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Frontiers in Physiology 2022Endocannabinoids (eCBS) are endogenously derived lipid signaling molecules that serve as tissue hormones and interact with multiple targets, mostly within the...
Endocannabinoids (eCBS) are endogenously derived lipid signaling molecules that serve as tissue hormones and interact with multiple targets, mostly within the endocannabinoid system (ECS). The ECS is a highly conserved regulatory system involved in homeostatic regulation, organ formation, and immunomodulation of chordates. The term "cannabinoid" evolved from the distinctive class of plant compounds found in , an ancient herb, due to their action on CB1 and CB2 receptors. CB1/2 receptors are the primary targets for eCBs, but their effects are not limited to the ECS. Due to the high interest and extensive research on the ECS, knowledge on its constituents and physiological role is substantial and still growing. Crosstalk and multiple targeting of molecules are common features of endogenous and plant compounds. Cannabimimetic molecules can be divided according to their origin, natural or synthetic, including phytocannabinoids (pCB's) or synthetic cannabinoids (sCB's). The endocannabinoid system (ECS) consists of receptors, transporters, enzymes, and signaling molecules. In this review, we focus on the effects of cannabinoids on Cys-loop receptors. Cys-loop receptors belong to the class of membrane-bound pentameric ligand gated ion channels, each family comprising multiple subunits. Mammalians possess GABA type A receptors (GABAAR), glycine receptors (GlyR), serotonin receptors type 3 (5-HT3R), and nicotinic acetylcholine receptors (nAChR). Several studies have shown different modulatory effects of CBs on multiple members of the Cys-loop receptor family. We highlight the existing knowledge, especially on subunits and protein domains with conserved binding sites for CBs and their possible pharmacological and physiological role in epilepsy and in chronic pain. We further discuss the potential for cannabinoids as first line treatments in epilepsy, chronic pain and other neuropsychiatric conditions, indicated by their polypharmacology and therapeutic profile.
PubMed: 36439263
DOI: 10.3389/fphys.2022.1044575 -
Neurological Sciences : Official... Apr 2023KCNT1 has been known to encode a subunit of the tetrameric sodium activated potassium channel (K1.1). Pathogenic variants of KCNT1, especially gain-of-function (GOF)... (Review)
Review
KCNT1 has been known to encode a subunit of the tetrameric sodium activated potassium channel (K1.1). Pathogenic variants of KCNT1, especially gain-of-function (GOF) variants, are associated with multiple epileptic disorders which are often refractory to conventional anti-seizure medications and summarized as KCNT1-related epilepsy. Although the detailed pathogenic mechanisms of KCNT1-related epilepsy remain unknown, increasing studies attempt to find effective medications for those patients by utilizing quinidine to inhibit hyperexcitable K1.1. However, it has been shown that controversial outcomes among studies and partial success in some individuals may be due to multiple factors, such as poor blood-brain barrier (BBB) penetration, mutation-dependent manner, phenotype-genotype associations, and rational therapeutic schedule. In recent years, with higher resolution of K1.1 structure in different activation states and advanced synthetic techniques, it improves the process performance of therapy targeting at K1.1 channel to achieve more effective outcomes. Here, we systematically reviewed the study history of quinidine on KCNT1-related epilepsy and its corresponding therapeutic effects. Then, we analyzed and summarized the possible causes behind the different outcomes of the application of quinidine. Finally, we outlooked the recent advances in precision medicine treatment for KCNT1-related epilepsy.
Topics: Humans; Quinidine; Anticonvulsants; Potassium Channels, Sodium-Activated; Epilepsy; Potassium Channels; Mutation; Nerve Tissue Proteins
PubMed: 36437393
DOI: 10.1007/s10072-022-06521-x -
Medicine Oct 2022Whether metformin is related to nonalcoholic fatty liver disease (NAFLD) is controversial. Our aim was to investigate the relationship between metformin and NAFLD that... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Whether metformin is related to nonalcoholic fatty liver disease (NAFLD) is controversial. Our aim was to investigate the relationship between metformin and NAFLD that may predict the metformin potential of these lesions and new prevention strategies in NAFLD patients.
