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关键词： 克罗恩病   肠道   纤维化   γδT细胞   IL-17  

摘要： 目的 基于克罗恩病（Crohn's disease，CD）肠纤维化模型探讨γδT细胞通过IL-17调控TGF-β/Smad信号通路对肠纤维化的作用及机制研究。方法 雄性BALB/c小鼠28只，随机分为对照组，模型组、抗IL-17A抗体干预组、抗TCRγ/δ抗体干预组。采用TNBS/50%酒精灌肠构建CD肠纤维化模型，注射相应抗体。记录小鼠体重，疾病活动度指数（DAI），第7周处死小鼠后取结肠组织并测量其长度。HE染色观察结肠组织形态结构变化；Masson染色观察结肠组织中胶原蛋白；免疫组化检测α-平滑肌肌动蛋白（α-SMA）的表达；ELISA检测白细胞介素-17（IL-17）、转化生长因子-β（TGF-β）、干扰素-γ（IFN-γ）和IL-10的表达水平；Westernblot法检测α-SMA、结缔组织生长因子（CTGF）、Ⅰ型胶原（CollagenⅠ）、CollagenⅢ及TGF-β/Smad信号通路相关蛋白。结果 与对照组相比，模型组DAI评分升高，结肠长度缩短；病理显示结肠组织损伤严重，Masson染色可见大量蓝染的胶原纤维；IFN-γ、IL-10表达下降，IL-17、TGF-β、α-SMA、CTGF、CollagenⅠ、Collagen Ⅲ、TGF-β1、Smad2/3、P-Smad2/3表达显著升高（P<0.05）。与模型组相比，给予抗IL-17A抗体或抗TCR γ/δ抗体处理后，明显抑制小鼠TNBS诱导的各项指标变化（P<0.05），减轻肠道纤维化。结论 γδT 细胞能促进肠道纤维化，作用机制可能与抑制相关IL-17信号通路有关。

关键词： Rheumatoid arthritis   Combination therapy   RNA interference   Macrophage-targeted delivery   Polymeric vesicles  

摘要： Rheumatoid arthritis (RA) is an autoimmune disease that has a complex pathogenesis and remains tough to treat. The clinical treatments with e.g. methotrexate (MTX) and TNF-alpha antibodies show fractional responses and lessen the symptoms only to a certain extent. Here, we developed inflammation-targeted vesicles codelivering methotrexate and TNF-alpha small interfering RNA (siTNF alpha) (ITV-MT) for effective ablation of collagen-induced arthritis (CIA) in mice. ITV-MT with tetra-mannose ligand and high loading of MTX (17.1 wt%) and siTNF alpha (9.0 wt%) displayed a small and uniform size (53 nm) and augmented uptake by inflammatory macrophages leading to superior regulation of macrophage phenotype from M1 to M2 in vitro compared to monotherapies. The intravenous injection of ITV-MT revealed clearly enhanced accretion in the inflamed joints. Interestingly, ITV-MT effectively repolarized M1 macrophages to M2 type, markedly reduced proinflammatory cytokine levels, and significantly attenuated symptoms including joint swelling, arthritis scores and bone damage in the CIA mouse models, by concurrently downregulating both adenosine and TNF-alpha pathways. This study highlights inflammation-targeted vesicles codelivering methotrexate and TNF alpha siRNA as a potential strategy to improved RA treatment. Statement of significance: Rheumatoid arthritis (RA) is regarded as an incurable disease, often referred to as an "incurable cancer". Current therapies, such as methotrexate (MTX) and anti-TNF alpha monoclonal antibodies, exhibit limited efficacy and severe adverse effects. The distinct physiochemical properties of MTX and siTNF alpha hinder their codelivery to RA joints and inflammatory cells. Here, we engineered inflammation-targeted vesicles (ITVMT) for the codelivery of MTX and siTNF alpha to enhance therapeutic outcomes. Our findings reveal that ITV-MT significantly improves the drug uptake by macrophages, facilitating repolarization from M1 to M2 phenotypes. In CIA m

关键词： Asthma   Oral tolerance   Immune memory   PLZF   Tissue-resident memory T cells  

