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Biochemical Pharmacology Feb 2022Cholesterol esterification proteins Sterol-O acyltransferases (SOAT) 1 and 2 are emerging prognostic markers in many cancers. These enzymes utilise fatty acids... (Meta-Analysis)
Meta-Analysis
Cholesterol esterification proteins Sterol-O acyltransferases (SOAT) 1 and 2 are emerging prognostic markers in many cancers. These enzymes utilise fatty acids conjugated to coenzyme A to esterify cholesterol. Cholesterol esterification is tightly regulated and enables formation of lipid droplets that act as storage organelles for lipid soluble vitamins and minerals, and as cholesterol reservoirs. In cancer, this provides rapid access to cholesterol to maintain continual synthesis of the plasma membrane. In this systematic review and meta-analysis, we summarise the current depth of understanding of the role of this metabolic pathway in pan-cancer development. A systematic search of PubMed, Scopus, Web of Science, and Cochrane Library for preclinical studies identified eight studies where cholesteryl ester concentrations were compared between tumour and adjacent-normal tissue, and 24 studies where cholesterol esterification was blocked by pharmacological or genetic approaches. Tumour tissue had a significantly greater concentration of cholesteryl esters than non-tumour tissue (p < 0.0001). Pharmacological or genetic inhibition of SOAT was associated with significantly smaller tumours of all types (p ≤ 0.002). SOAT inhibition increased tumour apoptosis (p = 0.007), CD8 + lymphocyte infiltration and cytotoxicity (p ≤ 0.05), and reduced proliferation (p = 0.0003) and metastasis (p < 0.0001). Significant risk of publication bias was found and may have contributed to a 32% overestimation of the meta-analysed effect size. Avasimibe, the most frequently used SOAT inhibitor, was effective at doses equivalent to those previously reported to be safe and tolerable in humans. This work indicates that SOAT inhibition should be explored in clinical trials as an adjunct to existing anti-neoplastic agents.
Topics: Animals; Anticholesteremic Agents; Antineoplastic Agents; Cholesterol; Clinical Trials as Topic; Esterification; Humans; Organic Anion Transporters; Tumor Burden; Urea; Xenograft Model Antitumor Assays
PubMed: 34407453
DOI: 10.1016/j.bcp.2021.114731 -
Genetics in Medicine : Official Journal... Nov 2014Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, have proven efficacy in both lowering low-density-lipoprotein levels and preventing major coronary... (Review)
Review
Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, have proven efficacy in both lowering low-density-lipoprotein levels and preventing major coronary events, making them one of the most commonly prescribed drugs in the United States. Statins exhibit a class-wide side effect of muscle toxicity and weakness, which has led regulators to impose both dosage limitations and a recall. This review focuses on the best-characterized genetic factors associated with increased statin muscle concentrations, including the genes encoding cytochrome P450 enzymes (CYP2D6, CYP3A4, and CYP3A5), a mitochondrial enzyme (GATM), an influx transporter (SLCO1B1), and efflux transporters (ABCB1 and ABCG2). A systematic literature review was conducted to identify relevant research evaluating the significance of genetic variants predictive of altered statin concentrations and subsequent statin-related myopathy. Studies eligible for inclusion must have incorporated genotype information and must have associated it with some measure of myopathy, either creatine kinase levels or self-reported muscle aches and pains. After an initial review, focus was placed on seven genes that were adequately characterized to provide a substantive review: CYP2D6, CYP3A4, CYP3A5, GATM, SLCO1B1, ABCB1, and ABCG2. All statins were included in this review. Among the genetic factors evaluated, statin-related myopathy appears to be most strongly associated with variants in SLCO1B1.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Amidinotransferases; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Genetic Variation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver-Specific Organic Anion Transporter 1; Muscular Diseases; Neoplasm Proteins; Organic Anion Transporters; Simvastatin
PubMed: 24810685
DOI: 10.1038/gim.2014.41 -
Cephalalgia : An International Journal... Nov 2010Data on the association between the SLC6A4 5-HTTLPR polymorphism and migraine are conflicting. We performed a systematic review and meta-analysis among studies published... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND METHODS
Data on the association between the SLC6A4 5-HTTLPR polymorphism and migraine are conflicting. We performed a systematic review and meta-analysis among studies published up to September 2009. For each study with genotype information, we calculated odds ratios (OR) and 95% confidence intervals (CI) assuming additive, dominant, and recessive genetic models. We then calculated pooled ORs and 95% CIs.
