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Cells Apr 2023Betel quid and areca nut are complex mixture carcinogens, but little is known about whether their derived single-agent arecoline or arecoline -oxide (ANO) is...
Betel quid and areca nut are complex mixture carcinogens, but little is known about whether their derived single-agent arecoline or arecoline -oxide (ANO) is carcinogenic, and the underlying mechanisms remain unclear. In this systematic review, we analyzed recent studies on the roles of arecoline and ANO in cancer and strategies to block carcinogenesis. In the oral cavity, flavin-containing monooxygenase 3 oxidizes arecoline to ANO, and both alkaloids conjugate with -acetylcysteine to form mercapturic acid compounds, which are excreted in urine, reducing arecoline and ANO toxicity. However, detoxification may not be complete. Arecoline and ANO upregulated protein expression in oral cancer tissue from areca nut users compared to expression levels in adjacent normal tissue, suggesting a causal relationship between these compounds and oral cancer. Sublingual fibrosis, hyperplasia, and oral leukoplakia were diagnosed in mice subjected to oral mucosal smearing of ANO. ANO is more cytotoxic and genotoxic than arecoline. During carcinogenesis and metastasis, these compounds increase the expression of epithelial-mesenchymal transition (EMT) inducers such as reactive oxygen species, transforming growth factor-β1, Notch receptor-1, and inflammatory cytokines, and they activate EMT-related proteins. Arecoline-induced epigenetic markers such as sirtuin-1 hypermethylation, low protein expression of miR-22, and miR-886-3-p accelerate oral cancer progression. Antioxidants and targeted inhibitors of the EMT inducers used reduce the risk of oral cancer development and progression. Our review findings substantiate the association of arecoline and ANO with oral cancer. Both of these single compounds are likely carcinogenic to humans, and their mechanisms and pathways of carcinogenesis are useful indicators for cancer therapy and prognosis.
Topics: Arecoline; Cyclic N-Oxides; Mouth Neoplasms; Carcinogenesis; Humans; Animals; Mice; Areca; Oxygenases; Oxidation-Reduction; Acetylcysteine; Epigenesis, Genetic; Carcinogens
PubMed: 37190117
DOI: 10.3390/cells12081208 -
Psychopharmacology Nov 2022While one of the basic axioms of pharmacology postulates that there is a relationship between the concentration and effects of a drug, the value of measuring blood... (Meta-Analysis)
Meta-Analysis Review
RATIONALE
While one of the basic axioms of pharmacology postulates that there is a relationship between the concentration and effects of a drug, the value of measuring blood levels is questioned by many clinicians. This is due to the often-missing validation of therapeutic reference ranges.
OBJECTIVES
Here, we present a prototypical meta-analysis of the relationships between blood levels of aripiprazole, its target engagement in the human brain, and clinical effects and side effects in patients with schizophrenia and related disorders.
METHODS
The relevant literature was systematically searched and reviewed for aripiprazole oral and injectable formulations. Population-based concentration ranges were computed (N = 3,373) and pharmacokinetic influences investigated.
RESULTS
Fifty-three study cohorts met the eligibility criteria. Twenty-nine studies report blood level after oral, 15 after injectable formulations, and nine were positron emission tomography studies. Conflicting evidence for a relationship between concentration, efficacy, and side effects exists (assigned level of evidence low, C; and absent, D). Population-based reference ranges are well in-line with findings from neuroimaging data and individual efficacy studies. We suggest a therapeutic reference range of 120-270 ng/ml and 180-380 ng/ml, respectively, for aripiprazole and its active moiety for the treatment of schizophrenia and related disorders.
CONCLUSIONS
High interindividual variability and the influence of CYP2D6 genotypes gives a special indication for Therapeutic Drug Monitoring of oral and long-acting aripiprazole. A starting dose of 10 mg will in most patients result in effective concentrations in blood and brain. 5 mg will be sufficient for known poor metabolizers.
Topics: Humans; Aripiprazole; Schizophrenia; Reference Values; Antipsychotic Agents; Cytochrome P-450 CYP2D6
PubMed: 36195732
DOI: 10.1007/s00213-022-06233-2 -
Psychological Medicine Aug 2023Impaired brain metabolism may be central to schizophrenia pathophysiology, but the magnitude and consistency of metabolic dysfunction is unknown. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Impaired brain metabolism may be central to schizophrenia pathophysiology, but the magnitude and consistency of metabolic dysfunction is unknown.
