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关键词： Cytoplasmic-nuclear transport   HuR   IL-1β   IL-8   STAT3   mRNA stabilization  

摘要： Signal transducer and activator of transcription 3 (STAT3) functions to regulate inflammation and immune response, but its mechanism is not fully understood. We report here that STAT3 inhibitors Stattic and Niclosamide up-regulated IL-1β-induced IL-8 production in C33A, CaSki, and Siha cervical cancer cells. As expected, IL-1β-induced IL-8 production was also up-regulated through the molecular inhibition of STAT3 by use of CRISPR/Cas9 technology. Unexpectedly, IL-1β induced IL-8 production via activating ERK and P38 signal pathways, but neither STAT3 inhibitors nor STAT3 knockout affected IL-1β-induced signal transduction, suggesting that STAT3 decreases IL-8 production not via inhibition of signal transduction. To our surprise, STAT3 inhibition increased the stabilization, and decreased the degradation of IL-8 mRNA, suggesting a post-transcriptional regulation of IL-1β-induced IL-8. Moreover, Dihydrotanshinone I, an inhibitor of RNA-binding protein HuR, down-regulated IL-1β-induced IL-8 dose-dependently. HuR inhibition by CRISPR/Cas9 also decreased IL-8 production induced by IL-1β. Mechanistically, co-immunoprecipitation results showed that STAT3 did not react with HuR directly, but STAT3 inhibition increased the protein levels of HuR in cytoplasm. And IL-6 activation of STAT3 induced HuR cytoplasmic-nuclear transport. Taken together, these results suggest that STAT3 contributes to HuR nuclear localization and inhibits Il-1β-induced IL-8 production through this non-transcriptional mechanism.

关键词： Gastric cancer   IL-13   MEF2D   Tumor Microenvironment   Tumor metastasis   β-CATENIN  

摘要： Liver metastasis is the most common occurrence in gastric cancer patients, although the precise mechanism behind it remains unclear. Through a combination of proteomics and quantitative RT-PCR, our study has revealed a significant correlation between the upregulation of myocyte enhancer factor-2D (MEF2D) and both distant metastasis and poor prognosis in gastric cancer patients. In mouse models, we observed that overexpressing or knocking down MEF2D in gastric cancer cells respectively promoted or inhibited liver metastasis. Furthermore, our research has demonstrated that MEF2D regulates the transcriptional activation of H1X by binding to the H1X promoter. This regulation leads to the upregulation of H1X, which, in turn, promotes the in vivo metastasis of gastric cancer cells along with the upregulation of the downstream gene β-CATENIN. Additionally, we found that the expression of MEF2D and H1X at both mRNA and protein levels can be induced by the inflammatory factor IL-13, and this induction exhibits a time gradient dependence. In human gastric cancer tissues, the expression of IL13RA1, the receptor for IL-13, positively correlates with the expression of MEF2D and H1X. IL13RA1 has been identified as an intermediate receptor through which IL-13 regulates MEF2D. In conclusion, our findings suggest that MEF2D plays a crucial role in promoting liver metastasis of gastric cancer by upregulating H1X and downstream target β-CATENIN in response to IL-13 stimulation. Targeting MEF2D could therefore be a promising therapeutic strategy for the clinical management of gastric cancer. STATEMENT OF SIGNIFICANCE: MEF2D promotes its transcriptional activation in gastric cancer cells by binding to the H1X promoter and is upregulated by IL-13-IL13RA1, thereby promoting distant metastasis of gastric cancer.

