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American Journal of Physiology. Cell... Apr 2021Several potassium channels (KCs) have been described throughout the gastrointestinal tract. Notwithstanding, their contribution to both physiologic and pathophysiologic...
Several potassium channels (KCs) have been described throughout the gastrointestinal tract. Notwithstanding, their contribution to both physiologic and pathophysiologic conditions, as inflammatory bowel disease (IBD), remains underexplored. Therefore, we aim to systematically review, for the first time, the evidence on the characteristics and modulation of KCs in intestinal epithelial cells (IECs). PubMed, Scopus, and Web of Science were searched to identify studies focusing on KCs and their modulation in IECs. The included studies were assessed using a reporting inclusiveness checklist. From the 745 identified records, 73 met the inclusion criteria; their reporting inclusiveness was moderate-high. Some studies described the physiological role of KCs, while others explored their importance in pathological settings. Globally, in IBD animal models, apical K1.1 channels, responsible for luminal secretion, were upregulated. In human colonocytes, basolateral K3.1 channels were downregulated. The pharmacological inhibition of K and K influenced intestinal barrier function, promoting inflammation. Evidence suggests a strong association between KCs expression and secretory mechanisms in human and animal IECs. Further research is warranted to explore the usefulness of KC pharmacological modulation as a therapeutic target.
Topics: Animals; Cell Line; Epithelial Cells; Humans; Intestinal Mucosa; Membrane Potentials; Potassium Channel Blockers; Potassium Channels; Signal Transduction
PubMed: 33326312
DOI: 10.1152/ajpcell.00393.2020 -
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 -
Journal of Affective Disorders Oct 2014Genetic factors may encourage or even cause the occurrence of mood disorders such as anxiety and/or depression. However, despite the significant amount of work and... (Review)
Review
BACKGROUND
Genetic factors may encourage or even cause the occurrence of mood disorders such as anxiety and/or depression. However, despite the significant amount of work and sophisticated technology is not fully elucidated which genes or regions of nuclear or mitochondrial DNA, or which types of genetic changes, alone or in combination, can represent reliable genetic markers of anxiety and/or depression.
OBJECTIVE
To identify whether there are genetic changes that can cause depression or anxiety and if there are genetic markers that can be used to detect these changes.
METHODS
A systematic review of 01.01.2004 to 03.28.2014 was held by VHL (Virtual Health Library). The search was performed with the descriptors ׳׳anxiety׳׳, ׳׳depression׳׳, "mutation" and "genetic markers׳׳. The selected articles were indexed in MEDLINE. The information pertinent to the study was selected, categorized and analyzed. Of the 374 articles found, 29 met the eligibility criteria.
RESULTS
FMR1 gene polymorphisms, dopaminergic (DAT, DRD, COMT), serotonin (5-HTTLPR, HTR1A, HTR2A), interleukins, MCR1, HCN (potassium channel), neurorregulinas, GABAergic (GABA, GAD, DBI) DBI, GABA (Gabra) receptors and GAD genes (GAD1, GAD2) appear to contribute to generate condition of depression or anxiety like. Mutations in mitochondrial DNA in 124pb allele of D2S2944 in ofil 1 and 2 loci of chromosomes 4 and 7, respectively, and the chromosomes 8p, 17p and 15q appear to be associated with the origin of depression or anxiety.
CONCLUSION
Some studies show only associations with one of the disorders, mainly anxiety. Few have shown association with both simultaneously. Other studies showed specific association of gender, or even specific ethnic groups. It was noticed, controversies over certain markers. Interesting results were observed in combination of changes, especially in cases of SNPs, indicating that perhaps this is the most appropriate way to find reliable markers.
