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关键词： 免疫检查点抑制剂   一线治疗   非小细胞肺癌   疗效   安全性   系统评价/Meta分析  

摘要： 目的 系统评价免疫检查点抑制剂（immune checkpoint inhibitors,ICIs）一线治疗晚期非小细胞肺癌（non-small cell lung cancer,NSCLC）的疗效及安全性。方法 计算机检索PubMed、The Cochrane Library、EMbase数据库，收集ICIs一线治疗NSCLC患者的临床随机对照试验，检索时限为建库至2023年1月。采用Revman 5.4软件进行Meta分析。结果 纳入12项临床研究，质量评价皆为高质量文献，共7 121例患者。Meta分析结果显示：相较于化疗，ICIs一线治疗NSCLC患者能显著提高中位总生存期（overall survival,OS）[HR=0.72,95%CI(0.64,0.80),P<0.000 01]和中位无进展生存期（progression free survival,PFS）[HR=0.65,95%CI(0.53,0.78),P<0.000 01]，改善客观缓解率（objective response rate,ORR）[RR=1.52,95%CI(1.28,1.79),P<0.000 01]。亚组分析显示，相较于ICIs单一治疗组，ICIs联合治疗组能显著提高NSCLC患者的OS、PFS、ORR；在安全性方面，ICIs组发生任何级别治疗相关不良事件（Treatment-related adverse events,TRAEs）和3～5级TRAEs的风险均低于化疗组。在导致治疗停止TRAEs发生率方面，ICIs组高于化疗组。亚组分析显示，免疫联合治疗组发生任何级别、3～5级、导致治疗停止TRAEs发生率都高于免疫单一治疗组。结论 ICIs抑制剂一线治疗NSCLC患者对比化疗能显著改善患者的OS、PFS、ORR。相对于免疫单一治疗，免疫联合化疗能显著提高NSCLC患者的疗效，但患者发生TRAEs风险较高。

关键词： IFN-λ   IRF1   Nsp1   Swine acute diarrhea syndrome coronavirus   innate immune evasion  

摘要： Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a novel porcine enteric coronavirus that causes acute watery diarrhea, vomiting, and dehydration in newborn piglets. The type III interferon (IFN-λ) response serves as the primary defense against viruses that replicate in intestinal epithelial cells. However, there is currently no information available on how SADS-CoV modulates the production of IFN-λ. In this study, we utilized IPI-FX cells (a cell line of porcine ileum epithelium) as an in vitro model to investigate the potential immune evasion strategies employed by SADS-CoV against the IFN-λ response. Our results showed that SADS-CoV infection suppressed the production of IFN-λ1 induced by poly(I:C). Through screening SADS-CoV-encoded proteins, nsp1, nsp5, nsp10, nsp12, nsp16, E, S1, and S2 were identified as antagonists of IFN-λ1 production. Specifically, SADS-CoV nsp1 impeded the activation of the IFN-λ1 promoter mediated by MAVS, TBK1, IKKε, and IRF1. Both SADS-CoV and nsp1 obstructed poly(I:C)-induced nuclear translocation of IRF1. Moreover, SADS-CoV nsp1 degraded IRF1 via the ubiquitin-mediated proteasome pathway without interacting with it. Overall, our study provides the first evidence that SADS-CoV inhibits the type III IFN response, shedding light on the molecular mechanisms employed by SADS-CoV to evade the host immune response.

