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关键词： 补阳还五汤   坏死性凋亡   心肌梗死   心室重构  

摘要： 目的：探索补阳还五汤对TNF/RIPK1通路的影响，阐明补阳还五汤抑制心肌梗死后心室病理性重构的作用机制。方法：将70只Wistar大鼠随机分为对照组，模型组，补阳还五汤低、中、高剂量组，西药组以及TNF-α 抑制剂组，每组10只。补阳还五汤低、中、高剂量组分别给予补阳还五汤3.22 g·kg-1·d-1、 6.44 g·kg-1·d-1、12.87 g·kg-1·d-1，西药组给予培哚普利叔丁胺片0.36 mg·kg-1·d-1，TNF-α 抑制剂组给予TNF-α 抑制剂依那西普5 mg·kg-1·w-1皮下注射，对照组与模型组均给予生理盐水灌胃，连续给药4周。采用多普勒超声检测各组大鼠心脏的左室射血分数（ejection fraction of left ventricular， LVEF）、左室短轴缩短率（left ventricular fractional shortening， FS）、左室舒张末期内径（left ventricular end diastolic diameter， LVEDD）和左室收缩末期内径（left ventricular end systolic diameter， LVESD）。病理切片进行HE染色和Masson染色观察心肌组织的病理形态及纤维化程度；Tunel染色观察心肌细胞凋亡情况。RT-qPCR检测心肌组织中TNF-α、RIPK1、RIPK3、MLKL的mRNA表达水平。Western blot检测心肌组织中TNF-α、RIPK1、P-RIPK1、RIPK3、MLKL的蛋白表达水平。结果：与对照组相比，模型组大鼠的正常心脏结构被破坏、室壁变薄、心肌细胞排列紊乱、局部出现纤维化重构，LVEF、FS明显降低，LVEDD、LVESD明显升高，TNF-α、RIPK1、RIPK3、MLKL的mRNA表达和TNF-α、P-RIPK1、RIPK3、MLKL的蛋白表达明显升高（P<0.05）；与模型组比较，补阳还五汤低、中、高剂量组、西药组以及TNF-α 抑制剂组大鼠的心脏结构破坏程度和心肌纤维化程度均有所改善，LVEF、FS明显增高，LVEDD、LVESD明显降低，TNF-α、RIPK1、RIPK3、MLKL的mRNA表达水平和TNF-α、P-RIPK1、RIPK3、MLKL的蛋白表达水平降低（P<0.05），且补阳还五汤高剂量组疗效最好。结论：补阳还五汤可能通过抑制TNF/RIPK1通路减少心肌细胞坏死性凋亡从而改善心肌梗死后心室病理性重构。

关键词： SARS-CoV-2   AMP-activated protein kinase   autophagy   lipid metabolism   antiviral agents  

摘要： AMP-activated protein kinase (AMPK) plays a central role in regulating cell energy balance. When activated, AMPK suppresses energy-consuming pathways, such as lipid and protein synthesis, while increasing nutrient availability through the activation of autophagy. These pathways downstream of AMPK activation contribute to SARS-CoV-2 infection, which hijacks autophagy and accumulates lipid droplets in viral factories to support viral replication. Here, we assessed the antiviral activity of the direct pan-AMPK allosteric activator MK-8722 in vitro. MK-8722 efficiently inhibited infection of Alpha and Omicron SARS-CoV-2 variants in Vero76 and human bronchial epithelial Calu-3 cells at micromolar concentration. This inhibition relied on restoring the autophagic flux, which redirected newly synthesized viral proteins for degradation, and reduced lipid metabolism, which affected viral factories. Furthermore, MK-8722 treatment increased the type I interferon (IFN-I) response. Post-infection treatment with MK-8722 was enough to inhibit efficient viral replication and restore the IFN-I response. Finally, MK-8722 treatment did not alter the SARS-CoV-2-specific CD8+ T cell response mounted upon Spike vaccination. Overall, by activating AMPK, MK-8722 acts as an effective antiviral against SARS-CoV-2 infection, even when applied post-exposure, paving the way for preclinical tests aimed at inhibiting viral replication and improving patients' *** disease 2019, caused by SARS-CoV-2 infection, has led to severe acute respiratory syndrome with very high mortality. Despite available vaccines and public health measures, new SARS-CoV-2 variants emerge with increased transmissibility requiring the development of novel therapeutic strategies. Recently, the AMP-activated protein kinase (AMPK), a cellular energy sensor, has emerged as a potential broad-spectrum antiviral target, as AMPK can modulate the intracellular environment in turn impeding viral replication.