RESULTS
Among the ten studies identified there was no overall association between the polymorphism and any migraine for Europeans or Asians. However, European women carrying the S allele had an increased risk for any migraine (dominant model: pooled OR=2.02; 95% CI 1.24-3.28). Results among Europeans further suggested an increased risk for migraine with aura among carriers of the S/S genotype (recessive model: pooled OR=1.41; 95% CI 0.83-2.40).
CONCLUSIONS
While our results indicate no overall association between the SLC6A4 5-HTTLPR polymorphism and migraine among Europeans and Asians, gender and migraine aura status may have modifying roles among Europeans.
Topics: Asian People; Female; Genetic Predisposition to Disease; Humans; Male; Migraine Disorders; Odds Ratio; Polymorphism, Single Nucleotide; Serotonin Plasma Membrane Transport Proteins; White People
PubMed: 20959425
DOI: 10.1177/0333102410362929 -
Archivio Italiano Di Urologia,... Jun 2023Although SGLT2 inhibitors have been initially employed in the treatment of type 2 diabetes, their clinical use was later extended to the treatment of other conditions... (Meta-Analysis)
Meta-Analysis
UNLABELLED
Although SGLT2 inhibitors have been initially employed in the treatment of type 2 diabetes, their clinical use was later extended to the treatment of other conditions such as heart failure, chronic kidney disease and obesity. In patients with type 2 diabetes, the administration of SGLT2 inhibitors has been associated with an increased incidence of urogenital infections, which may be linked to high glucose levels in the urine. The rate of urogenital side effects may be different in non-diabetic patients. The aim of this study was to review the risk of urogenital infections in non-diabetic patients taking SGLT2 inhibitors.
MATERIALS AND METHODS
We conducted a systematic review and meta-analysis by searching PubMed and EMBASE for randomized controlled trials (RCTs) reporting urogenital adverse effects in non-diabetic patients treated with SGLT2 inhibitors. Odds ratios for urogenital infections were calculated using random effect Mantel-Haenszel statistics.
RESULTS
Out of 387 citations retrieved, 12 eligible RCTs were assessed for risk of bias and included in the meta-analysis. Compared to placebo, SGLT2 inhibitors were associated with increased odds of genital infections (OR 3.01, 95% CI: 1.93- 4.68, 9 series, 7326 participants, Z = 5.74, p < 0.0001, I2 = 0%) as well as urinary tract infections (OR 1.33, 95% CI: 1.13-1.57, 9 series, 7326 participants, Z = 4.05, p < 0.0001, I2 = 0%). When four trials investigating the effects of SGLT2 inhibitors in populations including both diabetic and non-diabetic patients were considered, administration of SGLT2 inhibitors in diabetic patients was associated with significantly higher odds of genital infections but not urinary tract infections compared to patients without type 2 diabetes. In patients taking placebo, the odds for urinary tract infections were significantly increased in diabetic patients compared to non-diabetic patients.
CONCLUSIONS
The risk of genital infections is increased also in non-diabetic patients taking SGLT2 inhibitors although at a lesser extent that in diabetics. A careful assessment of the local anatomical conditions and of the history of previous urogenital infections is desirable to select those patients who need more intense follow-up, possibly combined with prophylactic measures of infections during treatment with SGLT2 inhibitors.
Topics: Humans; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Diabetes Mellitus, Type 2; Urinary Tract Infections; Body Fluids
PubMed: 37314421
DOI: 10.4081/aiua.2023.11509 -
Implementation Science : IS Jul 2022Many strategies aimed at deprescribing benzodiazepine receptor agonists (BZRA) in older adults have already been evaluated with various success rates. There is so far no... (Review)
Review
Barriers and enablers for deprescribing benzodiazepine receptor agonists in older adults: a systematic review of qualitative and quantitative studies using the theoretical domains framework.
BACKGROUND
Many strategies aimed at deprescribing benzodiazepine receptor agonists (BZRA) in older adults have already been evaluated with various success rates. There is so far no consensus on which strategy components increase deprescribing the most. Yet, despite an unfavourable benefit-to-risk ratio, BZRA use among older adults remains high. We systematically reviewed barriers and enablers for BZRA deprescribing in older adults.
METHODS
Two reviewers independently screened records identified from five electronic databases-Medline, Embase, PsycINFO, CINAHL and the Cochrane library-and published before October 2020. They searched for grey literature using Google Scholar. Qualitative and quantitative records reporting data on the attitudes of older adults, caregivers and healthcare providers towards BZRA deprescribing were included. Populations at the end of life or with specific psychiatric illness, except for dementia, were excluded. The two reviewers independently assessed the quality of the included studies using the mixed-methods appraisal tool. Barriers and enablers were identified and then coded into domains of the theoretical domains framework (TDF) using a combination of deductive and inductive qualitative analysis. The most relevant TDF domains for BZRA deprescribing were then identified.
