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Journal of Alzheimer's Disease Reports Apr 2020Nitric oxide/cyclic guanosine monophosphate (cGMP) signaling is compromised in Alzheimer's disease (AD), and phosphodiesterase 5 (PDE5), which degrades cGMP, is... (Review)
Review
Nitric oxide/cyclic guanosine monophosphate (cGMP) signaling is compromised in Alzheimer's disease (AD), and phosphodiesterase 5 (PDE5), which degrades cGMP, is upregulated. Sildenafil inhibits PDE5 and increases cGMP levels. Integrating previous findings, we determine that most doses of sildenafil (especially low doses) likely activate peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) via protein kinase G-mediated cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) phosphorylation and/or Sirtuin-1 activation and PGC1α deacetylation. Via PGC1α signaling, low-dose sildenafil likely suppresses β-secretase 1 expression and amyloid-β (Aβ) generation, upregulates antioxidant enzymes, and induces mitochondrial biogenesis. Plus, sildenafil should increase brain perfusion, insulin sensitivity, long-term potentiation, and neurogenesis while suppressing neural apoptosis and inflammation. A systematic review of sildenafil in AD was undertaken. sildenafil protected neural mitochondria from Aβ and advanced glycation end products. In transgenic AD mice, sildenafil was found to rescue deficits in CREB phosphorylation and memory, upregulate brain-derived neurotrophic factor, reduce reactive astrocytes and microglia, decrease interleukin-1β, interleukin-6, and tumor necrosis factor-α, decrease neural apoptosis, increase neurogenesis, and reduce tau hyperphosphorylation. All studies that tested Aβ levels reported significant improvements except the two that used the highest dosage, consistent with the dose-limiting effect of cGMP-induced phosphodiesterase 2 (PDE2) activation and cAMP depletion on PGC1α signaling. In AD patients, a single dose of sildenafil decreased spontaneous neural activity, increased cerebral blood flow, and increased the cerebral metabolic rate of oxygen. A randomized control trial of sildenafil (ideally with a PDE2 inhibitor) in AD patients is warranted.
PubMed: 32467879
DOI: 10.3233/ADR-200166 -
Frontiers in Nutrition 2023There is some debate about the effects of omega-3 fatty acids on the regulation of adipose tissue related genes. This systematic review and meta-analysis aimed to...
Impact of omega-3 fatty acids supplementation on the gene expression of peroxisome proliferator activated receptors-, and fibroblast growth factor-21 serum levels in patients with various presentation of metabolic conditions: a GRADE assessed systematic review and dose-response meta-analysis of...
UNLABELLED
There is some debate about the effects of omega-3 fatty acids on the regulation of adipose tissue related genes. This systematic review and meta-analysis aimed to evaluate the effects of omega-3 fatty acids supplementation on the gene expression of peroxisome proliferator activated receptors ( and ) and serum fibroblast growth factor-21 (FGF-21) levels in adults with different presentation of metabolic conditions. To identify eligible studies, a systematic search was conducted in the Cochrane Library of clinical trials, Medline, Scopus, ISI Web of Science, and Google Scholar up to April 2022. Eligibility criteria included a clinical trial design, omega-3 fatty acids supplementation in adults, and reporting of at least one of the study outcomes. Effect sizes were synthesized using either fixed or random methods based on the level of heterogeneity. Fifteen studies met the inclusion criteria. Omega-3 fatty acids supplementation significantly increased the (10 studies) and (2 studies) gene expression compared to the control group (WMD: 0.24; 95% CI: 0.12, 0.35; < 0.001 and 0.09; 95% CI: 0.04, 0.13; p < 0.001, respectively). Serum FGF-21 (8 studies) levels exhibited no significant change following omega-3 fatty acids supplementation ( = 0.542). However, a dose-response relationship emerged between the dose of omega-3 fatty acids and both gene expression and serum FGF-21 levels. Overall, this study suggests that omega-3 fatty acids supplementation may have positive effects on the regulation of adipose tissue related genes in patients with various presentation of metabolic condition. Further research is needed to validate these findings and ascertain the effectiveness of this supplementation approach in this population.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/display_record.php?, CRD42022338344.
PubMed: 38035345
DOI: 10.3389/fnut.2023.1202688 -
Frontiers in Endocrinology 2022The relationships between the rs1801282 and rs3856806 polymorphisms in nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) gene and obesity... (Meta-Analysis)
Meta-Analysis
G Allele of the rs1801282 Polymorphism in PPARγ Gene Confers an Increased Risk of Obesity and Hypercholesterolemia, While T Allele of the rs3856806 Polymorphism Displays a Protective Role Against Dyslipidemia: A Systematic Review and Meta-Analysis.
