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Frontiers in Medicine 2020Adolescent idiopathic scoliosis (AIS) is a complex three-dimensional deformity of the spine. Mesenchymal stem cells (MSCs) regulate bone mass homeostasis in AIS, which...
Adolescent idiopathic scoliosis (AIS) is a complex three-dimensional deformity of the spine. Mesenchymal stem cells (MSCs) regulate bone mass homeostasis in AIS, which might be related to the pathogenesis of AIS. However, the mRNA-miRNA-lncRNA network linked to the regulation of the genetic pathogenesis of MSCs remains unknown. We conducted an exhaustive literature search of PubMed, EMBASE, and the Gene Expression Omnibus database to find differentially expressed genes (DEGs), differentially expressed miRNAs (DE miRNAs), and differentially expressed lncRNAs (DE lncRNAs). Functional enrichment analysis was performed through Enrichr database. Protein-protein interaction (PPI) network was constructed using STRING database, and hub genes were identified by CytoHubba. Potential regulatory miRNAs and lncRNAs of mRNAs were predicted by miRTarBase and RNA22, respectively. We identified 551 upregulated and 476 downregulated genes, 42 upregulated and 12 downregulated miRNAs, and 345 upregulated and 313 downregulated lncRNAs as DEGs, DE miRNAs, and DE lncRNAs, respectively. Functional enrichment analysis revealed that they were significantly enriched in protein deglutamylation and regulation of endoplasmic reticulum unfolded protein response. According to node degree, one upregulated hub gene and eight downregulated hub genes were identified. After drawing the Venn diagrams and matching to Cytoscape, an mRNA-miRNA-lncRNA network linked to the pathogenesis of MSCs in AIS was constructed. We established a novel triple regulatory network of mRNA-miRNA-lncRNA ceRNA, among which all RNAs may be utilized as the pathogenesis biomarker of MSCs in AIS.
PubMed: 33195333
DOI: 10.3389/fmed.2020.583243 -
CNS & Neurological Disorders Drug... 2020Epilepsy is the second most common neurological disease with abnormal neural activity involving the activation of various intracellular signalling transduction...
Epilepsy is the second most common neurological disease with abnormal neural activity involving the activation of various intracellular signalling transduction mechanisms. The molecular and system biology mechanisms responsible for epileptogenesis are not well defined or understood. Neuroinflammation, neurodegeneration and Epigenetic modification elicit epileptogenesis. The excessive neuronal activities in the brain are associated with neurochemical changes underlying the deleterious consequences of excitotoxicity. The prolonged repetitive excessive neuronal activities extended to brain tissue injury by the activation of microglia regulating abnormal neuroglia remodelling and monocyte infiltration in response to brain lesions inducing axonal sprouting contributing to neurodegeneration. The alteration of various downstream transduction pathways resulted in intracellular stress responses associating endoplasmic reticulum, mitochondrial and lysosomal dysfunction, activation of nucleases, proteases mediated neuronal death. The recently novel pharmacological agents modulate various receptors like mTOR, COX-2, TRK, JAK-STAT, epigenetic modulators and neurosteroids are used for attenuation of epileptogenesis. Whereas the various molecular changes like the mutation of the cell surface, nuclear receptor and ion channels focusing on repetitive episodic seizures have been explored by preclinical and clinical studies. Despite effective pharmacotherapy for epilepsy, the inadequate understanding of precise mechanisms, drug resistance and therapeutic failure are the current fundamental problems in epilepsy. Therefore, the novel pharmacological approaches evaluated for efficacy on experimental models of epilepsy need to be identified and validated. In addition, we need to understand the downstream signalling pathways of new targets for the treatment of epilepsy. This review emphasizes on the current state of novel molecular targets as therapeutic approaches and future directions for the management of epileptogenesis. Novel pharmacological approaches and clinical exploration are essential to make new frontiers in curing epilepsy.
Topics: Animals; Brain; Cell Death; Epilepsy; Humans; Microglia; Mitochondria; Neurons; Signal Transduction
PubMed: 32914725
DOI: 10.2174/1871527319666200910153827 -
Frontiers in Pharmacology 2020Astragaloside IV (AS-IV) has a variety of biological activities and is widely used to treat kidney diseases. We conducted a systematic review of 24 animal studies...
