DJ-1 in neurodegenerative diseases: Pathogenesis and clinical application.

Parkinson’s disease (PD) is a disorder characterized by a triad of motor symptoms (akinesia, rigidity, resting tremor) related to loss of dopaminergic neurons mainly in the Substantia nigra pars compacta. Diagnosis is often made after a substantial loss of neurons has already occurred, and while dopamine replacement therapies improve symptoms, they do not modify the course of the disease. Although some biological mechanisms involved in the disease have been identified, such as oxidative stress and accumulation of misfolded proteins, they do not explain entirely PD pathophysiology, and a need for a better understanding remains. Neurodegenerative diseases, including PD, appear to be the result of complex interactions between genetic and environmental factors. The latter can alter gene expression by causing epigenetic changes, such as DNA methylation, post-translational modification of histones and non-coding RNAs. Regulation of genes responsible for monogenic forms of PD may be involved in sporadic PD. This review will focus on the epigenetic mechanisms regulating their expression, since these are the genes for which we currently have the most information available. Despite technical challenges, epigenetic epidemiology offers new insights on revealing altered biological pathways and identifying predictive biomarkers for the onset and progression of PD.

https://www.mdpi.com/2073-4425/13/3/479/pdf?version=1646808983

Does the Expression and Epigenetics of Genes Involved in Monogenic Forms of Parkinson’s Disease Influence Sporadic Forms?

ObjectiveIn recent years, a number of case–control studies have focused on the association between the DJ-1 g.168_185del polymorphism and the risk of Parkinson's disease (PD). However, the results ...

https://journals.sagepub.com/doi/pdf/10.1177/0300060520947943

Association between a DJ-1 polymorphism and the risk of Parkinson's disease: a PRISMA-compliant systematic review and meta-analysis.

Arrhythmia is characterized by abnormal heartbeat rhythms and frequencies caused by heart pacing and conduction dysfunction. Arrhythmia is the leading cause of death in patients with cardiovascular disease, with high morbidity and mortality rates, posing a serious risk to human health. Natural drugs and their active ingredients, such as matrine(MAT), tetrandrine(TET), dehydroevodiamine, tanshinone IIA, and ginsenosides, have been widely used for the treatment of atrial fibrillation, ventricular ectopic beats, sick sinus syndrome, and other arrhythmia-like diseases owing to their unique advantages. This review summarizes the mechanism of action of natural drugs and their active ingredients in the treatment of arrhythmia via the regulation of Ca2+, such as alkaloids, quinones, saponins, terpenoids, flavonoids, polyphenols, and lignan compounds, to provide ideas for the innovative development of natural drugs with potential antiarrhythmic efficacy. 

Pharmacological mechanism of natural drugs and their active ingredients in the treatment of arrhythmia via calcium channel regulation.

The objective of this study was to identify in Angus and Brangus breed animals with extreme temperament, measured as exit velocity, genomic regions and candidate genes associated with bovine temperament. The population was genotyped with the Genomic Profiler HD 150K chip and after the genome-wide association analysis, the SNPs rs133956611 (P=2.65 E-06) and rs81144933 (P=9.58 E-06) were associated with temperament. The mapping analysis of the regions close to the SNP rs81144933 identified the SNCA (alpha-synuclein) and MMRN1 (multimerin-1) genes at 222.8 and 435.9 Kb downstream respectively, while for the rs133956611 loci the gene GPRIN3 (GPRIN family-member-3) was identified at 245.7 Kb upstream, all three genes are located on the BTA6 chromosome. The analysis of SNCA protein-protein interactions allowed the identification of the genes APP (β-amyloid precursor protein), PARK7 (parkinsonism-associated-deglycase), UCHL1 (ubiquitin-C-terminal-hydrolase-L1), PARK2 (parkin-RBR- E3-ubiquitin-protein-ligase), and genes of the SLC family as candidates to be associated with bovine temperament. All these candidate genes and their interacting were resequenced, which allowed the discovery of new SNPs in the SNCA and APP genes. Of these, the SNPs located in introns 5, 8 and 11 of the APP gene affect splicing site motifs. These results indicate that SNCA and its interacting genes are candidates to be related to bovine temperament.

/pdf/identificacion-de-genes-candidatos-y-snp-relacionados-con-el-1lyewr6e.pdf

Identificación de genes candidatos y SNP relacionados con el temperamento del ganado utilizando un análisis GWAS junto con un análisis de redes interactuantes

Low DJ-1 protein level caused by DJ-1 gene mutation leads to autosomal recessive Parkinson's disease (PD) due to impaired antioxidative activity. In sporadic PD patients, although mutations were rarely found, lower DJ-1 protein level was also reported. Dysregulation of DJ-1 gene expression might contribute to low DJ-1 protein level. Since the promoter is the most important element to initiate gene expression, whether polymorphisms in the DJ-1 promoter result in the dysregulation of gene expression, thus leading to low protein level and causing PD, is worth exploring. The DJ-1 promoter region was sequenced in a Chinese cohort to evaluate possible links between DJ-1 promoter polymorphisms, PD risk and clinical phenotypes. Dual-luciferase reporter assay was conducted to evaluate the influence of promoter polymorphisms on DJ-1 transcriptional activity. Related information in an existing genome-wide association studies (GWAS) database were looked up, meta-analysis of the present study and other previous reports was conducted, and expression quantitative trait loci (eQTL) analysis was performed to further explore the association. Three single nucleotide polymorphisms (SNPs) (rs17523802, rs226249, and rs35675666) and one 18 bp deletion (rs200968609) were observed in our cohort. However, there was no significant association between the four detected genetic variations and the risk of PD either in allelic or genotype model, in single-point analysis or haplotype analysis. This was supported by the meta-analysis of this study and previous reports as well as that of GWAS database PDGene. Dual luciferase reporter assay suggested these promoter polymorphisms had no influence on DJ-1 transcriptive activity, which is consistent with the eQTL analysis results using the data from GTEx database. Thus, DJ-1 promoter polymorphisms may play little role in the dysregulation of DJ-1 expression and PD susceptibility in sporadic PD.

