肠道微生物与性激素相关疾病研究进展

数以万亿计的微生物生活在人类肠道中,形成了一个复杂的微生态群落。肠道微生物可为宿主提供营养和能量,并与人类疾病的发生发展密切相关。随着研究的不断深入,越来越多的证据表明肠道微生物的改变可引起性激素水平变化,进而导致一系列相关的疾病发生。本文就肠道微生物与多囊卵巢综合征、乳腺癌、卵巢癌等性激素相关疾病之间的关系进行阐述,旨在为人类疾病诊疗提供新思路。     

气候变化和经济发展对肾综合征出血热发生的影响

肾综合征出血热(hemorrhagic fever with renal syndrome, HFRS)是一种啮齿动物传播的自然疫源性疾病, 危害严重, 已成为全球重要的公共卫生问题。本研究采用数理统计模型及小波分析方法, 对陕西省西安市鄠邑区1984-2016年HFRS的发生与鼠类、气候和经济因素的关系进行分析, 探讨气候和经济因素对HFRS发生的影响。小波分析结果表明, 该地区的HFRS暴发史可能分为两个时期, 推测每个时期具有不同的主要宿主, 在2002年褐家鼠(Rattus norvegicus)可能取代黑线姬鼠(Apodemus agrarius)成为HFRS疫源地的主要宿主。广义可加模型模拟结果表明, HFRS的发生与1984-2001年黑线姬鼠密度间存在极显著非线性效应(F_2.06,9.02 = 102.415, P < 0.01), 两者间显现为正相关; 与2002-2016年的褐家鼠密度间呈正相关(F_1.67,9.02 = 73.929, P < 0.01); HFRS主要宿主的这种变化可能与当地气候变化和经济发展有关: HFRS的发生与年平均温度存在极显著的非线性效应(F_2.93,9.02 = 12.164, P < 0.01), 两者间呈负相关; 同样, HFRS的发生与上一年的国内生产总值(GDP)也存在显著非线性效应(F_1.70,9.02 = 2.917, P < 0.05), 两者间也呈负相关。结构方程模型通过直接和间接的影响途径证明了这种转移机制, 发现温度对HFRS发生有显著的直接负向影响以及通过褐家鼠的间接正向影响; GDP对HFRS发生有直接的负向影响。本研究表明HFRS的发生与气候变化和经济发展相关, 两者均能影响HFRS的暴发, 该结论有助于今后更好地对HFRS疾病进行预防和控制。     

Identification of novel inhibitors for the tyrosyl-DNA-phosphodiesterase 1 (Tdp1) mutant SCAN1 using virtual screening

Spinocerebellar ataxia syndrome with axonal neuropathy (SCAN1) is a debilitating neurological disease that is caused by the mutation the Tyrosyl-DNA phosphodiesterase 1 (TDP1) DNA repair enzyme. The crucial His493 in TDP1′s binding site is replaced with an arginine amino acid residue rendering the enzyme dysfunctional. A virtual screen was performed against the homology model of SCAN1 and seventeen compounds were identified and tested in a novel SCAN1 specific biochemical assay. Six compounds showed activity with IC₅₀ values between 3.5 and 25.1 µM. The most active ligand 5 (3.5 µM) is a dicoumarin followed by a close structural analogue 6 at 6.0 µM. A less potent series of β-carbolines (14 and 15) was found with potency in the mid-teens. According to molecular modelling an excellent fit for the active ligands into the binding pocket is predicted. To the best of our knowledge, data on inhibitors of the mutant form of TDP1 has not been reported previously. The virtual hits were also tested for wild type TDP1 activity and all six SCAN1 inhibitors are potent for the former, e.g., ligand 5 has a measured IC₅₀ at 99 nM.In the last decade, TDP1 is considered as a promising target for adjuvant therapy against cancer in combination with Topoisomerase 1 poisons. The active ligands are mostly non-toxic to cancer cell lines A-549, T98G and MCF-7 as well as the immortalized WI-38 human fetal lung cells. Furthermore, ligands 5 and 7, show promising synergy in conjunction with topotecan, a clinically used topoisomerase 1 anticancer drug. The active ligands 5, 7, 14 and 15 have a good balance of the physicochemical properties required for oral bioavailability making the excellent candidates for further development.     

肠道菌群与脊髓损伤并发症

脊髓损伤是严重的致残性神经系统疾病,脊髓损伤后产生的水肿、炎症反应和代谢紊乱等并发症是致使脊髓损伤继发性加重的主要原因。近年来,随着对肠道微生物的研究越来越深入,肠道菌群对神经系统疾病的影响得到广泛关注。肠道菌群可以通过调节机体能量代谢、炎症反应及作用于神经内分泌和脑-肠轴的途径影响中枢神经系统疾病。最近研究发现,肠道菌群与脊髓损伤并发症的关系非常紧密。脊髓损伤后肠道菌群的变化可能影响脊髓损伤后并发症发生以及加重。本文主要就肠道菌群对脊髓损伤后并发症的影响和可能的作用机制进行综述,为临床研究和治疗脊髓损伤提供新思路。     

Contrasting association of Leptin receptor polymorphisms and haplotypes with polycystic ovary syndrome in Bahraini and Tunisian women: a case–control study