摘要： BackgroundAllergic asthma is a chronic airway disease characterized by an allergic response and altered immune tolerance. CD4+ tissue-resident memory T (TRM) cells are crucial in the chronic and relapsing pathogenesis of asthma. Furthermore, promyelocytic leukemia zinc finger (PLZF) is an essential transcription factor involved in asthmatic tolerance and has been implicated in the regulation of CD4+CD44+ memory T cells. However, the role of CD4+ TRM cells in asthmatic tolerance, as well as their potential modulation by PLZF, remain unclear. Therefore, in the current study, we explore the role of CD4+ TRM cells in asthmatic immune tolerance and as well as the regulatory role of PLZF in this *** elucidate the role of CD4+ TRM cells in immune tolerance, asthma memory mouse models were treated with the immunomodulator FTY720. Subsequently, CD4+ T cells were isolated from the lungs and spleens and transferred to oral tolerance mouse models. To explore the regulation of PLZF in CD4+ TRM cells, asthma and oral tolerance were established in Zbtb16flox/flox CD4Cre and wild-type mice. Flow cytometry, histological analysis, and cytokine measurements were performed to characterize the immune response. The regulatory activity of PLZF on CD4+ TRM cells was analyzed through quantitative proteomics and verified in vitro and *** CD4+ TRM cell proportion positively correlated with the pathological phenotypes and molecular characteristics of asthma. Adoptive transfer of CD4+ TRM cells induced asthmatic phenotypes. This suggested that CD4+ TRM cells contributed to the pathogenesis of asthma. Conditional knockout of PLZF substantially reduced the proportion of CD4+ TRM cells, relieved asthmatic symptoms, and suppressed the interleukin (IL)-15/IL-15R alpha signaling pathway. Furthermore, exposure to the IL-15R alpha agonist restored asthma-related Th2 inflammation, accompanied by a markedly increased proportion of CD4+ TRM cells. Meanwhile, IL-15 and ovalbumin(O

关键词： Cumulus cells   Developmental potential   Oocyte aging   Ovine   Tumor necrosis factor-alpha  

摘要： Post-maturation oocyte aging (PMOA) is known to significantly impair the developmental potential of oocytes;however, comprehensive studies on ovine PMOA remain limited. In mice, cumulus cells (CCs) accelerate oocyte aging by releasing cytokines, but the roles of CCs and cytokines in PMOA of domestic animals are poorly understood. This study aimed to elucidate the involvement of CCs and tumor necrosis factor (TNF)-alpha in the PMOA of ovine oocytes. Our findings reveal that PMOA significantly reduced blastocyst rates and the expression of development-promoting genes, while increasing oocyte degeneration and activation rates, along with expression of development-inhibiting genes, compared to newly matured oocytes. These detrimental effects were more pronounced in oocytes aged as cumulus-oocyte complexes than as cumulus-denuded oocytes. Additionally, PMOA led to increased apoptotic rates, TNF-alpha production, and TNF receptor 1 (TNFR1) expression in CCs, coupled with a significant reduction in the expression of anti-apoptotic genes. Mature oocytes expressed TNFR1, with levels decreasing significantly during PMOA. Importantly, the addition of the TNF-alpha antagonist Etanercept to the aging medium markedly improved parthenogenetic embryo development and the expression of competence-related genes, while mitigating CC apoptosis during PMOA of COCs. In conclusion, PMOA compromises developmental potential while heightening oocyte degeneration and activation sensitivity in ovine oocytes. Cumulus cells exacerbate PMOA through increased TNF-alpha signaling activity, highlighting the potential of TNF-alpha antagonists as therapeutic agents to counteract the deleterious effects of PMOA.

关键词： Tendon healing   Chemically modified mRNA (cmRNA)   Poly(amidoamine) nanoparticles   PDGF-BB   IL1RA   Drug delivery systems   Tendinopathy  

摘要： Tendon injuries, common in both athletic and non-athletic populations, present significant challenges due to their slow healing and the formation of scar tissue, which impairs function and potentially increases the risk of (re-)rupture. Conventional treatments often yield suboptimal functional and structural repair. This study investigates the potential of mRNA-based therapeutics to enhance tendon healing by targeting 2 distinct pathways via the delivery of chemically modified ARCA-capped mRNAs (cmRNAs) encoding Interleukin-1 receptor antagonist (IL1RA) and Platelet-Derived Growth Factor-BB (PDGF-BB) using injectable nanoparticle (NP) carriers. In vitro experiments demonstrate successful cmRNA delivery and translation, resulting in increased tendon cell proliferation, migration, and anti-inflammatory responses. In vivo, cmRNA treatment notably enhances tendon repair in a rat patellar tendon defect model, by reducing pro-inflammatory cytokines and fibrotic markers while enhancing repair tissue structure. These findings suggest that NP-based cmRNA delivery represents a promising therapeutic strategy for improving tendon healing, offering better outcomes over existing treatments by targeting both inflammatory and regenerative pathways. Statement of significance: In this study, we investigate an mRNA-based therapeutic approach aimed at enhancing tendon healing in a small animal model. Utilizing bioreducible poly(amidoamine)-based polymeric nanoparticles (PAA PNPs) for the delivery of cmRNAs encoding Interleukin-1 receptor antagonist (IL1RA) and Platelet-Derived Growth Factor-BB (PDGF-BB), we demonstrate effective delivery and protein translation in vitro and ex vivo, resulting in enhanced tendon cell proliferation, migration, and robust anti-inflammatory responses. By combining these therapeutic cmRNAs, we show improved tendon repair in vivo, with accelerated tissue regeneration, better collagen fiber organization, and signs of reduced fibrotic scarring. These findings

