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关键词： 肺结核   DNA疫苗   免疫剂量   细胞免疫   体液免疫   免疫记忆  

摘要： 目的 评价不同剂量治疗性肺结核DNA疫苗B21免疫小鼠后的免疫应答水平,以期为建立该疫苗成品效力质量控制方法提供免疫剂量选择的实验依据。方法 将25(LD)、50(MD)、100(HD)μg/100μL B21疫苗经SPF级雌性C57BL/6小鼠大腿内侧肌内注射,并联合电脉冲穿孔刺激,共免疫3次,每次间隔2周。末次免疫3周后,分离脾淋巴细胞及外周血血清,通过酶联免疫斑点(enzyme-linked immunosorbent spot,ELISpot)试验和流式细胞术(flow cytometry,FCM)检测细胞免疫及免疫记忆效果,ELISA法检测体液免疫效果。结果 末次免疫3周后,HD组Ag85b及Rv1738特异性IFNγ斑点形成细胞(spot-forming cells,SFCs)数量均显著高于MD和LD组(F分别为11.22和15.89,P均<0.001);Rv2029c特异性IFNγ SFCs数量显著高于MD组(F=5.761,P<0.05),与LD组差异无统计学意义(F=5.761,P > 0.05)。HD组3种抗原的IL-2 SFCs数量均显著高于MD与LD组(F=8.044~33.07,P均<0.05)。HD组分泌IFNγ的CD4^(+)T细胞比例显著高于MD及LD组(F=5.976,P<0.05),3组间分泌IL-2的CD4+T细胞比例差异无统计学意义(F=2.836,P > 0.05)。HD组IFNγ+记忆T细胞(CD44^(+)CD62L^(+/-))比例显著高于MD及LD组(F=8.793,P<0.05);HD组活化记忆B细胞(CD19^(+)CD27^(+))比例显著高于MD和LD组(F=7.958,P<0.01)。3组B21蛋白特异性IgG抗体水平差异无统计学意义(F=5.765,P > 0.05)。结论 B21疫苗可有效诱导细胞免疫、体液免疫及免疫记忆反应,且呈剂量依赖性。100μg/100μL剂量诱导的免疫效果最优,ELISpot法检测IFNγ/IL-2 SFCs稳定性高、重复性好,有望作为B21疫苗效力质量控制的推荐免疫剂量、检测方法及评价指标。

关键词： Colorectal cancer   Postoperative complications   TNF-alpha   Uneventful course  

摘要： The development of novel biomarkers to predict postoperative complications (POCs) after colorectal cancer (CRC) surgery is essential, both for improving treatment outcomes and for facilitating the widespread use of same-day discharge following colectomy. This longitudinal observational study, a sub-study of a previous RCT, investigated the prognostic potential of a panel of novel biomarkers, including inflammatory cytokines (TNF-alpha, IL-1 beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-17 A, INF-gamma, IP-10, MCP-1, TGF-beta 1), alongside conventional biomarkers such as CRP and WBC levels, measured preoperatively and on postoperative day 6, for predicting POCs following CRC resection. Among 40 recruited patients, 38 were included in the final analysis. Patients who did not experience POCs had a significantly lower preoperative level of TNF-alpha (2.28 pg/mL vs. 68.77 pg/mL, p = 0.022). ROC curve analysis showed that TNF-alpha has significant (p = 0.012) discriminative capacity to distinguish between patients with POCs and those with an uneventful postoperative course, with an AUC of 0.722 (95% CI: 0.555, 0.889). Multivariable analysis suggested that a low preoperative TNF-alpha level (< 55.35 pg/mL) may be an independent predictor of an uneventful postoperative course (Odds Ratio = 0.137, 95% CI: 0.023, 0.836). This study showed that preoperative levels of TNF-alpha demonstrates a moderate discriminative capacity to distinguish between patients with POCs and those with an uneventful postoperative course in patients undergoing surgery for left-side CRC, although the findings are limited by the small sample size and should be validated in larger cohorts.

