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PloS One 2023Arylamine N-acetyltransferase 2 has been related to drug side effects and cancer susceptibility; its protein structure and acetylation capacity results from the...
Arylamine N-acetyltransferase 2 has been related to drug side effects and cancer susceptibility; its protein structure and acetylation capacity results from the polymorphism's arrays on the NAT2 gene. Absorption, distribution, metabolism, and excretion, cornerstones of the pharmacological effects, have shown diversity patterns across populations, ethnic groups, and even interethnic variation. Although the 1000 Genomes Project database has portrayed the global diversity of the NAT2 polymorphisms, several populations and ethnicities remain underrepresented, limiting the comprehensive picture of its variation. The NAT2 clinical entails require a detailed landscape of its striking diversity. This systematic review spans the genetic and acetylation patterns from 164 articles from October 1992 to October 2020. Descriptive studies and controls from observational studies expanded the NAT2 diversity landscape. Our study included 243 different populations and 101 ethnic minorities, and, for the first time, we presented the global patterns in the Middle Eastern populations. Europeans, including its derived populations, and East Asians have been the most studied genetic backgrounds. Contrary to the popular perception, Africans, Latinos and Native Americans have been significantly represented in recent years. NAT2*4, *5B, and *6A were the most frequent haplotypes globally. Nonetheless, the distribution of *5B and *7B were less and more frequent in Asians, respectively. Regarding the acetylator status, East Asians and Native Americans harboured the highest frequencies of the fast phenotype, followed by South Europeans. Central Asia, the Middle East, and West European populations were the major carriers of the slow acetylator status. The detailed panorama presented herein, expands the knowledge about the diversity patterns to genetic and acetylation levels. These data could help clarify the controversial findings between acetylator states and the susceptibility to diseases and reinforce the utility of NAT2 in precision medicine.
Topics: Arylamine N-Acetyltransferase; Acetylation; Polymorphism, Genetic; Haplotypes; Phenotype; Genotype
PubMed: 37023111
DOI: 10.1371/journal.pone.0283726 -
Expert Review of Clinical Pharmacology May 2023Isoniazid (INH) plays an important role in prevention and treatment of tuberculosis (TB). However, large pharmacokinetic (PK) variations are observed in patients...
INTRODUCTION
Isoniazid (INH) plays an important role in prevention and treatment of tuberculosis (TB). However, large pharmacokinetic (PK) variations are observed in patients receiving standard INH dosages. Considering the influence of PK variations on INH efficacy or adverse reactions, we reviewed the population PK studies of INH and explored significant covariates that influence INH PK.
METHODS
The PubMed and Embase databases were systematically searched from their inception to 30 January 2023. PPK studies on INH using a parametric nonlinear mixed-effect approach were included in this review. The characteristics and identified significant covariates of the included studies were summarized.
RESULTS
Twenty-one studies conducted in adults, and seven in pediatrics were included. A two-compartment model with first-order absorption and elimination was the frequently used structural model for INH. NAT2 genotype, body size, and age were identified as significant covariates affecting INH PK variation. The median clearance (CL) value in the fast metabolizers was 2.55-fold higher than that in the slow metabolizers. Infants and children had higher CL per weight values than adults with the same metabolic phenotype. In pediatric patients, CL value increased with postnatal age.
CONCLUSIONS
Compared with slow metabolizers, the daily dose of INH should be increased by 200-600 mg in fast metabolizers. To achieve effective treatment, pediatric patients need a higher dose per kilogram than adults. Further PPK studies of anti-tuberculosis drugs are needed to comprehensively understand the covariates that affect their PK characteristics and to achieve accurate dose adjustments.
Topics: Humans; Child; Isoniazid; Antitubercular Agents; Genotype; Phenotype; Area Under Curve; Arylamine N-Acetyltransferase
PubMed: 36971782
DOI: 10.1080/17512433.2023.2196401 -
Nutrition Reviews Jul 2023The relationship between food restriction (FR) and liver enzyme levels, such as alanine transferase (ALT), aspartate transferase (AST), and γ-glutamyl transferase... (Meta-Analysis)
Meta-Analysis
CONTEXT
The relationship between food restriction (FR) and liver enzyme levels, such as alanine transferase (ALT), aspartate transferase (AST), and γ-glutamyl transferase (GGT), has not yet been confirmed.
