelvic pain, and sexual dysfunction. The potential inhibitory effects of docosahexaenoic acid (DHA) in relation to dietary consumption on autoimmune disorders have been acknowledged. Nevertheless, the effect of consuming DHA on CP/CPPS is still uncertain. METHODS:We established an experimental autoimmune prostatitis (EAP) model, which is frequently employed in CP/CPPS research. Western blotting, RT-qPCR, immunohistochemical staining, hematoxylin and eosin staining, immunofluorescence staining and flow cytometry were used in this study to investigate the effects of dietary docosahexaenoic acid (DHA) intake on EAP and to elucidate the underlying mechanisms involved. During the establishment of EAP, nonobese diabetic (NOD) mice were administered either DHA-enriched water or conventional water. The severity of EAP and the Th17 cell responses were evaluated. Furthermore, we investigated the impact of the PPARγ inhibitor GW9662 and the NF-κB activator on mice with EAP that were administered DHA. RESULTS:The findings demonstrated that consumption of DHA reduced the severity of EAP and inhibited the production of Th17 cells. DHA was found to hinder the development of Th17 cells through the PPARγ/NF-κB/IL-17A pathway, as demonstrated by in vitro assays. The administration of GW9662 and NF-κB activator resulted in an increase in Th17 cell production, worsening the symptoms of EAP alleviated by the consumption of DHA. CONCLUSIONS:The consumption of DHA mitigates EAP by stimulating the PPARγ/NF-κB/IL-17A pathway, thereby influencing the process of Th17 cell differentiation. The results provide a valuable understanding of the molecular pathways that contribute to the beneficial impacts of dietary variables, including DHA, on CP/CPPS.

摘要： The authors regret careless mistakes in the sequence of the PA28γ morpholino, which was written in reverse, and the incorrect images were used for the HSC-3 sh-PA28γ1, OE-Vector and PA28γ-OE groups in Fig. 1D. The correct sequence of the PA28γ mor...

摘要： Chronic wound healing, particularly in diabetic wounds, remains a global challenge. The delayed or even stagnant healing process imposes a substantial burden on both society and individuals. A critical challenge lies in effectively reducing inflammatory levels and promoting vascular remodeling. As an adipokine, C1QTNF9 (CTRP9) has been demonstrated to suppress inflammatory responses under various pathological conditions. In diabetic wound healing, CTRP9 facilitates the proliferation, differentiation, and migration of keratinocytes, yet its specific regulatory mechanisms on local inflammation remain unclear. Transcriptomic analysis of diabetic wounds revealed significantly reduced CTRP9 transcription levels in non-healing wounds. Animal experiments showed lower CTRP9 expression in the skin tissues of diabetic mice compared to normal mice, suggesting a close association between CTRP9 and wound healing. Subsequent local supplementation of CTRP9 in diabetic mouse wounds significantly accelerated healing to near-normal levels. Notably, SLC7A11 (also known as xCT)-a key protein linked to impaired efferocytosis in dendritic cells at diabetic wounds-was downregulated by CTRP9, while CTRP9 enhanced efferocytic efficiency. ATF3, a transcriptional repressor of SLC7A11 involved in ferroptosis regulation, has not been previously explored in dendritic cell efferocytosis. This study found that ATF3 knockdown upregulated SLC7A11 expression and attenuated CTRP9-mediated efferocytosis enhancement, indicating ATF3 as a critical pathway through which CTRP9 regulates SLC7A11. Furthermore, CTRP9 enhances glycolysis to produce lactate, thereby providing energy support for dendritic cell efferocytosis. In summary, this study demonstrates that CTRP9, as an anti-inflammatory factor, promotes diabetic wound healing by enhancing dendritic cell efferocytosis and reducing local inflammation, offering a promising therapeutic strategy.

关键词： Sjogren's disease   SHP2   IL-17RA signaling   Salivary gland epithelial cells   Apoptosis  

摘要： Salivary gland (SG) dysfunction is a hallmark manifestation of Sjogren's disease (SjD). While SHP2 has been implicated in several autoimmune diseases, its specific function in SjD remains to be elucidated. Here, we investigated the involvement of SHP2 in SjD-induced SG damage and elucidate the underlying molecular mechanisms. Our findings revealed that SHP2 is elevated in SG tissues of SjD patients and SjD-like animals, with predominant localization to salivary gland epithelial cells (SGECs) of acini and ducts. Notably, pharmacological inhibition of SHP2 with the allosteric inhibitor SHP099 significantly alleviates SG histopathological damage and reduces inflammatory cell infiltration in SjD-like animals. In vitro studies in the human SGEC line A253 revealed that SHP2 inhibition attenuated poly(I:C)-induced SGEC apoptosis and proinflammatory cytokine production. Mechanistically, SHP099 treatment disrupted the IL-17RA/ACT1/TRAF6 signaling axis, phenocopying the effects of SHP2 knockdown and direct IL-17R antagonism, which leads to downregulation of JAK/STAT3 and NF-kappa B pathways. Collectively, our findings highlight the significant involvement of SHP2 in the pathogenesis of SjD and suggest that targeting SHP2 or its downstream signaling pathways may represent a promising therapeutic approach for SjD treatment.

