-
International Journal of Molecular... Apr 2024Preeclampsia, a serious complication of pregnancy, involves intricate molecular and cellular mechanisms. Fetal microchimerism, where fetal cells persist within maternal... (Review)
Review
Preeclampsia, a serious complication of pregnancy, involves intricate molecular and cellular mechanisms. Fetal microchimerism, where fetal cells persist within maternal tissues and in circulation, acts as a mechanistic link between placental dysfunction and maternal complications in the two-stage model of preeclampsia. Hormones, complements, and cytokines play pivotal roles in the pathophysiology, influencing immune responses, arterial remodeling, and endothelial function. Also, soluble HLA-G, involved in maternal-fetal immune tolerance, is reduced in preeclampsia. Hypoxia-inducible factor 1-alpha (Hif-α) dysregulation leads to placental abnormalities and preeclampsia-like symptoms. Alterations in matrix metalloproteinases (MMPs), endothelins (ETs), chemokines, and cytokines contribute to defective trophoblast invasion, endothelial dysfunction, and inflammation. Preeclampsia's genetic complexity includes circRNAs, miRNAs, and lncRNAs. CircRNA_06354 is linked to early-onset preeclampsia by influencing trophoblast invasion via the hsa-miR-92a-3p/VEGF-A pathway. The dysregulation of C19MC, especially miR-519d and miR-517-5p, affects trophoblast function. Additionally, lncRNAs like IGFBP1 and EGFR-AS1, along with protein-coding genes, impact trophoblast regulation and angiogenesis, influencing both preeclampsia and fetal growth. Besides aberrations in CD31+ cells, other potential biomarkers such as MMPs, soluble HLA-G, and hCG hold promise for predicting preeclampsia and its complications. Therapeutic interventions targeting factors such as peroxisome PPAR-γ and endothelin receptors show potential in mitigating preeclampsia-related complications. In conclusion, preeclampsia is a complex disorder with a multifactorial etiology and pathogenesis. Fetal microchimerism, hormones, complements, and cytokines contribute to placental and endothelial dysfunction with inflammation. Identifying novel biomarkers and therapeutic targets offers promise for early diagnosis and effective management, ultimately reducing maternal and fetal morbidity and mortality. However, further research is warranted to translate these findings into clinical practice and enhance outcomes for at-risk women.
Topics: Female; Humans; Pregnancy; Biomarkers; Hormones; MicroRNAs; Placenta; Pre-Eclampsia; Trophoblasts
PubMed: 38674114
DOI: 10.3390/ijms25084532 -
Nutrients Nov 2022The health benefits of omega-3 fatty acid (FA) supplementation on inflammatory gene expression (IGE) and multiple sclerosis (MS) are becoming more evident. However, an... (Meta-Analysis)
Meta-Analysis Review
The health benefits of omega-3 fatty acid (FA) supplementation on inflammatory gene expression (IGE) and multiple sclerosis (MS) are becoming more evident. However, an overview of the results from randomized controlled trials is lacking. This study aimed to conduct a meta-analysis to evaluate the effect of omega-3 fatty acid intake on MS (based on the criteria of the Expanded Disability Status Scale (EDSS)) and inflammatory gene expression (IGE). A search was conducted of PubMed, EMBASE, and Web of Science for cohort studies published from the inception of the database up to May 2022 that assessed the associations of omega-3 polyunsaturated fatty acids (n-3 PUFAs), docosahexaenoic acid (DHA), α-linolenic acid (ALA), and eicosapentaenoic acid (EPA) with EDSS and inflammatory gene expression (peroxisome proliferator-activated receptor gamma (PPAR-γ), tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), and interleukin-8 (IL-8)) outcomes. For the highest vs. lowest comparison, the relative risk (RR) estimates with a 95% confidence interval (CI) were pooled using the random-effect model. In total, 13 cohort studies with 1353 participants were included in the meta-analysis during periods of 3 to 144 weeks. A significant inverse relationship was found between DHA and EDSS scores (RR: 1.05; 95% CI: 0.62, 1.48; p < 0.00001). Our results also showed that omega-3 FAs significantly upregulated the gene expression of PPAR-γ (RR: 0.95; 95% CI: 0.52, 1.38; p < 0.03) and downregulated the expression of TNF-α (RR: −0.15; 95% CI: −0.99, 0.70; p < 0.00001) and IL-1 (RR: −0.60; 95% CI: −1.02, −0.18; p < 0.003). There was no clear evidence of publication bias with Egger’s tests for inflammatory gene expression (p = 0.266). Moreover, n-3 PUFAs and EPA were not significantly associated with EDSS scores (p > 0.05). In this meta-analysis of cohort studies, blood omega-3 FA concentrations were inversely related to inflammatory gene expression (IGE) and EDSS score, which indicates that they may hold great potential markers for the diagnosis, prognosis, and management of MS. However, further clinical trials are required to confirm the potential effects of the omega-3 FAs on MS disease management.
