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Biochimica Et Biophysica Acta.... Jul 2019The endolysosomal, non-selective cation channels, two-pore channels (TPCs) and mucolipins (TRPMLs), regulate intracellular membrane dynamics and autophagy. While... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The endolysosomal, non-selective cation channels, two-pore channels (TPCs) and mucolipins (TRPMLs), regulate intracellular membrane dynamics and autophagy. While partially compensatory for each other, isoform-specific intracellular distribution, cell-type expression patterns, and regulatory mechanisms suggest different channel isoforms confer distinct properties to the cell.
SCOPE OF REVIEW
Briefly, established TPC/TRPML functions and interaction partners ('interactomes') are discussed. Novel TRPML3 interactors are shown, and a meta-analysis of experimentally obtained channel interactomes conducted. Accordingly, interactomes are compared and contrasted, and subsequently described in detail for TPC1, TPC2, TRPML1, and TRPML3.
MAJOR CONCLUSIONS
TPC interactomes are well-defined, encompassing intracellular membrane organisation proteins. TRPML interactomes are varied, encompassing cardiac contractility- and chaperone-mediated autophagy proteins, alongside regulators of intercellular signalling.
GENERAL SIGNIFICANCE
Comprising recently proposed targets to treat cancers, infections, metabolic disease and neurodegeneration, the advancement of TPC/TRPML understanding is of considerable importance. This review proposes novel directions elucidating TPC/TRPML relevance in health and disease. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech.
Topics: Animals; Calcium Channels; Calcium Signaling; Humans; Transient Receptor Potential Channels
PubMed: 30395881
DOI: 10.1016/j.bbamcr.2018.10.020 -
Journal of Cardiothoracic Surgery Nov 2022Uniport video-assisted thoracoscopic surgery (VATS) has been applied widely for the treatment of lung cancer in recent years. Some studies have reported that uniport... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Uniport video-assisted thoracoscopic surgery (VATS) has been applied widely for the treatment of lung cancer in recent years. Some studies have reported that uniport VATS might provide better outcomes than multiport VATS. However, the perioperative outcomes of uniport VATS compared with two-port and three-port VATS, respectively, have yet to be studied at a comprehensive scale. This meta-analysis study compares the perioperative efficacy among uniport, two-port, and three-port VATS.
METHODS
We searched studies published before October 1, 2019, by using Web of Science databases, Ovid Medline, Embase, and PubMed. Studies that compared uniport VATS with two-port or three-port VATS for patients with lung cancer were included. Operative time, perioperative blood loss, number of lymph nodes retrieved, conversion rate, duration of postoperative chest tube drainage, length of hospital stay (LoS), visual analogue pain scores on postoperative day (POD) 1 and POD 3, and overall morbidity were evaluated.
RESULTS
Sixteen studies that compared uniport VATS with two-port or three-port VATS in the treatment of lung cancer were included. Uniport VATS showed less blood loss, a shorter duration of postoperative drainage and a lower visual analogue pain score on POD 3 than two-port VATS; it showed a shorter duration of postoperative drainage, a shorter LoS, and lower visual analogue pain scores on POD 1 and POD 3 than three-port VATS. There were no significant differences in the number of lymph nodes retrieved, operative time, conversion rate, and overall morbidity rate when comparing uniport VATS with two-port VATS or three-port VATS.
CONCLUSIONS
Uniport VATS might provide better perioperative outcomes than either two-port or three-port VATS in lung cancer treatment.
Topics: Humans; Thoracic Surgery, Video-Assisted; Lung Neoplasms; Operative Time; Ion Transport; Pain
PubMed: 36348498
DOI: 10.1186/s13019-022-02034-y -
Clinical Nutrition ESPEN Jun 2023Cystic fibrosis (CF) is a multisystem disease that can compromise several human body organs. The autosomal recessive genetic disorder is caused by different mutations in... (Meta-Analysis)
Meta-Analysis
BACKGROUND & AIMS
Cystic fibrosis (CF) is a multisystem disease that can compromise several human body organs. The autosomal recessive genetic disorder is caused by different mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, responsible for chloride ion transport across apical membranes of epithelial cells in tissues and bicarbonate secretion. In this study, we provide a systematic review of the profile of the intestinal microbiota of cystic fibrosis individuals.
