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摘要： Phospholipid scramblase 1 (PLSCR1) is an antiviral interferon-stimulated gene (ISG) that has several known anti-influenza functions such as interfering with viral nuclear import, regulating toll-like receptor (TLR) 9 and potentiating the expression of other ISGs. However, the exact mechanisms of anti-flu activity of PLSCR1 in relation to its expression compartment and enzymatic activity, and the molecular and cellular mechanisms involved have not been completely explored. Moreover, only limited animal models have been studied to delineate its role at the tissue level in influenza infections. We hypothesize that PLSCR1 protects hosts against IAV infection by regulating type 3 interferon (IFN-λ) signaling pathways. Our results showed that Plscr1 expression was highly induced by IAV infection and in epithelial cells treated with IFN-λ. We found that knockout (KO) mice exhibited exacerbated body weight loss, decreased survival rates, heightened viral replication, and increased lung damage. Interestingly, transcriptomic analyses demonstrated that Plscr1 was required for type 3 interferon receptor (Ifn-λr1) expression, and impaired expression of Ifn-λr1 and downstream ISGs may be responsible for delayed viral clearance in Plscr1 KO mice. In addition, Plscr1 interacted with Ifn-λr1 within the epithelial compartment following IAV infection, suggesting Plscr1 may modulate IFN-λ signaling via protein-protein interactions. Finally, single-cell RNA sequencing data indicated that expression was significantly upregulated in ciliated airway epithelial cells in mice following IAV infection. Consistently, mice with ciliated epithelial cell-specific Plscr1 overexpression showed reduced susceptibility, less inflammation and enhanced Ifn-λr1 expression in IAV infection. Our research will elucidate virus-host interactions and pave the way for the development of novel anti-influenza drugs that target human elements like PLSCR1, thereby mitigating the emergence of drug-resistant IAV s

关键词： Osteoporosis   IL-6   TGF-beta1   Bone density   Bone turnover   Diagnostic value  

摘要： PurposeThis research is intended to evaluate the correlations of serum IL-6 and TGF-beta 1 concentrations with bone density and turnover markers as well as their diagnostic value in elderly male patients with osteoporosis (OP).MethodsA retrospective analysis was conducted on 335 elderly men (>= 60 years;90 with normal bone mass, 120 osteopenia cases, and 125 OP cases). Lumbar spine/femoral neck BMD values were measured using dual-energy X-ray absorptiometry. Correlations of serum IL-6 and TGF-beta 1 concentrations with bone density and bone turnover markers in OP patients were analyzed utilizing Pearson or Spearman correlation coefficients. Independent influencing factors for OP were identified by logistic multivariate regression analysis. The diagnostic value of serum IL-6 and TGF-beta 1 was assessed with ROC curves and MedCalc *** history, drinking history, lumbar spine BMD, femoral neck BMD, PINP, and beta-CTX markedly differed among the normal bone mass, osteopenia, and OP groups. Elevated IL-6 and reduced TGF-beta 1 concentrations were observed in serum samples of OP. Serum IL-6 concentrations was inversely associated with bone density markers but positively lined to bone turnover markers. Conversely, serum TGF-beta 1 was positively related to bone density markers but negatively associated with bone turnover markers. Smoking history, PINP, and IL-6, were identified as independent risk factors while lumbar spine BMD, femoral neck BMD, and TGF-beta 1 were independent protective markers for OP. The combined assessment of serum IL-6 and TGF-beta 1 showed superior diagnostic performance for *** IL-6 in combination with TGF-beta 1 exhibits good diagnostic performance for *** of evidenceDiagnostic: individual cross-sectional studies with consistently applied reference standard and blinding

关键词： human leukocyte antigen   HLA-B35   optic neuritis   optic neuropathy   Beh & ccedil   ets disease  

摘要： Purpose To describe a unique presentation of optic neuritis associated with positive *** A woman presented with unilateral retro-orbital pain, mildly decreased vision, and optic disc edema with new-onset aphthous ulcers. Color vision was preserved, and no visual field deficits were noted. Diagnostic imaging demonstrated retrobulbar optic nerve enhancement, with genetic testing revealing HLA-B35 positivity. Treatment with high-dose oral steroids for 3 days resolved all symptoms, and the patient remained stable for at least 2 *** and importance In addition to rheumatic conditions and oral lesions, HLA-B35 can be linked to optic neuritis. This relationship highlights the need to further explore genetic risk factors associated with optic neuritis and the potential need for human leukocyte antigen (HLA) testing in unusual cases of optic neuritis.