BACKGROUND
The relationships between the rs1801282 and rs3856806 polymorphisms in nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) gene and obesity indexes as well as serum lipid levels have been extensively investigated in various studies, but the results were inconsistent and even contradictory.
METHODS
PubMed, Google Scholar, Embase, Cochrane Library, Web of Science, Wanfang, CNKI and VIP databases were searched for eligible studies. The random-effTPDEects model was used, and standardized mean difference (SMD) with 95% confidence interval (CI) was calculated to estimate the differences in obesity indexes and serum lipid levels between the subjects with different genotypes in a dominant model. Heterogeneity among studies was assessed by Cochran's x-based Q-statistic test. Publication bias was identified by using Begg's test.
RESULTS
One hundred and twenty studies (70,317 subjects) and 33 studies (18,353 subjects) were identified in the analyses for the rs1801282 and rs3856806 polymorphisms, respectively. The G allele carriers of the rs1801282 polymorphism had higher levels of body mass index (SMD = 0.08 kg/m, 95% CI = 0.04 to 0.12 kg/m, < 0.001), waist circumference (SMD = 0.12 cm, 95% CI = 0.06 to 0.18 cm, < 0.001) and total cholesterol (SMD = 0.07 mmol/L, 95% CI = 0.02 to 0.11 mmol/L, < 0.01) than the CC homozygotes. The T allele carriers of the rs3856806 polymorphism had lower levels of low-density lipoprotein cholesterol (SMD = -0.09 mmol/L, 95% CI = -0.15 to -0.03 mmol/L, < 0.01) and higher levels of high-density lipoprotein cholesterol (SMD = 0.06 mmol/L, 95% CI = 0.02 to 0.10 mmol/L, < 0.01) than the CC homozygotes.
CONCLUSIONS
The meta-analysis suggests that the G allele of the rs1801282 polymorphism confers an increased risk of obesity and hypercholesterolemia, while the T allele of the rs3856806 polymorphism displays a protective role against dyslipidemia, which can partly explain the associations between these polymorphisms and cardiovascular disease.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/, identifier [CRD42022319347].
Topics: Alleles; Cholesterol, HDL; Dyslipidemias; Humans; Hypercholesterolemia; Obesity; PPAR gamma; Polymorphism, Single Nucleotide
PubMed: 35846293
DOI: 10.3389/fendo.2022.919087 -
Frontiers in Endocrinology 2021Per- or polyfluoroalkyl substances (PFAS), a family of synthetic polyfluorinated compounds, are widely used in consumer products. Ubiquitous exposures to PFAS, in...
Per- or polyfluoroalkyl substances (PFAS), a family of synthetic polyfluorinated compounds, are widely used in consumer products. Ubiquitous exposures to PFAS, in consideration of their persistence, bioaccumulation potential, and toxicities have led to concerns regarding possible harmful effects during critical periods of development in early-life and long-term consequences on health. The potential effects of PFAS depend on various factors including the type of PFAS and the timing and level of exposure. We performed a systematic review of the epidemiologic literature to assess the effects of early-life PFAS exposure on prenatal and postnatal growth, adiposity, and puberty in children and adolescents. For birth size, most studies indicated that prenatal PFAS exposure, in particular long-chain PFAS, may impair fetal growth, albeit some reports of null associations with maternal PFAS. For growth within 2 years of age, prenatal PFAS exposure showed no associations with height and either null or negative associations with weight. However, postnatal PFAS exposures were inversely related to height and weight at 2 years in a cross-sectional study. For postnatal adiposity, prenatal PFAS may mostly have negative associations with body mass index in the first 2 years of life, but positive relationships with adiposity in childhood and adolescence, although some studies showed null associations. For puberty, the evidence for associations between early-life PFAS exposure and pubertal development or sex hormone levels were limited and inconclusive. From experimental studies, plausible mechanisms through which PFAS may affect early-life growth and puberty include PFAS-induced activation of peroxisome proliferator-activated receptor, alterations of thyroid or steroid hormone synthesis and metabolism, and their weak estrogenic or anti-androgenic properties. Although the published literature suggests possible effects of PFAS exposures on early-life growth, adiposity, and puberty, current human evidence is limited in establishing PFAS-induced effects on early-life physical development. Further investigation is warranted to clarify PFAS-induced effects on growth and physical development in consideration of the critical time-window of exposure, concomitant exposure to chemical mixtures including various PFAS types, and possible non-monotonic dose-response relationship for growth and adiposity trajectories.