METHODS
The meta-analysis was analyzed by Revman 5.3 softwares systematically searched for works published through July 29, 2022. Network pharmacology research based on databases, Cytoscape 3.7.1 software and R software respectively.
RESULTS
The following variables were associated with metformin in NAFLD patients: decreased of alanine aminotransferase (ALT) level (mean difference [MD] = -10.84, 95% confidence interval [CI] = -21.85 to 0.16, P = .05); decreased of aspartate amino transferase (AST) level (MD = -4.82, 95% CI = -9.33 to -0.30, P = .04); decreased of triglyceride (TG) level (MD = -0.17, 95% CI = -0.26 to -0.08, P = .0002); decreased of total cholesterol (TC) level (MD = -0.29, 95% CI = -0.47 to -0.10, P = .003); decreased of insulin resistance (IR) level (MD = -0.42, 95% CI = -0.82 to -0.02, P = .04). In addition, body mass index (BMI) (MD = -0.65, 95% CI = -1.46 to 0.16, P = .12) had no association with metformin in NAFLD patients. 181 metformin targets and 868 NAFLD disease targets were interaction analyzed, 15 core targets of metformin for the treatment of NAFLD were obtained. The effect of metformin on NAFLD mainly related to cytoplasm and protein binding, NAFLD, hepatitis B, pathway in cancer, toll like receptor signaling pathway and type 2 diabetes mellitus (T2DM). The proteins of hypoxia inducible factor-1 (HIF1A), nuclear factor erythroid 2-related factor (NFE2L2), nitric oxide synthase 3 (NOS3), nuclear receptor subfamily 3 group C member 1 (NR3C1), PI3K catalytic subunit alpha (PIK3CA), and silencing information regulator 2 related enzyme 1 (SIRT1) may the core targets of metformin for the treatment of NAFLD.
CONCLUSION
Metformin might be a candidate drug for the treatment of NAFLD which exhibits therapeutic effect on NAFLD patients associated with ALT, AST, TG, TC and IR while was not correlated with BMI. HIF1A, NFE2L2, NOS3, NR3C1, PIK3CA, and SIRT1 might be core targets of metformin for the treatment of NAFLD.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Metformin; Diabetes Mellitus, Type 2; Sirtuin 1; Network Pharmacology; Insulin Resistance; Class I Phosphatidylinositol 3-Kinases
PubMed: 36316840
DOI: 10.1097/MD.0000000000031437 -
BMC Medicine Oct 2022Dose fractionation of a coronavirus disease 2019 (COVID-19) vaccine could effectively accelerate global vaccine coverage, while supporting evidence of efficacy,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Dose fractionation of a coronavirus disease 2019 (COVID-19) vaccine could effectively accelerate global vaccine coverage, while supporting evidence of efficacy, immunogenicity, and safety are unavailable, especially with emerging variants.
METHODS
We systematically reviewed clinical trials that reported dose-finding results and estimated the dose-response relationship of neutralizing antibodies (nAbs) of COVID-19 vaccines using a generalized additive model. We predicted the vaccine efficacy against both ancestral and variants, using previously reported correlates of protection and cross-reactivity. We also reviewed and compared seroconversion to nAbs, T cell responses, and safety profiles between fractional and standard dose groups.
RESULTS
We found that dose fractionation of mRNA and protein subunit vaccines could induce SARS-CoV-2-specific nAbs and T cells that confer a reasonable level of protection (i.e., vaccine efficacy > 50%) against ancestral strains and variants up to Omicron. Safety profiles of fractional doses were non-inferior to the standard dose.
CONCLUSIONS
Dose fractionation of mRNA and protein subunit vaccines may be safe and effective, which would also vary depending on the characteristics of emerging variants and updated vaccine formulations.