摘要： Low back pain is the leading cause of global disability with intervertebral disc (IVD) degeneration a major cause. However, no current treatments target the underlying pathophysiological causes. PCRX-201 presents a novel gene therapy approach that addresses this issue. PCRX-201 codes for interleukin-1 receptor antagonist, the signalling inhibitor of the pro-inflammatory cytokine interleukin-1, which orchestrates the catabolic degeneration of the IVD. Here, the ability of PCRX-201 to transduce human nucleus pulposus cells to increase IL-1Ra production was assessed together with effects on catabolic pathways. When transduced with PCRX-201, the production and release of IL-1Ra was increased in degenerate human nucleus pulposus cells and tissue. Whereas, the production of downstream proteins, including IL-1 beta, IL-6, MMP3, ADAMTS4 and VEGF were decreased in both cells and tissue, indicating a reduction in IL-1-induced catabolic signalling. Here, a novel gene therapy vector, PCRX-201, was shown to transduce degenerate NP cells and tissue, increasing the production of IL-1Ra. The increased IL-1Ra resulted in decreased production of catabolic cytokines, enzymes and angiogenic factors, whilst also increasing aggrecan expression. This demonstrates PCRX-201 enables the inhibition of IL-1-driven IVD degeneration. The ability of PCRX-201 to elicit anti-catabolic responses is promising and warrants further development to determine the efficacy of this exciting, novel gene therapy.

关键词： 溃疡性结肠炎   四神丸   Th17/Treg信号通路   免疫功能   炎性细胞因子  

摘要： 目的：研究四神丸通过辅助性T细胞17(Thelpercell17，Th17)和调节性T细胞(regulatoryTcells，Treg)信号通路调控免疫平衡及其分泌炎性细胞因子治疗溃疡性结肠炎的机制。方法：选取2022年8月～2023年7月医院诊治的溃疡性结肠炎患者104例，按照随机数表法均分为两组、各52例。对照组患者常规给予美沙拉嗪治疗，观察组在对照组基础上增加四神丸治疗。用药12周后，观察并比较两组患者的疗效、疾病活动指数评分、免疫指标（Treg细胞比例、Th17细胞比例和Th17/Treg值）、炎性细胞因子[白介素（interleukin，IL）-2、IL-6、IL-10、IL-17]及不良反应发生情况。结果：观察组愈显率为86.54%，显著高于对照组69.23%，两组间差异有统计学意义（P＜0.05）；观察组、对照组总有效率分别为98.08%、90.38%，差异无统计学意义（P＞0.05）。治疗后，两组患者的疾病活动指数评分均显著下降，观察组显著低于对照组[(2.61±0.72)分vs (3.19±0.84) 分 ]（P＜0.05）。治疗后，两组患者Treg细胞比例升高，Th17细胞比例和Th17/Treg值降低，观察组各指标显著优于对照组[(7.61±1.80)%、(6.35±0.41)%、(1.61±0.32)% vs (6.57±1.64)%、(7.67±0.52)%、(1.13±0.28)]（P＜0.05）。治疗后，两组患者IL-2、IL-6、IL-17水平升高，IL-10水平降低，观察组上述各指标显著优于对照组[（5.39±1.13）pg/ml、（5.68±1.41）pg/ml、（53.82±5.20）pg/ml、（2.49±0.37）pg/ml vs （6.45±1.06）pg/ml、（6.62±1.70）pg/ml、（47.19±4.83）pg/ml、（2.98±0.30）pg/ml]（P＜0.05）。两组均无严重不良反应发生。结论：四神丸能够通过Th17/Treg信号通路调控免疫平衡，调节其分泌炎性细胞因子水平，进而显著改善溃疡性结肠炎症状，发挥更高的治疗价值。

关键词： 抗补体活性   测定   静脉注射人免疫球蛋白   血液制品  

摘要： 静注人免疫球蛋白(human intravenous immunoglobulin)是一种以合并血浆为原料的血液制品。抗补体活性测定是静注人免疫球蛋白的质量控制的重要环节。为确保安全性，静注人免疫球蛋白的抗补体活性要被严格限制。《中华人民共和国药典》2020版(三部)和《欧洲药典》11.0版收载的抗补体活性测定法都是基于Mayer补体消耗法建立的。现就国内外药典收载的抗补体活性测定法的建立过程、该方法的关键影响因素，以及其他抗补体活性测定方法作一概述。

