课程文献中心 更多>>

关键词： 偏头痛   降钙素基因相关肽   吉泮类   单克隆抗体  

摘要： 偏头痛是一种反复发作的神经系统疾病，被世界卫生组织列为致残的第二大原因。目前预防和治疗偏头痛的药物大多是非特异性的或存在禁忌证/严重不良反应，近年来通过对偏头痛病理生理机制中起关键作用的降钙素基因相关肽（CGRP）进行研究，开发出了靶向CGRP通路阻断剂，包括CGRP受体拮抗剂（吉泮类）和抗CGRP单克隆抗体。目前相关研究中此类药物被证明有良好的安全性、有效性及耐受性。本文对靶向CGRP通路的相关临床试验及研究结果进行综述，旨在为今后国内偏头痛治疗药物的选择提供依据。

关键词： ATF6 alpha   normal human dermal fibroblasts   skin   UPR   UVB-induced senescence  

摘要： Skin aging is influenced by both intrinsic and extrinsic factors, particularly UV radiation, and is characterized by an accumulation of senescent cells. Remarkably, exposure to UV can trigger senescence in different skin cell types, including dermal fibroblasts. However, the molecular mechanisms underlying UV-induced senescence and the impact of the related senescence-associated secretory phenotype (SASP) on the homeostasis of the overlying epidermis remain poorly understood. Here, we identified that both chronological aging and photoaging induce the unfolded protein response (UPR) in human dermal samples. We demonstrated that silencing ATF6 alpha disrupts the establishment of the UVB-induced senescent phenotype by preventing the onset of several senescent biomarkers and alters the composition of the SASP, consequently affecting its impact on the increased proliferation of keratinocytes embedded in reconstructed human epidermis. Moreover, we found that ATF6 alpha partially mediates IL8 expression involved in the hyperproliferation of cultured keratinocytes. Together, our findings highlight the importance of the ATF6 alpha/IL8 axis in regulating the homeostasis of neighboring cells during skin photoaging, thus suggesting ATF6 alpha as a potentially promising target for senotherapeutic interventions.

关键词： Tocilizumab   Interleukin-6   COVID-19   Viral pneumonia   Acute respiratory distress syndrome   Randomized controlled trial  

摘要： Background The objective of this clinical trial is to evaluate the efficacy and safety of IL-6 driven personalized treatment strategy with tocilizumab in patients with severe COVID-19 pneumonia. Trial design Randomized, controlled, open-label, single-center trial of a tocilizumab treatment strategy in adult patients hospitalized with severe COVID-19 pneumonia and IL-6 serum levels > 40 pg/mL. Methods Patients were randomized 1:1 to receive standard of care (SOC) or SOC plus one dose of tocilizumab. The primary outcome was death or need for invasive mechanical ventilation (IMV) within 28 days after randomization. Secondary outcomes included ICU admission, days on IMV and hospital stay. A meta-analysis of clinical trials to evaluate the effect of tocilizumab on mortality and need of IMV in patients with COVID-19 pneumonia was performed. Results Sixty-two patients were included: 30 in the SOC arm and 32 in the standard-treatment plus tocilizumab arm. The primary outcome occurred in 12.9% in the tocilizumab arm and 32.3% in the SOC arm(p = 0.068). There was a trend towards fewer days on IMV (7.5 vs 19.5 days, p = 0.073) and a shorter hospital stay (4 vs 8 days, p = 0.134) in the tocilizumab group. No serious adverse events were reported. The meta-analysis revealed a RR for death or IMV of 0.83 (95% CI: 0.77-0.89) in patients receiving tocilizumab, compared to patients receiving SOC. Conclusion Tocilizumab could be effective to prevent death or IMV in patients with severe COVID-19 pneumonia and high IL-6 serum levels. Safety profile of tocilizumab does not arise major concern in patients with severe COVID19.

关键词： IL-18BP   fibrosis   MASH   hepatic stellate cell   APB-R3   IFNγ  

摘要： Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver disease characterized by inflammation and fibrosis, with enhanced interleukin-18 (IL-18) signaling. IL-18-binding protein (IL-18BP) neutralizes IL-18, but its therapeutic potential in MASH is unclear. We find elevated IL-18BP and IL-18 levels in patients with MASH and mice, with free IL-18 correlating with disease severity. IL-18 stimulates interferon-gamma (IFNg) production in CD4 T cells, increasing hepatic IL-18BP. IL-18BP-deficient mice show worsened liver inflammation and fibrosis. We develop a human IL-18BP biologics (APB-R3) and inject it to mice to evaluate its pharmacologic efficacy. APB-R3 significantly improves MASH in reducing fibrosis and inflammation and inhibits hepatic stellate cell activation via the cGMP pathway. This study proposes that abrogation of IL-18 signaling by boosting IL-18BP can strongly inhibit the development of MASH-induced fibrosis, and our engineered IL-18BP biologics can become a promising therapeutic candidate for curing MASH.