Topics: Adiposity; Alkanesulfonic Acids; Carboxylic Acids; Child; Child Development; Environmental Exposure; Environmental Pollutants; Fetal Development; Fluorocarbons; Gonadal Steroid Hormones; Humans; Puberty
PubMed: 34566884
DOI: 10.3389/fendo.2021.683297 -
Frontiers in Endocrinology 2023The relationships of the rs17782313 polymorphism near melanocortin 4 receptor gene (MC4R) and the rs8192678 polymorphism in peroxisome proliferator-activated receptor... (Meta-Analysis)
Meta-Analysis
The rs17782313 polymorphism near MC4R gene confers a high risk of obesity and hyperglycemia, while PGC1α rs8192678 polymorphism is weakly correlated with glucometabolic disorder: a systematic review and meta-analysis.
BACKGROUND
The relationships of the rs17782313 polymorphism near melanocortin 4 receptor gene (MC4R) and the rs8192678 polymorphism in peroxisome proliferator-activated receptor gamma coactivator 1 alpha gene (PGC1α) with metabolic abnormalities have been explored in many populations around the world, but the findings were not all consistent and sometimes even a bit contradictory.
METHODS
Electronic databases including Medline, Scopus, Embase, Web of Science, CNKI and Google Scholar were checked for studies that met the inclusion criteria. Data were carefully extracted from eligible studies. Standardized mean differences (SMDs) were calculated by using a random-effects model to examine the differences in the indexes of obesity, glucometabolic disorder and dyslipidemia between the genotypes of the rs17782313 and rs8192678 polymorphisms. Cochran's Q-statistic test and Begg's test were employed to identify heterogeneity among studies and publication bias, respectively.
RESULTS
Fifty studies (58,716 subjects) and 51 studies (18,660 subjects) were respectively included in the pooled meta-analyses for the rs17782313 and rs8192678 polymorphisms. The C-allele carriers of the rs17782313 polymorphism had a higher average level of body mass index (SMD = 0.21 kg/m, 95% confidence interval [95% CI] = 0.12 to 0.29 kg/m, < 0.001), waist circumference (SMD = 0.14 cm, 95% CI = 0.06 to 0.23 cm, < 0.001) and blood glucose (SMD = 0.09 mg/dL, 95% CI = 0.02 to 0.16 mg/dL, = 0.01) than the TT homozygotes. Regarding the rs8192678 polymorphism, no significant associations with the indexes of obesity, glucometabolic disorder and dyslipidemia were detected. However, significant correlations between the rs8192678 polymorphism and multiple glucometabolic indexes were observed in subgroup analyses stratified by sex, age, ethnicity and health status.
CONCLUSION
The meta-analysis demonstrates that the C allele of the MC4R rs17782313 polymorphism confers a higher risk of obesity and hyperglycemia, and the PGC1α rs8192678 polymorphism is weakly correlated with glucometabolic disorder. These findings may partly explain the relationships between these variants and diabetes as well as cardiovascular disease.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/, identifier CRD42022373543.
Topics: Humans; Alleles; Genotype; Hyperglycemia; Obesity; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Receptor, Melanocortin, Type 4
PubMed: 37621650
DOI: 10.3389/fendo.2023.1210455 -
Nutrients Apr 2021Autism spectrum disorder (ASD) pathophysiology is not completely understood; however, altered inflammatory response and glutamate signaling have been reported, leading...
Autism spectrum disorder (ASD) pathophysiology is not completely understood; however, altered inflammatory response and glutamate signaling have been reported, leading to the investigation of molecules targeting the immune-glutamatergic system in ASD treatment. Palmitoylethanolamide (PEA) is a naturally occurring saturated N-acylethanolamine that has proven to be effective in controlling inflammation, depression, epilepsy, and pain, possibly through a neuroprotective role against glutamate toxicity. Here, we systematically reviewed all human and animal studies examining PEA and its biobehavioral correlates in ASD. Studies indicate altered serum/brain levels of PEA and other endocannabinoids (ECBs)/acylethanolamines (AEs) in ASD. Altered PEA signaling response to social exposure and altered expression/activity of enzymes responsible for the synthesis and catalysis of ECBs/AEs, as well as downregulation of the peroxisome proliferator activated receptor-α (PPAR-α) and cannabinoid receptor target GPR55 mRNA brain expression, have been reported. Stress and exposure to exogenous cannabinoids may modulate ECBs/AEs levels and expression of candidate genes for neuropsychiatric disorders, with implications for ASD. Limited research suggests that PEA supplementation reduces overall autism severity by improving language and social and nonsocial behaviors. Potential neurobiological underpinnings include modulation of immune response, neuroinflammation, neurotrophy, apoptosis, neurogenesis, neuroplasticity, neurodegeneration, mitochondrial function, and microbiota activity, possibly through peroxisome proliferator-activated receptor-α (PPAR-α) activation.