关键词： antisense oligonucleotide   cell transplant   inflammation   SC islets   TNF-α  

摘要： One of the many challenges for islet transplantation as a treatment for type 1 diabetes is inflammation that contributes to islet de-differentiation and death. Innate immune cells such as monocytes and macrophages secrete tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β), inducible nitric oxide synthase (iNOS), and IL-6, which directly contribute to islet dysfunction. Attenuation of the early inflammatory response post-transplantation may protect cell survival and subsequent function. Herein, we investigate the development of anti-TNF-α antisense-oligonucleotide-conjugated polylactide-co-glycolide nanoparticles (PLG-aTNF-α NPs) as an anti-inflammatory therapy after stem-cell-derived islet transplantation. PLG-aTNF-α NPs are shelf stable and successfully reduce TNF-α secretion and expression in inflammatory macrophages. Synergy between the aTNF-α antisense oligonucleotide and the polylactide-co-glycolide NPs results in further knockdown of IL-1β, IL-6, iNOS, and IL-12 in vitro indicating PLG-aTNF-α NPs may protect against the inflammatory cascade in vivo. In a diabetic mouse model, stem-cell-derived islets transplanted to the peritoneal fat were protected after treatment with PLG-aTNF-α NPs compared with PLG NPs alone. Tnfα and Il1β expression was reduced in mice treated with PLG-aTNF-α NPs, indicating inflammation was reduced after transplant. PLG-aTNF-α NPs reduce TNF-α and protect islets, supporting their potential use as a therapeutic in islet transplantation. © 2025 The Author(s)

关键词： Asthma   Dry eye disease   Human single-domain antibody   IL-33   Mucosal Inflammation   Topical administration  

摘要： Addressing mucosal inflammatory disorders in the ocular surface or respiratory system remains a formidable challenge owing to the limited penetration of biological therapeutics across epithelial barriers. In this study, we explored the potential of human single-domain antibodies (UdAbs) as topical therapeutics for the targeted modulation of interleukin-33 (IL-33) in two mucosal-associated inflammatory disorders. The anti-IL-33 UdAb A12 demonstrated potent inhibition of the IL-33-mediated signaling pathway, despite not potently blocking the IL-33 receptor interaction. Compared with the anti-IL-33 control IgG itepekimab, the topical delivery of A12 resulted in significantly elevated corneal concentrations in vivo, which resulted in negligible ocular penetration. Moreover, A12 considerably ameliorated dry eye disease severity by exerting anti-inflammatory effects. Furthermore, in another murine model of allergic asthma, inhaled A12 substantially reduced overall lung inflammation. Our findings revealed the capacity of UdAbs to penetrate mucosal barriers following noninvasive localized delivery, highlighting their potential as an innovative therapeutic strategy for modulating mucosal inflammation.

关键词： Nasopharyngeal carcinoma   Histamine N-methyltransferase   Tumor growth   IFN/TXNIP/p53 axis   RNA sequencing  

摘要： ObjectiveHistamine N-methyltransferase (HNMT) is involved primarily in histamine metabolism, but emerging evidence suggests its potential role in cancer progression. This study investigated the role of HNMT in nasopharyngeal carcinoma (NPC) and its impact on interferon (IFN) signaling, thioredoxin-interacting protein (TXNIP), and p53 tumor suppressor *** expression in NPC tissues and cell lines was analyzed via qPCR and Western blotting. Functional assays, including cell proliferation, migration, invasion, and apoptosis, were performed after HNMT knockdown or overexpression. Transcriptomic sequencing was used to identify differentially expressed genes (DEGs). In addition, we examined the relationship between HNMT and the IFN/TXNIP/p53 axis via rescue experiments in vitro and in vivo models via qPCR and Western *** knockdown reduced cell proliferation, migration, and invasion, and promoted apoptosis in NPC tissues and cell lines. TXNIP was the most significantly upregulated gene following HNMT knockdown. Inhibition of the IFN pathway reversed these effects, confirming the role of HNMT in downregulating the IFN/TXNIP/p53 pathway. An in vivo study revealed that HNMT overexpression correlated with reduced expression of TXNIP and p53 in NCG *** NPC, HNMT promotes tumor growth and progression by inhibiting the IFN/TXNIP/p53 axis. These findings suggest that targeting the HNMT axis or restoring its function could provide new therapeutic strategies for NPC.