关键词： Cancer immunotherapy   Oncogenes   Oncology   Therapeutics   Tumor suppressors  

摘要： The Hippo signaling pathway plays a key role in tumorigenesis in different cancer types. We investigated the role of the Hippo "effector" YAP1 on the tumor immune microenvironment (TIME) of urothelial carcinoma of bladder (UCB) and evaluated the efficacy of immunotherapy in the context of YAP1 signaling. We performed numerous in vitro and in vivo experiments to determine the role of YAP1 using genetic and pharmacological attenuation of YAP1 activity. Briefly, RNA sequencing was carried out with mice and human cell lines to identify novel YAP1-regulated downstream targets unbiasedly. We then experimentally confirmed that YAP1 regulates the TIME through the IL-6/STAT3 signaling pathway and varied C-X-C motif chemokine regulation. We analyzed several human sample sets to explore the TIME status in the context of YAP1 expression. Our data indicate that YAP1 attenuation decreases M2 macrophages and MDSCs in the TIME compared to YAP1 expressing cells. In summary, this study provides insights on YAP1 signaling as a driver for cancer stemness and an inducer of immunosuppressive TIME. Moreover, the therapeutic efficacy of YAP1 attenuation indicates that combined blockade of YAP1 and immune checkpoints may yield clinical value for treating UCB patients.

关键词： 补体C3   病理性疼痛   Janus蛋白酪氨酸激酶2/信号传导和转录激活因子3   核转录因子-κB   补体抑制剂  

摘要： 补体系统在识别和消除病原体、清除生理碎片、协调免疫反应以及稳态等方面发挥重要作用，作为炎症反应的一种早期预警信号，异常的补体活动是病理性疼痛发病的重要诱因。补体成分3（complement 3，C3）是病理性疼痛诱发过程中补体系统激活的重要指标。实验及临床流行病学研究发现，多种病理性疼痛中周围与中枢神经C3异常升高，通过结合特异性C3受体直接或间接通过补体信号调控神经元对神经病变的反应。C3可以通过在神经元质膜上表达的特异性补体受体直接调节神经元的生命和死亡的各个方面，也可以通过募集胶质细胞和免疫细胞经各种机制将补体信号传递给神经元间接调节，补体信号指导神经元对组织损伤、神经创伤和神经病变的反应。本文主要对C3在病理性疼痛涉及的细胞因子和信号通路的机制进行综述，探讨C3成为镇痛靶点的可能性。

关键词： Asthma   IL-17C   IL-17RE   Macrophages  

摘要： BackgroundIL-17C has been described in a variety of inflammatory diseases driven by neutrophils. However, the role of IL-17C in neutrophilic asthma has not been completely *** level of IL-17C in asthmatic patients and mice was assessed. Il-17c-deficient mice or mice treated with exogenous rmIL-17C were performed for OVA/CFA-induced asthmatic mice model. Pulmonary inflammation was evaluated by histological analysis, flow cytometry and cytokine analysis. Il-17re-overexpressed Raw264.7 were used in vitro to investigate the role of IL-17C in macrophage ***, we show IL-17C were increased in serum or plasma from asthmatic patients and OVA/CFA-induced asthma mice. In the OVA/CFA-induced model, exogenous rmIL-17C aggravated neutrophil- and Type 17-dominated inflammation and promoted M1 macrophage differentiation, whereas deficiency of Il-17c reversed the pro-inflammatory phenotypes and inhibited the expansion of M1 macrophages. In vitro, IL-17C in synergy with IFN-gamma induced STAT1 activation in Il-17re overexpressed Raw264.7 to upregulate M1-related genes expression, and promoted pro-inflammatory M1 polymerization, whereas IL-17C in contrast to the effect of IL-4 inhibited STAT6 activation, to reduce Raw264.7 differentiation to M2 macrophage and functional M2-related genes ***-17C promotes allergic inflammation via M1 polarization of pulmonary macrophages in neutrophilic asthma. Modulation of the IL-17C/IL-17RE axis represents a novel therapeutic target in neutrophilic asthma.