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Pharmacological Research Aug 2019Excessive adiposity in an obese state is known to drive the onset of metabolic dysregulations, mostly involving chronic immune activation and oxidative stress. Prolonged...
Excessive adiposity in an obese state is known to drive the onset of metabolic dysregulations, mostly involving chronic immune activation and oxidative stress. Prolonged inflammation and oxidative stress have been linked to impaired adipose tissue function and the development of the metabolic syndrome. Currently available therapies offer minimal prophylactic effects, while substantial experimental evidence supports the ameliorative effects of N-acetylcysteine (NAC) against various metabolic complications associated with obesity. The current review provides a comprehensive synthesis of studies published in major search engines such as PubMed, Cochrane library, Embase, and Google Scholar assessing the therapeutic effect of NAC against obesity associated complications. Overwhelming literature included in this review supports the ameliorative effects of NAC against such complications in both in vitro and in vivo models of obesity. In addition to attenuating an abnormal pro-inflammatory response and limiting oxidative damage, NAC could inhibit lipid accumulation by targeting adipogenic transcription factors such as peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer binding protein beta (C/EBPβ), and improve insulin sensitivity through augmenting phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway. Although necessary evidence informing on its optimal dose and its comparative effect with other well-studied pharmacological compounds is demonstrated, it is clear that future investigations are required to confirm the therapeutic effect of NAC in obese human subjects.
Topics: Acetylcysteine; Animals; Humans; Inflammation; Obesity; Oxidative Stress; Transcription Factors
PubMed: 31254666
DOI: 10.1016/j.phrs.2019.104332 -
Critical Care (London, England) Feb 2019With the development of new techniques to easily obtain lower respiratory tract specimens, bronchoalveolar lavage fluid and other lung fluids are gaining importance in... (Meta-Analysis)
Meta-Analysis
BACKGROUND
With the development of new techniques to easily obtain lower respiratory tract specimens, bronchoalveolar lavage fluid and other lung fluids are gaining importance in pulmonary disease diagnosis. We aimed to review and summarize lung fluid biomarkers associated with acute respiratory distress syndrome diagnosis and mortality.
METHODS
After searching PubMed, Embase, Web of Science, and the Cochrane Library for articles published prior to January 11, 2018, we performed a meta-analysis on biomarkers for acute respiratory distress syndrome diagnosis in at-risk patients and those related to disease mortality. From the included studies, we then extracted the mean and standard deviation of the biomarker concentrations measured in the lung fluid, acute respiratory distress syndrome etiologies, sample size, demographic variables, diagnostic criteria, mortality, and protocol for obtaining the lung fluid. The effect size was measured by the ratio of means, which was then synthesized by the inverse-variance method using its natural logarithm form and transformed to obtain a pooled ratio and 95% confidence interval.
RESULTS
In total, 1156 articles were identified, and 49 studies were included. Increases in total phospholipases A2 activity, total protein, albumin, plasminogen activator inhibitor-1, soluble receptor for advanced glycation end products, and platelet activating factor-acetyl choline were most strongly associated with acute respiratory distress syndrome diagnosis. As for biomarkers associated with acute respiratory distress syndrome mortality, interleukin-1β, interleukin-6, interleukin-8, Kerbs von Lungren-6, and plasminogen activator inhibitor-1 were significantly increased in the lung fluid of patients who died. Decreased levels of Club cell protein and matrix metalloproteinases-9 were associated with increased odds for acute respiratory distress syndrome diagnosis, whereas decreased levels of Club cell protein and interleukin-2 were associated with increased odds for acute respiratory distress syndrome mortality.
CONCLUSIONS
This meta-analysis provides a ranking system for lung fluid biomarkers, according to their association with diagnosis or mortality of acute respiratory distress syndrome. The performance of biomarkers among studies shown in this article may help to improve acute respiratory distress syndrome diagnosis and outcome prediction.
Topics: Antigens, Human Platelet; Biomarkers; Bronchoalveolar Lavage Fluid; Hepatocyte Growth Factor; Humans; Interleukin-8; Lung; Plasminogen Activator Inhibitor 1; Platelet Activating Factor; Receptor for Advanced Glycation End Products; Respiratory Distress Syndrome
PubMed: 30755248
DOI: 10.1186/s13054-019-2336-6 -
Journal of Psychopharmacology (Oxford,... Apr 2019Multiple N-methyl-d-aspartate (NMDA)-receptor-enhancing agents have demonstrated promising effects for cognition in schizophrenia. However, the results of studies have... (Meta-Analysis)
Meta-Analysis
Effect of N-methyl-D-aspartate-receptor-enhancing agents on cognition in patients with schizophrenia: A systematic review and meta-analysis of double-blind randomised controlled trials.