OBJECTIVE
A meta-analysis of research articles was conducted to investigate the association of FR and liver enzyme levels.
DATA SOURCES
The PubMed, Web of Science, Embase, and Cochrane Library databases were screened for articles published up to April 30, 2022.
DATA EXTRACTION
Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement methodology was used to search for research articles. Publication bias was detected using Begg's test. Finally, 17 trials involving 1982 participants and that reported mean value, mean difference, and standard deviation were identified.
DATA ANALYSIS
Data were described as the weighted mean difference of body mass index, body weight, and standardized mean difference (SMD) of ALT, AST, and GGT. A reduction in ALT level was observed after a FR intervention (total SMD, -0.36, 95% confidence interval [CI], -0.68 to -0.05). GGT levels also were decreased in 4 studies (total SMD, -0.23; 95%CI, -0.33 to -0.14). According to subgroup analysis, serum AST levels decreased in the medium-term (between 5 wk and 6 mo) group (subtotal SMD, -0.48; 95%CI, -0.69 to -0.28).
CONCLUSION
Existing evidence suggests that dietary restriction improves adult liver enzyme levels. The long-term maintenance of healthy liver enzyme levels, particularly in real-world applications, necessitates additional consideration.
Topics: Adult; Humans; Body Mass Index; Body Weight; Food; gamma-Glutamyltransferase; Liver
PubMed: 36860183
DOI: 10.1093/nutrit/nuad009 -
Reviews in Endocrine & Metabolic... Aug 2023Circadian clocks can be traced in nearly all life kingdoms, with the male reproductive system no exception. However, our understanding of the circadian clock in... (Review)
Review
Circadian clocks can be traced in nearly all life kingdoms, with the male reproductive system no exception. However, our understanding of the circadian clock in spermatogenesis seems to fall behind other scenarios. The present review aims to summarize the current knowledge about the role and especially the potential mechanisms of clock genes in spermatogenesis regulation. Accumulating studies have revealed rhythmic oscillation in semen parameters and some physiological events of spermatogenesis. Disturbing the clock gene expression by genetic mutations or environmental changes will also notably damage spermatogenesis. On the other hand, the mechanisms of spermatogenetic regulation by clock genes remain largely unclear. Some recent studies, although not revealing the entire mechanisms, indeed attempted to shed light on this issue. Emerging clues hinted that gonadal hormones, retinoic acid signaling, homologous recombination, and the chromatoid body might be involved in the regulation of spermatogenesis by clock genes. Then we highlight the challenges and the promising directions for future studies so as to stimulate attention to this critical field which has not gained adequate concern.
Topics: Animals; Humans; Male; Spermatogenesis; CLOCK Proteins; Circadian Clocks
PubMed: 36792803
DOI: 10.1007/s11154-022-09783-0 -
Indian Journal of Ophthalmology Feb 2023Genome-wide association studies (GWAS) have identified that single-nucleotide polymorphisms (SNPs) rs1258267 in CHAT and rs3753841 in COL11A1 are associated with primary... (Meta-Analysis)
Meta-Analysis
Genome-wide association studies (GWAS) have identified that single-nucleotide polymorphisms (SNPs) rs1258267 in CHAT and rs3753841 in COL11A1 are associated with primary angle-closure glaucoma (PACG). The purpose of the study was to evaluate the association of CHAT rs1258267 and COL11A1 rs3753841 with PACG. A comprehensive electronic database search was performed to include eligible studies, published from October 2010 to March 2022. By calculating summary odds ratios (ORs) and 95% confidence intervals (CI) under five genetic models, the risk of PACG related to these two SNPs could be estimated. Heterogeneity was measured with a Chi-square-based Q statistic test and the I statistic. By the Z test, we analyzed the overall effect of OR. We used funnel plots and Begg's funnel plots to evaluate the publication bias of included studies. The meta-analysis was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 checklist. There were eighteen studies associating CHAT rs1258267 with PACG indicating evidently decreased PACG risk in five genetic models. Thirty studies were included to demonstrate a notable increase in the risk of PACG-carrying COL11A1 rs3753841 genotypes. Subgroup analyses showed that the association of CHAT rs1258267 and COL11A1 rs3753841 with PACG was obvious in Asians, while no evidence was found to confirm this connection in Caucasians. This meta-analysis suggests that CHAT rs1258267 G/A polymorphisms could bring about a decreased risk of PACG susceptibility and COL11A1 rs3753841 G/A polymorphisms could cause an increased risk. These effects mainly manifest in Asians.