Astragaloside IV (AS-IV) has a variety of biological activities and is widely used to treat kidney diseases. We conducted a systematic review of 24 animal studies including 424 animals to evaluate the efficacy of AS-IV for diabetic nephropathy (DN); all current possible mechanisms were summarized. A search strategy was applied to eight databases from inception to June 2020. The CAMARADES 10-item quality checklist and Rev-Man 5.3 software were used to analyze the risks of bias of each study and data regarding outcome measures, respectively. The mean study quality score was 5.4 points (range 3-8 points). Meta-analyses data and comparisons between groups showed that AS-IV significantly slowed the progression of pathological signs in the kidney including glomeruli and tubules, increasing creatinine clearance rate, decreasing blood urea nitrogen, serum creatinine, 24-h urinary neutrophil gelatinase-associated lipocalin and N-acetyl--D-glucosaminidase, 24-h urinary albumin, 24-h urinary microalbumin and HbA1c. There were no significant differences between experimental and control groups with respect to mortality or levels of alanine aminotransferase and aspartate aminotransferase. In terms of the possible mechanisms of treatment of DN, AS-IV acts through antifibrotic, antioxidant, and antiapoptotic mechanisms, thereby alleviating endoplasmic reticulum stress, inhibiting mitochondrial fission, and increasing autophagic activity. Taken together, our findings suggest that AS-IV is a multifaceted renoprotective candidate drug for DN.
PubMed: 32695006
DOI: 10.3389/fphar.2020.00988 -
International Journal of Oncology Aug 2020Over the past two decades, quantitative proteomics has emerged as an important tool for deciphering the complex molecular events involved in cancers. The number of...
Over the past two decades, quantitative proteomics has emerged as an important tool for deciphering the complex molecular events involved in cancers. The number of references involving studies on the cancer metastatic process has doubled since 2010, while the last 5 years have seen the development of novel technologies combining deep proteome coverage capabilities with quantitative consistency and accuracy. To highlight key findings within this huge amount of information, the present review identified a list of tumor invasive biomarkers based on both the literature and data collected on a biocollection of experimental cell lines, tumor models of increasing invasiveness and tumor samples from patients with colorectal or breast cancer. Crossing these different data sources led to 76 proteins of interest out of 1,245 mentioned in the literature. Information on these proteins can potentially be translated into clinical prospects, since they represent potential targets for the development and evaluation of innovative therapies, alone or in combination. Herein, a systematical review of the biology of each of these proteins, including their specific subcellular/extracellular or multiple localizations is presented. Finally, as an important advantage of quantitative proteomics is the ability to provide data on all these molecules simultaneously in cell pellets, body fluids or paraffin‑embedded sections of tumors/invaded tissues, the significance of some of their interconnections is discussed.
Topics: Animals; Biomarkers, Tumor; Cell Line, Tumor; Disease Models, Animal; Humans; Neoplasm Invasiveness; Neoplasms; Proteomics
PubMed: 32468071
DOI: 10.3892/ijo.2020.5075 -
Acta Biochimica Et Biophysica Sinica Apr 2020Atherosclerosis is a progressive vascular disease with increasing morbidity and mortality year by year in modern society. Human cytomegalovirus (HCMV) infection is...
Atherosclerosis is a progressive vascular disease with increasing morbidity and mortality year by year in modern society. Human cytomegalovirus (HCMV) infection is closely associated with the development of atherosclerosis. HCMV infection may accelerate graft atherosclerosis and the development of transplant vasculopathy in organ transplantation. However, our current understanding of HCMV-associated atherosclerosis remains limited and is mainly based on clinical observations. The underlying mechanism of the involvement of HCMV infection in atherogenesis remains unclear. Here, we summarized current knowledge regarding the multiple influences of HCMV on a diverse range of infected cells, including vascular endothelial cells, vascular smooth muscle cells, monocytes, macrophages, and T cells. In addition, we described potential HCMV-induced molecular mechanisms, such as oxidative stress, endoplasmic reticulum stress, autophagy, lipid metabolism, and miRNA regulation, which are involved in the development of HCMV-associated atherogenesis. Gaining an improved understanding of these mechanisms will facilitate the development of novel and effective therapeutic strategies for the treatment of HCMV-related cardiovascular disease.
Topics: Atherosclerosis; Cytomegalovirus; Cytomegalovirus Infections; Endoplasmic Reticulum Stress; Endothelial Cells; Humans; Lipid Metabolism; Macrophages; MicroRNAs; Monocytes; Oxidative Stress; T-Lymphocytes
PubMed: 32253424
DOI: 10.1093/abbs/gmaa005 -
Gene Apr 2020Psoriasis has a complex genetic background with a strong heritable component. Herein, the present meta-analysis aims to evaluate the association of ERAP1 polymorphisms... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Psoriasis has a complex genetic background with a strong heritable component. Herein, the present meta-analysis aims to evaluate the association of ERAP1 polymorphisms with psoriasis susceptibility.
METHODS
PubMed, Web of Sciences, Scopus, and Cochrane Library databases were examined with no time limits up to March 2019, without language, age, and sex restrictions. The odds ratio (OR) and 95% confidence interval (CI) were calculated by CMA 2.0 software in a dichotomous analysis using computed effect sizes and having OR and confidence limits for each study. The subgroup analysis based on ethnicity, type of study, and genotyping method was performed.