关键词： 细胞因子风暴   细胞因子吸附   脓毒症   心脏手术  

摘要： 细胞因子风暴是一种危及生命的过度炎症反应。目前有限的循证研究结果提示:细胞因子吸附技术并不能降低心脏手术及脓毒性休克患者的死亡率,甚至不能改善血流动力学和降低白细胞介素-6水平。这些阴性结果可能与使用时机与方法不当、吸附效能不足及非特异性吸附抗菌药物、白蛋白、血小板等有关。该文对细胞因子吸附治疗的启动与终止时机、治疗的方式选择以及治疗时间与频率等进行了归纳,以期为临床提供指导。

关键词： Astaxanthin   Aging   Oocytes   Cumulus cells   TNF-alpha   TNFR2  

摘要： BackgroundMII oocytes undergo time-dependent aging after ovulation, which is closely associated with impaired fertilization potential, poor embryo quality, and an increased risk of miscarriage. The apoptosis of cumulus cells and their secretion of TNF-alpha are identified as the primary contributors to postovulatory oocyte *** this study, we demonstrated that astaxanthin supplementation in culture medium effectively prevents postovulatory oocyte aging and extends oocyte lifespan in vitro. Importantly, this protective effect does not operate through the inhibition of cumulus cell apoptosis or TNF-alpha release. Notably, astaxanthin selectively binds to TNFR2 in oocytes, thereby preventing TNFR2 from interacting with TNF-alpha and inhibiting the activation of the TNF signaling pathway within oocytes. Furthermore, oocytes cultured with astaxanthin exhibit enhanced potential for early embryonic development and significantly increased IVF-ET litter size compared to *** findings, based on a mouse model, provide valuable insights into the potential clinical application of astaxanthin in mitigating post-ovulatory oocyte aging.

关键词： 肺动脉高压   白细胞介素-9   β-神经生长因子   全基因组关联研究   孟德尔随机化  

摘要： 目的通过双向孟德尔随机化(MR)方法评估细胞因子对肺动脉高压的影响。方法41种细胞因子数据来自包含8293例欧洲裔个体的基因组关联研究(GWAS)数据集,肺动脉高压的遗传数据来自包含11744例欧洲裔个体的GWAS数据集,通过MR分析探讨细胞因子对肺动脉高压的潜在影响。结果逆方差加权(IVW)分析结果显示,IL-9与肺动脉高压之间可能存在因果关系(OR=0.63,95%CI:0.50~0.78,P<0.001),β-神经生长因子(β-NGF)也与肺动脉高压可能存在因果关系(OR=1.34,95%CI:1.01~1.79,P=0.049)。多变量MR分析结果显示,IL-9与肺动脉高压存在关联(OR=0.57,95%CI:0.44~0.72,P<0.001),β-NGF与肺动脉高压也存在关联(OR=1.47,95%CI:1.10~1.97,P=0.009)。结论IL-9水平升高与肺动脉高压风险降低可能存在因果关系,而β-NGF水平升高可能会增加肺动脉高压发生风险。

关键词： IL-23/IL-23R signaling   Ferroptosis   Neuron-macrophage interaction   Traumatic brain injury   Therapeutic targeting  

摘要： BackgroundTraumatic brain injury (TBI) causes significant neuronal death, but the underlying mechanisms remain poorly understood. The role of interleukin-23 (IL-23) signaling in post-traumatic neuronal injury requires *** examined IL-23 levels in clinical samples from TBI patients and healthy controls. Using a mouse TBI model, we investigated the effects of IL-23 neutralization and explored the cellular mechanisms through analysis of IL-23 receptor expression, JAK2/STAT3 pathway activation, and macrophage *** found elevated IL-23 levels in both serum and brain tissues of TBI patients. TBI induced neuronal IL-23 receptor expression and activated the JAK2/STAT3 pathway. Infiltrating macrophages were identified as the main IL-23 source, recruited by neuron-derived C-C motif chemokine ligand 2 (CCL2). IL-23 neutralization or CCL2 blockade reduced neuronal ferroptosis and improved neurological outcomes in the mouse *** findings reveal a novel CCL2-macrophage-IL-23 axis in TBI pathogenesis, where IL-23 promotes neuronal ferroptosis through direct receptor-mediated effects. Targeting this pathway represents a potential therapeutic strategy for TBI treatment.

