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关键词： Interleukin-6   Neuroinflammation   Ethanol   Alcohol use disorder   Mechanical allodynia   Spinal cord  

摘要： Alcohol use disorder (AUD) is defined by the emergence of negative affective symptoms during withdrawal. Neuroinflammation is a key contributor to AUD, and it is well known to play an essential role in the pathogenesis of pain states. The chronic-intermittent ethanol two-bottle choice (CIE-2BC) paradigm is well-established to generate alcohol-dependent (Dep) and non-dependent (Non-Dep) mice. Our recent work demonstrated that the CIE-2BC model promotes mechanical allodynia in Dep mice, with these mice developing mechanical allodynia during withdrawal. In this study, we examined the role of interleukin-6 (IL-6) in the development of mechanical allodynia by adapting the CIE-2BC mouse model and employing the von Frey test, in situ hybridization (RNAscope), and Multiplex protein analysis of the spinal cord, examining changes in this target including an array of cytokines associated with IL-6 signaling. CIE-2BC escalated alcohol drinking and enhanced mechanical allodynia in Dep versus Non-Dep mice, with Dep females displaying greater alcohol intake. Dep mice displayed increased IL-6 protein in the spinal cord while males additionally had increased Il6+ cell expression versus Non-Dep controls. Systemic treatment of an IL-6 receptor antibody (IL-6R Ab) did not decrease mechanical allodynia during abstinence. Collectively, these data suggest that alcohol exerts sex-dependent effects on spinal IL-6 levels. However, in our study, blocking IL-6 signaling did not reduce alcohol-associated pain sensitivity in a mouse model of comorbid pain and alcohol dependence.

关键词： Methamphetamine   IL-17A   IL-17RC   Methamphetamine use disorder   Mice  

摘要： We demonstrated previously that blocking IL-17A, a proinflammatory cytokine, prevents oxycodone-induced depression-like effects and anxiety-like effects during abstinence from MDPV (a psychostimulant) in rats. Here, we tested the hypothesis that eliminating IL-17A signaling (pharmacological antagonism using IL-17A Ab or genetic deletion of IL-17RC) would inhibit behavioral and neurochemical effects elicited by methamphetamine (METH) exposure and abstinence in adult mice. We investigated rewarding and locomotor-activating effects of METH and withdrawal-induced anxiety- and depression-like effects during METH abstinence. Mice received saline or METH (5 mg/kg, IP) once daily for 18 d. Locomotion was measured on days 1 and 15. Anxietyand depression-like effects were investigated 72 and 96 h after the last METH injection using the elevated plus maze and forced swim test, respectively. IL-17A antibody (Ab, 60 mu g/100 mu l, IP) was injected every 3rd day of METH exposure. METH-induced hyperlocomotion was significantly reduced in IL-17RC knockout mice or by treatment with the IL-17A Ab (100 mu g/100 mu l). Neutralization of IL-17A or genetic deletion of IL-17RC prevented development of depression-like effects during METH abstinence. Also, mRNA levels of IL-17RC, but not IL-17RA, in the NAC were enhanced during METH abstinence. Development of METH conditioned place preference (CPP) was prevented by IL-17A Ab but was not affected by IL-17RC deletion in mice conditioned with METH (3 mg/kg) for 4 d. Our data show that abolishing IL-17A signaling reduces METH-induced hyperlocomotion and CPP and attenuates depression-like effects during METH abstinence. These results highlight studying IL-17A blockade as a neuroimmune-based approach to mitigate METH adverse effects.