Topics: Alleles; Anxiety; Anxiety Disorders; Depression; Depressive Disorder; Genetic Markers; Genetic Predisposition to Disease; Humans; Mutation; Polymorphism, Genetic; Polymorphism, Single Nucleotide
PubMed: 25106036
DOI: 10.1016/j.jad.2014.07.016 -
Vascular Pharmacology Nov 2018A systematic review and meta-analysis was performed to test candidate therapeutic approaches in pulmonary hypertension (PH). The efficacy of 522 interventions with >200... (Meta-Analysis)
Meta-Analysis Review
A systematic review and meta-analysis was performed to test candidate therapeutic approaches in pulmonary hypertension (PH). The efficacy of 522 interventions with >200 unregistered drugs was tested on 7254 animals. We propose a modified formula to assess meta-data that concerns the contribution of PH animal model to the denoted efficacy of tested agents. The measure of efficacy expressed as a response ratio for right ventricle systolic pressure was 0.48 (95% CI, 0.46-0.50; P < 0.00001), mean pulmonary artery pressure was 0.54 (0.52-0.56; P < 0.00001), right ventricle hypertrophy was 0.49 (0.48-0.51; P < 0.00001) and pulmonary artery wall thickness was 0.58 (0.56-0.61; P < 0.00001). Only 41 out of 522 interventions were ineffective. The most potent agents to improve both haemodynamic and hypertrophic parameters were ATP-sensitive potassium channel openers with iptakalim, Rho/ROCK inhibitors with fasudil, RAAS regulators with adenosine and ACE2 activators, and anti-inflammatories with n-3 polyunsaturated fatty acids and NF-кB inhibitors.
Topics: Animals; Antihypertensive Agents; Arterial Pressure; Disease Models, Animal; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Molecular Targeted Therapy; Pulmonary Artery; Signal Transduction; Vascular Remodeling; Ventricular Function, Right; Ventricular Remodeling
PubMed: 30145225
DOI: 10.1016/j.vph.2018.08.004 -
American Journal of Physiology.... Apr 2016Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with a complex pathogenesis. Diarrhea is a highly prevalent and often debilitating symptom of IBD... (Review)
Review
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with a complex pathogenesis. Diarrhea is a highly prevalent and often debilitating symptom of IBD patients that results, at least in part, from an intestinal hydroelectrolytic imbalance. Evidence suggests that reduced electrolyte absorption is more relevant than increased secretion to this disequilibrium. This systematic review analyses and integrates the current evidence on the roles of epithelial Na(+)-K(+)-ATPase (NKA), Na(+)/H(+) exchangers (NHEs), epithelial Na(+) channels (ENaC), and K(+) channels (KC) in IBD-associated diarrhea. NKA is the key driving force of the transepithelial ionic transport and its activity is decreased in IBD. In addition, the downregulation of apical NHE and ENaC and the upregulation of apical large-conductance KC all contribute to the IBD-associated diarrhea by lowering sodium absorption and/or increasing potassium secretion.
Topics: Animals; Epithelial Cells; Epithelial Sodium Channels; Gastrointestinal Absorption; Gastrointestinal Agents; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; Ion Transport; Membrane Transport Modulators; Potassium Channels; Signal Transduction; Sodium-Hydrogen Exchangers; Sodium-Potassium-Exchanging ATPase
PubMed: 26744474
DOI: 10.1152/ajpgi.00369.2015 -
Sports Medicine - Open Sep 2019There is abundant and mounting information related to the molecular and biological structure and function of the Aquaporin-1 (AQP1) gene and the AQP1-Aquaporin channel.... (Review)
Review
BACKGROUND
There is abundant and mounting information related to the molecular and biological structure and function of the Aquaporin-1 (AQP1) gene and the AQP1-Aquaporin channel. Regulation of water flow across cell membranes is essential for supporting inter- and intracellular fluid balance, which is critical for health and exercise performance. The transmembrane water channel AQP1 is important for cardiorespiratory endurance (CE) because it influences fluid transfers in erythrocytes, endothelial, and pulmonary cells and is vital for transport of ammonium, bicarbonate, carbon dioxide, glycerol, nitric oxide, potassium ion, water, and trans-epithelial and renal water. Very recent publications suggest the association between a DNA sequence variant, rs1049305 (C > G), in the 3'-untranslated region of the AQP1 gene and CE performance. Other reports indicate further significant associations between AQP1 channel and CE phenotypes. The purposes of this systematic review were to examine the extent of the associations between the AQP1 rs1049305 genotype and CE exercise performance and body fluid loss in long-distance runners and AQP1 channel associations with other CE phenotypes.