Topics: Humans; Collagen Type XI; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Glaucoma, Angle-Closure; Polymorphism, Single Nucleotide; Choline O-Acetyltransferase
PubMed: 36727317
DOI: 10.4103/ijo.IJO_1226_22 -
Pathology, Research and Practice Jan 2023LncRNAs have the potential to play a regulatory role in different processes of cancer development and progression. We conducted a systematic review and meta-analysis of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
LncRNAs have the potential to play a regulatory role in different processes of cancer development and progression. We conducted a systematic review and meta-analysis of evidence on the clinical significance and prognostic value of lncRNA CERS6-AS1 in cancer.
METHODS
This systematic review was conducted following PRISMA guidelines. Medline and Embase databases were searched using the relevant key terms covering lncRNA CERS6-AS1 and cancer. We pooled the estimated effect sizes and their 95 % confidence interval (CI) using random-effects models in STATA 16.0 (StataCorp, College Station, TX, USA).
RESULTS
Eleven articles on pancreatic, colorectal, gastric, papillary thyroid, breast, and hepatocellular cancers fulfilled our eligibility criteria. Studies consistently found that lncRNA CERS6-AS1 expression is upregulated in all assessed cancers. Based on our meta-analysis, its aberrant expression was directly associated with unfavorable clinical outcomes, including higher stage (pooled Odds ratios (95 % CI): 3.15 (2.01-4.93; I = 0.0 %), tumor size (1.97 (1.27-3.05; I = 37.8 %), lymph node metastasis (6.48 (4.01-10.45; I = 0.40 %), and poor survival (Pooled log-rank test P-value < 0.001) in patients. Regarding potential mechanisms, functional studies revealed that LncRNA CERS6-AS1 is involved in cancer growth mainly by sponging miRNAs and regulating their downstream targets.
CONCLUSION
Available evidence suggests that LncRNA CERS6-AS1 is upregulated in different cancers and has an oncogenic role. LncRNA CERS6-AS1 expression level might predict cancer prognosis, highlighting its potential application as a prognostic biomarker for cancer.
Topics: Humans; RNA, Long Noncoding; MicroRNAs; Prognosis; Liver Neoplasms; Lymphatic Metastasis; Gene Expression Regulation, Neoplastic; Membrane Proteins; Sphingosine N-Acyltransferase
PubMed: 36580796
DOI: 10.1016/j.prp.2022.154245 -
Hormone and Metabolic Research =... Oct 2022Accumulating evidence has shown that the rs738409 polymorphism of patatin-like phospholipase domain-containing 3 (PNPLA3) is associated with non-alcoholic fatty liver... (Meta-Analysis)
Meta-Analysis
Accumulating evidence has shown that the rs738409 polymorphism of patatin-like phospholipase domain-containing 3 (PNPLA3) is associated with non-alcoholic fatty liver disease (NAFLD). Since NAFLD has been reported to be associated with lipid metabolism, this study is conducted to explore whether the rs738409 polymorphism of PNPLA3 was associated with lipid levels. By searching PubMed and the Cochrane database from May 31, 2020, to June 30, 2021. Sixty-three studies (81 003 subjects) were included for the analysis. The consistent findings for the associations of rs738409 polymorphism with lipid levels were the significantly decreased triglycerides (TG) (SMD=-0.04, 95% CI=-0.07 to -0.01, p=0.02) and total cholesterol (TC) (SMD=-0.03, 95% CI=-0.05 to -0.01, p<0.01) levels. Subgroup analysis indicated that the associations of rs738409 polymorphism with TG and TC levels were stronger in Caucasians, obesity patients, and adult subjects than in Asians, T2DM patients, and children subjects. The rs738409 polymorphism of PNPLA3 was associated with lower TG and TC levels in Caucasians, obese and adult subjects, which may contribute to the reduced coronary artery disease (CAD) risk between PNPLA3 rs738409 polymorphism and CAD.