关键词： Calcium handling   Cardiac function   Diet-induced obesity   Sucrose  

摘要： INTRODUCTION:High sucrose intake is linked to cardiovascular disease, a major global cause of mortality worldwide. Calcium mishandling and inflammation play crucial roles in cardiac disease pathophysiology. OBJECTIVE:Evaluate if sucrose-induced obesity is related to deterioration of myocardial function due to alterations in the calcium-handling proteins in association with proinflammatory cytokines. METHODS:Wistar rats were divided into control and sucrose groups. Over eight weeks, Sucrose group received 30% sucrose water. Cardiac function was determined in vivo using echocardiography and in vitro using papillary muscle assay. Western blotting was used to detect calcium handling protein; ELISA assay was used to assess TNF-α and IL-6 levels. RESULTS:Sucrose led to cardiac dysfunction. RYR2, SERCA2, NCX, pPBL Ser16 and L-type calcium channels were unchanged. However, pPBL-Thr17, and TNF-α levels were elevated in the S group. CONCLUSION:Sucrose induced cardiac dysfunction and decreased myocardial contractility in association with altered pPBL-Thr17 and elevated cardiac pro-inflammatory TNF-α.

关键词： AMPK   Brimonidine   Glaucoma   Ripasudi  

摘要： PURPOSE:The ROCK inhibitor ripasudil hydrochloride hydrate was shown to have axonal protective effects in TNF-induced optic nerve degeneration. The α2-adrenoreceptor agonist brimonidine was also shown to exert axonal protection. The current study aimed to elucidate whether additive axonal protection was achieved by the simultaneous injection of ripasudil and brimonidine and examine the association with AMPK activation. METHODS:Intravitreal administration was performed in the following groups: PBS, TNF, or TNF with ripasudil, with brimonidine, or with a combination of ripasudil and brimonidine. Axon numbers were counted to evaluate the effects against axon loss. Immunoblot analysis was performed to examine phosphorylated AMPK expression in optic nerves, and immunohistochemical analysis was performed to evaluate the expression levels of p-AMPK and neurofilament in the optic nerve. RESULTS:Both ripasudil alone or brimonidine alone resulted in significant neuroprotection against TNF-induced axon loss. The combination of ripasudil and brimonidine showed additive protective effects. Combined ripasudil and brimonidine plus TNF significantly upregulated p-AMPK levels in the optic nerve compared with the TNF groups. Immunohistochemical analysis revealed that p-AMPK is present in axons and enhanced by combination therapy. CONCLUSION:The combination of ripasudil and brimonidine may have additive protective effects compared with single-agent treatment alone. These protective effects may be at least partially associated with AMPK activation.

关键词： PDAC   HLA class I   B7-H3   Tumor microenvironment   NF-kB   ANTIGEN-PROCESSING MACHINERY   CANCER-CELLS   EXPRESSION   SURVIVAL   ASSOCIATION   DEFECTS  

摘要： Human leukocyte antigen (HLA) class I defects are associated with cancer progression. However, their prognostic significance is controversial and may be modulated by immune checkpoints. Here, we investigated whether the checkpoint B7-H3 modulates the relationship between HLA class I and pancreatic ductal adenocarcinoma (PDAC) prognosis. PDAC tumors were analyzed for the expression of B7-H3, HLA class I, HLA class II molecules, and for the presence of tumor-infiltrating immune cells. We observed defective HLA class I and HLA class II expressions in 75% and 59% of PDAC samples, respectively. HLA class I and B7-H3 expression were positively related at mRNA and protein level, potentially because of shared regulation by RELA, a sub-unit of NF-kB. High B7-H3 expression and low CD8+ T cell density were indicators of poor survival, while HLA class I was not. Defective HLA class I expression was associated with unfavorable survival only in patients with low B7-H3 expression. Favorable survival was observed only when HLA class I expression was high and B7-H3 expression low. Our results provide the rationale for targeting B7-H3 in patients with PDAC tumors displaying high HLA class I levels.