关键词： RIG-I   Swine acute diarrhea syndrome coronavirus   TRIM25   interferon   nucleocapsid  

摘要： Swine acute diarrhea syndrome coronavirus (SADS-CoV), an emerging Alpha-coronavirus, brings huge economic loss in swine industry. Interferons (IFNs) participate in a frontline antiviral defense mechanism triggering the activation of numerous downstream antiviral genes. Here, we demonstrated that TRIM25 overexpression significantly inhibited SADS-CoV replication, whereas TRIM25 deficiency markedly increased viral yield. We found that SADS-CoV N protein suppressed interferon-beta (IFN-β) production induced by Sendai virus (SeV) or poly(I:C). Moreover, we determined that SADS-CoV N protein interacted with RIG-I N-terminal two caspase activation and recruitment domains (2CARDs) and TRIM25 coiled-coil dimerization (CCD) domain. The interaction of SADS-CoV N protein with RIG-I and TRIM25 caused TRIM25 multimerization inhibition, the RIG-I-TRIM25 interaction disruption, and consequent the IRF3 and TBK1 phosphorylation impediment. Overexpression of SADS-CoV N protein facilitated the replication of VSV-GFP by suppressing IFN-β production. Our results demonstrate that SADS-CoV N suppresses the host IFN response, thus highlighting the significant involvement of TRIM25 in regulating antiviral immune defenses.

关键词： 失眠症   慢性失眠   炎症因子   过度觉醒   Insomnia   Chronic Insomnia   Inflammatory Factors   Hyperasoural  

摘要： 目的：探讨慢性失眠患者血清炎症细胞因子与过度觉醒的关系。方法：以方便取样法选取慢性失眠患者(失眠组)40例，选取健康体检人员(对照组)30例。采用过度觉醒量表和睡前觉醒量表对两组被试进行评定。对所有被试在入组后采集清晨空腹肘静脉血，测定IL-6、IL-8、TNF-α和IFN-γ等血清炎症细胞因子水平。使用SPSS22.0统计方法进行单因素和多因素分析。结果：失眠组和对照组外周血IL-6 [(125.38 ± 93.88) pg/ml和(4.23 ± 3.44) pg/ml]、IL-8 [(346.6 ± 253.00) pg/ml和(3.57 ± 2.04) pg/ml]水平比较，失眠组增高，差异有统计学意义(P均 < 0.001)。Pearson相关分析显示：失眠组IL-6与睡前觉醒和过度觉醒程度得分存在相关性(r = 0.335~0.428, 0.335, P ˂ 0.001)，IL-8与睡前觉醒、过度觉醒得分存在相关性(r = 0.321, 0.467, P ˂ 0.05)。多元逐步回归分析结果显示：失眠组IL-6 (t = 2.220, P = 0.033)和文化程度(t = 2.216, P = 0.033)进入以慢性失眠患者过度觉醒总分为因变量的回归方程。IL-8 (t = 3.098, P = 0.004)和文化程度(t = 2.373, P = 0.023)进入以慢性失眠患者睡前觉醒总分为因变量的回归方程。结论：IL-6影响慢性失眠患者过度觉醒，IL-8影响慢性失眠患者睡前觉醒，文化程度与慢性失眠患者过度觉醒与睡前觉醒有关。

关键词： 罗非鱼   硫酸软骨素   免疫刺激活性   免疫抑制   肠道屏障   RAW 264.7  

摘要： 本文采用了RAW 264.7细胞和免疫抑制模型，通过体内、体外实验研究罗非鱼头硫酸软骨素（CS）的免疫刺激活性。结果表明，罗非鱼头硫酸软骨素（CS）可以诱导RAW 264.7细胞产生NO，IL-1β，IL-6，IL-10，TNF-α；环磷酰胺（CTX）诱导小鼠的胸腺萎缩（0.11±0.01）%，低剂量CS（0.17±0.03）%、高剂量CS（0.18±0.02）%干预后，显著上调了小鼠胸腺指数；同时，CS干预显著上调CTX诱导小鼠脾脏指数，上调绒毛长度和V/C值并且高剂量CS显著上调了绒毛长度（330.92±21.55）μm；另外，罗非鱼头硫酸软骨素（CS）对环磷酰胺（CTX）诱导小鼠血清sIgA有促进作用。这些结果表明CS可以改善免疫抑制小鼠肠道屏障损伤及免疫功能。因此，本研究可为罗非鱼硫酸软骨素的肠道黏膜免疫调节作用提供理论基础，并表明罗非鱼头硫酸软骨素（CS）是一种潜在的可替代鲨鱼硫酸软骨素的免疫调节多糖，并可能成为干预免疫疾病相关功能食品的潜在材料。