METHODS
The review was conducted according to Preferred Items of Reports for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. PubMed/MEDLINE and Scopus databases were searched for relevant articles until Jully 2022.
RESULTS
Eighteen studies (1304 participants) met the inclusion criteria. The quality and bias was assessed using the Methodological index for non-randomized studies (MINORS) tool, with the majority of the studies indicating medium to high quality. Results showed significant changes in the composition of the intestinal microbiota of the individuals with CF compared with healthy controls, with increased of Enterococcus, Veillonella, and Streptococcus, and decreased of Bifidobacterium, Roseburia, and Alistipes genus. The intestinal bacterial community of CF patients was marked by a reduction in its richness and diversity.
CONCLUSION
The systematic review suggests a change in the intestinal microbiota of CF individuals, characterized by a reduction in microbial diversity and abundance of some bacterial markers.
Topics: Humans; Cystic Fibrosis; Gastrointestinal Microbiome; Bacteria; Mutation
PubMed: 37202074
DOI: 10.1016/j.clnesp.2023.04.008 -
The Cochrane Database of Systematic... Jun 2016Cystic fibrosis is caused by a defective gene encoding a protein called the cystic fibrosis transmembrane conductance regulator (CFTR), and is characterised by chronic... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Cystic fibrosis is caused by a defective gene encoding a protein called the cystic fibrosis transmembrane conductance regulator (CFTR), and is characterised by chronic lung infection resulting in inflammation and progressive lung damage that results in a reduced life expectancy.
OBJECTIVES
To determine whether topical CFTR gene replacement therapy to the lungs in people with cystic fibrosis is associated with improvements in clinical outcomes, and to assess any adverse effects.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching relevant journals and abstract books of conference proceedings.Date of most recent search: 05 May 2016.An additional search of the National Institutes for Health (NIH) Genetic Modification Clinical Research Information System (GeMCRIS) was also performed for the years 1992 to 2015.Date of most recent search: 20 April 2016.
SELECTION CRITERIA
Randomised controlled studies comparing topical CFTR gene delivery to the lung, using either viral or non-viral delivery systems, with placebo or an alternative delivery system in people with confirmed cystic fibrosis.
DATA COLLECTION AND ANALYSIS
The authors independently extracted data and assessed study quality. Authors of included studies were contacted and asked for any available additional data. Meta-analysis was limited due to differing study designs.
MAIN RESULTS
Four randomised controlled studies met the inclusion criteria for this review, involving a total of 302 participants lasting from 29 days to 13 months; 14 studies were excluded. The included studies differed in terms of CFTR gene replacement agent and study design, which limited the meta-analysis. One study only enrolled adult males, the remaining studies included both males and females aged 12 years and over.Risk of bias in the studies was moderate. Random sequence generation and allocation concealment was only described in the more recent study; the remaining three studies were judged to have an unclear risk of bias. All four studies documented double-blinding to the intervention, but there is some uncertainty with regards to participant blinding in one study. Some outcome data were missing from all four studies.There were no differences in either the number of respiratory exacerbations or the number of participants with an exacerbation between replacement therapy or placebo groups at any time point. Meta-analysis of most respiratory function tests showed no difference between treatment and placebo groups, but the smallest study (n = 16) reported forced vital capacity (litres) increased more in the placebo group at up to 24 hours. A further study reported a significant improvement in forced expiratory volume at one second (litres) at 30 days after participants had received their first dose of favouring the gene therapy agent, but this finding was not confirmed when combined with at second study in the meta-analysis. The more recent study (n = 140) demonstrated a small improvement in forced vital capacity (per cent predicted) at two and three months and again at 11 and 12 months for participants receiving CFTR gene replacement therapy compared to those receiving placebo. The same study reported a significant difference in the relative change in forced expiratory volume at one second (per cent predicted) at two months, three months and 12 months.One small study reported significant concerns with "influenza-like" symptoms in participants treated with CFTR gene replacement therapy; this was not reported on repeated use of the same agent in a larger recent study.There was no other evidence of positive impact on outcomes, in particular improved quality of life or reduced treatment burden.Two studies measured ion transport in the lower airways; one (n = 16) demonstrated significant changes toward normal values in the participants who received gene transfer agents (P < 0.0001), mean difference 6.86 (95% confidence interval 3.77 to 9.95). The second study (n = 140) also reported significant changes toward normal values (P = 0.032); however, aggregate data were not available for analysis. In the most recent study, there was also evidence of increased salt transport in cells obtained by brushing the lower airway. These outcomes, whilst important, are not of direct clinical relevance.