METHODS
Data sources: A comprehensive review was conducted using PubMed, EMBASE, CINAHL, and Cochrane electronic databases. The search ranged from January 1, 1988, to December 31, 2018. Studies reported in English, French, and Spanish were considered. Eligibility criteria: The criteria for inclusion in the review were (a) case-control study; (b) unequivocal definition of cases and controls; (c) CE was defined as performance in endurance events, laboratory tests, and/or maximal oxygen consumption; (d) exclusion criteria of known causes; (e) genotyping performed by PCR or sequencing; (f) genotype frequencies reported; and (g) no deviation of genotype frequencies from Hardy-Weinberg equilibrium in the control group. Study appraisal: The systematic review included studies examining the AQP1 gene and AQP1 channel structure and function, associations between the AQP1 gene sequence variant rs1049305 (C > G) and CE performance, body fluid loss in long-distance runners, and other studies reporting on the AQP1 gene and channel CE phenotype associations. Synthesis methods: For each selected study, the following data were extracted: authors, year of publication, sample size and number of cases and controls, CE definition, exclusion criteria, inclusion criteria for cases and controls, methods used for genotyping, genotype, allele frequencies and HWE for genotype frequencies in cases and control groups, and method of AQP1 gene and AQP1 channel analysis.
RESULTS
The initial databases search found 172 pertinent studies. Of those, 46 studies were utilized in the final synthesis of the systematic review. The most relevant findings were (a) the identification of an independent replication of the association between AQP1 gene sequence variant rs1049305 (C > G) and CE performance; (b) the association of the rs1049305 C-allele with faster CE running performance; (c) in knockout model, using a linear regression analysis of distance run as a function of Aqp1 status (Aqp1-null vs. wild-type mice) and conditions of hypoxia (ambient [O] = 16%), normoxia (21%), and hyperoxia (40%) indicated that the Aqp1 knockout ran less distance than the wild-type mice (p < 0.001); (d) in vitro, a reduced AQP1 expression was associated with the presence of the rs1049305 G-allele; (e) AQP1 null humans led normal lives and were entirely unaware of any physical limitations. However, they could not support fluid homeostasis when exposed to chronic fluid overload. The limited number of studies with "adequate sample sizes" in various racial and ethnic groups precluding to perform proper in-depth statistical analysis.
CONCLUSIONS
The AQP1 gene and AQP1 channel seems to support homeostatic mechanisms, yet to be totally understood, that are auxiliary in achieving an advantage during endurance exercise. AQP1 functions are vital during exercise and have a profound influence on endurance running performance. AQP1s are underappreciated structures that play vital roles in cellular homeostasis at rest and during CE endurance running exercise. The outcome of the present systematic review provide support to the statement of hypotheses and further research endeavors on the likely influence of AQP1 gene and AQP1 channel on CE performance. Registration: The protocol is not registered.
PubMed: 31486928
DOI: 10.1186/s40798-019-0213-0 -
Biomedicines Nov 2022The endothelium plays a pivotal role in homeostatic mechanisms. It specifically modulates vascular tone by releasing vasodilatory mediators, which act on the vascular... (Review)
Review
BACKGROUND
The endothelium plays a pivotal role in homeostatic mechanisms. It specifically modulates vascular tone by releasing vasodilatory mediators, which act on the vascular smooth muscle. Large amounts of work have been dedicated towards identifying mediators of vasodilation and vasoconstriction alongside the deleterious effects of reactive oxygen species on the endothelium. We conducted a systematic review to study the role of the factors released by the endothelium and the effects on the vessels alongside its role in atherosclerosis.
METHODS
A search was conducted with appropriate search terms. Specific attention was offered to the effects of emerging modulators of endothelial functions focusing the analysis on studies that investigated the role of reactive oxygen species (ROS), perivascular adipose tissue, shear stress, AMP-activated protein kinase, potassium channels, bone morphogenic protein 4, and P2Y2 receptor.