RESULTS
Thirteen articles were involved in the meta-analysis, in details eight were cohort studies and five were case-control studies. The results showed an association between rs27524 [OR = 1.179; 95%CI: 1.081, 1.286; p < 0.001] and rs30187 [OR = 1.237; 95%CI: 1.133, 1.351; p < 0.001] polymorphisms and psoriasis susceptibility; whereas no association was detected with rs26653 [OR = 1.013; 95%CI: 0.798, 1.286; p = 0.914] and rs27044 [OR = 1.164; 95%CI: 0.982, 1.381; p = 0.080] polymorphisms. Psoriasis susceptibility in both Caucasian and Asian ethnicities was related to rs27524 polymorphism, while rs30187 and rs27044 polymorphisms were over-represented in patients belonging to Caucasian ethnicity. In addition, in cohort studies, psoriasis susceptibility was related to rs27524 polymorphism, while the associated polymorphisms were rs26653 and rs27044 in case-control studies, and rs30187 in both cohort and case-control studies.
CONCLUSIONS
These findings showed an association between rs27524 and rs30187 polymorphisms and susceptibility to psoriasis, while lack of association was obtained for rs26653 and rs27044 polymorphisms. In order to confirm our results, further studies are needed, also considering different factors, such as type of psoriasis and ethnicity.
Topics: Aminopeptidases; Animals; Endoplasmic Reticulum; Genetic Predisposition to Disease; Humans; Polymorphism, Single Nucleotide; Psoriasis
PubMed: 32006595
DOI: 10.1016/j.gene.2020.144416 -
Journal of Human Genetics Apr 2020Genome-wide association studies (GWASs) have identified many genetic variations associated with type 2 diabetes mellitus (T2DM) in Asians, but understanding the... (Meta-Analysis)
Meta-Analysis
Genome-wide association studies (GWASs) have identified many genetic variations associated with type 2 diabetes mellitus (T2DM) in Asians, but understanding the functional genetic variants that influence traits is often a complex process. In this study, fine mapping and other analytical strategies were performed to investigate the effects of G protein signaling modulator 1 (GPSM1) on insulin resistance in skeletal muscle. A total of 128 single-nucleotide polymorphisms (SNPs) within GPSM1 were analysed in 21,897 T2DM cases and 32,710 healthy controls from seven GWASs. The SNP rs28539249 in intron 9 of GPSM1 showed a nominally significant association with T2DM in Asians (OR = 1.07, 95% CI = 1.04-1.10, P < 10). The GPSM1 mRNA was increased in skeletal muscle and correlated with T2DM traits across obese mice model. An eQTL for the cis-acting regulation of GPSM1 expression in human skeletal muscle was identified for rs28539249, and the increased GPSM1 expression related with T2DM traits within GEO datasets. Another independent Asian cohort showed that rs28539249 is associated with the skeletal muscle expression of CACFD1, GTF3C5, SARDH, and FAM163B genes, which are functionally enriched for endoplasmic reticulum stress (ERS) and unfolded protein response (UPR) pathways. Moreover, rs28539249 locus was predicted to disrupt regulatory regions in human skeletal muscle with enriched epigenetic marks and binding affinity for CTCF. Supershift EMSA assays followed luciferase assays demonstrated the CTCF specifically binding to rs28539249-C allele leading to decreased transcriptional activity. Thus, the post-GWAS annotation confirmed the Asian-specific association of genetic variant in GPSM1 with T2DM, suggesting a role for the variant in the regulation in skeletal muscle.
Topics: Animals; Asian People; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Genetic Predisposition to Disease; Genome-Wide Association Study; Guanine Nucleotide Dissociation Inhibitors; Humans; Mice; Muscle, Skeletal; Polymorphism, Single Nucleotide
PubMed: 31959871
DOI: 10.1038/s10038-019-0720-3 -
Journal of Inherited Metabolic Disease May 2020Since the first description of galactosemia in 1908 and despite decades of research, the pathophysiology is complex and not yet fully elucidated. Galactosemia is an...
