Melatonin induces apoptosis of colorectal cancer cells through HDAC4 nuclear import mediated by CaMKII inactivation

Melatonin induces apoptosis in many different cancer cell lines, including colorectal cancer. However, the precise mechanisms involved remain largely unresolved. In this study, we provide evidence to reveal a new mechanism by which melatonin induces apoptosis of colorectal cancer LoVo cells. Melatonin at pharmacological concentrations significantly suppressed cell proliferation and induced apoptosis in a dose‐dependent manner. The observed apoptosis was accompanied by the melatonin‐induced dephosphorylation and nuclear import of histone deacetylase 4 (HDAC4). Pretreatment with a HDAC4‐specific siRNA effectively attenuated the melatonin‐induced apoptosis, indicating that nuclear localization of HDAC4 is required for melatonin‐induced apoptosis. Moreover, constitutively active Ca²⁺/calmodulin‐dependent protein kinase II alpha (CaMKIIα) abrogated the melatonin‐induced HDAC4 nuclear import and apoptosis of LoVo cells. Furthermore, melatonin decreased H3 acetylation on bcl‐2 promoter, leading to a reduction of bcl‐2 expression, whereas constitutively active CaMKIIα(T286D) or HDAC4‐specific siRNA abrogated the effect of melatonin. In conclusion, the present study provides evidence that melatonin‐induced apoptosis in colorectal cancer LoVo cells largely depends on the nuclear import of HDAC4 and subsequent H3 deacetylation via the inactivation of CaMKIIα.     

Necroptotic TNFα-Syndecan 4-TNFα Vicious Cycle as a Therapeutic Target for Preventing Temporomandibular Joint Osteoarthritis

Temporomandibular joint osteoarthritis (TMJOA) is a chronic degenerative disease for which the underlying mechanism still remains unclear. Compared with apoptosis and autophagy, necroptosis causes greater harm to tissue homeostasis by releasing damage-associated molecular patterns (DAMPs). However, the role of necroptosis and downstream key DAMPs in TMJOA is unknown. Here, rodent models of TMJOA were established by the unilateral anterior crossbite (UAC). Transmission electron microscopy (TEM) and immunohistochemistry of receptor interacting protein kinase 3 (RIPK3)/phosphorylation of mixed lineage kinase domain-like protein (pMLKL) were conducted to evaluate the occurrence of necroptosis in vivo. The therapeutic effects of blocking necroptosis were achieved by intra-articularly injecting RIPK3 or MLKL inhibitors and using RIPK3 or MLKL knockout mice. In vitro necroptosis of condylar chondrocyte was induced by combination of tumor necrosis factor alpha (TNFα), second mitochondria-derived activator of caspases (SMAC) mimetics and carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]- fluoromethylketone (z-VAD-fmk). The possible DAMPs released by necroptotic chondrocytes were screened by quantitative proteomics and blocked by specific antibody. Translucent cytosol, swollen organelles, and ruptured cell membranes, features of necroptosis, were frequently manifested in chondrocytes at the early stage of condylar cartilage degeneration in TMJOA, which was accompanied by upregulation of RIPK3/pMLKL. Inhibiting or knocking out RIPK3/MLKL significantly prevented cartilage degeneration. DAMPs released by necroptotic condylar chondrocytes, such as syndecan 4 (SDC4) and heat shock protein 90 (HSP90), were verified. Furthermore, blocking the function of SDC4 significantly attenuated the expression of TNFα in cartilage and synovium, and accordingly increased cartilage thickness and reduced synovial inflammation. Thus, the necroptotic vicious cycle of TNFα-SDC4-TNFα contributes to cartilage degeneration and synovitis, and can serve as a potential therapeutic target for treating TMJOA. © 2022 American Society for Bone and Mineral Research (ASBMR).     

Henoch-Schönlein Purpura Nephritis and Cerebral Venous Sinus Thrombosis Due to Hereditary Deficiency of Antithrombin III

Indian Journal of Pediatrics -     

“互联网+”远程医疗体系建设实践研究

介绍以贵州医科大学附属医院为代表的贵州省“互联网+”远程医疗体系建设背景与规范、技术支撑及其成效，探索适合省情的远程医疗模式，实践证明该模式有利于实现优质医疗资源上下联通，具有可行性、推广性、科学性。     

局部晚期食管鳞癌新辅助放疗剂量与病理完全缓解关系分析

目的 探讨接受新辅助放化疗的局部晚期食管鳞癌患者新辅助放疗剂量与病理完全缓解(pCR)的关系。方法 收集2017-2019年间在四川大学华西医院肿瘤中心经病理确诊为食管鳞癌并接受新辅助放化疗和手术的 116例局部晚期患者临床资料。116例患者中 40~45Gy组 80例,≥45Gy组 36例,分析两组术后pCR率。结果 全组患者的pCR率为38.8%(45/116),40~45Gy组与≥45Gy组的pCR率分别为44%(35/80)和28%(10/36)(P=0.105)。结论 术前新辅助采用较高的放疗剂量不增加局部晚期食管鳞癌的pCR率,有必要进行前瞻性的临床研究确定合适的新辅助放疗剂量。     

Aloe‐emodin: A review of its pharmacology,toxicity, and pharmacokinetics

Aloe‐emodin is a naturally anthraquinone derivative and an active ingredient of Chinese herbs, such as Cassia occidentalis, Rheum palmatum L., Aloe vera, and Polygonum multiflorum Thunb. Emerging evidence suggests that aloe‐emodin exhibits many pharmacological effects, including anticancer, antivirus, anti‐inflammatory, antibacterial, antiparasitic, neuroprotective, and hepatoprotective activities. These pharmacological properties lay the foundation for the treatment of various diseases, including influenza virus, inflammation, sepsis, Alzheimer's disease, glaucoma, malaria, liver fibrosis, psoriasis, Type 2 diabetes, growth disorders, and several types of cancers. However, an increasing number of published studies have reported adverse effects of aloe‐emodin. The primary toxicity among these reports is hepatotoxicity and nephrotoxicity, which are of wide concern worldwide. Pharmacokinetic studies have demonstrated that aloe‐emodin has a poor intestinal absorption, short elimination half‐life, and low bioavailability. This review aims to provide a comprehensive summary of the pharmacology, toxicity, and pharmacokinetics of aloe‐emodin reported to date with an emphasis on its biological properties and mechanisms of action.     

泽泻化学成分及药理作用研究进展

泽泻为我国传统中药,广泛应用于中医临床复方及多种中成药中。目前从泽泻中分离到了220余个化合物,包括三萜、倍半萜、二萜、糖类、含氮化合物、苯丙素、黄酮、甾体等。药理学研究表明泽泻醇提物、水提物及一些单体类成分具有利尿、抗结石及肾脏保护、降血脂及保肝、降血糖、抗癌、抗氧化损伤、抗炎、抗补体等作用。该文对近五十年来泽泻的化学成分和药理作用进行了全面系统的整理,以期为泽泻的深入研究和开发利用提供理论依据。