Topics: Amides; Animals; Apoptosis; Autism Spectrum Disorder; Brain; Down-Regulation; Endocannabinoids; Ethanolamines; Glutamic Acid; Humans; Immune System Phenomena; Inflammation; Mitochondria; Neuroprotective Agents; PPAR alpha; Palmitic Acids; Receptors, Cannabinoid; Signal Transduction
PubMed: 33919499
DOI: 10.3390/nu13041346 -
Nutrients Dec 2022Genetic components may play an important role in the regulation of nutrient and energy metabolism. In the presence of specific genetic variants, metabolic dysregulation... (Review)
Review
Genetic components may play an important role in the regulation of nutrient and energy metabolism. In the presence of specific genetic variants, metabolic dysregulation may occur, especially in relation to the processes of digestion, assimilation, and the physiological utilization of nutrients supplied to the body, as well as the regulation of various metabolic pathways and the balance of metabolic changes, which may consequently affect the effectiveness of applied reduction diets and weight loss after training. There are many well-documented studies showing that the presence of certain polymorphic variants in some genes can be associated with specific changes in nutrient and energy metabolism, and consequently, with more or less desirable effects of applied caloric reduction and/or exercise intervention. This systematic review focused on the role of genes encoding peroxisome proliferator-activated receptors (PPARs) and their coactivators in nutrient and energy metabolism. The literature review prepared showed that there is a link between the presence of specific alleles described at different polymorphic points in genes and various human body characteristics that are crucial for the efficacy of nutritional and/or exercise interventions. Genetic analysis can be a valuable element that complements the work of a dietitian or trainer, allowing for the planning of a personalized diet or training that makes the best use of the innate metabolic characteristics of the person who is the subject of their interventions.
Topics: Humans; Peroxisome Proliferator-Activated Receptors; Nutrients; Energy Metabolism; Diet; Alleles
PubMed: 36558537
DOI: 10.3390/nu14245378 -
Journal of Dairy Science Jan 2021Development of ketosis in high-producing dairy cows contributes to several animal health issues and highlights the need for a better understanding of the genetic basis... (Meta-Analysis)
Meta-Analysis
Development of ketosis in high-producing dairy cows contributes to several animal health issues and highlights the need for a better understanding of the genetic basis of metabolic diseases. To evaluate the pattern of differential gene expression in the liver of cows under negative energy balance (NEB), and under subclinical and clinical ketosis, a meta-analysis of gene expression and genome-wide association studies results was performed. An initial systematic review identified 118 articles based on the key words "cow," "liver," "negative energy balance," "ketosis," "expression," "qPCR," "microarray," "proteomic," "RNA-Seq," and "GWAS." After further screening for only peer-reviewed and pertinent articles for gene expression during NEB and clinical and subclinical ketosis (considering plasma levels of β-hydroxybutyrate), 20 articles were included in the analysis. From the systematic review, 430 significant SNPs identified by genome-wide association studies (GWAS) were assigned to genes reported in gene expression studies by considering chromosome and base pair positions in the ARS-UCD 1.2 bovine assembly. Venn diagrams were created to integrate the data obtained in the systematic review, and Gene Ontology enrichment analysis was carried out using official gene names. A QTL enrichment analysis was also performed to identify potential positional candidate loci. Twenty-four significant SNPs were located within the coordinates of differentially expressed genes located on chromosomes 2, 3, 6, 9, 11, 14, 27, and 29. Three significant metabolic pathways were associated with NEB and subclinical and clinical ketosis. In addition, 2 important genes, PPARA (peroxisome proliferator activated receptor alpha) and ACACA (acetyl-coenzyme A carboxylase α), were identified, which were differentially expressed in the 3 metabolic conditions. The PPARA gene is involved in the regulation of lipid metabolism and fatty liver disease and the ACACA gene encodes an enzyme that catalyzes the carboxylation of acetyl-coenzyme A to malonyl-coenzyme A, which is a rate-limiting step in fatty acid synthesis. Gene network analysis revealed co-expression interactions among 34 genes associated with functions involving fatty acid transport and fatty acid metabolism. For the annotated QTL, 9 QTL were identified for ketosis. The genes FN1 (fibronectin 1) and PTK2 (protein tyrosine kinase 2), which are mainly involved in cell adhesion and formation of extracellular matrix constituents, were enriched for QTL previously associated with the trait "ketosis" on chromosome 2 and for the trait "milk iron content" on chromosome 14, respectively. This integration of gene expression and GWAS data provides an additional understanding of the genetic background of NEB and subclinical and clinical ketosis in dairy cattle. Thus, it is a useful approach to identify biological mechanisms underlying these metabolic conditions in dairy cattle.