METHODS
We searched MEDLINE, PsychINFO and EMBASE between 01/01/1980 and 13/05/2021 for studies comparing regional brain glucose metabolism using FDG-PET, in schizophrenia/first-episode psychosis controls. Effect sizes (Hedges ) were pooled using a random-effects model. Primary measures were regional absolute and relative CMRGlu in frontal, temporal, parietal and occipital lobes, basal ganglia and thalamus.
RESULTS
Thirty-six studies (1335 subjects) were included. Frontal absolute glucose metabolism (Hedge's = -0.74 ± 0.54, = 0.01; = 67%) and metabolism relative to whole brain ( = -0.44 ± 0.34, = 0.01; = 55%) were lower in schizophrenia controls with moderate heterogeneity. Absolute frontal metabolism was lower in chronic ( = -1.18 ± 0.73) first-episode patients ( = -0.09 ± 0.88) and controls. Medicated patients showed frontal hypometabolism relative to controls (-1.04 ± 0.26) while metabolism in drug-free patients did not differ significantly from controls. There were no differences in parietal, temporal or occipital lobe or thalamic metabolism in schizophrenia controls. Excluding outliers, absolute basal ganglia metabolism was lower in schizophrenia controls (-0.25 ± 0.24, = 0.049; = 5%). Studies identified reporting voxel-based morphometry measures of absolute FDG uptake (eight studies) were also analysed using signed differential mapping analysis, finding lower FDG uptake in the left anterior cingulate gyrus ( = -4.143; = 0.007) and the left inferior orbital frontal gyrus ( = -4.239; = 0.02) in schizophrenia.
CONCLUSIONS
We report evidence for hypometabolism with large effect sizes in the frontal cortex in schizophrenia without consistent evidence for alterations in other brain regions. Our findings support the hypothesis of hypofrontality in schizophrenia.
Topics: Humans; Glucose; Schizophrenia; Fluorodeoxyglucose F18; Brain; Positron-Emission Tomography
PubMed: 35730361
DOI: 10.1017/S003329172200174X -
Archives of Endocrinology and Metabolism Nov 2023FGF21 is a hormone produced primarily by the liver with several metabolic functions, such as induction of heat production, control of glucose homeostasis, and regulation... (Meta-Analysis)
Meta-Analysis Review
FGF21 is a hormone produced primarily by the liver with several metabolic functions, such as induction of heat production, control of glucose homeostasis, and regulation of blood lipid levels. Due to these actions, several laboratories have developed FGF21 analogs to treat patients with metabolic disorders such as obesity and diabetes. Here, we performed a systematic review and meta-analysis of randomized controlled trials that used FGF21 analogs and analyzed metabolic outcomes. Our search yielded 236 articles, and we included eight randomized clinical trials in the meta-analysis. The use of FGF21 analogs exhibited no effect on fasting blood glucose, glycated hemoglobin, HOMA index, blood free fatty acids or systolic blood pressure. However, the treatment significantly reduced fasting insulinemia, body weight and total cholesterolemia. None of the included studies were at high risk of bias. The quality of the evidence ranged from moderate to very low, especially due to imprecision and indirection issues. These results indicate that FGF21 analogs can potentially treat metabolic syndrome. However, more clinical trials are needed to increase the quality of evidence and confirm the effects seen thus far.
Topics: Humans; Blood Glucose; Metabolic Diseases; Metabolic Syndrome; Obesity; Diabetes Mellitus
PubMed: 37948566
DOI: 10.20945/2359-4292-2022-0493 -
Medicina (Kaunas, Lithuania) Jun 2023Type 2 Diabetes Mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) are part of metabolic syndrome and share multiple causal associations. Both conditions have...
The Effects of Sodium-Glucose Cotransporter 2-Inhibitors on Steatosis and Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease or Steatohepatitis and Type 2 Diabetes: A Systematic Review of Randomized Controlled Trials.