Topics: Humans; Multiple Sclerosis; Tumor Necrosis Factor-alpha; Peroxisome Proliferator-Activated Receptors; Fatty Acids, Omega-3; Eicosapentaenoic Acid; Docosahexaenoic Acids; Interleukin-1; Gene Expression; Immunoglobulin E
PubMed: 36364885
DOI: 10.3390/nu14214627 -
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 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 -
Advanced Pharmaceutical Bulletin Feb 2019As one of the four major families of pattern recognition receptors (PRRs), toll like receptors (TLRs) are crucial and important components of the innate immune system.... (Review)
Review
As one of the four major families of pattern recognition receptors (PRRs), toll like receptors (TLRs) are crucial and important components of the innate immune system. Peroxisome proliferatoractivated receptors (PPARs) with three isoforms are transcription factors classified as a subfamily of nuclear receptor proteins, and are of significant regulatory activity in cellular differentiation, development, metabolism, and tumorigenesis. It is well established that PPARs agonists display anti-inflammatory effects through inhibition of the nuclear factor-kappa B (NF-κB) pathway, a key regulator of immune and inflammatory responses, in a sense that TLRs signaling pathways are mainly toward activation of NF-κB. Through a systematic review of previous studies, we aimed to address and clarify the reciprocal interaction between TLRs and PPARs in hope to find alternative therapeutic approaches for inflammatory diseases. Among the available scientific database, 31 articles were selected for this review. A comprehensive review of this database confirms the presence of a cross-talk between PPARs and TLRs, indicating that not only PPARs stimulation may affect the expression level of TLRs via several mechanisms leading to modulating TLRs activities, but also TLRs have the potential to moderate the expression of PPARs. We, therefore, conclude that, as a key regulator of the innate immune system, the interaction between PPARs and TLRs is a potential therapeutic target in disease treatment.
PubMed: 31011554
DOI: 10.15171/apb.2019.003 -
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 -
Oncotarget Aug 2017Oxidative stress results from an imbalance of the reactive oxygen species/reactive nitrogen species (ROS/RNS) production and the oxidants defense system. Extensive... (Review)
Review
Oxidative stress results from an imbalance of the reactive oxygen species/reactive nitrogen species (ROS/RNS) production and the oxidants defense system. Extensive research during the last decades has revealed that oxidative stress can mediate cancer initiation and development by leading not only to molecular damage but also to a disruption of reduction-oxidation (redox) signaling. In order to provide a global overview of the redox signaling pathways, which play a role in cancer formation, we conducted a systematic literature search in PubMed and ISI Web of Science and identified 185 relevant reviews published in the last 10 years. The 20 most frequently described pathways were selected to be presented in this systematic review and could be categorized into 3 groups: Intracellular ROS/RNS generating organelles and enzymes, signal transduction cascades kinases/phosphatases and transcription factors. Intracellular ROS/RNS generation organelles are mitochondria, endoplasmic reticulum and peroxisomes. Enzymes, including NOX, COX, LOX and NOS, are the most prominent enzymes generating ROS/RNS. ROS/RNS act as redox messengers of transmembrane receptors and trigger the activation or inhibition of signal transduction kinases/phosphatases, such as the family members of protein tyrosine kinases and protein tyrosine phosphatases. Furthermore, these reactions activate downstream signaling pathways including protein kinase of the MAPK cascade, PI3K and PKC. The kinases and phosphatases regulate the phosphorylation status of transcription factors including APE1/Ref-1, HIF-1α, AP-1, Nrf2, NF-κB, p53, FOXO, STAT, and β-catenin. Finally, we briefly discuss cancer prevention and treatment opportunities, which address redox pathways and further research needs.
PubMed: 28881698
DOI: 10.18632/oncotarget.17128 -
International Journal of Molecular... May 2018The peroxisome proliferator-activated receptors (, , ) and their transcriptional coactivators' (, ) gene polymorphisms have been associated with muscle morphology,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The peroxisome proliferator-activated receptors (, , ) and their transcriptional coactivators' (, ) gene polymorphisms have been associated with muscle morphology, oxygen uptake, power output and endurance performance. The purpose of this review is to determine whether the PPARs and/or their coactivators' polymorphisms can predict the training response to specific training stimuli.
METHODS
In accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analyses, a literature review has been run for a combination of PPARs and physical activity key words.
RESULTS
All ten of the included studies were performed using aerobic training in general, sedentary or elderly populations from 21 to 75 years of age. The non-responders for aerobic training (VO₂peak increase, slow muscle fiber increase and low-density lipoprotein decrease) are the carriers of rs8192678 Ser/Ser. The negative responders for aerobic training (decrease in VO₂peak) are carriers of the rs2267668 G allele. The negative responders for aerobic training (decreased glucose tolerance and insulin response) are subjects with the rs1801282 Pro/Pro genotype. The best responders to aerobic training are rs8192678 Gly/Gly, rs1053049 TT, rs2267668 AA and rs1801282 Ala carriers.
CONCLUSIONS
The human response for aerobic training is significantly influenced by PPARs' gene polymorphism and their coactivators, where aerobic training can negatively influence glucose metabolism and VO₂peak in some genetically-predisposed individuals.
Topics: Adult; Aged; Carrier Proteins; Humans; Male; Middle Aged; Muscle, Skeletal; Oxygen Consumption; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Peroxisome Proliferator-Activated Receptors; Physical Conditioning, Human; Polymorphism, Single Nucleotide; RNA-Binding Proteins
PubMed: 29762540
DOI: 10.3390/ijms19051472 -
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