Team players in the pathogenesis of metabolic dysfunctionsassociated steatotic liver disease:The basis of development of pharmacotherapy

Nutrient metabolism is regulated by several factors.Social determinants of health with or without genetics are the primary regulator of metabolism,and an unhealthy lifestyle affects all modulators and mediators,leading to the adaptation and finally to the exhaustion of cellular functions.Hepatic steatosis is defined by presence of fat in more than 5%of hepatocytes.In hepatocytes,fat is stored as triglycerides in lipid droplet.Hepatic steatosis results from a combination of multiple intracellular processes.In a healthy individual nutrient metabolism is regulated at several steps.It ranges from the selection of nutrients in a grocery store to the last step of consumption of ATP as an energy or as a building block of a cell as structural component.Several hormones,peptides,and genes have been described that participate in nutrient metabolism.Several enzymes participate in each nutrient metabolism as described above from ingestion to generation of ATP.As of now several publications have revealed very intricate regulation of nutrient metabolism,where most of the regulatory factors are tied to each other bidirectionally,making it difficult to comprehend chronological sequence of events.Insulin hormone is the primary regulator of all nutrients’metabolism both in prandial and fasting states.Insulin exerts its effects directly and indirectly on enzymes involved in the three main cellular function processes;metabolic,inflammation and repair,and cell growth and regeneration.Final regulators that control the enzymatic functions through stimulation or suppression of a cell are nuclear receptors in especially farnesoid X receptor and peroxisome proliferator-activated receptor/RXR ligands,adiponectin,leptin,and adiponutrin.Insulin hormone has direct effect on these final modulators.Whereas blood glucose level,serum lipids,incretin hormones,bile acids in conjunction with microbiota are intermediary modulators which are controlled by lifestyle.The purpose of this review is to overview the key players in the pathogenesis of metabolic dysfunction-associated steatotic liver disease(MASLD)that help us understand the disease natural course,risk stratification,role of lifestyle and pharmacotherapy in each individual patient with MASLD to achieve personalized care and target the practice of precision medicine.PubMed and Google Scholar databases were used to identify publication related to metabolism of carbohydrate and fat in states of health and disease states;MASLD,cardiovascular disease and cancer.More than 1000 publications including original research and review papers were reviewed.

Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions

Active host-pathogen interactions take place during infection of human immunodeficiency virus type 1 (HIV-1). Outcomes of these interactions determine the efficiency of viral infection and subsequent disease progression. HIV- infected cells respond to viral invasion with various defensive strategies such as innate, cellular and humoral immune antiviral mechanisms. On the other hand, the virus has also developed various offensive tactics to suppress these host cellular responses. Among many of the viral offensive strategies, HIV-1 viral auxiliary proteins (Tat, Rev, Nef, Vif, Vpr and Vpu) play important roles in the host-pathogen interaction and thus have significant impacts on the outcome of HIV infection. One of the best examples is the interaction of Vif with a host cytidine deaminase APOBEC3G. Although specific roles of other auxiliary proteins are not as well described as Vif-APOBEC3G interaction, it is the goal of this brief review to summarize some of the preliminary findings with the hope to stimulate further discussion and investiga- tion in this exhilarating area of research.

Graves’ Disease as a Late Manifestation of Immune Reconstitution Syndrome after Highly Active Antiretroviral Therapy in an HIV-1 Infected Patient