关键词： 淋巴细胞亚群   白细胞分化抗原64   炎症因子   脓毒症   预后  

摘要： 目的探讨淋巴细胞亚群、白细胞分化抗原(CD)64、血清炎症因子与脓毒症严重程度的关系及对脓毒症预后的预测价值。方法选取60例脓毒症患者作为观察组,按疾病严重程度分为脓毒症组(30例)和脓毒性休克组(30例);另选取30例健康体检者作为对照组。检测并比较三组淋巴细胞亚群[CD3^(+)、CD4^(+)、CD8^(+)、CD4^(+)/CD8^(+)、自然杀伤细胞(NK细胞)、B细胞]、CD64、血清炎症因子[白细胞计数(WBC)、C反应蛋白(CRP)、降钙素原(PCT)、白细胞介素-6(IL-6)]水平;分析并比较脓毒症组与脓毒性休克组序贯器官衰竭评估(SOFA)评分;分析淋巴细胞亚群、CD64、血清炎症因子与SOFA评分的相关性;分析CRP、PCT、IL-6检测对脓毒症预后的预测效能。结果脓毒症组CD3^(+)、CD4^(+)、CD8^(+)、CD4^(+)/CD8^(+)、NK细胞、B细胞、WBC、CRP、PCT、IL-6、CD64分别为(846.24±222.24)μl、(322.24±31.42)μl、(914.24±11.42)μl、(1.50±0.14)、(524.24±16.24)μl、(345.24±21.24)μl、(16.21±2.24)×10^(9)/L、(70.24±12.44)mg/L、(16.92±4.22)ng/ml、(748.24±114.26)pg/ml、(2.64±0.14),脓毒性休克组分别为(464.24±111.64)μl、(268.24±22.64)μl、(1116.24±12.66)μl、(1.42±0.16)、(622.42±12.66)μl、(412.24±22.64)μl、(17.92±2.14)×10^(9)/L、(92.24±12.64)mg/L、(22.34±5.24)ng/ml、(1056.21±312.42)pg/ml、(2.78±0.11),对照组分别为(1642.24±322.24)μl、(744.24±26.24)μl、(511.24±12.24)μl、(2.31±0.26)、(214.24±12.16)μl、(152.24±12.24)μl、(7.42±2.24)×10^(9)/L、(3.24±1.24)mg/L、(1.21±0.42)ng/ml、(7.24±2.41)pg/ml、(0.91±0.11);脓毒症组与脓毒性休克组CD3^(+)、CD4^(+)、CD4^(+)/CD8^(+)低于对照组,CD8^(+)、NK细胞、B细胞、WBC、CRP、PCT、IL-6、CD64均高于对照组(P<0.05);脓毒症组CD3^(+)、CD4^(+)、CD4^(+)/CD8^(+)高于脓毒性休克组,CD8^(+)、NK细胞、B细胞、WBC、CRP、PCT、IL-6、CD64均低于脓毒性休克组(P<0.05)。脓毒症组的SOFA评分(2.68±0.32)分低于脓毒性休克组的(2.95±0.29)分(P<0.05)。Pearson相关性分析显示,CD4^(+)/CD8^(+)与SOFA评分呈负相关(r=-0.635,P<0.05),CRP、PCT、IL-6、CD64与SOFA评分均呈正相关(r=0.593、0.615、0.672、0.624,P<0.05)。受试者工作特征曲线(ROC曲线)分析显示,CRP、PCT、IL-6联合检测的曲线下面积(AUC)及灵敏度、特异度、阳性预测值、阴性预测值高于单一检测(P<0.05)。结论淋巴细胞亚群、CD64、血清炎症因子可帮助评估脓毒症患者病情的严重程度,且CD4^(+)/CD8^(+)、CRP、PCT、IL-6均与SOFA评分密切相关,临床工作中可监测CD4^(+)/CD8^(+)、CRP、PCT、IL-6水平变化预测早期脓毒症,且联合检测可作为脓毒症的预后预警指标,预测价值确切。

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关键词： Lymphoproliferative cytokines   Engineered fusion protein   Target-mediated drug disposition (TMDD)   Pharmacodynamic (PD)-enhanced TMDD   Quantitative systems pharmacology (QSP) model   Clinical translation  

摘要： Interleukin-15 (IL-15) is a key pleiotropic cytokine involved in innate and adaptive immunity, promoting proliferation, differentiation, and effector function in lymphocytes. The biologic functions of IL-15 provide a rationale for developing IL-15 agonists as potential cancer treatment, however, IL-15 exhibits a short half-life thereby limiting its therapeutic potential. Recombinant human IL-15 therapies have faced challenges in pharmacokinetics (PK), pharmacodynamics (PD), and safety due to a lack of understanding of the mechanisms leading to expansion of specific immune cell subpopulations following IL-15 therapies. In this work, we develop a quantitative systems pharmacology (QSP) model to capture the dynamics of lymphocyte expansion in response to three engineered IL-15/IL-15R alpha therapeutics: a potency engineered Fc-fusion referred to as Efbalropendekin alfa;a heterodimeric, PD-1 targeted cytokine assessed in non-clinical studies (PD1/IL15 TaCk);and an anti-respiratory syncytial virus targeted cytokine that serves as a non-binding isotype control (RSV/IL15 TaCk). The QSP model is able to capture systemic PK and lymphocyte expansion to each of the molecules across different dose levels, thereby offering insights into the complex relationship between PK and PD for these molecules. At molar matched doses, model simulations predict greater drug exposure in the terminal phase of the PK profile following treatment with Efbalropendekin alfa compared to PD1/IL15 TaCk due to the high levels of T cell expansion following administration of PD1/IL15 TaCk. Additionally, our results suggest that while the cell expansion levels in the blood are reflective of dynamics in the tissue, Efbalropendekin alfa and PD1/IL15 TaCk bind to different cell populations in the blood but similar cell populations in the tissue due to the relatively large number of PD1 expressing CD4+ and CD8+ T cells in tissue. Finally, we leverage our QSP modeling framework to generate virtual cohorts with