Topics: Humans; Antibodies, Neutralizing; Antibodies, Viral; COVID-19; COVID-19 Vaccines; Protein Subunits; RNA, Messenger; SARS-CoV-2; Viral Vaccines
PubMed: 36284331
DOI: 10.1186/s12916-022-02600-0 -
Frontiers in Medicine 2022β-hemoglobinopathies like sickle cell disease (SCD) and β-thalassemia are characterized by differing mutations in the hemoglobin subunit beta gene (HBB). These...
Using Clustered Regularly Interspaced Short Palindromic Repeats gene editing to induce permanent expression of fetal hemoglobin in β-thalassemia and sickle cell disease: A comparative meta-analysis.
β-hemoglobinopathies like sickle cell disease (SCD) and β-thalassemia are characterized by differing mutations in the hemoglobin subunit beta gene (HBB). These disorders vary in phenotypic presentation and severity, with more severe manifestations leading to transfusion dependence along with associated complications such as infection and iron overload. β-hemoglobinopathies symptoms rapidly worsen after birth as the levels of fetal hemoglobin (HbF) begin to decline. To reverse this decline, current treatment plans typically involve the use of pharmacological agents such as hydroxyurea to raise expression levels of HbF. However, these treatments only result in transient effects and must be consistently administered. Gene editing technologies such as CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats- CRISPR associated protein) offer the opportunity to create novel treatments which can raise HbF expression with potential permanent effects. Two gene targets, B-cell lymphoma/leukemia 11A gene (BCL11A) and the promoter regions of gamma globin genes (HBG1/2), have been identified to significantly increase HbF protein expression. In order to differentiate the effectiveness of BCL11A and HBG1/2 editing, a meta-analysis was performed by first identifying 119 studies for inclusion based on the search terms terms "β-Thalassemia," "beta-thal" "sickle cell disease," "SCD," and "CRISPR." Following application of exclusion and inclusion criteria, we performed analysis on 8 peer-reviewed published studies from 2018 to 2021 were included in the study. Forest plots were generated using R (version 4.1.2). Primary comparative analysis shows HBG1/2 had a significantly ( < 0.01)greater impact on induction of HbF expression compared to BCL11A. This analysis leads us to conclude that HBG1/2 merits further investigation as a possible gene editing target for treatment of SCD and β-thalassemia.
PubMed: 36250099
DOI: 10.3389/fmed.2022.943631 -
Frontiers in Endocrinology 2022It is currently controversial whether subclinical hyperthyroidism is associated with gene variants. We describe a man with subclinical hyperthyroidism and a gene...
BACKGROUND AND OBJECTIVES
It is currently controversial whether subclinical hyperthyroidism is associated with gene variants. We describe a man with subclinical hyperthyroidism and a gene variant who was diagnosed with Carney complex (CNC), and we performed a systematic review of published studies to assess the association between gene variants and the risk of subclinical hyperthyroidism.
DESIGN AND METHODS
The PubMed, EMBASE, OVID, Science Direct, and gray literature electronic databases were searched for articles published from January 2002 to May 2021 using predefined keywords and inclusion and exclusion criteria. Data on thyroid function from selected studies were extracted and analyzed.
RESULTS
We identified a CNC patient with a subclinical hyperthyroidism phenotype combined with multiple components and genetic sequenced data. In a subsequent systematic review, twenty selected studies (14 case studies and 6 series studies) enrolling 23 individuals were included in the final analysis. The patient's thyroid function data were qualitative in 11 cases and quantitative in 12 cases. The prevalence of subclinical hyperthyroidism in the CNC patients with a gene variant, including our patient, was markedly higher than that in the normal population (12.5% vs. 2%).
CONCLUSIONS
The findings of this systematic review provide helpful evidence that gene variants and subclinical hyperthyroidism are related and suggest that subclinical hyperthyroidism may be a neglected phenotype of gene variants and a novel component of CNC patients.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/PROSPERO, identifier CRD42021197655.
