4-(3-Alkyl/benzyl-guanidino)benzenesulfonamides as selective carbonic anhydrase VII inhibitors

The treatment of chronic neuropathic pain remains one of the most challenging of all neurological diseases and very much an art. There exists no consensus for the optimal management of this condition at the moment. Gaining inspiration from recent studies which pointed out the involvement of brain-associated carbonic anhydrase (CA, EC 4.2.1.1) isoform VII in the pathology of various neurodegenerative diseases, which highlighted the relationship between selective inhibition of this isozyme and relieve of neuropathic pain, herein we report the synthesis and CA VII inhibitory activity of novel 4-(3-alkyl/benzyl-guanidino)benzenesulfonamides. Ten benzyl-substituted and five alkyl-substituted 4-guanidinobenzenesulfonamide derivatives were obtained, some of which (7c, 7h, 7m and 7o) exhibited satisfactory selectivity towards CA VII over CA I and II, with K_I-s in the subnanomolar range and good selectivity indexes for inhibiting the target versus the off-target isoforms.     

Modifying mosquitoes to suppress disease transmission: Is the long wait over?

For more than 50 years it has been a dream of medical entomologists and public health workers to control diseases like malaria and dengue fever by modifying, through genetics and other methods, the arthropods that transmit them to humans. A brief synopsis of the history of these efforts as applied to mosquitoes is presented; none proved to be effective in reducing disease prevalence. Only in the last few years have novel approaches been developed or proposed that indicate the long wait may be over. Three recent developments are particularly promising: CRISPR-Cas9 driven genetic modification, shifting naturally occurring allele frequencies, and microbe-based modifications. The last is the furthest along in implementation. Dengue fever incidence has been reduced between 40% and 96% in 4 different regions of the world where Wolbachia-infected Aedes aegypti have been established in the field. It is not yet clear how sustainable such control programs will prove to be, but there is good reason for optimism. In light of this, the time is ripe for reinvigorated research on vectors, especially genetics. Vector-borne diseases primarily affect under-developed countries and thus have not received the attention they deserve from wealthier countries with well-developed and funded biomedical research establishments.     

MYH9: structure,functions and role of non-muscle myosin ⅡA in human disease

MYH9-related diseases (MYH9-RD) are a group of autosomal dominant diseases caused by mutations in the MYH9 gene, which are featured by thrombocytopenia, giant platelets and granulocyte cytoplasmic inclusion bodies. MYH9-RD patients generally suffer from bleeding syndromes, progressive kidney disease, deafness, or cataracts. Here, we reported on a case of MYH9-RD. A novel heterozygous mutation of MYH9 (c.2344-2345delGTinsTA, p.T782Y) was discovered by targeted sequencing technology. Immunofluorescence analysis of neutrophils confirmed abnormal aggregation of MYH9 protein. The results of this study should expand the MYH9 gene mutation spectrum and provide reference for subsequent researchers and genetic counseling.     

龈沟液炎性因子及TSP-1在拔牙正畸患者中的表达情况及发生牙周疾病的影响因素分析

摘要 目的：探讨龈沟液炎性因子及TSP-1在拔牙正畸患者中的表达情况及发生牙周疾病的影响因素。方法：选取我院2020年8月到2023年8月收治的80例拔牙正畸治疗患者进行回顾性分析,分别取所有患者正畸前、正畸后1个月、3个月及正畸结束时的龈沟液样本检测肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）、血小板反应蛋白-1（TSP-1）表达水平。随后依照患者正畸治疗过程中是否患有牙周疾病将其分为牙周疾病组（n=36）及非牙周疾病组（n=44）,对比两组患者正畸前及正畸结束时的TNF-α、IL-1β、IL-6、TSP-1表达水平,对比两组患者一般情况,采用logistics回归模型分析拔牙正畸患者牙周疾病的影响因素。结果：80例拔牙正畸患者中正畸后1个月、3个月 TNF-α、IL-1α、IL-6、TSP-1水平升高,正畸后3个月到正畸结束时TNF-α、IL-1β、IL-6、TSP-1水平趋于平稳,但正畸后1个月、3个月及结束时明显高于正畸前（P＜0.05）;牙周疾病组与非牙周疾病组患者正畸前、正畸后TNF-α、IL-1β、IL-6、TSP-1表达水平对比差异显著,牙周疾病组明显高于非牙周疾病组（P＜0.05）;牙周疾病组及非牙周疾病组患者性别、年龄、BMI对比无明显差异（P＞0.05）,牙周疾病组及非牙周疾病组患者正畸治疗时间、拔牙数量、正畸方式、口腔清洁度对比差异显著（P＜0.05）;logistic回归分析结果表明：TNF-α、IL-1β、IL-6、TSP-1、正畸方式、口腔清洁度为拔牙正畸患者牙周疾病的独立危险因素（P＜0.05）。结论：拔牙正畸患者随着正畸时间延长龈沟液炎性因子及TSP-1水平明显升高,且TNF-α、IL-1β、IL-6、TSP-1、正畸方式、口腔清洁度为拔牙正畸患者牙周疾病的独立危险因素。     

Deciphering the SUMO code in the kidney

SUMOylation of proteins is an important regulatory element in modulating protein function and has been implicated in the pathogenesis of numerous human diseases such as cancers, neurodegenerative diseases, brain injuries, diabetes, and familial dilated cardiomyopathy. Growing evidence has pointed to a significant role of SUMO in kidney diseases such as DN, RCC, nephritis, AKI, hypertonic stress and nephrolithiasis. Recently, emerging studies in podocytes demonstrated that SUMO might have a protective role against podocyte apoptosis. However, the SUMO code responsible for beneficial outcome in the kidney remains to be decrypted. Our recent experiments have revealed that the expression of both SUMO and SUMOylated proteins is appreciably elevated in hypoxia‐induced tubular epithelial cells (TECs) as well as in the unilateral ureteric obstruction (UUO) mouse model, suggesting a role of SUMO in TECs injury and renal fibrosis. In this review, we attempt to decipher the SUMO code in the development of kidney diseases by summarizing the defined function of SUMO and looking forward to the potential role of SUMO in kidney diseases, especially in the pathology of renal fibrosis and CKD, with the goal of developing strategies that maximize correct interpretation in clinical therapy and prognosis.     

Dynamic control of neuroexocytosis by phosphoinositides in health and disease

Phosphoinositides are a group of phospholipids whose inositol headgroups can be phosphorylated at three distinct positions thereby generating seven different isotypes. The conversion between these lipid species depends on the activity of specific sets of phosphoinositide kinases and phosphatases whose targeting and activity is critical to establish the landscape of phosphoinositides on the cytosol-facing hemi-membrane of all organelles and plasmalemma. Phosphoinositides play pleiotropic roles ranging from signalling and membrane trafficking to modulation of ion channels and survival. In neurons and neurosecretory cells, whose main function is to communicate through the release of neurotransmitter, most of the work has focused on the role played by phosphatidylinositol (4,5) bisphosphate in controlling the mechanism underpinning neurotransmitter release through the fusion of secretory vesicles with the plasmalemma. Emerging evidence supports a multi-faceted regulation of neuroexocytosis by 3-phosphorylated phosphoinositides. In this review, we summarise the molecular mechanism by which these lipids control exocytosis and how minute changes in their metabolism can have devastating effects in the nervous system and lead to neurodegeneration.