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International Journal of Medical... 2023The members of the transmembrane emp24 domain-containing protein (TMED) family are summarized in human as four subfamilies, α (TMED 4, 9), β (TMED 2), γ (TMED1, 3, 5,... (Review)
Review
The members of the transmembrane emp24 domain-containing protein (TMED) family are summarized in human as four subfamilies, α (TMED 4, 9), β (TMED 2), γ (TMED1, 3, 5, 6, 7) and δ (TMED 10), with a total of nine members, which are important regulators of intracellular protein transport and are involved in normal embryonic development, as well as in the pathogenic processes of many human diseases. Here we systematically review the composition, structure and function of TMED family members, and describe the progress of TMED family in human diseases, including malignancies (head and neck tumors, lung cancer, breast cancer, ovarian cancer, endometrial cancer, gastrointestinal tumors, urological tumors, osteosarcomas, etc.), immune responses, diabetes, neurodegenerative diseases, and nonalcoholic fatty liver disease, dilated cardiomyopathy, mucin 1 nephropathy (MKD), and desiccation syndrome (SS). Finally, we discuss and prospect the potential of TMED for disease prognosis prediction and therapeutic targeting, with a view to laying the foundation for therapeutic research based on TMED family causative genes.
Topics: Pregnancy; Female; Humans; Membrane Proteins; Protein Transport; Non-alcoholic Fatty Liver Disease; Vesicular Transport Proteins
PubMed: 37928880
DOI: 10.7150/ijms.87272 -
The Cochrane Database of Systematic... Dec 2020Cystic fibrosis (CF) is a common life-shortening genetic condition caused by a variant in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. A class... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Cystic fibrosis (CF) is a common life-shortening genetic condition caused by a variant in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. A class II CFTR variant F508del (found in up to 90% of people with CF (pwCF)) is the commonest CF-causing variant. The faulty protein is degraded before reaching the cell membrane, where it needs to be to effect transepithelial salt transport. The F508del variant lacks meaningful CFTR function and corrective therapy could benefit many pwCF. Therapies in this review include single correctors and any combination of correctors and potentiators.
OBJECTIVES
To evaluate the effects of CFTR correctors (with or without potentiators) on clinically important benefits and harms in pwCF of any age with class II CFTR mutations (most commonly F508del).
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Cystic Fibrosis Trials Register, reference lists of relevant articles and online trials registries. Most recent search: 14 October 2020.
SELECTION CRITERIA
Randomised controlled trials (RCTs) (parallel design) comparing CFTR correctors to control in pwCF with class II mutations.
DATA COLLECTION AND ANALYSIS
Two authors independently extracted data, assessed risk of bias and evidence quality (GRADE); we contacted investigators for additional data.
MAIN RESULTS
We included 19 RCTs (2959 participants), lasting between 1 day and 24 weeks; an extension of two lumacaftor-ivacaftor studies provided additional 96-week safety data (1029 participants). We assessed eight monotherapy RCTs (344 participants) (4PBA, CPX, lumacaftor, cavosonstat and FDL169), six dual-therapy RCTs (1840 participants) (lumacaftor-ivacaftor or tezacaftor-ivacaftor) and five triple-therapy RCTs (775 participants) (elexacaftor-tezacaftor-ivacaftor or VX-659-tezacaftor-ivacaftor); below we report only the data from elexacaftor-tezacaftor-ivacaftor combination which proceeded to Phase 3 trials. In 14 RCTs participants had F508del/F508del genotypes, in three RCTs F508del/minimal function (MF) genotypes and in two RCTs both genotypes. Risk of bias judgements varied across different comparisons. Results from 11 RCTs may not be applicable to all pwCF due to age limits (e.g. adults only) or non-standard design (converting from monotherapy to combination therapy). Monotherapy Investigators reported no deaths or clinically-relevant improvements in quality of life (QoL). There was insufficient evidence to determine any important effects on lung function. No placebo-controlled monotherapy RCT demonstrated differences in mild, moderate or severe adverse effects (AEs); the clinical relevance of these events is difficult to assess with their