Context: Highly active antiretroviral therapy (HAART) inhibits the HIV replication and consequently increases CD4 levels and decreases viral load. This immune system improvement can trigger various immunological phenomena, entity called Immune Reconstitution Syndrome (IRS). Graves’ disease is a late Immune Reconstitution consequence. Patient: We report the case of a 48 years old man with HIV infection who developed Graves’ disease three years after he was on effective HAART because of the Immune Reconstitution Syndrome. At presentation he had a very low CD4 T-cell count (17 cells/μL). When he started HAART he presented a lipodystrophy syndrome. HAART was changed because of the persistent low CD4-T cells count (less than 100 cell/μL). Afterwards serum lipid levels began to decrease and that was the first manifestation of Graves’ disease, which was diagnosed when CD4 T-cells increased up to 343 cell/μL. Our patient developed Graves’ disease 36 months after initiating effective HAART with protease inhibitors which was coincident with viral suppression and a rise of CD4 T cells. Conclusion: The most immunosuppressed patients with a CD4 T cell count less than 100 cells/μL are at greatest risk for the development of Immune Reconstitution Syndrome after HAART initiation. We conclude that clinicians will have to consider the importance of the early diagnosis of thyroid disease to bring an adequate treatment.

Upregulation of caveolin-1 and SR-B1 in mice with non-alcoholic fatty liver disease

BACKGROUND:Non-alcoholic fatty liver disease(NAFLD)is one of the most frequent causes of liver diseases,with markedly increased prevalence.However,its mechanisms are not clear.The present study was undertaken to illustrate the role of caveolin-1(cav1)and the scavenger receptor class B type 1(SR-B1)in NAFLD.METHODS:Adult male C57BL/6 mice were fed with a normal diet or high fat and cholesterol(HFC)diet for 14 weeks.The mice were sacrificed to collect plasma and harvest the liver;their plasma lipid concentration was measured.Hepatic cav1and SR-B1 mRNA and protein expression were determined by real-time quantitative polymerase chain reaction(qPCR)and Western blotting,respectively.In order to study cav1 and SR-B1distribution and change in hepatocytes,immunohistochemical analysis was performed.RESULTS:HFC diet increased plasma lipids,induced NAFLD and increased the liver/body weight ratio.Compared to the control mice(n=6),the mRNA and protein levels of cav1 and SR-B1 in liver tissue of the NAFLD mice(n=12)increased significantly(cav1 mRNA:1.536±0.226 vs 0.980±0.272,P【0.05;protein:0.643±0.240 vs 0.100±0.130,P【0.01;SR-B1 mRNA:1.377±0.125 vs 0.956±0.151,P【0.01;protein:2.156±0.507vs 0.211±0.211,P【0.01).Furthermore,both cav1 and SR-B1immunoreactivity increased and their distribution was also changed,mainly in the plasma membrane of hepatocytes,cytoplasm and membrane of lipid droplets and around.CONCLUSION:NAFLD is associated with increased concentration of plasma lipids and upregulation of hepatic cav1 and SR-B1 gene and protein expressions,which indicate that cav1 and SR-B1 might play crucial roles in the pathogenesis of NAFLD.

Abundance and significance of neuroligin-1 and glutamate in Hirschsprung's disease

AIM: To investigate the abundance and potential diagnostic significance of neuroligin-1 and glutamate(Glu) in Hirschsprung's disease(HSCR).METHODS: Ninety children with HSCR and 50 children without HSCR matched for similar nutritional status, age and basal metabolic index were studied. The expression and localization of neuroligin-1 and Glu were assessed using double-labeling immunofluorescence staining of longitudinal muscles with adherent myenteric plexus from the surgically excised colon of children with HSCR. Western blot analysis, quantitative real-time PCR(q RT-PCR) and immunohistochemistry were performed to evaluate the abundance of neuroligin-1 and Glu in different HSCR-affected segments(ganglionic, transitional, and aganglionic segments). Enzyme-linked immunosorbent assay(ELISA) was used to detect and compare serum Glu levels in the long-segment HSCR, short-segment HSCR and non-HSCR samples.RESULTS: Neuroligin-1 and Glu were co-expressed highest to lowest in the ganglionic, transi tional and aganglionic segments based on Western blot(neuroligin-1: 0.177 ± 0.008 vs 0.101 ± 0.006, 0.177 ± 0.008 vs 0.035 ± 0.005, and 0.101 ± 0.006 vs 0.035 ±0.005, P < 0.005; Glu: 0.198 ± 0.006 vs 0.115 ± 0.008, 0.198 ± 0.006 vs 0.040 ± 0.003, and 0.115 ± 0.008 vs 0.040 ± 0.003, P < 0.005) and q RT-PCR(neuroligin-1: 9.58 × 10-5 ± 9.94 × 10-6 vs 2.49 × 10-5 ± 1.38 × 10-6, 9.58 × 10-5 ± 9.94 × 10-6 vs 7.17 × 10-6 ± 1.12 × 10-6, and 2.49 × 10-5 ± 1.38 × 10-6 vs 7.17 × 10-6 ± 1.12 × 10-6, P < 0.005). Serum Glu level was the highest to lowest in the non-HSCR, short-type HSCR and long-type HSCR samples based on ELISA(in nmol/μL, 0.93 ± 0.31 vs 0.57 ± 0.25, 0.93 ± 0.31 vs 0.23 ± 0.16, and 0.57 ± 0.25 vs 0.23 ± 0.16, P < 0.005).CONCLUSION: Neuroligin-1 and Glu may represent new markers of ganglion cells, whose expression may correlate with the pathogenesis, diagnosis, differential diagnosis or classification of HSCR.