BACKGROUND
Multiple N-methyl-d-aspartate (NMDA)-receptor-enhancing agents have demonstrated promising effects for cognition in schizophrenia. However, the results of studies have been conflicting. This updated meta-analysis explored the effect of NMDA-receptor-enhancing agents on cognitive function.
METHODS
We searched PubMed, the Cochrane Collaboration Central Register of Controlled Clinical Trials and Cochrane Systematic Reviews for studies on the effect of NMDA-receptor-enhancing agents on cognitive function in patients with schizophrenia up to September 2018. Double-blind randomised placebo trials with cognition rating scales were included. We pooled studies by using a random-effect model for comparisons with add-on NMDA-receptor-enhancing agents. Cognitive function scores were compared between baseline and subsequent levels, and NMDA-receptor-positive modulators were assessed using the standardised mean difference (SMD) with 95% confidence intervals (CIs). We evaluated statistical heterogeneity through visual inspection of funnel plots and by using the I statistic.
RESULTS
We identified 25 trials with 1951 participants meeting the inclusion criteria. NMDA-receptor-enhancing agents had a small but nonsignificant effect compared with the placebo on overall cognitive function (SMD = 0.068, CI = -0.056 to 0.193, P = 0.283). We identified trials enrolling patients aged between 30 and 39 years old, which reported significant positive effects (SMD: 0.163, 95% CI: 0.016-0.310, P = 0.030). Men were associated with a smaller effect of NMDA-receptor-positive modulators on overall cognitive function. Moreover, subgroup meta-analysis of cognitive domains revealed that N-acetyl cysteine (NAC) had a significant effect on working memory ( P-value for interaction = 0.038; SMD = 0.679, CI = 0.397-0.961, P < 0.001).
CONCLUSIONS
Our meta-analysis revealed no significant effect of NMDA-enhancing agents on overall cognition. However, subgroup analysis suggested that NMDAR-enhancing agents may benefit young patients with schizophrenia, and NAC may have an effect on working memory. Additional trials with larger samples are suggested to evaluate these cognitive domains and ascertain the possible mechanisms.
Topics: Age Factors; Cognition; Excitatory Amino Acid Agonists; Humans; Randomized Controlled Trials as Topic; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Sex Factors
PubMed: 30730250
DOI: 10.1177/0269881118822157 -
Current Genomics Nov 2018Involvement of life stress in Late-Onset Alzheimer's Disease (LOAD) has been evinced in longitudinal cohort epidemiological studies, and endocrinologic evidence suggests... (Review)
Review
Involvement of life stress in Late-Onset Alzheimer's Disease (LOAD) has been evinced in longitudinal cohort epidemiological studies, and endocrinologic evidence suggests involvements of catecholamine and corticosteroid systems in LOAD. Early Life Stress (ELS) rodent models have successfully demonstrated sequelae of maternal separation resulting in LOAD-analogous pathology, thereby supporting a role of insulin receptor signalling pertaining to GSK-3beta facilitated tau hyper-phosphorylation and amyloidogenic processing. Discussed are relevant ELS studies, and findings from three mitogen-activated protein kinase pathways (JNK/SAPK pathway, ERK pathway, p38/MAPK pathway) relevant for mediating environmental stresses. Further considered were the roles of autophagy impairment, neuroinflammation, and brain insulin resistance. For the meta-analytic evaluation, 224 candidate gene loci were extracted from reviews of animal studies of LOAD pathophysiological mechanisms, of which 60 had no positive results in human LOAD association studies. These loci were combined with 89 gene loci confirmed as LOAD risk genes in previous GWAS and WES. Of the 313 risk gene loci evaluated, there were 35 human reports on epigenomic modifications in terms of methylation or histone acetylation. 