Topics: Carney Complex; Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; Humans; Hyperthyroidism; Phenotype
PubMed: 36213268
DOI: 10.3389/fendo.2022.951133 -
Journal of Digestive Diseases Aug 2022To summarize the associations between potential causal factors and colorectal cancer (CRC) risk based on existing Mendelian randomization studies. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To summarize the associations between potential causal factors and colorectal cancer (CRC) risk based on existing Mendelian randomization studies.
METHODS
This systematic review and meta-analysis involved a literature search in Embase and Medline. All published articles using Mendelian randomization to explore potential causal factors of CRC were included. Studies that reported Mendelian randomization estimates of standard deviation changes in exposures were included in the meta-analysis. Subgroup analyses based on sex and anatomical sites were performed.
RESULTS
One hundred and ninety studies presented in 51 articles were included in systematic review, and 114 studies conducted in 32 articles were included in the meta-analysis. Adult body mass index, waist circumference, waist hip ratio, body height, body fat percentage, arm fat ratio, childhood obesity, lifetime cigarette consumption, short sleep, coffee consumption, and blood levels of vitamin B , arachidonic acid, stearic acid, and insulin-like growth factor binding protein 3 were positively associated with CRC risk. Conversely, acceleration-vector-magnitude physical activity, milk consumption, and blood levels of adiponectin, linoleic acid, α-linolenic acid, oleic acid, palmitoleic acid, interleukin-6 receptor subunit-α, and tumor necrosis factor were inversely associated with CRC risk.
CONCLUSIONS
Most obesity-related anthropometric characteristics, several unhealthy lifestyles, and blood levels of some micronutrients, fatty acids, and diabetes-related biomarkers were positively associated with CRC risk. In contrast, some lifestyles and blood levels of some fatty acids and inflammatory biomarkers were inversely associated with CRC risk. Future studies with more valid genetic variants are needed for factors with discrepancies between Mendelian randomization and epidemiological studies.
Topics: Child; Adult; Humans; Mendelian Randomization Analysis; Polymorphism, Single Nucleotide; Colorectal Neoplasms; Pediatric Obesity; Risk Factors; Biomarkers; Fatty Acids; Genome-Wide Association Study
PubMed: 36169182
DOI: 10.1111/1751-2980.13130 -
BMC Cancer Sep 2022Approximately 40% of hormone receptor positive/human epidermal receptor 2 negative (HR + /HER2-) metastatic breast cancer (mBC) patients harbor... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Approximately 40% of hormone receptor positive/human epidermal receptor 2 negative (HR + /HER2-) metastatic breast cancer (mBC) patients harbor phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations. However, associations between PIK3CA mutation status and clinical outcomes among patients with HR + /HER2- mBC have been heterogeneous across clinical trials. This meta-analysis was conducted to survey recently available trial data to assess the prognostic effects of PIK3CA among patients with HR + /HER2- mBC. METHODS: Randomized clinical trials reporting progression-free survival (PFS) or overall survival (OS) stratified by PIK3CA status in HR + /HER2- mBC were identified via systematic literature review. Trial arms receiving phosphatidylinositol 3-kinase (PI3K)-targeted therapies were excluded. Meta-regression analysis was used to estimate the association between PIK3CA status and PFS and OS among included studies.
RESULTS
The analyzed data included 3,219 patients from 33 study arms across 11 trials (PIK3CA mutated: 1,386, wild type: 1,833). PIK3CA mutation was associated with shorter median PFS (difference [95% CI] (months): -1.8 [-3.4, -0.1], I = 35%) and shorter median OS (-8.4 [-13.4, -3.5], I = 58%, N = 1,545). Findings were similar for PFS rates at 6 months (odds ratio [95% CI]: 0.74 [0.59, 0.94], I = 42%, N = 3,160) and 12 months (0.76 [0.59, 0.99], I = 42%, N = 2,468) and directionally consistent but not statistically significant at 18 months (N = 1,726).
CONCLUSIONS
Pooling evidence across multiple studies, PIK3CA mutation was associated with shorter PFS and OS. These findings suggest a negative prognostic value of PIK3CA mutations in patients with HR + /HER2- mBC.
Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Class I Phosphatidylinositol 3-Kinases; Disease-Free Survival; Female; Humans; Mutation; Phosphatidylinositol 3-Kinases; Phosphatidylinositols; Receptor, ErbB-2
PubMed: 36131248
DOI: 10.1186/s12885-022-10078-5 -
Tumour Biology : the Journal of the... 2022Controversy exists regarding the association of apolipoprotein B mRNA editing enzyme catalytic subunit 3B APOBEC3B, (A3B) overexpression and poor prognosis, metastasis,... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Controversy exists regarding the association of apolipoprotein B mRNA editing enzyme catalytic subunit 3B APOBEC3B, (A3B) overexpression and poor prognosis, metastasis, and chemotherapy drug resistance in cancers. Here we conducted a systematic review and meta-analysis to determine its prognostic value and clinicopathological features in breast cancer and some other malignancies.
MATERIALS AND METHODS
PubMed, Scopus, Cochrane Library, Web of Science, and EMBASE were searched up to Feb 2022 for the association of A3B with breast, ovarian, gastrointestinal and lung cancers. The pooled hazard ratios with 95% confidence interval (CI) were evaluated to assess disease-free survival (DFS), overall survival (OS), and recurrence-free survival (RFS) in cancers under study.
RESULTS
Over 3700 patients were included in this meta-survey. Elevated levels of A3B were significantly related to low OS (pooled HR = 1.30; 95% CI:1.09-1.55, P < 0.01), poor DFS (pooled HR = 1.66; 95% CI:1.17-2.35, P < 0.01) and poor RFS (HR = 1.51, 95% CI:1.11-2.04, P = 0.01). Subgroup analysis revealed that high A3B expression was associated with poor OS in lung (HR = 1.85, 95% CI: 1.40-2.45), and breast cancers (HR = 1.38, 95% CI: 1.00-1.89). High expression of A3B did not display any significant association with clinicopathologic features.
CONCLUSION
APOBEC3B overexpression is related to poor OS, DFS and RFS only in some cancer types and no generalized role could be predicted for all cancers.
Topics: Breast Neoplasms; Cytidine Deaminase; Disease-Free Survival; Female; Humans; Lung Neoplasms; Minor Histocompatibility Antigens; Proportional Hazards Models
PubMed: 36093650
DOI: 10.3233/TUB-211577 -
Archives of Academic Emergency Medicine 2022Knowledge of the safety of vaccines is crucial, both to prevent and cure them and to decrease the public hesitation in receiving vaccines. Therefore, this study aimed to... (Review)
Review
INTRODUCTION
Knowledge of the safety of vaccines is crucial, both to prevent and cure them and to decrease the public hesitation in receiving vaccines. Therefore, this study aimed to systematically review the adverse events reported for inactivated vaccines and Novavax.
METHODS
In this systematic review, the databases of PubMed, Scopus, Cochrane, and Web of Science were searched on September 15, 2021. Then we identified the eligible studies using a two-step title/abstract and full-text screening process. Data on the subjects, studies, and types of adverse events were extracted and entered in a word table, including serious, mild, local, and systemic adverse events as well as the timing of side effects' appearance.
RESULTS
Adverse effects of inactivated coronavirus vaccines side effects were reported from phases 1, 2, and 3 of the vaccine trials. The most common local side effects included injection site pain and swelling, redness, and pruritus. Meanwhile, fatigue, headache, muscle pain, fever, and gastrointestinal symptoms including abdominal pain and diarrhea were among the most common systemic adverse effects.
CONCLUSION
This systematic review indicates that inactivated COVID-19 vaccines, including Sinovac, Sinopharm, and Bharat Biotech, as well as the protein subunit vaccines (Novavax) can be considered as safe choices due to having milder side effects and fewer severe life-threatening adverse events.
PubMed: 36033990
DOI: 10.22037/aaem.v10i1.1585