/pdf/lack-of-association-between-dj-1-gene-promoter-polymorphism-1vwh9fv6yk.pdf

Lack of Association Between DJ-1 Gene Promoter Polymorphism and the Risk of Parkinson's Disease.

The CCL2-CCR2 axis is one of the major chemokine signaling pathways that has received special attention because of its function in the development and progression of cardiovascular disease. Numerous investigations have been performed over the past decades to explore the function of the CCL2-CCR2 signaling axis in cardiovascular disease. Laboratory data on the CCL2-CCR2 axis for cardiovascular disease have shown satisfactory outcomes, yet its clinical translation remains challenging. In this article, we describe the mechanisms of action of the CCL2-CCR2 axis in the development and evolution of cardiovascular diseases including heart failure, atherosclerosis and coronary atherosclerotic heart disease, hypertension and myocardial disease. Laboratory and clinical data on the use of the CCL2-CCR2 pathway as a targeted therapy for cardiovascular diseases are summarized. The potential of the CCL2-CCR2 axis in the treatment of cardiovascular diseases is explored.

/pdf/role-of-the-ccl2-ccr2-axis-in-cardiovascular-disease-12t2bhmz.pdf

Role of the CCL2-CCR2 axis in cardiovascular disease: Pathogenesis and clinical implications

SUMO1 regulates post-infarct cardiac repair based on cellular heterogeneity

The failing heart is characterized by an increase in glucose uptake and glycolytic rates that is not accompanied by a concomitant increase in glucose oxidation. Lower coupling of glucose oxidation to glycolysis possibly owes to unchanged or reduced pyruvate oxidation in mitochondria. Therefore, increasing pyruvate oxidation may lead to new therapies for heart disease. Dihydrolipoamide dehydrogenase (DLD) is a component of the pyruvate dehydrogenase complex (PDH). DLD mutations or defects are closely associated with metabolic diseases. However, few studies explore the effects of DLD mutants or acylation status on PDH activity and pyruvate metabolism. P300 is protein 2-hydroxyisobutyryltransferases in cells, and P300-dependent lysine 2-hydroxyisobutyrylation of glycolytic enzymes affects glucose metabolism. However, there are no relevant reports on the effect of 2-hydroxyisobutyrylation on the energy metabolism of heart failure, and it is worth further in-depth study. In this study, we showed that 2-hydroxyisobutyrylation is an essential protein translational modification (PTM) that regulates the activity of pyruvate dehydrogenase complex (PDHc). In a mouse model of transverse aortic constriction (TAC)-induced cardiac hypertrophy, the 2-hydroxyisobutylation of DLD was significantly increased, related to the decrease in PDH activity. In addition, our data provide clear evidence that DLD is a direct substrate of P300. As one of the main active ingredients of ginseng, ginsenoside Rg3 (Rg3) can reduce the 2-hydroxyisobutylation levels of DLD and restore the PDH activity by inhibiting the acyltransferase activity of P300, thereby producing beneficial effects whenever the heart is injured. Therefore, this study suggests a novel strategy for reversing myocardial hypertrophy. 

/pdf/rg3-regulates-myocardial-pyruvate-metabolism-via-p300-26zasrim.pdf

Rg3 regulates myocardial pyruvate metabolism via P300-mediated dihydrolipoamide dehydrogenase 2-hydroxyisobutyrylation in TAC-induced cardiac hypertrophy

Aging is characterized by the gradual loss of physiological integrity, leading to impaired function and increased risk of death. This deterioration is the main risk factor for the great majority of chronic diseases, which account for most of the morbidity, death and medical expenses. The hallmarks of aging comprise diverse molecular mechanisms and cell systems, which are interrelated and coordinated to drive the aging process. This review focuses on telomere to analyze the interrelationships between telomere dysfunction and other aging hallmarks and their relative contributions to the initiation and progression of age-related diseases (such as neurodegeneration, cardiovascular disease, and cancer), which will contribute to determine drug targets, improve human health in the aging process with minimal side effects and provide information for the prevention and treatment of age-related diseases. 

Zhihao Liu

Papers

Lack of Association Between DJ-1 Gene Promoter Polymorphism and the Risk of Parkinson's Disease.

Role of the CCL2-CCR2 axis in cardiovascular disease: Pathogenesis and clinical implications

SUMO1 regulates post-infarct cardiac repair based on cellular heterogeneity

Rg3 regulates myocardial pyruvate metabolism via P300-mediated dihydrolipoamide dehydrogenase 2-hydroxyisobutyrylation in TAC-induced cardiac hypertrophy

Links between telomere dysfunction and hallmarks of aging.