64 microRNA gene regulation mechanisms were published for the compiled loci. Genomic association studies support close relations of both noradrenergic and glucocorticoid systems with LOAD. For HPA involvement, a CRHR1 haplotype with MAPT was described, but further association of only HSD11B1 with LOAD found; however, association of FKBP1 and NC3R1 polymorphisms was documented in support of stress influence to LOAD. In the brain insulin system, IGF2R, INSR, INSRR, and plasticity regulator ARC, were associated with LOAD. Pertaining to compromised myelin stability in LOAD, relevant associations were found for BIN1, RELN, SORL1, SORCS1, CNP, MAG, and MOG. Regarding epigenetic modifications, both methylation variability and de-acetylation were reported for LOAD. The majority of up-to-date epigenomic findings include reported modifications in the well-known LOAD core pathology loci MAPT, BACE1, APP (with FOS, EGR1), PSEN1, PSEN2, and highlight a central role of BDNF. Pertaining to ELS, relevant loci are FKBP5, EGR1, GSK3B; critical roles of inflammation are indicated by CRP, TNFA, NFKB1 modifications; for cholesterol biosynthesis, DHCR24; for myelin stability BIN1, SORL1, CNP; pertaining to (epi)genetic mechanisms, hTERT, MBD2, DNMT1, MTHFR2. Findings on gene regulation were accumulated for BACE1, MAPK signalling, TLR4, BDNF, insulin signalling, with most reports for miR-132 and miR-27. Unclear in epigenomic studies remains the role of noradrenergic signalling, previously demonstrated by neuropathological findings of childhood nucleus caeruleus degeneration for LOAD tauopathy.
PubMed: 30386171
DOI: 10.2174/1389202919666171229145156 -
Pharmacological Research Oct 2018Selective Serotonin Reuptake Inhibitors (SSRIs) may have side effects, such as stiffness, tremors and altered tonic activity, as well as an increased risk of developing...
Selective Serotonin Reuptake Inhibitors (SSRIs) may have side effects, such as stiffness, tremors and altered tonic activity, as well as an increased risk of developing insulin resistance and diabetes mellitus. However, little is known about the structural, functional and metabolic changes of skeletal muscle after administration of SSRIs. The aim of this systematic review was to explore and discuss the effects of SSRIs on skeletal muscle properties described in human and rodent studies. A systematic search of PUBMED, SCOPUS, and WEB OF SCIENCE was performed. The inclusion criteria were intervention studies in humans and rodents that analysed the effects of SSRIs on skeletal muscle properties. The research found a total of six human studies, including two randomized controlled trials, one non-randomized controlled trial, one uncontrolled before-after study and two case reports, and six preclinical studies in rodents. Overall, the studies in humans and rodents showed altered electrical activity in skeletal muscle function, assessed through electromyography (EMG) and needle EMG in response to chronic treatment or local injection with SSRIs. In addition, rodent studies reported that SSRIs may exert effects on muscle weight, the number of myocytes and the cross-sectional area of skeletal muscle fibre. The results showed effects in energy metabolism associated with chronic SSRI use, reporting altered levels of glycogen synthase activity, acetyl-CoA carboxylase phosphorylation, citrate synthase activity, and protein kinase B Ser phosphorylation. Moreover, changes in insulin signalling and glucose uptake were documented. In this context, we concluded based on human and rodent studies that SSRIs affect electrical muscle activity, structural properties and energy metabolism in skeletal muscle tissue. However, these changes varied according to pre-existing metabolic and functional conditions in the rodents and humans.
Topics: Animals; Humans; Muscle, Skeletal; Selective Serotonin Reuptake Inhibitors
PubMed: 30196103
DOI: 10.1016/j.phrs.2018.09.004 -
British Journal of Clinical Pharmacology Dec 2018The aim of this study is to evaluate the potential association between N-acetyltransferase type 2 (NAT2) polymorphisms and drug-induced liver injury during anti-TB... (Meta-Analysis)
Meta-Analysis
AIMS
The aim of this study is to evaluate the potential association between N-acetyltransferase type 2 (NAT2) polymorphisms and drug-induced liver injury during anti-TB treatment (AT-DILI).
METHODS
We conducted a systematic review and performed a meta-analysis to clarify the role of NAT2 polymorphism in AT-DILI. PubMed, Medline and EMBASE databases were searched for studies published in English to December 31, 2017, on the association between the NAT2 polymorphism and AT-DILI risk. Outcomes were pooled with random-effects meta-analysis. Details were registered in the PROSPERO register (number: CRD42016051722).