AUTHORS' CONCLUSIONS
One study of liposome-based CFTR gene transfer therapy demonstrated some improvements in respiratory function in people with CF, but this limited evidence of efficacy does not support this treatment as a routine therapy at present. There was no evidence of efficacy for viral-mediated gene delivery.Future studies need to investigate clinically important outcome measures.
Topics: Adolescent; Adult; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Gene Transfer Techniques; Genetic Therapy; Humans; Liposomes; Male; Randomized Controlled Trials as Topic; Respiratory Function Tests; Targeted Gene Repair
PubMed: 27314455
DOI: 10.1002/14651858.CD005599.pub5 -
Gender Medicine Jun 2008Women are at an increased risk of drug-induced long QT syndrome (LQTS). This major cardiac adverse effect may lead to malignant polymorphic ventricular tachycardias,... (Review)
Review
BACKGROUND
Women are at an increased risk of drug-induced long QT syndrome (LQTS). This major cardiac adverse effect may lead to malignant polymorphic ventricular tachycardias, termed torsades de pointes, which may degenerate into ventricular fibrillation and cause sudden death.
OBJECTIVE
This article reviews current evidence and remaining gaps in knowledge about drug-induced LQTS in women.
METHODS
Using the search terms gender, sex, and sex differences in combination with cardiac electrophysiology, long QT syndrome, HERG, membrane transporters, and cytochromes, we conducted a systematic review of the available literature in the PubMed database. Relevant English- and French-language publications (to October 2007) on sex differences in LQTS were identified.
RESULTS
Clinical and experimental studies have reported that gonadal hormones play a role in sex-related differences of QT interval prolongation. Androgens may diminish drug effects on heart repolarization, and estrogens may facilitate arrhythmias. Furthermore, sex-related differences in the density of ion channels may partially explain this phenomenon. However, the magnitude of hormone-dependent differences observed in these studies remains very small compared with the large differences observed in clinical settings. Therefore, many scientists agree that the mechanisms responsible for sex-related differences in the risk of proarrhythmia from drugs remain largely undefined.
CONCLUSIONS
Other factors, such as sex-related modulation of drug disposition in situ, may fill the gaps in our understanding of the sex differences observed in drug-induced LQTS. We suggest that mechanisms such as the modulation of the pharmacokinetics of IKr (rapid component of the delayed rectifier potassium current) blockers, via modulation of intra- and extracellular concentrations, may be of major importance. Sex-specific changes in drug transport and metabolism will result in different plasma and intracellular levels acting along a dose-response effect on IKr block. Consequently, important hormone-dependent factors such as metabolic enzymes and membrane transporters need to be investigated in new basic research studies.