Association of Nurr1 gene mutations with Parkinson's disease in the Han population living in the Hubei province of China

Nurr1 defects could in part underlie Parkinson’s disease pathogenesis,and Nurr1 gene polymorphism has been found in Caucasian patients with Parkinson’s disease.In this study,heteroduplex technology was applied to compare the DNA sequences of eight exons of Nurr1 among 200 sporadic Parkinson’s disease patients and 200 healthy controls in the Han population in the Hubei province,China.One allele amplified from exon 3 of Nurr1 was polymorphic in five Parkinson’s disease patients（2.5%,5/200）,and two individuals had a polymorphic allele amplified from exon 2 （1%,2/200）.The anomalous electrophoresis fragment in exon 3 of Nurr1 gene contained a 709C/A missense mutation,and a polymorphic single nucleotide polymorphism at 388G/A was identified in exon 2.Compared with the control group,the Nurr1 gene expression level in the Parkinson’s disease group was decreased,and the Nurr1 gene expression levels in Parkinson’s disease patients carrying the polymorphisms at exons 2 and 3 were significantly decreased.Our data indicate that the single nucleotide polymorphism 388G/A in exon 2 and the 709C/A missense mutation in exon 3 of the Nurr1 gene in the Chinese population might affect the pathogenesis of Parkinson’s disease.

Insights on ZEB1-AS1:emerging role from cancer to neurodegeneration

Implications for lncRNAs in the central nervous system:Transcriptional dysregulation is a key contributor to the pathogenesis of a wide range of diseases and long non-coding RNAs(lncRNAs)are highly expressed in the nervous system.Indeed,amongst the over 50,000 lncRNAs expressed in the human genome,more than 40%are specifically expressed in the brain where their roles in brain development,neuron functions,maintenance.

SIRT1在儿童呼吸系统疾病中的研究进展

沉默信息调节因子2相关酶1(SIRT1)是一种高度保守的烟酰胺腺嘌呤二核苷酸(NAD+)依赖的Ⅲ类组蛋白去乙酰化酶,通过对组蛋白和非组蛋白在内的靶蛋白的去乙酰化作用发挥生理学效应。在呼吸系统中,SIRT1参与调节炎症反应、氧化应激、细胞凋亡和自噬等过程。SIRT1的活性异常与肺炎、哮喘、急性肺损伤、慢性阻塞性肺疾病、特发性肺纤维化、肺癌等呼吸系统疾病的发生与发展密切相关。近年来,随着对SIRT1与呼吸系统疾病的关系以及调控SIRT1药物的深入研究,为呼吸系统疾病的治疗提供了新的思路。本文就SIRT1在儿童呼吸系统疾病发病机制中的作用及其最新研究进展做一综述,以更好地将SIRT1作为一个靶点服务于儿童呼吸系统疾病。