RESULTS
Thirty-seven studies involving 1527 cases and 7184 controls were included in this meta-analysis. The overall odds ratio (OR) of AT-DILI associated with NAT2 slow acetylator phenotype was 3.15 (95% CI 2.58-3.84, I = 51.3%, P = 0.000). The OR varied between different ethnic populations, ranging from 6.42 (95% CI 2.41-17.10, I = 2.3%) for the West Asian population to 2.32 (95% CI 0.58-9.24, I = 80.3%) for the European population. Within the slow NAT2 genotype, variation was also observed; NAT2*6/*7 was associated with the highest risk of AT-DILI (OR = 1.68, 95% CI 1.09-2.59) compared to the other slow NAT2 acetylators combined.
CONCLUSIONS
NAT2 slow acetylation was observed to increase the risk of AT-DILI in tuberculosis patients. Our results support the hypothesis that the slow NAT2 genotype is a risk factor for AT-DILI.
Topics: Antitubercular Agents; Arylamine N-Acetyltransferase; Chemical and Drug Induced Liver Injury; Genetic Predisposition to Disease; Genotype; Humans; Polymorphism, Genetic
PubMed: 30047605
DOI: 10.1111/bcp.13722 -
International Journal of Sport... May 2018Coffee is one of the most consumed beverages in the world, and it can improve insulin sensitivity, stimulating glucose uptake in skeletal muscle when adequate... (Review)
Review
Coffee is one of the most consumed beverages in the world, and it can improve insulin sensitivity, stimulating glucose uptake in skeletal muscle when adequate carbohydrate intake is observed. The aim of this review is to analyze the effects of coffee and coffee components on muscle glycogen metabolism. A literature search was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis, and seven studies were included, that explored the effects of coffee components on various substances and signaling proteins. In one of the studies with humans, caffeine was shown to increase glucose levels, Ca/calmodulin-dependent protein kinase phosphorylation, glycogen resynthesis rates, and glycogen accumulation after exercise. After intravenous injection of caffeine in rats, caffeine increased adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) phosphorylation, and glucose transport. In in vitro studies, caffeine raised AMPK and ACC phosphorylation, increasing glucose transport activity and reducing energy status in rat muscle cells. Cafestol and caffeic acid increased insulin secretion in rat beta cells and glucose uptake into human muscle cells. Caffeic acid also increased AMPK and ACC phosphorylation, reducing the energy status and increasing glucose uptake in rat muscle cells. Chlorogenic acid did not show any positive or negative effect. The findings from this review must be taken with caution due to the limited number of studies on the subject. In conclusion, various coffee components had a neutral or positive role in the metabolism of glucose and muscle glycogen, whereas no detrimental effect was described. Coffee beverages should be tested as an option for athletes' glycogen recovery.
Topics: AMP-Activated Protein Kinases; Acetyl-CoA Carboxylase; Animals; Coffee; Exercise; Glycogen; Humans; Insulin Resistance; Insulin-Secreting Cells; Muscle Cells; Muscle, Skeletal; Phosphorylation; Rats
PubMed: 29345166
DOI: 10.1123/ijsnem.2017-0342 -
Drug Metabolism Reviews May 2018N-acetyltransferase 1 (NAT1), a polymorphic Phase II enzyme, plays an essential role in metabolizing heterocyclic and aromatic amines, which are implicated in urinary... (Meta-Analysis)
Meta-Analysis Review
N-acetyltransferase 1 (NAT1), a polymorphic Phase II enzyme, plays an essential role in metabolizing heterocyclic and aromatic amines, which are implicated in urinary bladder cancer (BCa). This systematic review investigates a possible association between the different NAT1 genetic polymorphisms and BCa risk. Medline, PubMed, EMBASE, Scopus, Web of Science, OpenGrey, and BASE databases were searched to identify eligible studies. The random-effect model was used to calculate pooled effects estimates. Statistical heterogeneity was tested with Chi-square and I. Twenty case-control studies, including 5606 cases and 6620 controls, met the inclusion criteria. Pooled odds ratios (OR) analyses showed a statistically significant difference in NAT1*10 versus non-NAT1*10 acetylators in the total sample (OR: 0.87; 95% CI: 0.79-0.96) but was borderline among Caucasians (OR: 0.88 with 95% CI: 0.77-1.01). No statistically significant differences in BCa risk were found for: NAT1*10 versus NAT1*4 wild type (OR: 0.97; 95% CI: 0.78-1.19), NAT1 'Fast' versus 'Normal' acetylators (OR: 1.03; 95% CI: 0.84-1.27), and NAT1 'Slow' versus 'Fast' (OR: 2.32; 95% CI: 0.93-5.84) or 'Slow' versus 'Normal' acetylators (OR: 1.84; 95% CI: 0.92-3.68). When stratifying by smoking status, no statistically significant differences in BCa risk were found for NAT1*10 versus non-NAT1*10 acetylators among the different subgroups. Our study suggests a modest protective role for NAT1*10 and a possible risk contributory role for slow acetylation genotypes in BCa risk. Further research is recommended to confirm these associations.