RESULTS
530 citations were reviewed, with 35 studies included in the final systematic review. The endpoints were evaluated in these studies which offered an extensive discussion on emerging modulators of endothelial functions. Specific factors such as reactive oxygen species had deleterious effects, especially in the obese and elderly. Another important finding included the shear stress-induced endothelial nitric oxide (NO), which may delay development of atherosclerosis. Perivascular Adipose Tissue (PVAT) also contributes to reparative measures against atherosclerosis, although this may turn pathological in obese subjects. Some of these factors may be targets for pharmaceutical agents in the near future.
CONCLUSION
The complex role and function of the endothelium is vital for regular homeostasis. Dysregulation may drive atherogenesis; thus, efforts should be placed at considering therapeutic options by targeting some of the factors noted.
PubMed: 36359402
DOI: 10.3390/biomedicines10112884 -
British Journal of Anaesthesia Dec 2016Although several patient characteristic, clinical, and psychological risk factors for chronic postsurgical pain (CPSP) have been identified, genetic variants including... (Review)
Review
BACKGROUND
Although several patient characteristic, clinical, and psychological risk factors for chronic postsurgical pain (CPSP) have been identified, genetic variants including single nucleotide polymorphisms have also become of interest as potential risk factors for the development of CPSP. The aim of this review is to summarize the current evidence on genetic polymorphisms associated with the prevalence and severity of CPSP in adult patients.
METHODS
A systematic review of the literature was performed, and additional literature was obtained by reference tracking. The primary outcome was CPSP, defined as pain at least 2 months after the surgery. Studies performed exclusively in animals were excluded.
RESULTS
Out of the 1001 identified studies, 14 studies were selected for inclusion. These studies described 5269 participants in 17 cohorts. A meta-analysis was not possible because of heterogeneity of data and data analysis. Associations with the prevalence or severity of CPSP were reported for genetic variants in the COMT gene, OPRM1, potassium channel genes, GCH1, CACNG, CHRNA6, P2X7R, cytokine-associated genes, human leucocyte antigens, DRD2, and ATXN1 CONCLUSIONS: Research on the topic of genetic variants associated with CPSP is still in its initial phase. Hypothesis-free, genome-wide association studies on large cohorts are needed in this field. In addition, future studies may also integrate genetic risk factors and patient characteristic, clinical, and psychological predictors for CPSP.
Topics: Chronic Pain; Humans; Pain, Postoperative; Polymorphism, Genetic; Prevalence; Risk Factors; Severity of Illness Index
PubMed: 27956669
DOI: 10.1093/bja/aew378 -
The Cochrane Database of Systematic... Jan 2008Primary periodic paralyses are rare inherited muscle diseases characterised by episodes of flaccid weakness affecting one or more limbs, lasting several hours to several... (Review)
Review
BACKGROUND
Primary periodic paralyses are rare inherited muscle diseases characterised by episodes of flaccid weakness affecting one or more limbs, lasting several hours to several days, caused by mutations in skeletal muscle channel genes.
OBJECTIVES
The objective of this review was to systematically review treatment of periodic paralyses.
SEARCH STRATEGY
We searched the Cochrane Neuromuscular Disease Group Trials Register, MEDLINE (from January 1966 to July 2007), and EMBASE (from January 1980 to July 2007) and any other available international medical library sources from the University of Milan for randomised trials.
SELECTION CRITERIA
We included randomised (including cross-over studies) and quasi-randomised trials in participants with primary periodic paralyses, in which any form of treatment, including physical therapy and alternative therapies, was compared to placebo or another treatment.
DATA COLLECTION AND ANALYSIS
Our primary outcome measure was the change in attack severity or frequency by eight weeks from the start of treatment. Our secondary outcome measures were: change in muscle strength and mass; change in Quality of Life, using Short Form 36 (SF36) or similar; preference of treatment strategy; adverse effects at eight weeks.