关键词： 性别差异   免疫检查点抑制剂   非小细胞肺癌   系统评价/Meta分析  

摘要： 目的 系统评价免疫检查点抑制剂治疗不同性别非小细胞肺癌（non-small cell lung cancer,NSCLC）患者的疗效差异。方法 计算机检索Medline、The Cochrane Library、EMbase数据库，收集免疫检查点抑制剂（immune checkpoint inhibitors,ICIs）治疗NSCLC患者的随机对照试验，检索时限均为建库至2022年11月。采用RevMan 5.4软件进行Meta分析。结果 纳入16项随机对照试验，经改良版Jadad量表评价皆为高质量文献，共9 653例患者。Meta分析结果显示：在免疫治疗NSCLC患者中女性中位总生存期[HR=0.72,95%CI(0.61,0.85),P<0.001]比男性[HR=0.73,95%CI(0.69,0.78),P=0.401]更具有优势。男性在中位无进展生存期方面[HR=0.64,95%CI(0.58,0.71),P=0.171]比女性[HR=0.76,95%CI(0.57,1.03),P<0.001]更具有优势。结论 接受ICIs治疗的女性在中位总生存期方面比男性具有免疫治疗优势。在中位无进展生存期方面，男性比女性更能获得统计学上的受益。

关键词： 输血   异种移植   基因修饰猪   异种抗原   红细胞   抗原抗体结合   凝集   补体依赖性细胞毒性  

摘要： 目的 探讨野生型（WT）、四基因修饰（TKO/hCD55）和六基因修饰（TKO/hCD55/hCD46/hTBM）猪红细胞与人血清的免疫相容性和免疫差异。方法 收集了20名不同血型志愿者的血液，将WT、TKO/hCD55和TKO/hCD55/hCD46/hTBM猪红细胞、ABO-相容（ABO-C）及ABO-不相容（ABO-I）人红细胞分别暴露于不同血型人血清中，检测血凝集、抗原抗体结合（IgG、IgM）水平和补体依赖细胞毒性，评估2种基因修饰猪红细胞与人血清的免疫相容性。结果 ABO-C组未出现明显凝集；WT组和ABO-I组凝集水平高于TKO/hCD55组和TKO/hCD55/hCD46/hTBM组（均为P<0.001）。WT组猪红细胞裂解水平高于ABO-C组、TKO/hCD55组和TKO/hCD55/hCD46/hTBM组；ABO-I组猪红细胞裂解水平高于TKO/hCD55组、TKO/hCD55/hCD46/hTBM组（均为P<0.01）。TKO/hCD55组猪红细胞IgM和IgG结合水平均低于WT组和ABO-I组；TKO/hCD55/hCD46/hTBM组猪红细胞IgG和IgM结合水平低于WT组，IgG低于ABO-I组（均为P<0.05）。结论基因修饰猪红细胞的免疫相容性优于野生型猪，并接近于ABO-C，人源化猪红细胞在血资源奇缺时可考虑作为血液来源。

关键词： Fatty liver (MASLD/MASH)   Inflammation and fibrosis   Fructose diet   Bulk RNAseq   Fatty acid oxidation   Interferon gamma  