摘要： Importance:There is no US Food and Drug Administration-approved treatment for pityriasis rubra pilaris (PRP), and it is common for patients to fail to experience improvement with several systemic options. Involvement of interleukin (IL) 23 suggests a potential therapeutic target. Objective:To determine whether guselkumab, an IL-23p19 inhibitor, provides clinical improvement for participants with PRP and better understand gene and protein dysregulation in PRP. Design, Setting, and Participants:This single-arm, investigator-initiated nonrandomized trial was conducted from October 2019 to August 2022 at a single-center academic university with participants from 8 states in the US. In total, 14 adults with moderate to severe PRP were enrolled; 12 completed the trial. Age-matched and sex-matched healthy controls provided skin and blood for proteomic and transcriptomic studies. The primary outcome was observed at 24 weeks, and additional follow-up occurred at 36 weeks. Intervention:Guselkumab is a fully human immunoglobulin G1 λ monoclonal antibody that selectively binds and inhibits the p19 subunit of IL-23. Subcutaneous injections were given at the US Food and Drug Administration-approved dosing schedule for psoriasis over a 24-week period. Main Outcomes and Measures:The primary outcome was the mean change in the Psoriasis Area Severity Index (PASI) score at week 24. Secondary outcomes included pruritus, Dermatology Life Quality Index score, clinical response at week 36, and association with transcriptomics and proteomics expression. Results:A per-protocol analysis was performed for the cohort of 4 female and 8 male patients who had a mean (SD) age of 56.5 (18.7) years. The mean improvement in PASI score, pruritus, and Dermatology Life Quality Index score was 61.8% (P < .001), 62.3% (P = .001), and 60.2% (P < .001), respectively. Nine participants (75%) achieved a 50% improvement in PASI. Among these clinical responders, at week 36, 8 of 9 achieved PASI75, and 6 of 9 achieved PASI90. No participants had pathogenic CA

关键词： 太子参皂苷   鸡毒支原体弱毒疫苗   免疫功能   细胞因子  

摘要： 【目的】旨在研究口服太子参皂苷（RP）对鸡免疫功能和炎症反应的影响，为使用RP作为免疫增强剂提供科学依据，对家禽养殖业的疾病预防和健康维护具有实际应用价值。【方法】试验以鸡毒支原体（MG）抗原、抗体均为阴性的30日龄健康河田鸡为研究对象，根据初始体重平均分为五组，空白组不给药及疫苗，疫苗对照组口服灭菌生理盐水7 d后免疫MG弱毒疫苗，3个剂量RP组分别连续口服RP（100 mg/kg、20 mg/kg、5 mg/kg）7 d后免疫MG弱毒疫苗，一免后28 d进行二免，试验期49 d。采用间接ELISA法检测血清中MG特异性抗体消长规律及抗体阳性率和细胞因子（IFN-γ、IL-4、IL-5、IL-1α、CCL4、IL-17A、IL-6）含量。【结果】（1）RP组与疫苗对照组相比，口服RP能有效提高一免及二免后7天的MG特异性抗体滴度及抗体阳性率（P<0.05），其中以RP高剂量（100 mg/kg）效果最佳。（2）细胞因子表达水平中，与疫苗对照组相比，RP高剂量（100 mg/kg）和中剂量（20 mg/kg）组血清中免疫因子（IFN-γ、IL-4、IL-5）的含量在一免后3天呈现显著上升（P<0.05），一免后7天无明显差异；（3）与疫苗对照组相比，RP组炎症细胞因子（IL-1α、CCL4、IL-17A、IL-6）血清中的含量显著降低（P<0.05），高剂量组（100 mg/kg）下降最为显著。【结论】免前口服太子参皂苷（RP）能够提高河田鸡的免疫功能，并降低由MG弱毒疫苗引起的炎症反应，其中RP 100 mg/kg的剂量效果最优。

