关键词： 白细胞介素11   心血管疾病   纤维化   炎症反应   氧化应激  

摘要： 白细胞介素（IL）-11隶属于IL-6家族，虽与IL-6结构存在差异，但其功能联系紧密。近年来，研究发现IL-11在心血管疾病的发生、心脏纤维化及重构进程中占据关键地位，极有可能成为心血管疾病治疗的崭新靶点。现全面综述IL-11与心血管疾病之间的相互作用、作用机制、研究进展，并对其未来发展趋向进行了前瞻性探讨，旨在为临床治疗提供有价值的参考依据。

关键词： Hydrogen sulfide   Cadmium stress   Calcium signaling pathway   Calmodulin   Detoxification  

摘要： The blood clam Tegilarca granosa is an economically important shellfish in Asia. The complex living environment often exposes the clams to cadmium (Cd) and hydrogen sulfide (H2S). H2S is well-known for its toxic effects, however, it is still unclear whether it can participate in regulating the heavy metal adaptation in clams. Here, we subjected T. granosa to chronic Cd stress (50 mu g/L, 14 days) to explore their physiological and molecular response patterns under the addition of 0.2, 0.4, and 0.8 mM H2S. The results indicated that the Cd stress induced the immune-toxicity and neurotoxicity in the gills and viscera. H2S could alleviate the toxicity by inducing phagocytosis rate, maintaining AChE and Ca2 +- ATPase activities, reducing MDA and O2-contents, promoting the excretion or degradation of Cd, and inhibiting the Ca2+ signaling pathway (CaM, CaMK2, CaMKK2). However, high concentrations of H2S also inhibited the ATPase activities and the apoptotic signaling pathway. Altogether, our results indicated that H2S has a special regulatory mechanism for Cd toxicity in the clam T. granosa, and this regulation may depend on the Ca2+ signaling pathway. Our results would offer insights into the sulfide and Cd-tolerant molecular mechanisms in this species and provide a useful tool for assessing the integrated biological impacts of Cd and sulfide on shellfish.

关键词： Alzheimer's disease   Innovative peptide   Ca 2+homeostasis   Targeted therapy   Amyloid-beta  

摘要： Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive and behavioral impairments. Despite extensive research into the pathogenesis of AD, there is still a lack of effective clinical treatments drugs. In this study, we identified calmodulin (CaM) as a key molecule in the pathological process of AD through bioinformatics analysis and innovatively designed a peptide, TI-16, based on the binding specificity between CaM and amyloid-beta (A beta). We evaluated the improvement effect of TI-16 on the activity and apoptosis of A beta 25-35-induced SHSY5Y cells damage by Cell Counting Kit 8 (CCK-8) and Flow cytometry. MOE molecular docking and GST pull-down experiments demonstrated that TI-16 possesses binding affinity for A beta, and Immunofluorescence staining and Ca2+ concentration determination experiments showed that TI-16 reduced the co-localization of A beta and CaM, and could inhibit intracellular calcium overload. Subsequently, Morris water maze tests were conducted to assess the impact of TI-16 on learning and memory abilities in AD model mice. Furthermore, HE staining, Th-S staining, and Western blot analysis were utilized to investigate the improvement effect of TI-16 on the pathological damage of AD. The results indicate that TI-16 can target A beta to increase the intracellular free concentration of CaM, and effectively regulate intracellular Ca2+ homeostasis. Notably, TI-16 significantly enhanced cognitive function in AD model mice, reduced A beta deposition, alleviated neuronal damage, inhibited neuronal apoptosis, and thereby improved AD progression. As a potentially effective peptide therapeutic drug for AD, TI-16 offers a novel target and introduces a fresh perspective for future clinical applications.