Topics: Arylamine N-Acetyltransferase; Genotype; Humans; Isoenzymes; Phenotype; Polymorphism, Genetic; Urinary Bladder Neoplasms
PubMed: 29258340
DOI: 10.1080/03602532.2017.1415928 -
Anti-cancer Agents in Medicinal... 2018This systematic review aims to elucidate the role of melatonin (N-acetyl-5-metoxy-tryptamine) (MLT) in the prevention and treatment of cancer. MLT is a pineal gland...
This systematic review aims to elucidate the role of melatonin (N-acetyl-5-metoxy-tryptamine) (MLT) in the prevention and treatment of cancer. MLT is a pineal gland secretory product, an evolutionarily highly conserved molecule; it is also an antioxidant and an impressive protector of mitochondrial bioenergetic activity. MLT is characterized by an ample range of activities, modulating the physiology and molecular biology of the cell. Its physiological functions relate principally to the interaction of G Protein-Coupled MT1 and MT2 trans-membrane receptors (GPCRs), a family of guanidine triphosphate binding proteins. MLT has been demonstrated to suppress the growth of various tumours both, in vivo and in vitro. In this review, we analyze in depth, the antioxidant activity of melatonin, aiming to illustrate the cancer treatment potential of the molecule, by limiting or reversing the changes occurring during cancer development and growth.
Topics: Animals; Antineoplastic Agents; Antioxidants; Humans; Melatonin; Neoplasms; Oxidative Stress; Receptors, Melatonin
PubMed: 29173185
DOI: 10.2174/1871520617666171121120223 -
Journal of Nutrigenetics and... 2017Epigenetics refers to modifications in gene activity and expression without alteration at the DNA sequence. Environment and diet could influence gene expression. Diet... (Meta-Analysis)
Meta-Analysis Review
Sulforaphane and Epigallocatechin Gallate Restore Estrogen Receptor Expression by Modulating Epigenetic Events in the Breast Cancer Cell Line MDA-MB-231: A Systematic Review and Meta-Analysis.
BACKGROUND/AIMS
Epigenetics refers to modifications in gene activity and expression without alteration at the DNA sequence. Environment and diet could influence gene expression. Diet modifications may be meaningful in preventing and treating chronic diseases, cancer included. Dietary bioactive compounds, such as polyphenols (e.g., curcumin, resveratrol, or epigallocatechin gallate [EGCG]) or isothiocyanate (e.g., sulforaphane [SFN]), can regulate histone acetylation. The aim of this systematic review and meta-analysis was to evaluate the effect of SFN and EGCG on breast cancer (BC) cells cultured in vitro.
METHODS
Due to the enormous variability observed in study protocols and the innumerable genes involved, only studies analyzing the number of apoptotic cells in the MDA-MB-231 cell line were evaluated. The effect size (ES) was computed as the ratio of means.
RESULTS
We identified 7 studies, 4 regarding the effect of 10 µM SFN on MDA-MB-231 cells (ES = 4.59, 95% confidence interval 4.05-5.20) and 3 focusing on the impact of 20 µM EGCG (ES = 2.84, 95% confidence interval 2.60-3.10).
CONCLUSION
The findings suggest beneficial effects of dietary bioactive compounds such as SFN and EGCG and their effect on BC cells by restoring estrogen receptor gene expression, modulating epigenetic changes and events, and interfering with tumor growth rate. Publication bias limits the generalizability of the conclusions. High-quality studies are needed.
Topics: Anticarcinogenic Agents; Apoptosis; Breast Neoplasms; Catechin; Cell Line, Tumor; Epigenesis, Genetic; Female; Gene Expression; Humans; Isothiocyanates; Nutrigenomics; Receptors, Estrogen; Sulfoxides
PubMed: 29040973
DOI: 10.1159/000480636