Type 2 Diabetes Mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) are part of metabolic syndrome and share multiple causal associations. Both conditions have an alarmingly increasing incidence and lead to multiple complications, which have an impact on a variety of organs and systems, such as the kidneys, eyes, and nervous and cardiovascular systems, or may cause metabolic disruptions. Sodium-glucose cotransporter 2-inhibitors (SGLT2-i), as an antidiabetic class with well-established cardiovascular benefits, and its class members have also been studied for their presumed effects on steatosis and fibrosis improvement in patients with NAFLD or non-alcoholic steatohepatitis (NASH). The MEDLINE and Cochrane databases were searched for randomized controlled trials examining the efficacy of SGLT2-i on the treatment of NAFLD/NASH in patients with T2DM. Of the originally identified 179 articles, 21 articles were included for final data analysis. Dapagliflozin, empagliflozin, and canagliflozin are some of the most used and studied SGLT2-i agents which have proven efficacy in treating patients with NAFLD/NASH by addressing/targeting different pathophysiological targets/mechanisms: insulin sensitivity improvement, weight loss, especially visceral fat loss, glucotoxicity, and lipotoxicity improvement or even improvement of chronic inflammation. Despite the considerable variability in study duration, sample size, and diagnostic method, the SGLT2-i agents used resulted in improvements in non-invasive markers of steatosis or even fibrosis in patients with T2DM. This systematic review offers encouraging results that place the SGLT2-i class at the top of the therapeutic arsenal for patients diagnosed with T2DM and NAFLD/NASH.
Topics: Canagliflozin; Diabetes Mellitus, Type 2; Fatty Liver; Non-alcoholic Fatty Liver Disease; Randomized Controlled Trials as Topic; Sodium-Glucose Transporter 2 Inhibitors; Humans
PubMed: 37374340
DOI: 10.3390/medicina59061136 -
BMC Endocrine Disorders Jul 2023Childhood obesity is one of the main concerns of public health. Considering its long-term adverse health effect, various studies investigated the effect of drug therapy... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Childhood obesity is one of the main concerns of public health. Considering its long-term adverse health effect, various studies investigated the effect of drug therapy on anthropometric parameters and provided mixed results. In this systematic review and meta-analysis, we aimed to determine the effect of Orlistat on anthropometrics and biochemical parameters in children and adolescents.
MATERIALS AND METHODS
The databases of PubMed, Scopus, and Web of Science were searched until September 2022. Experimental and semi-experimental studies were included if they evaluated the effect of Orlistat on obesity-related parameters in children and reported the before and after anthropometric values. A revised Cochrane risk-of-bias (Rob2) was used to evaluate the methodological quality. STATA software version 16.0 was used for the meta-analysis of the random-effect model.
RESULTS
Of 810 articles retrieved in the initial search, four experimental and two semi-experimental studies were selected for systematic review. The result of the meta-analysis of experimental studies indicated the significant effect of Orlistat on waist circumference (SMD: -0.27, 95% CI: -0.47, -0.07) and serum insulin level (SMD: -0.89, 95% CI: -1.52, 0.26). However, there were no significant effects of orlistat on body weight, body mass index, lipid profile, and serum glucose level.
CONCLUSION
The present meta-analysis showed the significant effect of Orlistat on the reduction of waist circumference and insulin level in overweight and obese adolescents. However, due to the paucity of studies included in the meta-analysis, more prospective studies with longer duration and more sample sizes will be needed in this age group.
Topics: Child; Adolescent; Humans; Orlistat; Anti-Obesity Agents; Prospective Studies; Pediatric Obesity; Lactones; Insulins
PubMed: 37420181
DOI: 10.1186/s12902-023-01390-7 -
Minerva Medica Aug 2021The antimicrobial trimethoprim is structurally related to potassium-sparing diuretics and may consequently lead to derangements in electrolyte and acid-base balance....
INTRODUCTION
The antimicrobial trimethoprim is structurally related to potassium-sparing diuretics and may consequently lead to derangements in electrolyte and acid-base balance. Since no report so far analyzed the literature documenting individual cases with electrolyte and acid-base derangements induced by trimethoprim, a systematic review was carried out.
EVIDENCE ACQUISITION
We retained 53 reports documenting 68 cases (42 males and 26 females 23 to 96 years of age) of electrolyte or acid-base derangements occurring on trimethoprim for about 5 days.
EVIDENCE SYNTHESIS
One hundred five electrolyte imbalances were detected in the 68 patients: hyperkalemia (>5.0 mmol/L) in 62 (91%), hyponatremia (<135 mmol/L) in 29 (43%) and metabolic acidosis (pH<7.38 and bicarbonate <19 mmol/L) in 14 (21%) cases. Following possible predisposing factors for electrolyte and acid-base abnormalities were found in 54 (79%) patients: high-dose trimethoprim, comedication with drugs that have been associated with electrolyte and acid-base derangements, preexisting kidney disease, age ≥80 years and diabetes mellitus.