关键词： Fibroblasts   Inflammation   Pulmonary Fibrosis   Scleroderma, Systemic  

摘要： BACKGROUND:The interleukin (IL)-1 receptor accessory protein (IL1RAP) is an essential coreceptor required for signalling through the IL-1, IL-33 and IL-36 receptors. Here, we investigate the antifibrotic potential of the combined inhibition of these cytokines by an anti-IL1RAP antibody to provide a scientific background for clinical development in systemic sclerosis (SSc). METHODS:The expression of IL1RAP-associated signalling molecules was determined by data mining of publicly available RNA sequencing (RNAseq) data as well as by imaging mass cytometry. The efficacy of therapeutic dosing of anti-IL1RAP antibodies was determined in three complementary mouse models: sclerodermatous chronic graft-versus-host disease (cGvHD), bleomycin-induced dermal fibrosis model and topoisomerase-I (topo)-induced fibrosis. RESULTS:SSc skin showed upregulation of IL1RAP and IL1RAP-related signalling molecules on mRNA and protein level compared with normal skin. IL-1, IL-33 and IL-36 all regulate distinct gene sets related to different pathophysiological processes in SSc. The responses of human fibroblasts and endothelial cells to IL-1, IL-33 and IL-36 were completely blocked by treatment with an anti-IL1RAP antibody in vitro. Moreover, anti-IL1RAP antibody treatment reduced dermal and pulmonary fibrosis in cGvHD-induced, bleomycin-induced and topoisomerase-induced fibrosis. Importantly, RNAseq analyses revealed effects of IL1RAP inhibition on multiple processes related to inflammation and fibrosis that are also deregulated in human SSc skin. CONCLUSION:This study provides the first evidence for the therapeutic benefits of targeting IL1RAP in SSc. Our findings have high translational potential as the anti-IL1RAP antibody CAN10 has recently entered a phase one clinical trial.

关键词： 天山花楸   哮喘   气道高反应性   Th细胞   细胞因子   Toll样受体4   髓样分化因子88   高迁移率蛋白1  

摘要： 目的：探讨天山花楸抗哮喘作用及机制。方法：将SPF级60只雄性SD大鼠随机分为正常对照组、模型对照组、天山花楸1、2、4 g/kg组、地塞米松2 mg/kg组。除了正常对照组外，其余组采用卵清蛋白进行腹腔注射（10% OVA）和雾化（2% OVA）进行造模，造模成功后，各组灌胃给予相应药物，1次/d，连续给药14天，每天观察大鼠一般状态。采用无创肺功能测试仪检测哮喘大鼠肺功能、收集其血清、BALF、肺脏及脾脏等样本。HE染色观察肺组织病理改变；流式细胞术检测Th1、Th2细胞含量；ELISA法检测血清及BALF中的总IgE、OVA-IgE、IFN-γ、IL-4、TNF-α及IL-6水平；Western-blot法检测肺组织中HMGB1、TLR4、MyD88、NF-kBp65、IκBα 蛋白表达。结果：与正常对照组比较，模型对照组大鼠出现明显的哮喘症状、气道高反应性明显增强（P<0.05）、肺组织出现明显病变情况、脾脏中Th2细胞含量显著增高（P<0.05）、Th1细胞含量显著降低（P<0.05）、血清和肺泡灌洗液中总IgE、OVA-IgE、IL-4、TNF-α和IL-6含量明显增高（P<0.05）、IFN-γ含量明显降低（P<0.05）、肺组织中HMGB1、TLR4、MyD88、NF-κB蛋白表达量明显上调（P<0.05），IκBα蛋白表达明显下调（P<0.05）；与模型对照组比较，天山花楸1、2、4 g/kg组、地塞米松2 mg/kg组大鼠哮喘症状明显减少、气道高反应性明显降低（P<0.05）、肺组织病变情况有所改善、脾脏Th2细胞含量明显降低（P<0.05），Th1细胞含量明显增高（P<0.05），Th1/Th2趋向平衡、血清和肺泡灌洗液中总IgE、OVA-IgE、IL-4、TNF-α和IL-6含量明显降低（P<0.05），IFN-γ含量明显增高（P<0.05）、肺组织中HMGB1、TLR4、MyD88、NF-κB蛋白表达量明显下调（P<0.05），IκBα蛋白表达量明显上调（P<0.05）。结论：天山花楸水提物具有抗哮喘药理活性，其抗哮喘作用机制可能是通过调节Th1/Th2免疫失衡，抑制HMGB1/TLR4/NF-κB信号通路激活来实现的。