Since the first description of galactosemia in 1908 and despite decades of research, the pathophysiology is complex and not yet fully elucidated. Galactosemia is an inborn error of carbohydrate metabolism caused by deficient activity of any of the galactose metabolising enzymes. The current standard of care, a galactose-restricted diet, fails to prevent long-term complications. Studies in cellular and animal models in the past decades have led to an enormous progress and advancement of knowledge. Summarising current evidence in the pathophysiology underlying hereditary galactosemia may contribute to the identification of treatment targets for alternative therapies that may successfully prevent long-term complications. A systematic review of cellular and animal studies reporting on disease complications (clinical signs and/or biochemical findings) and/or treatment targets in hereditary galactosemia was performed. PubMed/MEDLINE, EMBASE, and Web of Science were searched, 46 original articles were included. Results revealed that Gal-1-P is not the sole pathophysiological agent responsible for the phenotype observed in galactosemia. Other currently described contributing factors include accumulation of galactose metabolites, uridine diphosphate (UDP)-hexose alterations and subsequent impaired glycosylation, endoplasmic reticulum (ER) stress, altered signalling pathways, and oxidative stress. galactokinase (GALK) inhibitors, UDP-glucose pyrophosphorylase (UGP) up-regulation, uridine supplementation, ER stress reducers, antioxidants and pharmacological chaperones have been studied, showing rescue of biochemical and/or clinical symptoms in galactosemia. Promising co-adjuvant therapies include antioxidant therapy and UGP up-regulation. This systematic review provides an overview of the scattered information resulting from animal and cellular studies performed in the past decades, summarising the complex pathophysiological mechanisms underlying hereditary galactosemia and providing insights on potential treatment targets.
Topics: Animals; Disease Models, Animal; Galactokinase; Galactose; Galactosemias; Genotype; Humans; Oxidative Stress; Phenotype; UDPglucose 4-Epimerase; UTP-Hexose-1-Phosphate Uridylyltransferase
PubMed: 31808946
DOI: 10.1002/jimd.12202 -
Current Diabetes Reviews 2020This article presents a scoping review and synthesis of research findings investigating the toxic cellular accumulation of dysregulated inorganic phosphate-phosphate...
This article presents a scoping review and synthesis of research findings investigating the toxic cellular accumulation of dysregulated inorganic phosphate-phosphate toxicity-as a pathophysiological determinant of diabetes and diabetic complications. Phosphorus, an essential micronutrient, is closely linked to the cellular metabolism of glucose for energy production, and serum inorganic phosphate is often transported into cells along with glucose during insulin therapy. Mitochondrial dysfunction and apoptosis, endoplasmic reticulum stress, neuronal degeneration, and pancreatic cancer are associated with dysregulated levels of phosphate in diabetes. Ectopic calcification involving deposition of calcium-phosphate crystals is prevalent throughout diabetic complications, including vascular calcification, nephropathy, retinopathy, and bone disorders. A low-glycemic, low-phosphate dietary intervention is proposed for further investigations in the treatment and prevention of diabetes and related diabetic pathologies.
Topics: Cell Physiological Phenomena; Cells; Diabetes Complications; Diabetes Mellitus; Glucose; Humans; Micronutrients; Phosphates
PubMed: 31686640
DOI: 10.2174/1573399815666191104113236 -
Nutrients Oct 2019In physiological conditions, the gut is heavily infiltrated with various subsets of inflammatory cells, whose activity is tightly controlled by counter-regulatory...
In physiological conditions, the gut is heavily infiltrated with various subsets of inflammatory cells, whose activity is tightly controlled by counter-regulatory mechanisms. Defects in such mechanisms can favour the development of chronic intestinal disorders, such as Crohn's disease (CD) and ulcerative colitis (UC), the principal forms of inflammatory bowel diseases (IBD) in humans, as well as systemic disorders. Over the last years, the frequency of intestinal and systemic immune-inflammatory disorders has increased in previously low incidence areas, likely due to the Westernization of lifestyles, including dietary habits. The Western diet is characterized by high consumption of proteins, saturated fats and sweets, as well as by a broad use of food additives (e.g., emulsifiers, bulking agents), which are used to preserve and enhance food quality. Accumulating evidence suggests that food additives can perturb gut homeostasis, thereby contributing to promote tissue-damaging inflammatory responses. For instance, mice given the emulsifiers carboxymethylcellulose and polysorbate 80 develop dysbiosis with overgrowth of mucus-degrading bacteria. Such an effect triggers colitis in animals deficient in either interleukin-10, a cytokine exerting anti-inflammatory and regulatory functions, or Toll-like receptor 5, a receptor recognizing the bacterial flagellin. Similarly, the polysaccharide maltodextrin induces endoplasmic reticulum stress in intestinal goblet cells, thereby impairing mucus release and increasing host susceptibility to colitis. In this review, we report and discuss the current knowledge about the impact of food additives on gut homeostasis and their potential contribution to the development of inflammatory disorders.
Topics: Animals; Colitis; Diet, Western; Dysbiosis; Food Additives; Gastrointestinal Microbiome; Homeostasis; Humans; Immunity, Mucosal; Intestines; Metabolic Diseases; Risk Assessment; Risk Factors
PubMed: 31581570
DOI: 10.3390/nu11102334