CONCLUSIONS
High-dose trimethoprim, comedicated with drugs that have been associated with electrolyte and acid-base derangements, poor kidney function, age ≥80 years and diabetes mellitus predispose to trimethoprim-associated electrolyte and acid-base abnormalities. Clinicians must recognize patients at risk, possibly avoid drug combinations that may worsen the problem and monitor the laboratory values.
Topics: Acidosis; Adult; Aged; Aged, 80 and over; Anti-Infective Agents, Urinary; Bicarbonates; Diabetes Complications; Female; Humans; Hyperkalemia; Hyponatremia; Kidney Diseases; Male; Middle Aged; Trimethoprim; Young Adult
PubMed: 32697061
DOI: 10.23736/S0026-4806.20.06660-4 -
Women's Health (London, England) 2024Polycystic ovary syndrome is a common reproductive endocrine condition that affects women of fertile age and is characterized by three main features, including... (Review)
Review
Polycystic ovary syndrome is a common reproductive endocrine condition that affects women of fertile age and is characterized by three main features, including hyperandrogenism, chronic anovulation, and polycystic ovaries. In addition, half of women with polycystic ovary syndrome have insulin resistance, and obesity or overweight, type 2 diabetes, hypertension, and hyperlipidemia are the most common metabolic abnormalities affecting (30%) women with polycystic ovary syndrome. Weight loss is regarded as the first-line treatment as it can potentially improve polycystic ovary syndrome parameters (androgen levels, menstrual cyclicity, lipid and glucose metabolism). However, achieving and maintaining weight loss can be challenging, and pharmacological agents could be essential to achieve optimal glycemic control and improve the endocrine disturbance associated with polycystic ovary syndrome. Glucagon-like peptide-1 receptor agonist has been demonstrated as monotherapy or in combination with metformin for managing obesity and insulin resistance associated with polycystic ovary syndrome. Yet, its effect on endocrine and metabolic parameters remains elusive, and further research is needed to close the gap. The aim is to evaluate the efficacy of glucagon-like peptide-1 receptor agonist monotherapy and/or a combined treatment between glucagon-like peptide-1 receptor agonist and metformin for improving anthropometric measurements, endocrine and metabolic parameters in lean and obese women with polycystic ovary syndrome. A systematic review of longitudinal cohort studies was conducted across databases including Ovid Medline, PubMed Central, and Cochrane Library between 2015 and 2022. Eligible studies included participants with polycystic ovary syndrome diagnosed according to the 2003 Rotterdam or the 1990 National Institutes of Health criteria. A total of eight studies including 486 patients with polycystic ovary syndrome were analyzed. The mean age was between 18 and 45 years with mean follow-up period between 12 and 32 weeks. In all these studies, results were comparable for the reduction in body mass index, waist circumference, fat mass, and visceral fat mass; however, it was more in combination therapy versus comparator. In conclusion, glucagon-like peptide-1 receptor agonists effectively reduce body weight and improve some of the endocrine and metabolic parameters of polycystic ovary syndrome. A combined treatment with glucagon-like peptide-1 receptor agonist and metformin had significant effects on weight loss and favorable results on endocrine and metabolic parameters, yet further research is needed to discover the long-term safety of combined therapy in women diagnosed with polycystic ovary syndrome and obesity or overweight.
Topics: Female; Humans; Infant; Male; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor Agonists; Insulin Resistance; Longitudinal Studies; Metformin; Obesity; Overweight; Polycystic Ovary Syndrome; United States; Weight Loss
PubMed: 38444070
DOI: 10.1177/17455057241234530 -
International Journal of Molecular... Nov 2023Diabetes is a serious chronic metabolic disease that causes complications over time, bringing serious public health challenges that affect different countries across the... (Review)
Review
Diabetes is a serious chronic metabolic disease that causes complications over time, bringing serious public health challenges that affect different countries across the world. The current clinical drugs for diabetes may lead to adverse effects such as hypoglycemia and liver and abdominal distension and pain, which prompt people to explore new treatments for diabetes without side effects. The research objective of this review article is to systematically review studies on vitamins and diabetes and to explain their possible mechanism of action, as well as to assess the role of vitamins as drugs for the prevention and treatment of diabetes. To achieve our objective, we searched scientific databases in PubMed Central, Medline databases and Web of Science for articles, using "vitamin" and "diabetes" as key words. The results of numerous scientific investigations revealed that vitamin levels were decreased in humans and animals with diabetes, and vitamins show promise for the prevention and/or control of diabetes through anti-inflammation, antioxidation and the regulation of lipid metabolism. However, a few studies showed that vitamins had no positive effect on the development of diabetes. Currently, studies on vitamins in the treatment of diabetes are still very limited, and there are no clinical data to clarify the dose-effect relationship between vitamins and diabetes; therefore, vitamins are not recommended as routine drugs for the treatment of diabetes. However, we still emphasize the great potential of vitamins in the prevention and treatment of diabetes, and higher quality studies are needed in the future to reveal the role of vitamins in the development of diabetes.