关键词： ferroptosis   P53   protein kinase D   vascular calcification  

摘要： Vascular calcification results in the hardening and weakening of the vascular wall, thereby increasing the risk of cardiovascular disease. Protein kinase D (PKD) is implicated in the regulation of numerous physiological processes, including cell growth, proliferation, differentiation, apoptosis, and intracellular signaling. PKD plays a pivotal role in regulating the function and phenotypic transformation of vascular smooth muscle cells (VSMCs);however, further studies are necessary to elucidate the role of PKD in vascular calcification. VSMCs were used to establish an in vitro calcification model. Six-week-old male C57BL/6J mice were selected to establish a vitamin D3 (Vitd3)-induced calcification model in vivo. Adeno-associated virus serotype 9 (AAV 9)-PKD or AAV 9-negative control was injected via tail vein 2 weeks before injecting Vitd3 into the mice. Protein expression levels of the P53-SLC7A11 pathway were determined in both ex vivo and in vivo experiments. The degree of calcification was assessed by Alizarin red S (ARS) staining and calcium content measurement. We found that PKD was upregulated in ex vivo and in vivo models of vascular calcification. The inhibition of PKD resulted in a reduction in the expression of ferroptosis-related genes and osteogenic differentiation of VSMCs, which in turn led to a mitigation of vascular calcification. Subsequent experiments demonstrated that the P53-SLC7A11 signaling pathway is a key mediator of PKD-induced vascular calcification. The results of this study indicate that PKD knockdown alleviates vascular calcification through the P53-SLC7A11 axis-mediated ferroptosis.

关键词： P53   Cancer   Metastasis   Apoptosis   Necroptosis   Ferroptosis   Reactive oxygen species  

摘要： Approximately half of all cancers bear mutations in the tumor suppressor p53. Despite decades of research studying p53 function, treatment of p53-mutant cancers remains challenging owing to the effects of p53 mutations on many complex and interrelated signaling networks that promote tumor metastasis and chemoresistance. Mutations in p53 promote tumor survival by dysregulating cellular homeostasis and preventing activation of regulated cell death (RCD) pathways, which normally promote organismal health by eliminating dysregulated cells. Activation of RCD is a hallmark of effective cancer therapies, and p53-mutant cancers may be particularly susceptible to activation of certain RCD pathways. In this review, we discuss four RCD pathways that are the targets of emerging cancer therapeutics to treat p53-mutant cancers. These RCD pathways include E2F1-dependent apoptosis, necroptosis, mitochondrial permeability transition-driven necrosis, and ferroptosis. We discuss mechanisms of RCD activation, effects of p53 mutation on RCD activation, and current pharmaceutical strategies for RCD activation in p53-mutant cancers.

关键词： 糖尿病肾病   长链非编码RNA HOX转录本反义RNA   结节性硬化症复合体1   足细胞损伤  

摘要： 目的 探究长链非编码RNA HOX转录本反义RNA（LnRNA HOTAIR）靶向结节性硬化症复合体1（tuberous sclerosis complex 1，TSC1）对糖尿病肾病足细胞损伤的调控作用。方法：将小鼠肾足细胞（MPC5）分为6组：对照组、高糖组（HG组）、HG+si-NC组、HG+si-HOTAIR组、HG+si-HOTAIR+sh-NC组、HG+si-HOTAIR+sh-TSC1组。实时荧光定量PCR（Real-time quantitative PCR，qRT-PCR）检测LnRNA HOTAIR及TSC1 mRNA表达，细胞计数试剂盒8检测细胞活力，流式细胞术检测细胞凋亡，酶联免疫吸附试验（Enzyme-linked immunosorbent assay，ELISA）试剂盒检测炎症因子[白细胞介素-6（Interleukin-6，IL-6）和肿瘤坏死因子-α（Tumor necrosis factor-α，TNF-α）]表达，相关试剂盒检测氧化应激指标[活性氧（Reactive oxygen species，ROS）、丙二醛（Malondialdehyde，MDA）、超氧化物歧化酶（Superoxide dismutase，SOD）]。结果 与对照组相比，HG组LnRNA HOTAIR水平、MPC5细胞凋亡率、IL-6、TNF-α、ROS及MDA水平明显升高（P<0.05），TSC1 mRNA、细胞活力、SOD水平降低（P<0.05）；与HG+si-NC组相比，HG+si-HOTAIR组LnRNA HOTAIR表达、MPC5细胞凋亡率、IL-6、TNF-α、ROS及MDA水平降低（P<0.05），TSC1mRNA、细胞活力、SOD水平升高（P<0.05）；与HG+si-HOTAIR+sh-NC组相比，HG+si-HOTAIR+sh-TSC1组MPC5细胞凋亡率、IL-6、TNF-α、ROS及MDA水平明显升高（P<0.05），TSC1 mRNA、细胞活力、SOD水平降低（P<0.05）。结论 沉默LnRNA HOTAIR靶向TSC1介导MPC5细胞活性、凋亡率、炎症水平及氧化应激水平，进而减轻糖尿病肾病足细胞损伤。