腺苷1型受体在肾脏疾病中的研究进展

腺苷在细胞内、外具有多种信号转导功能,通过激活不同类型的腺苷受体发挥生物学作用。腺苷1型受体作为高亲和力受体,在肾脏组织中广泛表达,参与炎症、免疫、血流动力学调节。目前,糖尿病肾病、高血压肾病、急性肾损伤等常见肾脏疾病的发病机制尚未完全明确。腺苷1型受体参与了糖尿病肾病、肾脏缺血再灌注损伤、造影剂肾病的等多种肾脏疾病的病理过程。本文针对腺苷1型受体在肾脏疾病中的研究进展进行综述。

RT-PCR克隆广谱抗病基因NPR1及其蛋白表达载体构建

[目的]克隆植物广谱抗病基因NPR1并构建其蛋白表达载体。[方法]提取拟南芥总RNA,设计相关引物,采用反转录PCR方法克隆NPR1基因;利用酶切连接方法,将该基因正向导入蛋白表达载体。[结果]经过相关检验,将NPR1正向插入pMXB10载体中,得到了pMXB10-NPR1蛋白表达载体。[结论]成功构建了包含NPR1的蛋白表达载体。

MMP-9/TIMP-1与川崎病发病机制关系的研究进展

川崎病（KD）是一种急性、自限性的全身性血管炎,好发于6个月~5岁的儿童,可导致严重的心血管并发症,是儿童后天获得性心脏病最常见的原因。流行病学调查表明,KD的发病率在亚裔人群中稳步的增长,严重影响未来儿童的公共健康,然而其病因和发病机制尚不完全清楚。基质金属蛋白酶-9（MMP-9）/金属蛋白酶组织抑制剂-1（TIMP-1）是调节细胞外基质（ECM）合成与降解的主要酶类,研究MMP-9/TIMP-1与KD发病机制的关系对了解KD的发病机制、预防心血管系统并发症起重要作用。

缺氧诱导因子-1与酒精性肝病

缺氧诱导因子(HIF)-1是一种由α和β亚单位组成的二聚体核转录因子,是体内氧平衡调节机制中最重要的转录激活因子,其转录系统主要受细胞内氧浓度的调节,通过下游的信号转导参与病理生理反应,大量研究发现酒精性肝病中存在缺氧状态,本文诣在阐述HIF-1在酒精性肝病发病机制中的作用。

胰高血糖素样肽-1改善非酒精性脂肪性肝病作用机制研究进展

近期研究表明,胰高血糖素样肽-1受体激动剂可从改善肝细胞脂质代谢、抑制炎症反应、调节细胞自噬等多个环节减轻非酒精性脂肪性肝病(NAFLD)患者肝脏脂质沉积,改善组织学损伤,有望成为治疗NAFLD药物的新选择。

小胶质细胞通过IL-1加重帕金森病进展

帕金森病(PD)是一种常见的神经系统变性病。研究表明,遗传及环境因素可诱导小胶质细胞分泌白细胞介素-1(IL-1),IL-1通过多种机制促进多巴胺能神经元死亡,包括促进其他致炎因子的合成及自由基的生成,增加细胞内钙离子浓度以及α-synuclein的合成等,从而作为帕金森病的治疗靶点。