variety and small number of participants (all F508del/F508del). Dual therapy Investigators reported no deaths (moderate- to high-quality evidence). QoL scores (respiratory domain) favoured both lumacaftor-ivacaftor and tezacaftor-ivacaftor therapy compared to placebo at all time points. At six months lumacaftor 600 mg or 400 mg (both once daily) plus ivacaftor improved Cystic Fibrosis Questionnaire (CFQ) scores slightly compared with placebo (mean difference (MD) 2.62 points (95% confidence interval (CI) 0.64 to 4.59); 1061 participants; high-quality evidence). A similar effect was observed for twice-daily lumacaftor (200 mg) plus ivacaftor (250 mg), but with low-quality evidence (MD 2.50 points (95% CI 0.10 to 5.10)). The mean increase in CFQ scores with twice-daily tezacaftor (100 mg) and ivacaftor (150 mg) was approximately five points (95% CI 3.20 to 7.00; 504 participants; moderate-quality evidence). At six months, the relative change in forced expiratory volume in one second (FEV) % predicted improved with combination therapies compared to placebo by: 5.21% with once-daily lumacaftor-ivacaftor (95% CI 3.61% to 6.80%; 504 participants; high-quality evidence); 2.40% with twice-daily lumacaftor-ivacaftor (95% CI 0.40% to 4.40%; 204 participants; low-quality evidence); and 6.80% with tezacaftor-ivacaftor (95% CI 5.30 to 8.30%; 520 participants; moderate-quality evidence). More pwCF reported early transient breathlessness with lumacaftor-ivacaftor, odds ratio 2.05 (99% CI 1.10 to 3.83; 739 participants; high-quality evidence). Over 120 weeks (initial study period and follow-up) systolic blood pressure rose by 5.1 mmHg and diastolic blood pressure by 4.1 mmHg with twice-daily 400 mg lumacaftor-ivacaftor (80 participants; high-quality evidence). The tezacaftor-ivacaftor RCTs did not report these adverse effects. Pulmonary exacerbation rates decreased in pwCF receiving additional therapies to ivacaftor compared to placebo: lumacaftor 600 mg hazard ratio (HR) 0.70 (95% CI 0.57 to 0.87; 739 participants); lumacaftor 400 mg, HR 0.61 (95% CI 0.49 to 0.76; 740 participants); and tezacaftor, HR 0.64 (95% CI, 0.46 to 0.89; 506 participants) (moderate-quality evidence). Triple therapy Three RCTs of elexacaftor to tezacaftor-ivacaftor in pwCF (aged 12 years and older with either one or two F508del variants) reported no deaths (high-quality evidence). All other evidence was graded as moderate quality. In 403 participants with F508del/minimal function (MF) elexacaftor-tezacaftor-ivacaftor improved QoL respiratory scores (MD 20.2 points (95% CI 16.2 to 24.2)) and absolute change in FEV (MD 14.3% predicted (95% CI 12.7 to 15.8)) compared to placebo at 24 weeks. At four weeks in 107 F508del/F508del participants, elexacaftor-tezacaftor-ivacaftor improved QoL respiratory scores (17.4 points (95% CI 11.9 to 22.9)) and absolute change in FEV (MD 10.0% predicted (95% CI 7.5 to 12.5)) compared to tezacaftor-ivacaftor. There was probably little or no difference in the number or severity of AEs between elexacaftor-tezacaftor-ivacaftor and placebo or control (moderate-quality evidence). In 403 F508del/F508del participants, there was a longer time to protocol-defined pulmonary exacerbation with elexacaftor-tezacaftor-ivacaftor over 24 weeks (moderate-quality evidence).
AUTHORS' CONCLUSIONS
There is insufficient evidence that corrector monotherapy has clinically important effects in pwCF with F508del/F508del. Both dual therapies (lumacaftor-ivacaftor, tezacaftor-ivacaftor) result in similar improvements in QoL and respiratory function with lower pulmonary exacerbation rates. Lumacaftor-ivacaftor was associated with an increase in early transient shortness of breath and longer-term increases in blood pressure (not observed for tezacaftor-ivacaftor). Tezacaftor-ivacaftor has a better safety profile, although data are lacking in children under 12 years. In this population, lumacaftor-ivacaftor had an important impact on respiratory function with no apparent immediate safety concerns; but this should be balanced against the blood pressure increase and shortness of breath seen in longer-term adult data when considering lumacaftor-ivacaftor. There is high-quality evidence of clinical efficacy with probably little or no difference in AEs for triple (elexacaftor-tezacaftor-ivacaftor) therapy in pwCF with one or two F508del variants aged 12 years or older. Further RCTs are required in children (under 12 years) and those with more severe respiratory function.