Background: The present study examined the contribution of ethnicity to the association of leptin receptor gene (LEPR) gene variants with polycystic ovary syndrome (PCOS) in Tunisian and Bahraini Arabic-speaking women.Methods: Subjects consisted of 320 women with PCOS, and 446 eumenorrhic women from Tunisia, and 242 women with PCOS and 238 controls from Bahrain. Genotyping of (exonic) rs1137100 and rs1137101 and (intronic) rs2025804 LEPR variants was done by allelic exclusion.Results: The minor allele frequencies (MAFs) of rs1137100 and rs1137101 were significantly different between PCOS cases and control women from Bahrain but not Tunisia, and LEPR rs1137101 was associated with increased PCOS susceptibility only in Bahraini subjects. Furthermore, rs1137100 was associated with decreased PCOS risk among Bahrainis under codominant and recessive models; rs1137100 was negatively associated with PCOS in Tunisians after controlling for testosterone. In addition, rs2025804 was associated with increased PCOS risk among Tunisian but not Bahraini women, after adjusting for key covariates. Negative correlation was seen between rs1137101 and triglycerides in Tunisians, while homeostasis model assessment of insulin resistance (HOMA-IR) and insulin correlated with rs2025804 and rs1137101 among Bahraini subjects, and rs1137101 correlated with estradiol and prolactin. Taking TAG haplotype as common, positive association of TAA and negative association of TGG haplotype with PCOS was seen among Bahraini women; no three-locus PCOS-associated haplotypes were found in Tunisians.Conclusions: The present study is the first to demonstrate the contribution of ethnicity to the association of LEPR gene variants with PCOS, thereby highlighting the significance of controlling for ethnicity in gene association investigations.     

Serum biomarker discovery related to pathogenesis in acute coronary syndrome by proteomic approach

Acute coronary syndrome (ACS) results from inadequate supply of blood flow from the coronary arteries to the heart or ischemia. ACS has an extremely high morbidity and mortality. The levels of biomarkers currently used for detection of ACS also increase in response to myocardial necrosis and other diseases and are not elevated immediately after symptoms appear, thus limiting their diagnostic capacity. Therefore, we aimed to discover new ACS diagnostic biomarkers with high sensitivity and specificity that are specifically related to ACS pathogenesis. Sera from 50 patients with ACS and healthy controls (discovery cohort) each were analyzed using mass spectrometry (MS) to identify differentially expressed proteins, and protein candidates were evaluated as ACS biomarkers in 120 people in each group (validation cohort). α-1-acid glycoprotein 1 (AGP1), complement C5 (C5), leucine-rich α-2-glycoprotein (LRG), and vitronectin (VN) were identified as biomarkers whose levels increase and gelsolin (GSN) as a biomarker whose levels decrease in patients with ACS. We concluded that these biomarkers are associated with the pathogenesis of ACS and can predict the onset of ACS prior to the appearance of necrotic biomarkers.     

Metabolic syndrome during gestation and lactation: An important renal problem in dams. selenium renal clearance

BackgroundMetabolic syndrome (MS) in lactating dams leads to several cardiometabolic changes related to selenium (Se) status and selenoproteins expression which produce hypertension. However, little is known about the state of these dams’ kidney functions and their Se deposits.MethodsTwo experimental groups of dam rats were used: control (Se: 0.1 ppm) and MS (Fructose 65 % and Se: 0.1 ppm). At the end of lactation (21d postpartum) kidney weight and protein content, Se deposits, and the activity of the antioxidant selenoprotein glutathione peroxidase (GPx) were measured in dams. Kidney functional parameters: albuminuria, creatinine clearance, serum aldosterone and uric acid levels and water and electrolyte (Na⁺ and K⁺) balance were also evaluated. Systolic blood pressure (SBP) was measured.ResultsIn MS dams at the end of lactation Se deposits and GPx activity are higher in the kidney; however, lipid renal peroxidation appears, relative Se clearance increases, and the dams have lost Se by urine. MS dams have polyuria and polydipsia, high uric acid serum levels, albuminuria and high creatinine clearance, implying glomerular renal malfunction with protein loss. They also present hypernatremia, hypokalemia and hyperaldosteronemia, leading to high SBP; however, a natriuretic process is taking place.ConclusionSince these alterations appear, at least in part, to be related to oxidative stress in renal cells, Se supplementation could be beneficial to avoiding greater lipid renal oxidation during lactation.     

A novel inhibitor rescues cerebellar defects in a zebrafish model of Down syndrome–associated kinase Dyrk1A overexpression

The highly conserved dual-specificity tyrosine phosphorylation–regulated kinase 1A (Dyrk1A) plays crucial roles during central nervous system development and homeostasis. Furthermore, its hyperactivity is considered responsible for some neurological defects in individuals with Down syndrome. We set out to establish a zebrafish model expressing human Dyrk1A that could be further used to characterize the interaction between Dyrk1A and neurological phenotypes. First, we revealed the prominent expression of dyrk1a homologs in cerebellar neurons in the zebrafish larval and adult brains. Overexpression of human dyrk1a in postmitotic cerebellar Purkinje neurons resulted in a structural misorganization of the Purkinje cells in cerebellar hemispheres and a compaction of this cell population. This impaired Purkinje cell organization was progressive, leading to an age-dependent dispersal of Purkinje neurons throughout the cerebellar molecular layer with larval swim deficits resulting in miscoordination of swimming and reduced exploratory behavior in aged adults. We also found that the structural misorganization of the larval Purkinje cell layer could be rescued by pharmacological treatment with Dyrk1A inhibitors. We further reveal the in vivo efficiency of a novel selective Dyrk1A inhibitor, KuFal194. These findings demonstrate that the zebrafish is a well-suited vertebrate organism to genetically model severe neurological diseases with single cell type specificity. Such models can be used to relate molecular malfunction to cellular deficits, impaired tissue formation, and organismal behavior and can also be used for pharmacological compound testing and validation.