MAIN RESULTS
Three studies met our inclusion criteria. In one study dichlorphenamide (DCP) vs placebo was tested in two groups of participants: 42 with hypokalemic periodic paralysis (HypoPP) and 31 with hyperkalemic periodic paralysis (HyperPP), based on clinical criteria. Thirty-four of 42 participants with hypokalemic periodic paralysis completed both treatment phases. For the 34 participants having attack rate data for both treatment phases, the mean improvement in attack rate (P = 0.02) and severity-weighted attack rate (P = 0.01) on DCP relative to placebo were statistically significant. Fifteen preferred DCP, three placebo and six their baseline medication. Twenty-four of 31 participants with hyperkalemic periodic paralysis completed both treatment phases: for the 16 participants who had attack rate data for both treatment phases, the mean improvement in attack rate (P = 0.006) and in severity-weighted attack rate (P = 0.02) on DCP relative to placebo were significant. Fifteen preferred DCP, one placebo and five their baseline medication. Acetazolamide proved to improve muscle strength in eight participants with HypoPP in one other study and pinacidil, a potassium channel opener, also improved muscle strength in 2/4 participants with HypoPP in a third study.
AUTHORS' CONCLUSIONS
The largest included study that met our inclusion criteria suggested that DCP was effective in the prevention of episodic weakness in both hypokalemic and hyperkalemic periodic paralyses. The other two studies provide some evidence that either acetazolamide or pinacidil may improve muscle strength. However we still lack sufficient evidence to provide full guidelines for the treatment of people with periodic paralysis.
Topics: Acetazolamide; Carbonic Anhydrase Inhibitors; Dichlorphenamide; Humans; Hypokalemic Periodic Paralysis; Paralysis, Hyperkalemic Periodic; Pinacidil; Randomized Controlled Trials as Topic
PubMed: 18254068
DOI: 10.1002/14651858.CD005045.pub2 -
Translational Psychiatry Jul 2023Obsessive-compulsive disorder (OCD) is a frequent and debilitating mental illness. Although efficacious treatment options are available, treatment resistance rates are...
Obsessive-compulsive disorder (OCD) is a frequent and debilitating mental illness. Although efficacious treatment options are available, treatment resistance rates are high. Emerging evidence suggests that biological components, especially autoimmune processes, may be associated with some cases of OCD and treatment resistance. Therefore, this systematic literature review summarizing all case reports/case series as well as uncontrolled and controlled cross-sectional studies investigating autoantibodies in patients with OCD and obsessive-compulsive symptoms (OCS) was performed. The following search strategy was used to search PubMed: "(OCD OR obsessive-compulsive OR obsessive OR compulsive) AND (antib* OR autoantib* OR auto-antib* OR immunoglob* OR IgG OR IgM OR IgA)". Nine case reports with autoantibody-associated OCD/OCS were identified: five patients with anti-neuronal autoantibodies (against N-methyl-D-aspartate-receptor [NMDA-R], collapsin response mediator protein [CV2], paraneoplastic antigen Ma2 [Ma2], voltage gated potassium channel complex [VGKC], and "anti-brain" structures) and four with autoantibodies associated with systemic autoimmune diseases (two with Sjögren syndrome, one with neuropsychiatric lupus, and one with anti-phospholipid autoantibodies). Six patients (67%) benefited from immunotherapy. In addition, eleven cross-sectional studies (six with healthy controls, three with neurological/psychiatric patient controls, and two uncontrolled) were identified with inconsistent results, but in six studies an association between autoantibodies and OCD was suggested. In summary, the available case reports suggest an association between OCD and autoantibodies in rare cases, which has been supported by initial cross-sectional studies. However, scientific data is still very limited. Thus, further studies on autoantibodies investigated in patients with OCD compared with healthy controls are needed.
Topics: Humans; Autoantibodies; Cross-Sectional Studies; Obsessive-Compulsive Disorder; Receptors, N-Methyl-D-Aspartate; Brain
PubMed: 37400462
DOI: 10.1038/s41398-023-02545-9