关键词： IL‐6   aggregates   cadherin   mesenchymal stromal cells   systemic sclerosis  

摘要： Umbilical cord-derived mesenchymal stromal cells (MSCs) transplantation is a promising therapy for systemic sclerosis (SSc) because of their distinctive antifibrotic and immunomodulatory properties. To enhance the effects of MSCs transplantation, novel engineered MSC aggregates preconditioned with human E/N-cadherin fusion protein (hE/N-cad-Fc) and interleukin-6 (IL-6) for SSc treatment are fabricated and named 3D-Cad/IL6-MSCs. These novel-engineered MSC aggregates possess tighter cellular cohesion and exhibit enhanced antiapoptotic, immunosuppressive, and proangiogenic capabilities according to transcriptomic analyses. Moreover, 3D-Cad/IL6-MSCs have improved immunoregulatory effects on peripheral blood mononuclear cells (PBMCs), CD4 T cells, and CD8 T cells in vitro because of the synergistic preconditioning from IL-6 and bioactive hE/N-cad-Fc. Upon intravenous injection, 3D-Cad/IL6-MSCs significantly mitigate skin and lung fibrosis and prolong the retention duration in bleomycin (BLM)-induced SSc mouse model. In detail, they suppress excessive infiltration of macrophages and T cells in the injured skin and lungs and reestablish the immune equilibrium of circulating CD4 T-cell subsets in vivo. These results suggest that 3D-Cad/IL6-MSCs are ideal candidates for SSc therapy and optimize the clinical utilization of MSCs.

关键词： IGF-2   L-glutamine   Lipopolysaccharide   NF-κB/NLRP3/IL-18 axis   Retinal inflammation  

摘要： Regarding retinal inflammation, NF-κB activation has been demonstrated to stimulate the NLRP3 inflammasome, which subsequently promotes IL-18 production, resulting in heightened inflammatory damage. Concurrently, GLP-1 has shown a role in reducing the likelihood of retinal inflammation. Nonetheless, the exact mechanism by which GLP-1 can reduce inflammation in the retina by modulating NF-κB/NLRP3/IL-18 axis remains unknown. Therefore, it may be worthwhile investigating the effects of L-glutamine (L-glu), a GLP-1 inducer, on LPS-induced retinal inflammation in rats, considering the involvement of NF-κB/NLRP3/IL-18 signaling. This study utilized the strategy of network pharmacology with subsequent experimental validation to predict the targets and associated pathways related to L-glu and retinal inflammation. To authenticate the in vivo pharmacological efficacy of L-glu, 60 mice were divided into 4 groups. The expression and level of GLP-1, in addition to IGF-2 and IL-18 levels were assayed. Gene expression of PPARγ and XO, as well as protein expression of p-TLR4, SIRT1, NLRP3, and caspase-1 were determined. The Nrf2/HO-1, MDA, and TAC were also detected. Retinal histopathology and immunostaining were lastly done. Network analysis identified 251 overlapping targets and 462 pathways between L-glu and retinal inflammation. Experimentally, L-glu enhanced the IGF-2-dependent PPARγ expression by boosting GLP-1 secretion. PPARγ then restricted TLR4 phosphorylation and XO expression to activate SIRT1/Nrf2 and alleviate oxidative stress. SIRT1 simultaneously inhibited the NF-κB-driven secretion of TNF-α and IL-6, as well as the ensuing activation of NLRP3/caspase-1/IL-18. These findings suggested that L-glu may confer protection against LPS-induced retinal inflammation in a GLP-1-dependent manner via prohibiting NF-κB/NLRP3/IL-18 pathway.