Topics: Acyltransferases; Adult; Case-Control Studies; Child; Cholesterol; Genetic Predisposition to Disease; Genotype; Humans; Lipase; Membrane Proteins; Non-alcoholic Fatty Liver Disease; Obesity; Phospholipases; Phospholipases A2, Calcium-Independent; Polymorphism, Single Nucleotide; Triglycerides
PubMed: 36206762
DOI: 10.1055/a-1929-1677 -
Nutrition Research (New York, N.Y.) Oct 2022Nonalcoholic fatty liver disease has become the most common liver disorder worldwide, reaching a prevalence of 60% and 24% in patients with chronic liver disease and the... (Meta-Analysis)
Meta-Analysis Review
Coffee consumption has no effect on circulating markers of liver function but increases adiponectin concentrations: A systematic review and meta-analysis of randomized controlled trials.
Nonalcoholic fatty liver disease has become the most common liver disorder worldwide, reaching a prevalence of 60% and 24% in patients with chronic liver disease and the general population, respectively. Liver function is often assessed using standard liver tests such as alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and alkaline phosphatase. Randomized controlled trials (RCTs) investigating the potential beneficial effects of coffee consumption on liver function are scarce and their results are inconclusive. Some clinical trials have shown a significant increase in adiponectin concentrations following coffee consumption; however, there are few studies in this field. Hence, the hypothesis of this meta-analysis of RCTs is that coffee consumption decreases blood markers of liver function and increases adiponectin concentrations. A systematic search was conducted in PubMed-MEDLINE, Scopus, Web of Science, ClinicalTrials.gov, and Google Scholar databases. Meta-analysis was performed using a random-effects model followed by sensitivity analysis. Meta-analysis of 14 RCTs, including a total of 897 subjects, showed that coffee consumption has no significant effect on alanine aminotransferase (weighted mean difference [WMD], -0.89 mg/mL; 95% CI, -2.90 to 1.12; P = .39), aspartate aminotransferase (WMD, -0.29 mg/mL; 95% CI, -1.25 to 0.66; P = .55), gamma-glutamyl transferase (WMD, .10 mg/mL; 95% CI, -3.94 to 4.15; P = .96), alkaline phosphatase (WMD, -4.60 mg/mL; 95% CI, -9.26 to 0.07; P = .05), and lactate dehydrogenase (WMD, -0.65 mg/mL; 95% CI, -10.80 to 9.49; P = .90). However, coffee administration significantly increased adiponectin concentrations (WMD, 1.19 mg/mL; 95% CI, 0.08-2.31; P = .04). The results of this meta-analysis of RCTs suggest that coffee consumption may improve liver dysfunction through the elevation of adiponectin levels; however, further clinical trials are needed to corroborate our findings.
Topics: Adiponectin; Alanine; Alanine Transaminase; Alkaline Phosphatase; Aspartate Aminotransferases; Biomarkers; Coffee; Humans; Lactate Dehydrogenases; Liver; Randomized Controlled Trials as Topic; gamma-Glutamyltransferase
PubMed: 36126527
DOI: 10.1016/j.nutres.2022.07.010 -
Annals of Hepatology 2022We performed a systematic review and meta-analysis to evaluate the prevalence of concomitant Sjögren's syndrome (SS) with primary biliary cholangitis (PBC) in adults... (Meta-Analysis)
Meta-Analysis
INTRODUCTION AND OBJECTIVES
We performed a systematic review and meta-analysis to evaluate the prevalence of concomitant Sjögren's syndrome (SS) with primary biliary cholangitis (PBC) in adults and quantify the impact of SS on PBC.
METHODS
PubMed, Web of Science and Cochrane library were searched using subject terms and predefined inclusion and exclusion criteria.