关键词： Alzheimer's disease   PDK3   Oxidative stress   TNF-alpha   Paeoniflorin   BDNF   Neuroprotection  

摘要： Metabolic dysregulation causes diseases like diabetes and cancer, making PDKs attractive targets. However, a thorough investigation into the unique roles played by the different members of the PDK family, especially PDK3, about memory loss and related diseases like Alzheimer's disease (AD) is still lacking. The current study investigates PF's potential to reduce PDK3-associated toxicity in neurodegenerative illnesses, including AD. The association between PF and PDK3 presents a significant opportunity for medication development and AD therapy approaches. PF efficiently suppresses PDK3 activity, as demonstrated by molecular docking and biophysical characterization, providing an in-depth understanding of their molecular interactions. PF significantly inhibited PDK3 in a concentration-dependent manner with an IC50 value of 4.88 mu M. Considering this, the current investigation also explores the biological component of PF, which exhibits potential in treating AD and is primarily associated with neuroprotection. In the present study, a 3-hour pre-treatment of PF was administered at varying concentrations (4, 6, and 8 mu M) in response to the 24-hour SCP (2 mM)-mediated toxicity. Based on the results of in silico and biophysical characterization, it is concluded that PF inhibits the PDK3 activity. Additionally, it can enhance cell viability, suppress ROS expression, impede apoptosis, and downregulate TNF-alpha expression. When combined, these actions help to prevent neuronal death in an in vitro model of SCP. PF strengthens the memory marker, which is confirmed through BDNF expression. This study found that all results were more effective at lower and moderate doses of PF. Our research indicates that PF boosts memory, decelerates the progression of oxidative stress, and could potentially serve as a dose-dependent treatment for AD.

关键词： Ancianos   Benign prostatic hyperplasia   Diagnosis   Diagnóstico   Elderly   Hiperplasia prostática benigna   Homocysteine   Homteína   IL-6  

摘要： OBJECTIVE:To investigate the diagnostic value of serum metabolic markers such as HCY, sdLDL-C, Crea, inflammatory factor IL-6 and prostate-specific antigen in elderly patients with prostatic hyperplasia (BPH). METHODS:150 senile patients with hyperplasia of prostate were selected as observation group and 169 healthy senile patients were selected as control group. The tPSA, fPSA, fPSA/t PSA and prostate size data of the two groups were collected, and serum samples of the subjects were collected for the detection of HCY, sdLDL, Crea, IL-6 and other indicators. Univariate analysis, correlation analysis and Logistic regression analysis were conducted to analyze the relationship between each index and senility prostatic hyperplasia. The diagnostic efficiency of each serum metabolite was analyzed by receiver operating characteristic curve (ROC). RESULTS:Serum levels of tPSA, fPSA, Crea, HCY, sdLDL-C and IL-6 were significantly increased, fPSA/tPSA ratio and HDL were significantly decreased, and TCHO, TG and LDL had no statistical significance. Serum tPSA and fPSA levels were positively correlated with prostate size, serum IL-6, Crea and HCY levels were positively correlated with tPSA and fPSA levels, and serum sdLDL-C levels were negatively correlated with fPSA levels. Logistic regression analysis showed that tPSA, fPSA, prostate size, HCY, Crea and IL-6 were risk factors for prostate hyperplasia. HDL and fPSA/tPSA are protective factors for benign prostatic hyperplasia. ROC curve analysis showed that the sensitivity and specificity of fPSA/tPSA and IL-6 were 82.7% and 72%, 83.4% and 80.5%, and the area under ROC curve were 0.840 and 0.825, respectively. tPSA and fPSA combined with HCY, IL-6 and Crea had the best diagnostic efficiency, with the area under ROC curve reaching 0.881, specificity and sensitivity reaching 84% and 77.3%, respectively. CONCLUSION:The combined detection of prostate-specific antigen, HCY, Crea and IL-6 can significantly improve the diagnostic effi