Topics: Animals; Causality; Cytochrome P-450 Enzyme System; Female; Gonadal Steroid Hormones; Humans; Long QT Syndrome; Membrane Transport Proteins; Potassium Channel Blockers; Risk Factors; Sex Characteristics; Sex Distribution; Sex Factors; Torsades de Pointes; Women's Health
PubMed: 18573480
DOI: 10.1016/j.genm.2008.05.005 -
Molecular Neurobiology Dec 2023Migraine is a complex neurovascular disorder that is characterized by severe behavioral, sensory, visual, and/or auditory symptoms. It has been labeled as one of the ten... (Review)
Review
Migraine is a complex neurovascular disorder that is characterized by severe behavioral, sensory, visual, and/or auditory symptoms. It has been labeled as one of the ten most disabling medical illnesses in the world by the World Health Organization (Aagaard et al Sci Transl Med 6(237):237ra65, 2014). According to a recent report by the American Migraine Foundation (Shoulson et al Ann Neurol 25(3):252-9, 1989), around 148 million people in the world currently suffer from migraine. On the basis of presence of aura, migraine is classified into two major subtypes: migraine with aura (Aagaard et al Sci Transl Med 6(237):237ra65, 2014) and migraine without aura. (Aagaard K et al Sci Transl Med 6(237):237ra65, 2014) Many complex genetic mechanisms have been proposed in the pathophysiology of migraine but specific pathways associated with the different subtypes of migraine have not yet been explored. Various approaches including candidate gene association studies (CGAS) and genome-wide association studies (Fan et al Headache: J Head Face Pain 54(4):709-715, 2014). have identified the genetic markers associated with migraine and its subtypes. Several single nucleotide polymorphisms (Kaur et al Egyp J Neurol, Psychiatry Neurosurg 55(1):1-7, 2019) within genes involved in ion homeostasis, solute transport, synaptic transmission, cortical excitability, and vascular function have been associated with the disorder. Currently, the diagnosis of migraine is majorly behavioral with no focus on the genetic markers and thereby the therapeutic intervention specific to subtypes. Therefore, there is a need to explore genetic variants significantly associated with MA and MO as susceptibility markers in the diagnosis and targets for therapeutic interventions in the specific subtypes of migraine. Although the proper characterization of pathways based on different subtypes is yet to be studied, this review aims to make a first attempt to compile the information available on various genetic variants and the molecular mechanisms involved with the development of MA and MO. An attempt has also been made to suggest novel candidate genes based on their function to be explored by future research.
PubMed: 38135854
DOI: 10.1007/s12035-023-03837-3 -
The Cochrane Database of Systematic... Nov 2011The creatine kinase system, the central regulatory system of cellular energy metabolism, provides ATP in situ at ATP-ases involved in ion transport and muscle... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The creatine kinase system, the central regulatory system of cellular energy metabolism, provides ATP in situ at ATP-ases involved in ion transport and muscle contraction. Furthermore, the enzyme system provides relative protection from tissue ischaemia and acidosis. The system could therefore be a target for pharmacologic intervention.
OBJECTIVES
To systematically evaluate evidence regarding the effectiveness of interventions directly targeting the creatine kinase system as compared to placebo control in adult patients with essential hypertension or cardiovascular disease.
SEARCH METHODS
Electronic databases searched: Medline (1950 - Feb 2011), Embase (up to Feb 2011), the Cochrane Controlled Trials Register (issue 3, Aug 2009), Latin-American/Caribbean databank Lilacs; references from textbooks and reviews; contact with experts and pharmaceutical companies; and searching the Internet. There was no language restriction.
SELECTION CRITERIA
Randomized controlled trials comparing creatine, creatine phosphate, or cyclocreatine (any route, dose or duration of treatment) with placebo; in adult patients with essential hypertension, heart failure, or myocardial infarction. We did not include papers on the short-term use of creatine during cardiac surgery.
DATA COLLECTION AND ANALYSIS
The outcomes assessed were death, total myocardial infarction (fatal or non-fatal), hospitalizations for congestive heart failure, change in ejection fraction, and changes in diastolic and systolic blood pressure in mm Hg or as percent change.