摘要： BACKGROUND:Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common complication of obesity and in severe cases progresses to metabolic dysfunction-associated steatohepatitis (MASH). Small heterodimer partner (SHP) is an orphan member of the nuclear receptor superfamily and regulates metabolism and inflammation in the liver via a variety of pathways. In this study, we investigate the molecular foundation of MASH progression in mice with hepatic SHP deletion and explore possible therapeutic means to reduce MASH. METHODS:Hepatic SHP knockout mice (SHP) and their wild-type littermates (SHP) of both sexes were fed a fructose diet for 14 weeks and subjected to an oral glucose tolerance test. Then, plasma lipids were determined, and liver lipid metabolism and inflammation pathways were analyzed with immunoblotting, RNAseq, and qPCR assays. To explore possible therapeutic intersections of SHP and inflammatory pathways, SHP mice were reconstituted with bone marrow lacking interferon γ (IFNγ) to suppress inflammation. RESULTS:Hepatic deletion of SHP in mice fed a fructose diet decreased liver fat and increased proteins for fatty acid oxidation and liver lipid uptake including UCP1, CPT1α, ACDAM, and SRBI. Despite lower liver fat, hepatic SHP deletion increased liver inflammatory F4/80 cells and mRNA levels of inflammatory cytokines (IL-12, IL-6, Ccl2, and IFNγ) in both sexes and elevated endoplasmic reticulum stress markers of Cox2 and CHOP in female mice. Liver bulk RNAseq data showed upregulation of genes whose protein products regulate lipid transport, fatty acid oxidation, and inflammation in SHP mice. The increased inflammation and fibrosis in SHP mice were corrected with transplantation of bone marrow-derived IFNγ myeloid cells. CONCLUSION:Hepatic deletion of SHP improves fatty liver but worsens hepatic inflammation possibly by driving excess fatty acid oxidation, which is corrected by deletion of IFNγ specifically in myeloid cells. This suggests that hepatic SHP limits fatty acid oxidation durin

关键词： HLJDD drug-containing serum   IL-1 beta secretion   D-glucose and PA induced BV2 cells   Autophagy   NLRP3 Inflammasome   COGNITIVE DYSFUNCTION   MEDIATED NEUROINFLAMMATION   ALZHEIMERS-DISEASE   IMPAIRMENT   INFLAMMASOME   ACTIVATION   BERBERINE   NEURODEGENERATION   EXPRESSION   PROTECTS  

摘要： Aim of the study The aim of this study was to investigate the effect and potential mechanism of HLJDD on IL-1 beta secretion in a DACD model of BV2 cells induced by D-glucose and palmitic acid (PA). Materials and method sUltra-performance liquid chromatography-quadrupole/electrostatic field orbital well high-resolution mass spectrometry technology was used to analyze the compounds in HLJDD drug-containing serum. The cytotoxicity was detected by cell counting kit-8. Enzyme-linked immunosorbent assay was used to measure the secretion of IL-1 beta in BV2 cells. Reactive oxygen species, glutathione, superoxide dismutase, and malondialdehyde kits were used to detect the intracellular oxidative stress levels. The autophagy level was determined by autophagy staining kit and transmission electron microscope. The expression levels of autophagy-related 7 (Atg7), P62, LC3, nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3(NLRP3), Caspase1, and IL-1 beta were detected by real-time PCR, immunofluorescence, and western blotting. The Atg7siRNA was transfected into BV2 cells to produce autophagy inhibitory effect. Then the effect of HLJDD drug-containing serum on IL-1 beta secretion in D-glucose and PA induced BV2 cells and the potential mechanism of autophagy-NLRP3 inflammasome activation were further observed. Results Eighty-eight compounds were preliminarily identified in HLJDD drug-containing serum, among which geniposide, baicalin, palmatine, berberine, wogonoside, wogonin, and geniposidic acid were identified as the main prototype components of HLJDD into the blood. In this study, the DACD model of BV2 cells induced by high concentrations of glucose and PA was successfully constructed. HLJDD drug-containing serum significantly reduced the secretion of IL-1 beta and the activity of NLRP3 inflammasome with improving the oxidative stress level. Interestingly, the enhanced autophagy level was also found. After transfection of Atg7siRNA into BV2 cells, the effect of HLJDD drug-containing serum