关键词： 生骨再造丸   激素性股骨头坏死   炎性因子  

摘要： 目的探讨生骨再造丸治疗早期激素性股骨头坏死(SONFH)的可能作用靶点,验证生骨再造丸治疗早期SONFH的临床疗效。方法实验以雄性SD大鼠为研究对象,随机抽取15只大鼠作为空白对照组(NC组),实验组75只采用脂多糖联合糖皮质激素(GC)肌肉注射建立早期SONFH大鼠模型。从中随机抽取8只大鼠采用空气栓塞法处死并取出双侧股骨头标本制作病理切片,证实早期SONFH造模成功,然后进行分组。将剩余的SONFH大鼠模型按照随机数字表法分为5组:激素模型组(Model组)11只,生骨再造丸高剂量组(SGZZ-H组)、生骨再造丸中剂量组(SGZZ-M组)、生骨再造丸低剂量组(SGZZ-L组)各10只,阳性对照组(JGSW组)11只。按照预先的实验设计进行药物灌胃治疗,灌胃期间密切观察并记录各组SD大鼠一般情况的变化,直至给药第8周末治疗结束后2 h,各组大鼠称重、取血,离心后分离血清并在-20℃保存。采用空气栓塞法处死大鼠,无菌条件下用手术剪及手术刀取出双侧的股骨头标本,剔除软骨,生理盐水漂洗,滤纸拭干,称重完成后左侧股骨头标本迅速放入液氮中速冻过夜后转移至-80℃冰箱保存,采用ELISA法检测大鼠血清相关炎性细胞因子(IL-1β、IL-6、TNF-α)、血清碱性磷酸酶(ALP)、血清钙(S-Ca)、血清磷(S-P)、骨钙素(BGP)、降钙素(CT)、抗酒石酸酸性磷酸酶(TRACP)等骨代谢相关指标的含量。结果(1)大鼠行为学观察:经生骨再造丸灌胃治疗至第8周末,SGZZ-H组、SGZZ-M组、SGZZ-L组与JGSW组较Model组精神状况、活动量、饮食饮水、后肢肌力及跛行状况均有不同程度改善,其中以SGZZ-H组和JGSW组症状改善更加明显,但较NC组未恢复正常。(2)股骨头标本形态学观察:Model组股骨头明显出现皲裂、缺损且血运较差,有骨质疏松、坏死的表现,SGZZ-H组、SGZZ-M组、SGZZ-L组与JGSW组较Model组均有不同程度改观。(3)ELISA试验检测血清IL-1β、IL-6、TNF-α、ALP、S-Ca、S-P、BGP、CT和TRACP指标水平:Model组大鼠血清IL-1β、IL-6、TNF-α、ALP、CT和TRACP表达水平相对NC组均明显升高(P<0.001),Model组大鼠血清S-Ca、S-P和BGP表达水平相对NC组均明显下降(P<0.001),且各治疗组大鼠血清IL-1β、IL-6、TNF-α、S-Ca、S-P、BGP、ALP、CT和TRACP表达水平相对Model组均有不同程度改善,其中以SGZZ-H组、SGZZ-M组及JGSW组大鼠血清IL-1β、IL-6、TNF-α、ALP、CT和TRACP表达水平降低最为明显(P<0.01),SGZZ-H组及JGSW组大鼠血清S-Ca、S-P、BGP表达水平升高最为明显(P<0.001)。SGZZ-H组与JGSW组大鼠血清IL-1β、IL-6、TNF-α、S-Ca、S-P、BGP、ALP、CT和TRACP表达水平比较差异均无统计学意义(P>0.05)。结论(1)该实验证明采用脂多糖联合GC肌肉注射可以成功诱导SD大鼠早期SONFH的发生。(2)生骨再造丸可通过抑制IL-1β、IL-6、TNF-α、ALP、CT和TRACP的表达,促进S-Ca、S-P和BGP的表达,改善骨代谢,防治早期SONFH。

关键词： 胸腺肿瘤   B3型胸腺瘤   胸腺癌   CD5阳性   CD117阳性   TdT  

摘要： 目的探讨伴CD5和(或)CD117阳性及缺乏TdT阳性淋巴细胞的纵隔B3型胸腺瘤临床病理学特征。方法收集广东医科大学附属医院病理科2023年12月至2024年7月明确诊断的2例伴CD5和(或)CD117阳性及缺乏TdT阳性淋巴细胞的纵隔B3型胸腺瘤,结合文献复习,分析总结其临床病理学特征。结果2例患者均为男性,年龄分别为54岁、73岁,均无明显呼吸系统临床症状,无吸烟史,均为前纵隔占位,肿瘤直径分别为53 mm、72 mm,镜下肿瘤细胞均呈B3型胸腺瘤样形态,免疫组化显示CD5和(或)CD117阳性表达,并缺乏TdT阳性的淋巴细胞;均点灶表达MUC1、部分表达GLUT1;例1患者行根治性手术切除,术后行局部放疗,随访至今19个月无瘤生存,例2患者明确诊断时已伴胸膜、肝脏转移,拒绝进一步放化疗,随访2个月肿瘤进展后失访。结论伴CD5和(或)CD117阳性及缺乏TdT阳性淋巴细胞的纵隔B3型胸腺瘤罕见,好发于男性、前纵隔,结合形态学及免疫组织化学联合CD5、CD117、TdT、MUC1、GLUT1有助于鉴别胸腺癌。该肿瘤生物学行为及生存趋势可能介于B3型胸腺瘤与胸腺癌之间,相关研究报道甚少,仍有待积累更多的病例进一步深入研究与分析。