关键词： Hepatitis B virus   Peg-IFN-alpha   LY6E   TRIM6  

摘要： BackgroundPegylated interferon alpha (Peg-IFN-alpha) has the potential to eradicate hepatitis B surface antigen (HBsAg). This study aimed to investigate whether the expression levels of lymphocyte antigen 6 family member E (LY6E) and tripartite motif-containing protein 6 (TRIM6) mRNAs in peripheral blood mononuclear cells (PBMCs) of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B virus (HBV) patients is associated with the response to Peg-IFN-alpha treatment and HBsAg *** this prospective study, HBeAg-negative chronic HBV patients treated with Peg-IFN-alpha were followed for 48 weeks. The participants were classified into two groups, the virological response (VR) group and nonvirological response (NVR) group, according to the changes in HBV DNA and HBsAg levels observed at week 48 of treatment. Furthermore, these patients were divided into a serological response (SR) group and a nonserological response (NSR) group, depending on whether they exhibited a loss of serum HBsAg or evidence of seroconversion. The expression levels of LY6E and TRIM6 mRNAs in PBMCs were evaluated using real-time quantitative PCR with fluorescence detection. The diagnostic performance of LY6E and TRIM6 was assessed by analyzing the receiver operating characteristic (ROC) curve and calculating the area under the ROC curve (AUC).ResultsAfter the treatment period, the observed VR and SR rates were 44.64% and 28.57%, respectively. Dynamic changes in LY6E and TRIM6 mRNA levels were significantly different between the VR and NVR groups and between the SR and NSR groups. Multivariate analysis revealed that TRIM6 was independently associated with VR at weeks 12 and 24 of Peg-IFN-alpha therapy and with SR at week 12;in addition, LY6E was independently associated with VR at week 12 and SR at week 24. At week 24, the area under the curve (AUC) for LY6E in the prediction of VR was 0.6942, and the AUC for the prediction of SR was 0.7766;at week 12, TRIM6 had AUCs of 0.7600 for t

关键词： Chlamydia trachomatis   Helicobacter pylori   Varicella zoster virus   Alzheimer   Cytokines   Real-time RT-PCR  

摘要： Objectives: This study aimed to use the real-time RT-PCR method to detect the gene expression cytokines IL-10, TNF alpha, IFN-gamma, and TGF-(3 in the serum of Alzheimer's patients. Methods: This study was conducted on 100 serum samples of Alzheimer's patients. DNA extraction was performed on the samples with the Cinnaclone kit and PCR techniques were used to detect the presence of Helicobacter pylori, Chlamydia trachomatis, and Varicella zoster virus. Real-time RT-PCR was performed to measure the expression of TNF alpha, IFNT, TGF(3, and IL-10 genes with a Smobio kit. Results: The relative changes in the expression of TNF alpha, IFNT, TGF(3, and IL-10 genes were observed in Alzheimer's patients compared to the control samples without microorganisms, and a significant increase was observed (P < 0.05). Conclusion: This study showed that the cytokines TNF alpha, IFNT, TGF(3, and IL-10, have an increase in Alzheimer's patients(P < 0.05). Therefore, the presence of the microorganisms accompanied by the rise and inducing the expression of cytokines compared to the groups without the mentioned microorganisms causes a significant increase in the production of cytokines effective in the occurrence or exacerbation of Alzheimer's disease.

关键词： Ventriculomegaly   ASD   MIA   IFN-gamma   Choroid plexus   Ependyma  

摘要： Maternal immune activation (MIA) is a principal environmental risk factor contributing to autism spectrum disorder (ASD) and can be causally linked to ASD symptoms. In our study, we found that MIA triggered by poly (I: C) injection caused ventriculomegaly in offspring due to the dysfunction of the choroid plexus (Chp) and ependyma. We subsequently identified a sustained enhancement of interferon-gamma (IFN-gamma) signaling in the brain and serum of MIA offspring. Further study revealed that increased IFN-gamma signaling could disrupt the barrier function of Chp epithelial cells by activating macrophages, and suppress the differentiation of primary ependymal cells via the signal transducer and activator of transcription 1/3 signaling. The effects of MIA on the offspring were mitigated by administration of IFNGR-blocking antibody in pregnant dams, while systemic maternal administration of IFN-gamma was sufficient to mimic the effect of MIA. Overall, our findings revealed that ventriculomegaly caused by IFN-gamma signaling could be a critical factor in compromising fetal brain development in MIA-induced ASD and provide a mechanistic framework for the association between maternal inflammation and abnormal development of ventricles in the offspring.