关键词： IL-2 mutein   IL-2Fc   IL-2Rβ   effector cells   superagonist  

摘要： The main limitations of cancer treatment with high doses of recombinant interleukin 2 (IL-2) are high toxicity and the undesired expansion of regulatory T cells. The generation of IL-2 mutated variants (muteins) with changes in the affinity for different chains of the IL-2 receptor (IL-2R) allows selective stimulation of effector cells while overcoming its toxicity. As increasing the IL-2 affinity for the IL-2R beta chain leads to better antitumor effect, we generated a group of these muteins using phage display technology, in a previous work. Recombinant Fc-fusion proteins, including these variants, resulted in improved developability properties and better in vivo effect than variants containing the IL-2 (IL-2Fc). Here, we assessed one such improved mutein, named superbeta 834 (SB834Fc), and performed a comprehensive characterization of its properties. This mutein showed a stronger antitumor effect than IL-2Fc in 5 murine tumor models: 3LL-D122, B16F10, CT26, MC38, and 4T1 at very low doses. Different from other IL-2 variants, SB834Fc, as single therapy, shows antitumor effect in a therapeutic injection scheme. This antitumor effect was coincident with strong stimulation of effector T cells in the spleen and in the tumor microenvironment, far above that observed with IL-2Fc, despite maintaining the same level of Treg stimulation. Additionally, induction of proliferation was demonstrated in CD8+ T cells isolated from human healthy donors, highlighting its translational value. These results support the SB834Fc fusion protein as a suitable candidate to develop a new cancer immunotherapy based in IL-2.

关键词： TLR3 pathway   IL-36 signaling   Macrophage activation   NETosis   Acute liver failure  

摘要： Background: Acute liver failure (ALF), characterized by inflammation-mediated hepatocyte dysfunction, poses a significant global health burden. Although neutrophils and macrophages are central to driving inflammatory responses in ALF, the molecular mechanisms governing IL-36-driven inflammation in toll-like receptor 3 (TLR3)-mediated NETosis and macrophage activation remain poorly understood. This study systematically delineates wherein TLR3 activation induces IL-36 hyperactivation and NETosis, which cooperatively trigger macrophage activation to accelerate ALF progression. Methods: First, the role of IL-36 signaling was evaluated in the TLR3-provoked mouse peritoneal macrophages (MPMs) and murine bone-derived macrophages (BMDMs) in vitro. Further, the murine model of ALF was established with polyinosinic-polycytidylic acid (Poly(I:C))/D-GalN and acute ethanol gavage in Il1rl2-deficient mice generated by lentivirus-mediated shRNA, and the released NETs were evaluated with immunoblotting and immunofluorescence staining. Results: We observed Poly(I:C), the specific ligand of TLR3, when combined with extracellular ATP, provoked the IL-36 signaling and the release of IL-1 beta in macrophages. In contrast, Il36g deficiency reduced the secretion of proinflammatory cytokines, such as IL-1 beta and HMGB1, upon macrophage activation. While Poly(I:C)/D-GalN or binge ETOH-induced ALF in mice was accompanied by the enhanced level of IL-36 gamma and NET formation, IL-36R knockdown reversed the liver damage by decreasing the expressions of proinflammatory cytokines and chemokines, reducing the lipid accumulation and preventing the NET formation as well. Conclusion: Our study demonstrates that TLR3-mediated NET formation was enhanced in ALF, and this process was tightly regulated by IL-36 signaling. These findings suggest that targeting IL-36 represents a potential therapeutic target for modulating inflammation in ALF.

摘要： While immune checkpoint inhibitors have led to durable responses in various cancer types, a substantial proportion of patients do not respond to these interventions. To uncover potential factors associated with a positive response to immunotherapy, we used a bilateral tumor model using P815 mastocytoma implanted in DBA/2 mice. In this model, only a fraction of tumor-bearing mice responds to anti-PD-1 treatment. Thus, it provides a valuable model to explore the influence of the tumor microenvironment (TME) in determining the efficacy of immune checkpoint blockade (ICB)-based immunotherapies. It also allows for the analysis of a pretreatment tumor and inference of its treatment outcome based on the response observed in the contralateral tumor. Herein, we report that tumor-reactive CD8+ T-cell clones expressing high levels of Tim-3 were associated with a positive antitumor response following anti-PD-1 administration. Our study also revealed distinct differentiation dynamics in tumor-infiltrating myeloid cells in responding and non-responding mice. An IFNγ-enriched TME promoted the differentiation of monocytes into PD-L1posMHC IIhigh cells in mice responding to immunotherapy. Monocytes present in the TME of non-responding mice failed to reach the same final stage of differentiation trajectory, suggesting that an altered monocyte to macrophage differentiation route may hamper the response to ICB. These insights will direct future research towards a temporal analysis of tumor-associated macrophages (TAMs), aiming to identify factors responsible for transitions between differentiation states within the TME. This approach may pave the way to novel strategies to enhance the efficacy of PD-1 blockade.