RESULTS
Twenty-three studies were included 13 quantitative, 8 qualitative and 2 mixed-method studies. The points of view of older adults, general practitioners and nurses were reported in 19, 9 and 3 records, respectively. We identified barriers and enablers in the majority of TDF domains and in two additional themes: "patient characteristics" and "BZRA prescribing patterns". Overall, the most relevant TDF domains were "beliefs about capabilities", "beliefs about consequences", "environmental context and resources", "intention", "goals", "social influences", "memory, attention and decision processes". Perceived barriers and enablers within domains differed across settings and across stakeholders.
CONCLUSION
The relevant TDF domains we identified can now be linked to behavioural change techniques to help in the design of future strategies and health policies. Future studies should also assess barriers and enablers perceived by under-evaluated stakeholders (such as pharmacists, psychiatrists and health care professionals in the hospital setting).
TRIAL REGISTRATION
This work was registered on PROSPERO under the title "Barriers and enablers to benzodiazepine receptor agonists deprescribing".
REGISTRATION NUMBER
CRD42020213035.
Topics: Aged; Deprescriptions; General Practitioners; Humans; Intention; Pharmacists; Qualitative Research; Receptors, GABA-A
PubMed: 35804428
DOI: 10.1186/s13012-022-01206-7 -
Biomolecules Jun 2022Schizophrenia has been conceptualized as a neurodevelopmental disorder with synaptic alterations and aberrant cortical-subcortical connections. Antipsychotics are the... (Review)
Review
Schizophrenia has been conceptualized as a neurodevelopmental disorder with synaptic alterations and aberrant cortical-subcortical connections. Antipsychotics are the mainstay of schizophrenia treatment and nearly all share the common feature of dopamine D2 receptor occupancy, whereas glutamatergic abnormalities are not targeted by the presently available therapies. D-amino acids, acting as N-methyl-D-aspartate receptor (NMDAR) modulators, have emerged in the last few years as a potential augmentation strategy in those cases of schizophrenia that do not respond well to antipsychotics, a condition defined as treatment-resistant schizophrenia (TRS), affecting almost 30-40% of patients, and characterized by serious cognitive deficits and functional impairment. In the present systematic review, we address with a direct and reverse translational perspective the efficacy of D-amino acids, including D-serine, D-aspartate, and D-alanine, in poor responders. The impact of these molecules on the synaptic architecture is also considered in the light of dendritic spine changes reported in schizophrenia and antipsychotics' effect on postsynaptic density proteins. Moreover, we describe compounds targeting D-amino acid oxidase and D-aspartate oxidase enzymes. Finally, other drugs acting at NMDAR and proxy of D-amino acids function, such as D-cycloserine, sarcosine, and glycine, are considered in the light of the clinical burden of TRS, together with other emerging molecules.
Topics: Amino Acids; Antipsychotic Agents; Humans; Neurobiology; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Schizophrenia, Treatment-Resistant
PubMed: 35883465
DOI: 10.3390/biom12070909 -
Clinical Neurophysiology : Official... Jan 2020Measurement of axonal excitability provides an in vivo indication of the properties of the nerve membrane and of the ion channels expressed on these axons. Axonal...
Measurement of axonal excitability provides an in vivo indication of the properties of the nerve membrane and of the ion channels expressed on these axons. Axonal excitability techniques have been utilised to investigate the pathophysiological mechanisms underlying neurological diseases. This document presents guidelines derived for such studies, based on a consensus of international experts, and highlights the potential difficulties when interpreting abnormalities in diseased axons. The present manuscript provides a state-of-the-art review of the findings of axonal excitability studies and their interpretation, in addition to suggesting guidelines for the optimal performance of excitability studies.
Topics: Action Potentials; Axons; Consensus; Electric Stimulation; Electrodes, Implanted; Equipment Design; Humans; Ion Channels; Membrane Potentials; Models, Neurological; Nervous System Diseases; Neurophysiology; Sensory Thresholds; Software
PubMed: 31471200
DOI: 10.1016/j.clinph.2019.07.023 -
Oncotarget Jan 2017Karyopherin α2 (KPNA2), a member of the Karyopherin α family, has recently been reported to play an important role in tumor progression. However, the association... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Karyopherin α2 (KPNA2), a member of the Karyopherin α family, has recently been reported to play an important role in tumor progression. However, the association between KPNA2 expression and prognosis in cancer remains controversial. So we performed this meta-analysis to evaluate whether expression of KPNA2 was associated with prognosis in patients with solid tumor.
