Molecular Mechanisms Underlying TDP-43 Pathology in Cellular and Animal Models of ALS and FTLD

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are neurodegenerative disorders that exist on a disease spectrum due to pathological, clinical and genetic overlap. In up to 97% of ALS cases and ~50% of FTLD cases, the primary pathological protein observed in affected tissues is TDP-43, which is hyperphosphorylated, ubiquitinated and cleaved. The TDP-43 is observed in aggregates that are abnormally located in the cytoplasm. The pathogenicity of TDP-43 cytoplasmic aggregates may be linked with both a loss of nuclear function and a gain of toxic functions. The cellular processes involved in ALS and FTLD disease pathogenesis include changes to RNA splicing, abnormal stress granules, mitochondrial dysfunction, impairments to axonal transport and autophagy, abnormal neuromuscular junctions, endoplasmic reticulum stress and the subsequent induction of the unfolded protein response. Here, we review and discuss the evidence for alterations to these processes that have been reported in cellular and animal models of TDP-43 proteinopathy.     

The Protective Effect of Icariin on Mitochondrial Transport and Distribution in Primary Hippocampal Neurons from 3× Tg-AD Mice

Icariin, a pharmacologically active component isolated from the Chinese herb Epimedium, has been shown to improve spatial learning and memory abilities in Alzheimer’s disease (AD) rats through inhibition of Aβ production and tau protein hyperphosphorylation. However, the potential mechanism of icariin-induced protective effects against mitochondrial dysfunctions in AD still remains unclear. In the present study, we investigated the effect of icariin on the modulation of mitochondrial transport and distribution in primary hippocampal cultures from triple-transgenic (3× Tg) AD mice. The results showed that icariin enhanced mitochondrial motility and increased mitochondrial index and mitochondrial length and size in the diseased neurons. Additionally, the expression of the key mitochondrial enzyme, pyruvate dehydrogenase-E1α (PDHE1α), and the post synaptic density protein 95 (PSD95), was preserved in AD neurons after icariin treatment, accompanied by a downregulation of Aβ and phosphorylated tau expression in the corresponding areas. Further study showed that icariin treatment resulted in a decrease in mitochondrial fission protein dynamin-related protein 1 (Drp1) and an increase in fusion protein Mitofusin 2 (Mfn2). These data indicate that icariin can promote mitochondrial transport, protect mitochondria against fragmentation and preserve the expression of mitochondrial and synaptic functional proteins in AD neurons. Thus, icariin may be a potential therapeutic complement for AD and other mitochondrial malfunction-related neuronal degenerative diseases.     

Impact of meibomian gland width on successful contact lens use

PurposeTo evaluate meibomian gland (MG) width and determine its impact on successful contact lens (CL) use and ocular health.MethodsA five-site study was conducted by recruiting 18- to 45-year-old subjects who had dropped out of CLs because of discomfort. CL dropouts were compared to age- and sex-matched successful CL wearers. Right eyes were evaluated for tear break-up time, tear meniscus height, MG expressibility, meibum quality, and meibography. Central MG widths were evaluated with a custom MATLAB program.ResultsCL dropouts (n = 56) and successful CL (n = 56) wearers had similar grades for upper (p = 1.0) and lower (p = 0.22) MG atrophy, upper (p = 0.07) and lower (p = 0.89) MG tortuosity, and upper (p = 0.92) and lower (p = 0.97) MG widths. Upper eyelid MG widths were narrower than lower eyelid MG widths (p = 0.03). Upper and lower MG tortuosity (p < 0.001) and widths (p = 0.03) were associated, but not atrophy (p = 0.42). Lower eyelid MG widths were associated with MG expressibility (p = 0.01), but MG widths were not with any other factors.ConclusionsSuccessful CL wear does not appear to be clinically influenced by MG width or other measures of MG structural integrity. Lower eyelid MGs were wider than upper eyelid MGs and narrower lower eyelid MGs were associated with worse MG expressibility, suggesting that narrower MGs may produce abnormal meibum. Data also suggests that MG factors of both eyelids should be evaluated in practice.     