关键词： Black-legged kittiwake   Corynebacterium   Parasite-mediated selection   Pathogen recognition   Quantitative PCR   Reproductive success  

摘要： The major histocompatibility complex (MHC) is a gene cluster essential for pathogen recognition in jawed vertebrates. It encompasses the MHC class I genes which primarily recognize intracellular parasites, and the MHC class II genes which primarily recognize extracellular parasites. In wild birds, most studies investigating associations between MHC variants and parasites have been carried out in passerines, and have repeatedly shown that specific MHC class I variants provide resistance to intracellular haemosporidian parasites. In contrast, research on the associations between MHC variants and parasites in non-passerine birds remains limited. In this study, we examined the association between MHC-IIB supertypes and the bacterial load of a sexually transmitted bacterium (named C34) in the black-legged kittiwake (Rissa tridactyla), a genetically monogamous seabird. We focused on MHC class II genes because extracellular parasites are particularly prevalent in non-passerines and may therefore exert strong selection on the studied host. We found that females with lower C34 load had better reproductive performance, and higher probability to carry the MHC-IIB supertype SUP6. In contrast, in males, we observed a positive association between C34 load and reproductive performance, but no association between C34 load and MHC-IIB supertypes. While sexually transmitted diseases are not expected to be a strong selective force in genetically monogamous species, our study suggests that C34 might exert a selective pressure on the evolution of the MHC-IIB. Therefore, further research should explore the influence of sexually transmitted diseases on the reproductive biology of genetically monogamous species.

关键词： 心肌梗死   抑郁   炎症   芪黄逐瘀方  

摘要： 目的 探讨芪黄逐瘀方改善心肌梗死后抑郁的作用机制,重点揭示其对心脑炎症反应的调控作用。方法 采用超高效液相色谱-高分辨质谱联用技术(UPLC-Q-TOF/MS)结合网络药理学和分子对接分析芪黄逐瘀方活性成分及干预心肌梗死后抑郁的作用靶点;通过冠状动脉左前降支结扎联合慢性束缚应激建立心肌梗死后抑郁大鼠模型;超声心动图评估心功能,苏木素-伊红(HE)、马松(Masson)染色评估心肌损伤,行为学实验检测抑郁样行为,尼氏(Nissl)染色评估海马神经元损伤,蛋白免疫印迹(Western blot)检测心脏及海马组织中肿瘤坏死因子受体2 (TNFR2)、磷脂酰肌醇-3-羟激酶(PI3K)、磷酸化丝苏氨酸蛋白激酶(p-AKT)、丝苏氨酸蛋白激酶(AKT)、肿瘤坏死因子受体1 (TNFR1)、磷酸化核因子κB (p-NF-κB)、核因子κB (NF-κB)的表达;酶联免疫吸附测定法(ELISAs)检测血清IL-6、IL-10水平,免疫组化技术(IHC)检测TNFR1、TNFR2表达;体外实验中,通过大鼠心肌细胞系H9C2细胞和大鼠肾上腺嗜铬细胞瘤细胞系高分化PC12细胞共培养,给予TNFR1抑制剂(H398)和TNFR2激动剂(C-6His)干预,通过Western blot检测相关蛋白表达;TUNEL染色观察细胞凋亡情况;ELISAs检测细胞上清IL-6、IL-10水平。结果 网络药理学分析表明,TNF信号通路是芪黄逐瘀方治疗心肌梗死后抑郁的关键靶点;体内实验证实,芪黄逐瘀方干预可显著改善心肌梗死后抑郁大鼠的心功能、心肌组织与海马神经元结构损伤,并改善其抑郁样行为。分子层面,相较模型组,芪黄逐瘀方高剂量组显著上调心脏和海马组织中的TNFR2、p-AKT/AKT、IL-10(P<0.01),下调TNFR1、p-NF-κB/NF-κB、IL-6 (P<0.01)水平。体外实验表明,芪黄逐瘀方含药血清在H9C2和PC12细胞中显著上调TNFR2、p-AKT/AKT、IL-10 (P<0.01),下调TNFR1、p-NF-κB/NF-κB、IL-6 (P<0.01)的表达,并显著抑制细胞凋亡(P<0.01)。此外,联合应用H398或C-6His的实验进一步证实,其保护及抗炎作用是通过调控TNFR2/PI3K/AKT与TNFR1/NF-κB通路介导的。结论 芪黄逐瘀方通过调节TNF通路改善心脑炎症稳态,并改善心肌梗死后抑郁大鼠的心肌损伤和抑郁状态。