关键词： 凡纳滨对虾   茶多酚   生长   非特异性免疫   亚硝酸盐胁迫  

摘要： 本试验旨在探究饲料中添加茶多酚(TP)对凡纳滨对虾生长、非特异性免疫及亚硝酸盐耐受性的影响。选择840尾平均体重为(0.25±0.00) g的健康凡纳滨对虾幼虾,随机分为7组,每组3个重复,每个重复40尾虾。对照组(TP0组)饲喂基础饲料,试验组分别饲喂在基础饲粮的基础上添加100(TP100组)、300(TP300组)、500(TP500组)、700(TP700组)、1 500(TP1500组)和3 000 mg/kg(TP3000组)TP的饲料。试验期56 d。结果表明:1)饲料中添加TP对凡纳滨对虾终末体重、增重率、特定生长率、成活率和饲料系数均无显著影响(P>0.05)。与TP0组相比,TP500组、TP700组和TP1500组肝体比显著提高(P<0.05),TP500组肥满度显著提高(P<0.05)。2)各组间凡纳滨对虾全虾水分、粗灰分和粗蛋白质含量均无显著差异(P>0.05)。与TP0组相比,TP500组、TP700组、TP1500组和TP3000组全虾粗脂肪含量显著降低(P<0.05)。3)与TP0组相比,TP300组凡纳滨对虾肝胰腺甘油三酯含量、TP700组肝胰腺总胆固醇含量以及TP500组肝胰腺低密度脂蛋白胆固醇含量显著降低(P<0.05),TP700组肝胰腺酸性磷酸酶活性显著提高(P<0.05)。4)与TP0组相比,油红O染色结果显示,TP500组凡纳滨对虾肝胰腺脂滴密度显著降低(P<0.05);Masson染色结果显示,试验组肝胰腺阳性面积均显著降低(P<0.05)。5)与TP0组相比,各试验组凡纳滨对虾肝胰腺热休克蛋白70(HSP70)相对表达量均显著提高(P<0.05),TP700组肝胰腺缺氧诱导因子-1α(HIF-1α)相对表达量显著降低(P<0.05),TP500组和TP700组肝胰腺酚氧化酶(PO)相对表达量均显著提高(P<0.05),TP700组肝胰腺免疫缺陷蛋白(IMD)、对虾抗菌肽(Pen)、甲壳素(crustin)、抗脂多糖因子(ALF)和溶菌酶(LZM)相对表达量显著提高(P<0.05)。6)亚硝酸盐胁迫后,与TP0组相比,TP700组凡纳滨对虾肝胰腺B细胞淋巴瘤-2(Bcl-2)相对表达量显著提高(P<0.05),肝胰腺P53、半胱天冬蛋白酶-3(Caspase-3)、半胱天冬蛋白酶-8(Caspase-8)和B细胞淋巴瘤-2相关X蛋白(Bax)相对表达量显著降低(P<0.05)。综上所述,饲料中添加500～700 mg/kg TP能够改善凡纳滨对虾肝胰腺脂质沉积,提高其非特异性免疫能力,并增强其对亚硝酸盐的耐受性。

关键词： HERC5   IFN-β   IRF3   Lupus nephritis   Podocyte injury  

摘要： Podocytes may mediate local production of Type I interferon (IFN-I), which play a crucial role in the pathogenesis of lupus nephritis (LN). ISGylation is widely involved in the innate immune activation and IFN-I production. Here, we discovered that in patients with LN and pristane-induced model mouse the staining of HERC5, a E3 protein ligase in ISGylation, was markedly elevated in renal glomerulus and associated with podocyte injury. Knockdown of HERC5 in Human podocyte cells significantly decreased the transcription level of Ifn-b1 and subsequently pro-inflammatory factors Tnf-α, Il-6, and Cxcl10, while increasing anti-inflammatory factor Il-10 levels, and reduced podocyte injury induced by LN plasma or IFN-β. Conversely, overexpression of HERC5 reversed the above results, that increased IFN-β generation and excessive activation, and induced podocyte injury. Mechanistically, HERC5 interacts with and facilitates the ISGylation of IRF3, preventing its ubiquitination and subsequent degradation. This interaction stabilizes IRF3, enhancing its activity and leading to sustained IFN-β production and inflammation. In conclusion, our study identifies HERC5 as a key regulator in LN, promoting IRF3 activation and driving sustained IFN-β production and overactivation. This process induces an inflammatory phenotype in podocytes, contributing to their self-injury.

关键词： breast neoplasms   interleukin-6   tumor necrosis factor-alpha   prognosis  

摘要： Although cytokines mediate inflammation and inflammation facilitates cancer progression, few studies have evaluated the association between specific cytokines and the prognostic value of breast cancer. Therefore, this study aims to address the following question: What is the prognostic relevance of serum IL-6 and TNF-alpha levels on overall survival and treatment response in women with breast cancer? A systematic review and meta-analysis of cohort studies was conducted. The databases consulted included PubMed/Medline, Web of Science, and EMBASE. A total of 1748 articles were identified, of which 10 were included in the review. A significant association was found between elevated levels of IL-6 and TNF-alpha with poor overall survival and poor treatment response. The meta-analysis showed an HR of 3.74 (95% CI: 1.84–7.6) for elevated IL-6 with high heterogeneity (I2: 61%; p = 0.07) and an HR of 3.13 (95% CI: 1.57–6.23) for TNF-alpha with low heterogeneity (I2: 0%; p = 0.9). The overall response rate was 75% (95% CI: 31–100%; I2: 92%). In conclusion, IL-6 and TNF-alpha emerge as prognostic inflammatory biomarkers in women with breast cancer and are associated with poor survival and poor treatment response. This study highlights the need to establish an international consensus on cutoff points and standardized determination methods to implement these biomarkers in clinical practice.