关键词： bioluminescence imaging   HiBiT   luciferase   NanoLuc   TNF-alpha  

摘要： Tumor necrosis factor alpha (TNF-alpha) is a pleiotropic cytokine crucial for immune function, cellular homeostasis, and disease progression, yet its complex roles in vivo remain unclear. Challenges in studying TNF-alpha include its widespread gene expression, variability in expression levels, diverse protein forms, and low baseline expression, which complicate traditional detection and tracking methods. To address these challenges, we constructed three distinct transgenic luciferase reporter mouse models (TNF-IRES-Luc, TNF-Nanoluc, and TNF-HiBiT) driven by the endogenous TNF-alpha gene, using CRISPR/Cas9 technology through homology-directed repair. The firefly luciferase gene, secreted NanoLuc gene, and HiBiT gene were individually integrated into the mouse genome under the control of the endogenous TNF-alpha promoter. Our results demonstrate that endogenous TNF-alpha expression can be effectively monitored by measuring luciferase levels in vivo and in vitro, using an in vivo imaging system and a luminometer. This was validated during inflammatory processes such as lipopolysaccharide (LPS)-induced sepsis and phorbol ester (TPA)-induced mouse ear edema. Furthermore, the anti-inflammatory drug dexamethasone (DXM) significantly inhibited TNF-alpha and luciferase expression in both inflammatory models. Our study demonstrates these mouse models are valuable tools for studying TNF-alpha expression in inflammatory responses and related diseases, as well as evaluating anti-inflammatory drug efficacy.

关键词： lncRNA   HIV-1   CHCHD2   miR-145-5p   IFN-I pathway   AGO2   argonaute 2   CHCHD2   coiled-coil-helix-coiled-coil-helix domain-containing 2   EZH2   enhancer of zust homolog 2   GEO   Gene Expression Omnibus   HEAL   HIV-enhanced lncRNA   ISG   interferon-stimulated gene   lncRNAs   Long noncoding RNAs   MALAT1   Metastasis-associated lung adenocarcinoma transcript 1   MDM   monocyte-derived macrophages   PBMCs   peripheral blood mononuclear cells   RIP   RNA-Binding Protein Immunoprecipitation   siRNAs   small interfering RNAs  

摘要： Long noncoding RNAs (lncRNAs) are effective regulators of both RNA and protein functions throughout cell biology, including viral replication. Emerging studies have shown that lncRNAs activate or inhibit the replication and latency of HIV-1 by regulating different cellular mechanisms. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is an oncogenic lncRNA required for paraspeckle integrity and has been proven to be linked to viral infection. However, the mechanisms by which it influences HIV-1 infection in macrophages remain unclear. In this study, we performed RNA-deep sequencing to compare the profiles of lncRNAs in macrophages with or without HIV-1 and found that MALAT1 was dramatically upregulated in HIV-1-infected macrophages. MALAT1 knockdown inhibited HIV-1 infection, whereas MALAT1 overexpression enhanced viral replication, indicating that MALAT1 promotes HIV-1 replication. We further performed proteomics analysis and found that coiled-coil-helix-coiled-coil-helix domain-containing 2 (CHCHD2) was the most downregulated protein affected by RNAi-mediated knockdown of MALAT1. We next demonstrated that MALAT1 favored HIV-1 replication in a CHCHD2-dependent manner and functioned as a competing endogenous RNA to regulate CHCHD2 expression by sponging miR-145-5p, which could mutually bind the MALAT1 and 3 ' UTR of chchd2 mRNA. Furthermore, knockdown of endogenous MALAT1 or CHCHD2 with specific small interfering RNAs (siRNAs) promoted the expression of IRF7, and enhanced the promoter activities of interferons-alpha and-beta, increasing their production as well as that of a critical interferon-stimulated gene (ISG), myxovirus resistance protein B (MxB). Moreover, MALAT1 or CHCHD2 knockdown promoted the expression of STAT2 to enhance the production of downstream MxB, which expanded the role of CHCHD2 as a negative regulator of the innate immune response. These findings improve our understanding of MALAT1/miR-145-5p/CHCHD2 pathway regulation of HIV-1 rep