RESULTS
Seventeen articles were included. The prevalence of SS in PBC patients ranged from 3.5 to 73% (35% pooled) (95% CI: 28-41%; p < 0.01). Seven studies included various biochemical indicators, including alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), γ-glutamyltransferase (γ-GT), total bilirubin (TBiL), albumin (ALB) and platelet (PLT), and immunological indexes including IgG, IgM, antinuclear antibody (ANA), anti-mitochondrial antibody (AMA), AMA-M2 and anti-Ro/Sjögren's syndrome antigen A (SSA) antibodies. Meta-analysis showed that there were no significant differences in ALT, AST, ALP, γ-GT, TBiL and IgM levels between PBS and PBC with SS. Pooled analysis showed that ALB (MD=0.82; 95% CI: 0.08-1.56) and PLT (MD=30.41; 95% CI: 10.16-50.66) levels were lower, IgG levels (MD=-1.55; 95% CI: -2.39 to -0.72) were higher, and the positive ratios of ANA (RR=0.92; 95% CI: 0.87-0.98), AMA (RR=0.94; 95% CI: 0.89-0.98), AMA-M2 (RR=0.77; 95% CI: 0.70-0.85) and anti-Ro/SSA antibodies (RR=0.29; 95% CI: 0.08-1.01) were significantly higher in PBC patients with SS than in PBC patients.
CONCLUSIONS
Our study confirms that SS is common in PBC. Comorbid SS appears to influence the clinical phenotype of PBC and may therefore influence the management of PBC.
Topics: Humans; Sjogren's Syndrome; Liver Cirrhosis, Biliary; Autoantibodies; Prevalence; Antibodies, Antinuclear; gamma-Glutamyltransferase; Alkaline Phosphatase; Alanine Transaminase; Immunoglobulin M; Immunoglobulin G
PubMed: 35970319
DOI: 10.1016/j.aohep.2022.100746 -
European Journal of Clinical... Oct 2022Significant pharmacokinetic variabilities have been reported for isoniazid across various populations. We aimed to summarize population pharmacokinetic studies of... (Review)
Review
Influence of N-acetyltransferase 2 (NAT2) genotype/single nucleotide polymorphisms on clearance of isoniazid in tuberculosis patients: a systematic review of population pharmacokinetic models.
PURPOSE
Significant pharmacokinetic variabilities have been reported for isoniazid across various populations. We aimed to summarize population pharmacokinetic studies of isoniazid in tuberculosis (TB) patients with a specific focus on the influence of N-acetyltransferase 2 (NAT2) genotype/single-nucleotide polymorphism (SNP) on clearance of isoniazid.
METHODS
A systematic search was conducted in PubMed and Embase for articles published in the English language from inception till February 2022 to identify population pharmacokinetic (PopPK) studies of isoniazid. Studies were included if patient population had TB and received isoniazid therapy, non-linear mixed effects modelling, and parametric approach was used for building isoniazid PopPK model and NAT2 genotype/SNP was tested as a covariate for model development.
RESULTS
A total of 12 articles were identified from PubMed, Embase, and hand searching of articles. Isoniazid disposition was described using a two-compartment model with first-order absorption and linear elimination in most of the studies. Significant covariates influencing the pharmacokinetics of isoniazid were NAT2 genotype, body weight, lean body weight, body mass index, fat-free mass, efavirenz, formulation, CD4 cell count, and gender. Majority of studies conducted in adult TB population have reported a twofold or threefold increase in isoniazid clearance for NAT2 rapid acetylators compared to slow acetylators.
CONCLUSION
The variability in disposition of isoniazid can be majorly attributed to NAT2 genotype. This results in a trimodal clearance pattern with a multi-fold increase in clearance of NAT2 rapid acetylators compared to slow acetylators. Further studies exploring the generalizability/adaptability of developed PopPK models in different clinical settings are required.
Topics: Adult; Humans; Antitubercular Agents; Arylamine N-Acetyltransferase; Body Weight; Genotype; Isoniazid; Polymorphism, Single Nucleotide; Tuberculosis
PubMed: 35852584
DOI: 10.1007/s00228-022-03362-7