Topics: Adult; Aminophenols; Aminopyridines; Benzodioxoles; Bias; Child; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Indoles; Mutation; Phenylbutyrates; Pyrazoles; Pyridines; Quality of Life; Quinolines; Quinolones; Randomized Controlled Trials as Topic
PubMed: 33331662
DOI: 10.1002/14651858.CD010966.pub3 -
The Japanese Dental Science Review Dec 2023The mechanisms modulated by periodontal pathogens in atherosclerosis are not fully understood. Aim: to perform an integrative analysis of gene and protein expression... (Review)
Review
UNLABELLED
The mechanisms modulated by periodontal pathogens in atherosclerosis are not fully understood. Aim: to perform an integrative analysis of gene and protein expression modulated by periodontal pathogens in cells and animal models for atherosclerosis.
METHODS
Cochrane, PRISMA and AMSTAR2 guidelines for systematic reviews were followed. Data search was conducted in Pub-med, LILACS and Science Direct databases. Gene and protein expression data were collected from the included papers to perform an overrepresentation analysis using the Reactome Pathway Analysis tool and the KEGG database.
RESULTS
Thirty-two papers were included in the review, they analyzed the effect of , , , , , and or/and their virulent factors on gene and protein expression in human cells and animal models of atherosclerosis. Some of the modulated pathways include the immune system, programmed cell death, cellular responses to external stimuli, transport of small molecules, and signal transduction (p < 0.05). Those pathways are known to be involved in different stages of atherosclerosis progression.
CONCLUSION
Based on the performed analysis, it is possible to state that periodontal pathogens have the potential to be a contributing factor for atherosclerosis even in absence of a high-fat diet or high shear stress.
PubMed: 36654677
DOI: 10.1016/j.jdsr.2022.12.001 -
Journal of Inherited Metabolic Disease Mar 2023In patients with ATP7A-related disorders, counseling is challenging due to clinical overlap between the entities, the absence of predictive biomarkers and a clear... (Review)
Review
In patients with ATP7A-related disorders, counseling is challenging due to clinical overlap between the entities, the absence of predictive biomarkers and a clear genotype-phenotype correlation. We performed a systematic literature review by querying the MEDLINE and Embase databases identifying 143 relevant papers. We recorded data on the phenotype and genotype in 162 individuals with a molecularly confirmed ATP7A-related disorder in order to identify differentiating clinical criteria, evaluate genotype-phenotype correlations and propose management guidelines. Early seizures are specific for classical Menkes disease (CMD), that is characterized by early-onset neurodegenerative disease with high mortality rates. Ataxia is an independent indicator for atypical Menkes disease, that shows better survival rates than CMD. Bony exostoses, radial head dislocations, herniations and dental abnormalities are specific for occipital horn syndrome (OHS) that may further present with developmental delay and connective tissue manifestations. Intracranial tortuosity and bladder diverticula, both with high risk of complications, are common among all subtypes. Low ceruloplasmin is a more sensitive and discriminating biomarker for ATP7A-related disorders than serum copper. Truncating mutations are frequently associated with CMD, in contrast with splice site and intronic mutations which are more prevalent in OHS.