关键词： ECs pyroptosis   DR   circTHADA   CASP1   ceRNA network  

摘要： Our study aimed to elucidate the mechanism by which circTHADA competitively adsorbs miR-494-3p to regulate CASP1-mediated endothelial cell (EC) pyroptosis in diabetic retinopathy (DR). To be specific, we used high glucose (HG)-induced human retinal microvascular endothelial cells (HRMECs) as DR cell models and streptozotocin (STZ)-treated mice as DR mouse models. The expression levels of circTHADA, miR-494-3p, CASP1, NLRP3, GSDMD-N and IL-1 beta were detected and flow cytrometry was applied to measure cell pyroptosis rate and dual luciferase reporter assays were utilized to determine the direct binding sites. As a result, exacerbated EC pyroptosis in DR was detected in DR cell and mouse models. Based on differentially expressed circRNA profiles by microarray and experimental verification, circTHADA was filtered and identified to regulate CASP1-mediated EC pyroptosis. miR-494-3p was then proven to be involved in circTHADA-mediated ceRNA network by bioinformatics analysis and experimental verification. Further gain- and loss-of-function experiments and rescue experiments revealed the function of the circTHADA/miR-494-3p/CASP1 axis in pyroptosis.

关键词： Obesity-related hypertension   Sympathetic nerve   Gut microbiota   Intestinal barrier   Interleukin-22  

摘要： BackgroundGut microbiota and its metabolites, as well as the intestinal barrier, play important roles in the development of obesity-related hypertension. Sympathetic nerves are critical for intestinal homeostasis. Carotid baroreceptor stimulation (CBS) has been shown to exert protective effects against hypertension via sympathetic tone reduction. This study aimed to reveal the effects of CBS treatment on intestinal homeostasis and its underlying mechanisms in obesity-related *** animal model of obesity-related hypertension was established with Sprague-Dawley rats by a high-fat diet and 10% fructose solution for 13 weeks. CBS devices were implanted at the 5 th week. The effects of CBS on body weight, blood pressure, gut microbiota, intestinal autonomic nerve, intestinal barrier, and type 3 innate lymphoid cells (ILC3 s) were *** treatment significantly reduced blood pressure and body weight in rats with obesity-related hypertension. In addition, CBS obviously improved gut microbial dysbiosis and intestinal barrier damage. Interestingly, after an 8-week CBS intervention, the obesity-related hypertensive rats exhibited a dramatic decrease in sympathetic nerve distribution and norepinephrine concentration, as well as an increase in IL- 22 production by ILC3 s in the *** increased IL- 22 production in ILC3 s to alleviate gut microbial dysbiosis and intestinal barrier destruction, thus improving obesity-related hypertension in rats.

关键词： 叶酸   单克隆抗体   酶联免疫吸附试验   应用  

摘要： 为实现叶酸含量的高灵敏快速检测，本研究通过制备叶酸单克隆抗体，并对检测体系进行优化，建立了高灵敏竞争酶联免疫吸附试验方法（Competitive enzyme-linked immunosorbent assay， cELISA）。结果表明，当包被抗原浓度为0.5 μg/mL，抗体稀释倍数为16000，二抗稀释倍数为10000，一抗、二抗孵育时间和显色时间分别为15、30、10 min时，建立的cELISA方法半数抑制浓度为1.12 ng/mL，最低检测限为0.028 ng/mL。该方法与维生素B1、B2、烟酸等B族维生素无交叉反应，特异性良好，与叶酸结构类似物二氢叶酸、四氢叶酸、蝶酸的交叉反应率分别为12.21%、2.07%和2.72%，检测牛奶和能量饮料样品的加标回收率分别为88.32%～94.12%和88.00%～93.29%，初步应用于复合B族维生素片和婴幼儿奶粉中叶酸含量的检测一致率分别为102.01%～114.72%和99.04%～111.62%，相对标准偏差均小于5%。本研究为快速检测叶酸含量提供了一种灵敏、特异、准确的方法，能够提高现场检测效率，对于营养强化剂含量的快速检测方法研究具有参考价值。