关键词： 肺炎   支原体   心肌损伤   淋巴细胞/单核细胞比值   乳酸脱氢酶   预测  

摘要： 目的探讨淋巴细胞/单核细胞比值(LMR)联合乳酸脱氢酶(LDH)对重症肺炎支原体(MP)肺炎患儿发生心肌损伤的预测价值。方法选取2021年4月—2024年12月在衡水市妇幼保健院接受治疗的重症MP肺炎患儿164例为研究对象。根据患儿是否发生心肌损伤将其分为心肌损伤组(n=46)和非心肌损伤组(n=118)。重症MP肺炎患儿发生心肌损伤的影响因素分析采用多因素Logistic回归分析。绘制ROC曲线以评估LMR、LDH及二者联合对重症MP肺炎患儿发生心肌损伤的预测价值。结果心肌损伤组LMR低于非心肌损伤组,心肌肌钙蛋白I、肌酸激酶同工酶、LDH、IL-6高于非心肌损伤组(P<0.05)。多因素Logistic回归分析结果显示,LMR、心肌肌钙蛋白I、肌酸激酶同工酶、LDH、IL-6是重症MP肺炎患儿发生心肌损伤的独立影响因素(P<0.05)。ROC曲线分析结果显示,LMR、LDH及二者联合预测重症MP肺炎患儿发生心肌损伤的AUC分别为0.83[95%CI(0.76~0.90)]、0.73[95%CI(0.64~0.82)]、0.91[95%CI(0.86~0.97)]。结论LMR、LDH是重症MP肺炎患儿发生心肌损伤的独立影响因素,LMR、LDH对重症MP肺炎患儿发生心肌损伤具有一定预测价值,且二者联合的预测价值较高。

关键词： NcRNAs   Non-coding RNAs   LncRNAs   Long non-coding RNAs   SncRNAs   Small non-coding RNAs   MiRNAs   MicroRNAs   SiRNAs   Small interfering RNAs   PiRNAs   piwi-interacting RNA   TME   Tumor microenvironment   HEIH   Hepatocellular carcinoma upregulated EZH2-associated lncRNA   LincRNAs   intergenic lncRNA   GC   Gastric cancer   HCC   Hepatocellular carcinoma   CRC   Colorectal cancer   BC   Breast cancer   PCa   Prostate cancer   BCAR4   Breast cancer anti-estrogen resistance 4   SNIP1   Smad nuclear interacting protein   CCL21   Chemokines chemokine C-C motif ligand 21   PP1   Protein Phosphate 1   PNUTS   Phosphatase 1 nuclear targeting subunit   H3K18ac   Histone 3 at lysine placed on position 18   GLI2   GLI family zinc finger 2   MALAT-1   Metastasis Associated Lung Adenocarcinoma Transcript 1   HNF1A-AS1   HNFIA-antisense 1   BCL-2   B-cell lymphoma 2 family protein   HNF1A-AS1   HNF1A- antisense 1   BCL-2   B-cell lymphoma-2 family protein   TSLC1-AS1   TSLC1-antisense RNA 1   SNHG12   small nucleolar RNA host gene 12   PBRM1   polybromo 1 protein   MMP10   matrix metalloproteinases 10   MEG3   maternally expressed 3   TERT   Telomerase reverse transcriptase   TERC   Telomerase RNA component   GBCDRlnc1   Gallbladder cancer drug resistance associated lncRNA1   DOX   Doxorubicin   PGK1   Phosphoglycerate kinase 1   LNMAT1   lymph node metastasis-associated transcript 1   H3K4me3   hnRNPL-mediated H3 lysine 4 trimethylation   Lnc-sox5   lncRNA SRY-box transcription factor 5   Treg   T regulatory cells   IDO1   indoleamine 2,3-dioxygenase 1   XIST   X-inactive specific transcript   IL-1   Interleukin 1   IL-6   Interleukin 6   TNF- α   Tumor necrosis factor-alpha   MDSCs   Myeloid-derived suppressor cells   PD-1   programmed cell death 1   PD-L1   programmed cell death ligand 1   CTLA-4   Cytotoxic T-lymphocyte-associated protein 4   TNBC   Triple negative breast cancer-related   GATA3-AS1   GATA-binding protein 3- antisense RNA 1   TIM-3   T cell immunoglobulin- and mucin-domain-containing molecule 3   OSCC   oral squamous cell carcinoma   CRNDE   Colorectal Neoplasia Differentially Expressed   Lnc-SGK1   Lnc-serum and glucocorticoid-inducible kinase 1   Th2   T-helper 2   Th17   T-helper 17   Lnc-INSR   insulin receptor   Foxp3   Fo  

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关键词： Pregnancy   anti-TNF   congenital malformations   inflammatory bowel disease   thiopurines  

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