负压吸引技术应用于大面积烧伤患者围术期的效果探究

目的:探究环磷酸腺苷联合负压吸引技术应用于大面积烧伤患者围术期的效果及肾保护作用探究。方法:选择2018年12月到2020年12月于医院治疗的120例大面积烧伤患者为研究对象,以随机数字表法对患者分组,60例患者为研究组,60例患者为对照组,对照组给予负压吸引技术治疗,研究组在此基础上给予环磷酸腺苷治疗,治疗前、后测定两组患者干扰素-γ(IFN-γ)、白细胞介素-2(IL-2)、白细胞介素-10(IL-0)、白细胞介素-6(IL-6)、可溶性血管细胞粘附分子-1(sVCAM-1)、一氧化氮(NO)、内皮素(ET-1)、血管内皮生长因子(VEGF)、胱抑素C(Cys-C)、肌酐(Scr)、血尿素氮(BUN)、肾损伤分子-1(KIM-1)水平,记录两组患者手术时间、麻醉苏醒时间、住院时间。结果:研究组IFN-γ、IL-6水平低于对照组(P<0.05),研究组患者IL-2、IL-10水平高于对照组(P<0.05),研究组NO、VEGF水平高于对照组(P<0.05),研究组患者sVCAM-1、ET-1水平低于对照组(P<0.05),研究组患者Cys-C、Scr、BUN、KIM-1水平低于对照组(P<0.05),研究组手术时间低于对照组(P>0.05),研究组麻醉苏醒时间、住院时间低于对照组(P<0.05)。结论:环磷酸腺苷联合负压吸引技术应用于大面积烧伤围术期患者,可降低患者IFN-γ、IL-6水平,提升患者IL-2、IL-10水平,抑制患者炎症,改善患者血管内皮功能,降低患者Cys-C、Scr、BUN、KIM-1水平,减少患者肾功能损伤,减少患者麻醉苏醒时间及住院时间。     

Drugs – Do we need them? Applications of non-pharmaceutical therapy in anterior eye disease: A review

Natural products have been in use long before the introduction of modern drug therapies and are still used in various communities worldwide for the treatment of anterior eye disease. The aim of this review is to look at the current non-pharmaceutical modalities that have been tried and assess the body of existing evidence behind them. This includes alternative medicine, existing non-pharmaceutical therapy and more recent low and high tech solutions.A detailed search of all available databases including MEDLINE, Pubmed and Google was made to look for English-language studies for complementary and alternative treatment modalities (CAM), natural therapies and new modalities for anterior eye disease such as blepharitis, dry eye and microbial keratitis. We have included a broad discussion ranging from traditional treatments like honey and aloe vera which have been used for centuries, to the more recent technological advances like Intense Pulsed Light (IPL), LipiFlow and photoactivated chromophore for corneal cross linking in infectious keratitis (PACK-CXL).Alternative management strategies may have a role in anterior eye diseases and have a potential in changing the way we currently approach them. Some of the available CAM could play a role if incorporated in to current management practices of not only chronic diseases like blepharitis and dry eye, but also acute conditions with significant morbidity like microbial keratitis. Further large-scale randomized control trials stratified by disease severity are required to improve our understanding and to evaluate the use of non-pharmaceutical therapy against current practice.     

EGCG升高cTnIR193H限制型心肌病模型小鼠未突变cTnI的表达水平

目的:研究表没食子儿茶素没食子酸酯（EGCG）升高cTnIR193H限制型心肌病模型小鼠未突变cTnI的表达水平。方法:8周龄野生型C57小鼠及8周龄cTnIR193H限制型心肌病模型小鼠分别随机分为EGCG干预组、DMSO干预组以及未干预组。每周干预5 d,3个月后采集小鼠心脏组织。分别以Western blot与RT-PCR分别检测HDAC1、GATA4及cTnI 的mRNA表达水平。组蛋白H3K9乙酰化水平、cTnI基因启动子区域中的GATA4与HDAC1结合水平以ChIP-Q-PCR方式检测。结果:EGCG干预组未突变cTnI蛋白表达水平与mRNA表达水平、GATA4的mRNA表达水平、组蛋白H3K9乙酰化水平、cTnI启动子区域GATA4的结合水平均高于未干预组（P<0.05）。cTnI启动子区域HDAC1结合水平、HDAC1的mRNA表达水平均低于未干预组（P<0.05）。 结论:在EGCG干预R193H模型小鼠实验中,EGCG可抑制HDAC1的表达,抑制cTnI启动子区域HDAC1的结合,促进心脏核心转录因子GATA4的表达、组蛋白H3K9的乙酰化、及cTnI启动子区域GATA4的结合,上调心肌的未突变cTnI的表达水平。     

Inducing Energetic Switching Using Klotho Improves Vascular Smooth Muscle Cell Phenotype