METHODS/FINDINGS
24 published eligible studies, including 6164 cases, were identified and included in this meta-analysis through searching of PubMed, EMBASE and Web of Science. We found that KPNA2 expression was an independent predictor for the prognosis of solid tumor with primary outcome (overall survival [OS]: pooled HR=1.767, 95% CI=1.503-2.077, P<0.001) and secondary outcomes (time to recurrence [TTR], recurrence free survival [RFS] and progression free survival [PFS]). However, the association between KPNA2 overexpression and disease free survival [DFS] in solid tumors was not significant (pooled HR=1.653, 95% CI=0.903-3.029, P=0.104). Furthermore, the subgroup analysis revealed that KPNA2 overexpression was associated with poor OS in East-Asian patients and European patients, as well as patients with gastric and colorectal cancer.
CONCLUSION
KPNA2 expression may be a useful prognostic biomarker to monitor cancer prognosis. Further prospective studies with larger sample sizes are required to confirm our findings.
Topics: Asian People; Biomarkers, Tumor; Colorectal Neoplasms; Disease-Free Survival; Humans; Neoplasm Recurrence, Local; Prognosis; Stomach Neoplasms; Up-Regulation; White People; alpha Karyopherins
PubMed: 27974678
DOI: 10.18632/oncotarget.13863 -
Oncotarget Feb 2017The role of glucose transporters in cancers remains contradictory. We conducted a systematic review and meta-analysis to assess the association between overall survival... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND OBJECTIVE
The role of glucose transporters in cancers remains contradictory. We conducted a systematic review and meta-analysis to assess the association between overall survival and glucose transporter s (GLUTs) 1 and 3 to find an accurate prognostic biomarker.
METHODS
We systematically searched the PubMed, EMbase and Medline databases for relevant published studies that were consistent with the eligible criteria up to January 2016, and calculated pooled estimated hazard ratios of GLUT-1 and -3's expressions in different cancer types and ethnic populations. Random-effects models were used to assess estimates from studies with significant heterogeneities.
RESULTS
Overall, 12 studies concerning GLUT 1 and 2 studies concerning GLUT 3, which involved 2008 participants when combined, were included in this analysis. We found that overexpression of GLUTs were significantly correlated to poorer survival rates (HR=1.63, 95%CI=1.09-2.44 and HR=1.89, 95%CI=1.28-2.81). In the subgroup analysis, the GLUT 1 up-regulation was correlated with negative overall survival in pancreatic cancer and gastric cancer and with better overall survival in colorectal cancer. In addition, overexpression of GLUT 1 was associated with a poorer prognosis in the Asian population, while no significance was found in the non-Asian subgroup. However, limitations do exist, which could be handled better.
CONCLUSIONS
A combination of GLUTs 1 and 3 might help predict malignancy of cancers and direct effective cancer therapy.
Topics: Asian People; Biomarkers, Tumor; Glucose Transporter Type 1; Glucose Transporter Type 3; Humans; Neoplasms; Predictive Value of Tests; Prognosis; Survival Analysis
PubMed: 28086215
DOI: 10.18632/oncotarget.14570 -
Toxins Apr 2020Centipedes are among the oldest venomous arthropods that use their venom to subdue the prey. The major components of centipede venom are a variety of...
Centipedes are among the oldest venomous arthropods that use their venom to subdue the prey. The major components of centipede venom are a variety of low-molecular-weight peptide toxins that have evolved to target voltage-gated ion channels to interfere with the central system of prey and produce pain or paralysis for efficient hunting. Peptide toxins usually contain several intramolecular disulfide bonds, which confer chemical, thermal and biological stability. In addition, centipede peptides generally have novel structures and high potency and specificity and therefore hold great promise both as diagnostic tools and in the treatment of human disease. Here, we review the centipede peptide toxins with reported effects on ion channels, including Nav, Kv, Cav and the nonselective cation channel polymodal transient receptor potential vanilloid 1 (TRPV1).
Topics: Animals; Arthropod Proteins; Arthropod Venoms; Bites and Stings; Chilopoda; Drug Discovery; Humans; Ion Channels; Membrane Transport Modulators; Protein Conformation; Signal Transduction; Structure-Activity Relationship
PubMed: 32260499
DOI: 10.3390/toxins12040230