Topics: Humans; Vitamins; Dietary Supplements; Vitamin A; Vitamin K; Diabetes Mellitus
PubMed: 38003557
DOI: 10.3390/ijms242216371 -
Frontiers in Endocrinology 2023The aim was to conduct a systematic review and meta-analysis for assessing the effectiveness and safety of dietary polyphenol curcumin supplement on metabolic,... (Meta-Analysis)
Meta-Analysis Review
Effects of dietary polyphenol curcumin supplementation on metabolic, inflammatory, and oxidative stress indices in patients with metabolic syndrome: a systematic review and meta-analysis of randomized controlled trials.
OBJECTIVE
The aim was to conduct a systematic review and meta-analysis for assessing the effectiveness and safety of dietary polyphenol curcumin supplement on metabolic, inflammatory, and oxidative stress indices in patients with metabolic syndrome (MetS).
METHODS
A comprehensive search for clinical trials was conducted in the following scientific databases: PubMed, SCOPUS, Cochrane Library, EMBASE, Web of Science, and China Biological Medicine. Randomized controlled trials (RCTs) evaluating the efficacy and safety of curcumin supplement for MetS were identified. A random-effects meta-analysis was performed using inverse variance, and efficacy was expressed as mean difference (MD) with 95% confidence interval (CI). The metabolic syndrome markers that were evaluated in the present study included waist circumference (WC), fasting blood sugar (FBS), systolic blood pressure (SBP), diastolic blood pressure (DBP), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), tumor necrosis factor-a (TNF-a), interleukin 6 (IL-6), C-reactive protein (CRP), ultrasensitive c-reactive protein (hsCRP), and malondialdehyde (MDA). By employing the Cochrane tool, RCTs were assessed for bias risk.
RESULTS
A total of 785 participants from 13 RCTs were included, with intervention durations ranging from 4 to 12 weeks. Compared with the control group, the curcumin group had positive effects on WC (MD = -2.16, 95% CI: -3.78 to -0.54, = 0.009, seven studies), FBS (MD = -8.6, 95% CI: -15.45 to -1.75, = 0.01, nine studies), DBP (MD = -2.8, 95% CI: -4.53 to - 1.06, = 0.002, five studies), HDL-C (MD = 4.98, 95% CI: 2.58 to 7.38, < 0.0001, eight studies), TNF-a (MD = -12.97, 95% CI: -18.37 to -7.57, < 0.00001, two studies), CRP (MD = - 1.24, 95% CI: -1.71 to -0.77, < 0.00001, two studies), and MDA (MD = -2.35, 95% CI: -4.47 to -0.24, = 0.03, three studies). These improvements were statistically significant. Meanwhile, there was no significant improvement in SBP (MD = -4.82, 95% CI: -9.98 to 0.35, = 0.07, six studies), TG (MD = 1.28, 95% CI: -3.75 to 6.30, = 0.62, eight studies), IL-6 (MD = -1.5, 95% CI: -3.97 to 0.97, = 0.23, two studies), or hsCRP (MD = -1.10, 95% CI: -4.35 to 2.16, < 0.51, two studies). FBS, SBP, HDL-C, IL-6, CRP, hsCRP, and MDA had a relatively high heterogeneity.
CONCLUSION
Curcumin exhibited promising potential in enhancing markers associated with metabolic syndrome, including inflammation. However, additional studies are required to confirm such findings since the included evidence is limited and has a relatively high heterogeneity.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero, identifier CRD42022362553.
Topics: Randomized Controlled Trials as Topic; Curcumin; Dietary Supplements; Metabolic Syndrome; Oxidative Stress; Polyphenols; Inflammation; Humans; Curcuma
PubMed: 37522129
DOI: 10.3389/fendo.2023.1216708