The cardiovascular disease of atherosclerosis is characterised by aged vascular smooth muscle cells and compromised cell survival. Analysis of human and murine plaques highlights markers of DNA damage such as p53, Ataxia telangiectasia mutated (ATM), and defects in mitochondrial oxidative metabolism as significant observations. The antiageing protein Klotho could prolong VSMC survival in the atherosclerotic plaque and delay the consequences of plaque rupture by improving VSMC phenotype to delay heart attacks and stroke. Comparing wild-type VSMCs from an ApoE model of atherosclerosis with a flox’d Pink1 knockout of inducible mitochondrial dysfunction we show WT Pink1 is essential for normal cell viability, while Klotho mediates energetic switching which may preserve cell survival. Methods: Wild-type ApoE VSMCs were screened to identify potential drug candidates that could improve longevity without inducing cytotoxicity. The central regulator of cell metabolism AMP Kinase was used as a readout of energy homeostasis. Functional energetic switching between oxidative and glycolytic metabolism was assessed using XF24 technology. Live cell imaging was then used as a functional readout for the WT drug response, compared with Pink1 (phosphatase-and-tensin-homolog (PTEN)-induced kinase-1) knockout cells. Results: Candidate drugs were assessed to induce pACC, pAMPK, and pLKB1 before selecting Klotho for its improved ability to perform energetic switching. Klotho mediated an inverse dose-dependent effect and was able to switch between oxidative and glycolytic metabolism. Klotho mediated improved glycolytic energetics in wild-type cells which were not present in Pink1 knockout cells that model mitochondrial dysfunction. Klotho improved WT cell survival and migration, increasing proliferation and decreasing necrosis independent of effects on apoptosis. Conclusions: Klotho plays an important role in VSMC energetics which requires Pink1 to mediate energetic switching between oxidative and glycolytic metabolism. Klotho improved VSMC phenotype and, if targeted to the plaque early in the disease, could be a useful strategy to delay the effects of plaque ageing and improve VSMC survival.     

Impact of Uremic Toxins on Endothelial Dysfunction in Chronic Kidney Disease: A Systematic Review

Patients with chronic kidney disease (CKD) are at a highly increased risk of cardiovascular complications, with increased vascular inflammation, accelerated atherogenesis and enhanced thrombotic risk. Considering the central role of the endothelium in protecting from atherogenesis and thrombosis, as well as its cardioprotective role in regulating vasorelaxation, this study aimed to systematically integrate literature on CKD-associated endothelial dysfunction, including the underlying molecular mechanisms, into a comprehensive overview. Therefore, we conducted a systematic review of literature describing uremic serum or uremic toxin-induced vascular dysfunction with a special focus on the endothelium. This revealed 39 studies analyzing the effects of uremic serum or the uremic toxins indoxyl sulfate, cyanate, modified LDL, the advanced glycation end products N-carboxymethyl-lysine and N-carboxyethyl-lysine, p-cresol and p-cresyl sulfate, phosphate, uric acid and asymmetric dimethylarginine. Most studies described an increase in inflammation, oxidative stress, leukocyte migration and adhesion, cell death and a thrombotic phenotype upon uremic conditions or uremic toxin treatment of endothelial cells. Cellular signaling pathways that were frequently activated included the ROS, MAPK/NF-κB, the Aryl-Hydrocarbon-Receptor and RAGE pathways. Overall, this review provides detailed insights into pathophysiological and molecular mechanisms underlying endothelial dysfunction in CKD. Targeting these pathways may provide new therapeutic strategies reducing increased the cardiovascular risk in CKD.     

Experimental Animal Model Systems for Understanding Salivary Secretory Disorders

Salivary secretory disorders are life-disrupting pathologic conditions with a high prevalence, especially in the geriatric population. Both patients and clinicians frequently feel helpless and get frustrated by the currently available therapeutic strategies, which consist mainly of palliative managements. Accordingly, to unravel the underlying mechanisms and to develop effective and curative strategies, several animal models have been developed and introduced. Experimental findings from these models have contributed to answer biological and biomedical questions. This review aims to provide various methodological considerations used for the examination of pathological fundamentals in salivary disorders using animal models and to summarize the obtained findings. The information provided in this review could provide plausible solutions for overcoming salivary disorders and also suggest purpose-specific experimental animal systems.     

Sirtuins Modulation: A Promising Strategy for HIV-Associated Neurocognitive Impairments

HIV-Associated neurocognitive disorder (HAND) is one of the major concerns since it persists in 40% of this population. Nowadays, HAND neuropathogenesis is considered to be caused by the infected cells that cross the brain–blood barrier and produce viral proteins that can be secreted and internalized into neurons leading to disruption of cellular processes. The evidence points to viral proteins such as Tat as the causal agent for neuronal alteration and thus HAND. The hallmarks in Tat-induced neurodegeneration are endoplasmic reticulum stress and mitochondrial dysfunction. Sirtuins (SIRTs) are NAD+-dependent deacetylases involved in mitochondria biogenesis, unfolded protein response, and intrinsic apoptosis pathway. Tat interaction with these deacetylases causes inhibition of SIRT1 and SIRT3. Studies revealed that SIRTs activation promotes neuroprotection in neurodegenerative diseases such Alzheimer’s and Parkinson’s disease. Therefore, this review focuses on Tat-induced neurotoxicity mechanisms that involve SIRTs as key regulators and their modulation as a therapeutic strategy for tackling HAND and thereby improving the quality of life of people living with HIV.