sPD-1和sPD-Ls在结缔组织病发病机制中的作用

膜结合型程序性死亡受体1(membrane-bound programmed cell death-1,mPD-1)及膜结合型程序性死亡受体配体(membrane-bound programmed cell death-ligands,mPD-Ls)存在可溶性形式,分别为可溶性程序性死亡受体1(soluble programmed cell death-1,sPD-1)和可溶性程序性死亡受体配体(soluble programmed cell death-ligands,sPD-Ls)[包括可溶性程序性死亡受体配体1(soluble programmed cell death-ligand 1,sPD-L1)和可溶性程序性死亡受体配体2(soluble programmed cell death-ligand 2,sPD-L2)]。sPD-1和sPD-L2主要由PD-1 mRNA的选择性剪接异构体翻译产生,而sPD-L1则是由基质金属蛋白酶(matrix metalloproteinases,MMPs)剪切膜结合型程序性死亡受体配体1(membrane-bound programmed cell death-ligand 1,mPD-L1)产生。sPD-1和sPD-Ls通过阻断mPD-1/mPD-L1通路在自身免疫调节中起重要作用,而结缔组织病(connective tissue disease,CTD)是由自身免疫反应等引起的一类疾病,并且多种自身免疫性疾病在发生、发展过程中均可出现mPD-1/mPD-L1的功能异常。故sPD-1和sPD-Ls通过阻断mPD-1/mPD-L1通路,在由自身免疫反应引起的CTD发病机制中起重要作用。了解sPD-1和sPD-Ls在CTD中的作用机制和临床价值对改善患者的生活质量具有重要的现实意义。

High level HIV-1 DNA concentrations in brain tissues differentiate patients with post-HAART AIDS dementia complex or cardiovascular disease from those with AIDS

Highly active antiretroviral treatment(HAART) has had a significant impact on survival of individuals with acquired immunodeficiency syndrome(AIDS);however,with the longer life-span of patients with AIDS,there is increasing prevalence of AIDS dementia complex(ADC) and other non-AIDS-defining illness,and cardiovascular diseases(CVD) are also common.The influence of these varied disease processes on HIV-1 DNA concentration in brain tissues has not been thoroughly assessed in the post-HAART era.The purpose of the current study is to clarify the impacts of ADC and other complications of HIV disease on the viral load in the brains in AIDS patients with post-HARRT.We examined autopsy specimens from the brains of thirteen patients who died from complications of AIDS with quantitative polymerase chain reaction(QPCR).All but one patient had received HAART prior to death since 1995.Two patients died with severe CVD,multiple cerebrovascular atherosclerosis(CVA) throughout the brain and five patients died with ADC.Six patients had no ADC/CVA.A QPCR was used to measure the presence of HIV-1 DNA in six brain tissues(meninges,frontal grey matter,frontal white matter,temporal subcortex,cerebellum and basal ganglia).In the post-HARRT era,for non-ADC/CVA patients,HIV-1 DNA concentration in brain tissues was statistically higher than that in patients with ADC.In a new finding,two patients who suffered from severe CVD,especially CVA,also had high concentrations of HIV-1 in brain compartments not showing ADC related changes.To our knowledge,this is the first report of a relationship between the CVA and HIV-1 viral burden in brain.The current observations suggest that HAART-resistant HIV reservoirs may survive within ADC lesions of the brain as well as the macrophage rich atherosclerosis,which needs to be confirmed by more AIDS cases with CVA.

Prognostic value of endothelial dysfunction in type 1 diabetes mellitus

Patients with diabetes mellitus are at high risk of developing atherosclerosis, associated with higher rates of micro and macro vascular involvement such as coronary artery disease and renal disease. The role of hyperglycemia to induce synthesis of reactive oxygen species by the oxidation of glucose, leading to an increased production of advanced glycosylation end products, as well as inflammation and oxidative stress has been proposed as a possible mechanism in the pathogenesis of endothelial dysfunction(ED). The interaction between C-peptide- the connecting segment of pro-insulin-and nitric oxide in vasodilation is also discussed. Therefore, endothelial dysfunction has been identified as an early marker of vascular disorder in type 1 and type 2 diabetes mellitus. In some other diseases, ED has been considered an independent predictor of vascular disease, regardless of the method used. Studies have demonstrated the importance of endothelial dysfunction as an useful tool for identifying the risk of vascular complications in patients with type 1 diabetes mellitus, particularly as regards to renal impairment. The aim of this review is to clarify the prognostic value of endothelial dysfunction as a marker of vascular disease in these subjects.