关键词： 膝骨关节炎   滑膜炎症   壮骨健膝方   人滑膜巨噬细胞   LXRs   NF-κB   信号通路  

摘要： 背景：滑膜巨噬细胞是滑膜组织中的主要组成细胞之一，是引起滑膜炎症的主要细胞类型。作为目前膝骨关节炎相关研究的热点，课题组前期已针对性开展系列研究，从兔滑膜组织及细胞层面上初步验证了壮骨健膝方可通过调控LXRs/NF-κB通路减缓滑膜炎症，以人滑膜巨噬细胞为研究对象，更贴近膝骨关节炎患者的真实状态，以期进一步阐明壮骨健膝方减轻滑膜炎症的机制。目的：探究壮骨健膝方含药血清对脂多糖诱导的人滑膜巨噬细胞炎症的影响及潜在分子机制。方法：(1)取3月龄新西兰大白兔12只制备壮骨健膝方含药血清及空白血清；(2)采用1.0μg/mL脂多糖诱导人滑膜巨噬细胞12 h建立炎症损伤模型，随机分为模型组(体积分数10%空白血清)、含药血清组(体积分数10%含药血清)、LXRα阻滞剂组(体积分数10%含药血清+5μg LXRα阻滞剂)、N-CoR阻滞剂组(体积分数10%含药血清+5μg N-CoR阻滞剂)、正常组(体积分数10%空白血清)，干预24 h;(3)Western blot、RT-qPCR检测各组细胞中LXRα、N-CoR、P50、P65的蛋白及mRNA表达，ELISA检测各组细胞上清液中白细胞介素1β、肿瘤坏死因子α水平。结果与结论：(1)与正常组相比，模型组LXRα、N-CoR蛋白和mRNA表达均显著降低(P <0.01)，模型组P50、P65蛋白和mRNA表达及白细胞介素1β、肿瘤坏死因子α水平均显著升高(P <0.01);(2)与模型组相比，含药血清组LXRα、N-CoR蛋白和mRNA表达均显著升高(P <0.01),P50、P65蛋白和mRNA表达及白细胞介素1β、肿瘤坏死因子α水平均显著降低(P <0.01);LXRα阻滞剂组、N-CoR阻滞剂组P50、P65蛋白和mRNA表达及白细胞介素1β、肿瘤坏死因子α水平均降低(P <0.01,P <0.05);(3)与含药血清组相比，LXRα阻滞剂组、N-CoR阻滞剂组LXRα、N-CoR蛋白和mRNA表达均显著降低(P <0.01),P50、P65蛋白和mRNA表达及白细胞介素1β、肿瘤坏死因子α水平均升高(P <0.01,P <0.05);(4)结果表明，壮骨健膝方含药血清能通过上调LXRα、N-CoR蛋白及mRNA表达，下调P50、P65蛋白及mRNA表达，抑制LXRs/NF-κB信号通路的传导，减少下游白细胞介素1β、肿瘤坏死因子α炎症相关指标的分泌，从而缓解人滑膜巨噬细胞炎症反应，起到防治膝骨关节炎的作用。

关键词： 信使RNA疗法   信使RNA递送系统   脂质纳米粒   靶向递送   基因治疗   综述  

摘要： 信使RNA(mRNA)疗法是一种将体外转录的mRNA递送至特定细胞，生成目标蛋白以治疗或预防疾病的生物技术。mRNA疗法离不开有效的mRNA递送系统，而脂质纳米粒（LNP）是目前临床应用最为广泛的一类mRNA递送载体。LNP由可电离脂质、磷脂、胆固醇和聚乙二醇化脂质四种脂质材料组成，可有效解决mRNA药物存在的体内稳定性较差、难以跨越体内多级生物屏障等难题，并能够针对肝脏、肺和脾脏等器官实现mRNA安全、高效和靶向递送。本文阐述了LNP四个脂质组分在递送mRNA中的作用，介绍了通过抗体修饰、改变脂质结构和使用特殊的给药方式等策略实现LNP针对肝脏、肺、脾脏、胰腺、骨髓及胎盘等不同器官/组织的靶向递送，并探讨了基于LNP的mRNA药物在疾病治疗领域的应用及面临的挑战，以期为mRNA疗法的临床转化和LNP递送系统的优化创新提供参考。