MAIN RESULTS
Full reports or abstracts from 1164 papers were reviewed, yielding 11 trials considering treatment with creatine or creatine analogues in 1474 patients with heart failure, ischemic heart disease or myocardial infarction. No trial in patients with hypertension was identified. Eleven trials (1474 patients, 35 years or older) comparing add-on therapy of the creatine-based drug on standard treatment to placebo control in patients with heart failure (6 trials in 1226 / 1474 patients ), or acute myocardial infarction (4 trials in 220 / 1474 patients) or 1 in ischemic heart disease (28 / 1474 patients) were identified. The drugs used were either creatine, creatine phosphate (orally, intravenously, or intramuscular) or phosphocreatinine. In the trials considering heart failure all three different compounds were studied; creatine orally (Gordon 1995, Kuethe 2006), creatine phosphate via intravenous infusion (Ferraro 1996, Grazioli 1992), and phosphocreatinine orally (Carmenini 1994, Maggi 1990). In contrast, the acute myocardial infarction trials studied intravenous creatine phosphate only. In the ischemic heart disease trial (Pedone 1984) creatine phosphate was given twice daily through an intramuscular injection to outpatients and through an intravenous infusion to inpatients. The duration of the study intervention was shorter for the acute patients, from a two hour intravenous infusion of creatine phosphate in acute myocardial infarction (Ruda 1988, Samarenko 1987), to six months in patients with heart failure on oral phosphocreatinine therapy (Carmenini 1994). In the acute myocardial infarction patients the follow-up period varied from the acute treatment period (Ruda 1988) to 28 days after start of the symptoms (Samarenko 1987) or end of the hospitalization period (Zochowski 1994). In the other trials there was no follow-up after discontinuation of treatment, except for Gordon 1995 which followed the patients until four days after stopping the intervention.Only two out of four trials in patients with acute myocardial infarction reported mortality outcomes, with no significant effect of creatine or creatine analogues (RR 0.73, CI: 0.22 - 2.45). In addition, there was no significance on the progression of myocardial infarction or improvement on ejection fraction. The main effect of the interventions seems to be on improvement of dysrhythmia.
AUTHORS' CONCLUSIONS
This review found inconclusive evidence to decide on the use of creatine analogues in clinical practice. In particular, it is not clear whether there is an effect on mortality, progression of myocardial infarction and ejection fraction, while there is some evidence that dysrhythmia and dyspnoea might improve. However, it is not clear which analogue, dose, route of administration, and duration of therapy is most effective. Moreover, given the small sample size of the discussed trials and the heterogeneity of the population included in these reports, larger clinical studies are needed to confirm these observations.
Topics: Cardiovascular Diseases; Creatine; Creatine Kinase; Heart Failure; Humans; Hypertension; Molecular Targeted Therapy; Myocardial Infarction; Myocardial Ischemia; Phosphocreatine
PubMed: 22071819
DOI: 10.1002/14651858.CD005184.pub2 -
Molecular Brain Jun 2020The present review systematically summarized existing publications regarding the genetic associations between voltage-gated calcium channels (VGCCs) and autism spectrum...
OBJECTIVES
The present review systematically summarized existing publications regarding the genetic associations between voltage-gated calcium channels (VGCCs) and autism spectrum disorder (ASD).
METHODS
A comprehensive literature search was conducted to gather pertinent studies in three online databases. Two authors independently screened the included records based on the selection criteria. Discrepancies in each step were settled through discussions.
RESULTS
From 1163 resulting searched articles, 28 were identified for inclusion. The most prominent among the VGCCs variants found in ASD were those falling within loci encoding the α subunits, CACNA1A, CACNA1B, CACNA1C, CACNA1D, CACNA1E, CACNA1F, CACNA1G, CACNA1H, and CACNA1I as well as those of their accessory subunits CACNB2, CACNA2D3, and CACNA2D4. Two signaling pathways, the IP3-Ca pathway and the MAPK pathway, were identified as scaffolds that united genetic lesions into a consensus etiology of ASD.