Topics: Animals; Cattle; Cattle Diseases; Energy Metabolism; Female; Gene Expression
PubMed: 33189279
DOI: 10.3168/jds.2020-18883 -
Journal of Alzheimer's Disease Reports Jun 2020Preclinical studies, clinical trials, and reviews suggest increasing 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) with... (Review)
Review
BACKGROUND
Preclinical studies, clinical trials, and reviews suggest increasing 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) with phosphodiesterase inhibitors is disease-modifying in Alzheimer's disease (AD). cAMP/protein kinase A (PKA) and cGMP/protein kinase G (PKG) signaling are disrupted in AD. cAMP/PKA and cGMP/PKG activate cAMP response element binding protein (CREB). CREB binds mitochondrial and nuclear DNA, inducing synaptogenesis, memory, and neuronal survival gene (e.g., brain-derived neurotrophic factor) and peroxisome proliferator-activated receptor- coactivator-1 (PGC1). cAMP/PKA and cGMP/PKG activate Sirtuin-1, which activates PGC1. PGC1 induces mitochondrial biogenesis and antioxidant genes (e.g.,Nrf2) and represses BACE1. cAMP and cGMP inhibit BACE1-inducing NFB and tau-phosphorylating GSK3β.
OBJECTIVE AND METHODS
We review efficacy-testing clinical trials, epidemiology, and meta-analyses to critically investigate whether phosphodiesteraseinhibitors prevent or treat AD.
RESULTS
Caffeine and cilostazol may lower AD risk. Denbufylline and sildenafil clinical trials are promising but preliminary and inconclusive. PF-04447943 and BI 409,306 are ineffective. Vinpocetine, cilostazol, and nicergoline trials are mixed. Deprenyl/selegiline trials show only short-term benefits. Broad-spectrum phosphodiesterase inhibitor propentofylline has been shown in five phase III trials to improve cognition, dementia severity, activities of daily living, and global assessment in mild-to-moderate AD patients on multiple scales, including the ADAS-Cogand the CIBIC-Plus in an 18-month phase III clinical trial. However, two books claimed based on a MedScape article an 18-month phase III trial failed, so propentofylline was discontinued. Now, propentofylline is used to treat canine cognitive dysfunction, which, like AD, involves age-associated wild-type Aβ deposition.
CONCLUSION
Phosphodiesterase inhibitors may prevent and treat AD.
PubMed: 32715279
DOI: 10.3233/ADR-200191 -
Scientific Reports Jul 2020Type 2 diabetes mellitus (T2DM) is a complex disease caused by the interaction between genetic and environmental factors. A growing number of evidence suggests that the... (Meta-Analysis)
Meta-Analysis
Type 2 diabetes mellitus (T2DM) is a complex disease caused by the interaction between genetic and environmental factors. A growing number of evidence suggests that the peroxisome proliferator-activated receptor gamma (PPARG) gene plays a major role in T2DM development. Meta-analysis of genetic association studies is an efficient tool to gain a better understanding of multifactorial diseases and potentially to provide valuable insights into gene-disease interactions. The present study was focused on assessing the association between Pro12Ala variation in the PPARG and T2DM risk through a comprehensive meta-analysis. We searched PubMed, WoS, Embase, Scopus and ProQuest from 1990 to 2017. The fixed-effect or random-effect model was used to evaluate the pooled odds ratios (ORs) and 95% confidence intervals (CIs) depending on the heterogeneity among studies. The sources of heterogeneity and publication bias among the included studies were assessed using I statistics and Egger's tests. A total of 73 studies, involving 62,250 cases and 69,613 controls were included. The results showed that the minor allele (G) of the rs1801282 variant was associated with the decreased risk of T2DM under different genetic models. Moreover, the protective effect of minor allele was detected to be significantly more in some ethnicities including the European (18%), East Asian (20%), and South East Asian (18%). And the reduction of T2DM risk in Ala12 carriers was stronger in individuals from North Europe rather than Central and South Europe. Our findings indicated that the rs1801282 variant may contribute to decrease of T2DM susceptibility in different ancestries.
Topics: Alleles; Diabetes Mellitus, Type 2; Disease Progression; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Odds Ratio; PPAR gamma; Polymorphism, Single Nucleotide; Precision Medicine; Risk
PubMed: 32728045
DOI: 10.1038/s41598-020-69363-7