CONCLUSIONS
Evidence generated from this review supports the role of VGCC genetic variants in the pathogenesis of ASD, making it a promising therapeutic target. Future research should focus on the specific mechanism that connects VGCC genetic variants to the complex ASD phenotype.
Topics: Autism Spectrum Disorder; Calcium Channels; Calcium Signaling; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Protein Subunits
PubMed: 32571372
DOI: 10.1186/s13041-020-00634-0 -
The Cochrane Database of Systematic... Jul 2006People with cystic fibrosis (CF) have increased transport of the salt, sodium across their airway lining. Over-absorption of sodium results in the dehydration of the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
People with cystic fibrosis (CF) have increased transport of the salt, sodium across their airway lining. Over-absorption of sodium results in the dehydration of the liquid that lines the airway surface and is a primary defect in people with CF.
OBJECTIVES
To determine whether the topical administration of drugs that block sodium transport improves the respiratory condition of people with CF.
SEARCH STRATEGY
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching relevant journals and abstract books of conference proceedings. We contacted principal investigators known to work in the field, previous authors and pharmaceutical companies who manufacture ion transport agents for unpublished or follow-up data. Most recent search of the Group's register: March 2006
SELECTION CRITERIA
Published or unpublished randomised controlled trials (RCTs) or quasi-randomised controlled trials of sodium channel blockers compared to placebo or another sodium channel blocker or the same sodium channel blocker at a different dosing regimen.
DATA COLLECTION AND ANALYSIS
Two authors independently extracted data. Meta-analysis was limited due to differing study designs.
MAIN RESULTS
Four RCTs, with a total of 205 participants, examining the topical administration of the short-acting sodium channel blocker, amiloride, compared to placebo were identified as eligible for inclusion in the review. For three studies, interventions for six months were completed and it was possible to calculate relative change in respiratory function (FVC). There was a significant difference found in relative change in FVC in favour of placebo (GIV analysis of weighted mean difference for FVC; 1.51% (95% confidence interval -2.77 to -0.25). There were no significant differences identified in other clinically relevant outcomes.
AUTHORS' CONCLUSIONS
We found no evidence that the topical administration of a short-acting sodium channel blocker improves respiratory condition in people with cystic fibrosis and some limited evidence of deterioration in lung function.
Topics: Cystic Fibrosis; Humans; Randomized Controlled Trials as Topic; Sodium Channel Blockers
PubMed: 16856076
DOI: 10.1002/14651858.CD005087.pub2 -
International Journal of Molecular... Dec 2021Pesticides of different chemical classes exert their toxic effects on the nervous system by acting on the different regulatory mechanisms of calcium (Ca) homeostasis....
Pesticides of different chemical classes exert their toxic effects on the nervous system by acting on the different regulatory mechanisms of calcium (Ca) homeostasis. Pesticides have been shown to alter Ca homeostasis, mainly by increasing its intracellular concentration above physiological levels. The pesticide-induced Ca overload occurs through two main mechanisms: the entry of Ca from the extracellular medium through the different types of Ca channels present in the plasma membrane or its release into the cytoplasm from intracellular stocks, mainly from the endoplasmic reticulum. It has also been observed that intracellular increases in the Ca concentrations are maintained over time, because pesticides inhibit the enzymes involved in reducing its levels. Thus, the alteration of Ca levels can lead to the activation of various signaling pathways that generate oxidative stress, neuroinflammation and, finally, neuronal death. In this review, we also discuss some proposed strategies to counteract the detrimental effects of pesticides on Ca homeostasis.
Topics: Animals; Calcium; Calcium Channels; Calcium Signaling; Calcium, Dietary; Cell Membrane; Homeostasis; Humans; Neuroinflammatory Diseases; Neurotoxicity Syndromes; Oxidative Stress; Pesticides
PubMed: 34948173
DOI: 10.3390/ijms222413376