Topics: Humans; Menkes Kinky Hair Syndrome; Copper; Neurodegenerative Diseases; Copper-Transporting ATPases; Cutis Laxa; Mutation; Peptide Fragments
PubMed: 36692329
DOI: 10.1002/jimd.12590 -
Reviews in Medical Virology Sep 2023Genome-wide association studies (GWASs) have identified single nucleotide polymorphisms (SNPs) associated with susceptibility and severity of coronavirus disease 2019... (Meta-Analysis)
Meta-Analysis Review
Genome-wide association studies (GWASs) have identified single nucleotide polymorphisms (SNPs) associated with susceptibility and severity of coronavirus disease 2019 (COVID-19). However, identified SNPs are inconsistent across studies, and there is no compelling consensus that COVID-19 status is determined by genetic factors. Here, we conducted a systematic review and meta-analysis to determine the effect of genetic factors on COVID-19. A random-effect meta-analysis was performed to estimate pooled odds ratios (ORs) of SNP effects, and SNP-based heritability (SNP-h ) of COVID-19. The analyses were performed using meta-R package, and Stata version 17. The meta-analysis included a total of 96,817 COVID-19 cases and 6,414,916 negative controls. The meta-analysis showed that a cluster of highly correlated 9 SNPs (R > 0.9) at 3p21.31 gene locus covering LZTFL1 and SLC6A20 genes was significantly associated with COVID-19 severity, with a pooled OR of 1.8 [1.5-2.0]. Meanwhile, another 3 SNPs (rs2531743-G, rs2271616-T, and rs73062389-A) within the locus was associated with COVID-19 susceptibility, with pooled estimates of 0.95 [0.93-0.96], 1.23 [1.19-1.27] and 1.15 [1.13-1.17], respectively. Interestingly, SNPs associated with susceptibility and SNPs associated with severity in this locus are in linkage equilibrium (R < 0.026). The SNP-h on the liability scale for severity and susceptibility was estimated at 7.6% (Se = 3.2%) and 4.6% (Se = 1.5%), respectively. Genetic factors contribute to COVID-19 susceptibility and severity. In the 3p21.31 locus, SNPs that are associated with susceptibility are not in linkage disequilibrium (LD) with SNPs that are associated with severity, indicating within-locus heterogeneity.
Topics: Humans; Genetic Predisposition to Disease; Genome-Wide Association Study; COVID-19; Linkage Disequilibrium; Polymorphism, Single Nucleotide; Membrane Transport Proteins
PubMed: 37303119
DOI: 10.1002/rmv.2466 -
European Journal of Medical Research Mar 2023Glaucoma is a chronic neurodegenerative process of the optic nerve that is the leading cause of blindness worldwide, and early diagnosis of the disease could greatly... (Meta-Analysis)
Meta-Analysis Review
Glaucoma is a chronic neurodegenerative process of the optic nerve that is the leading cause of blindness worldwide, and early diagnosis of the disease could greatly affect patients' prognoses. The pathophysiology of glaucoma is complicated by a combination of genetic and epigenetic factors. Deciphering the early diagnostic biomarkers in glaucoma could attenuate the disease's global burden and help us understand the exact mechanisms involved in glaucoma. The microRNAs are members of a larger family of non-coding RNAs that play an essential role in the epigenetic basis of glaucoma. A systematic study and meta-analysis of diagnostic microRNAs in glaucoma, jointly with network analysis of target genes, were carried out on published papers assessing differentially expressed microRNAs in human subjects. In total, 321 articles were found, and, after screening, six studies were eligible for further analysis. 52 differentially expressed microRNAs were found, of which 28 and 24 were up-regulated and down-regulated, respectively. Only 12 microRNAs were qualified for meta-analysis, with overall sensitivity and specificity of 80% and 74%, respectively. Then, using network analysis, it became apparent that the VEGF-A, AKT1, CXCL12, and HRAS genes were the most important targets for the microRNAs. Perturbations in WNT signaling, protein transport, and extracellular matrix organization pathways were discovered to be important in the etiology of glaucoma using the community detection approach. This study tries to uncover the promising microRNAs and their target genes that govern the epigenetics of glaucoma.
Topics: Humans; MicroRNAs; Glaucoma; Prognosis; Early Diagnosis
PubMed: 36973823
DOI: 10.1186/s40001-023-01093-8 -
Cureus Oct 2022Hypertension (HTN) is one of the most prevalent and dangerous cardiovascular diseases worldwide. Recently, its direct or indirect association with gut dysbiosis has been... (Review)
Review
Hypertension (HTN) is one of the most prevalent and dangerous cardiovascular diseases worldwide. Recently, its direct or indirect association with gut dysbiosis has been an interest of study for many. It also includes the metabolomic and functional gene changes in hypertensives compared with healthy individuals. This systematic review aims to study quantitative and qualitative interactions between the two and re-defining the heart-gut axis. We have strictly followed the (PRISMA), 2020, guidelines. We conducted an in-depth search of databases such as PubMed, PubMed Central (PMC), Medline, and ScienceDirect to find relevant studies for our topic of interest. After the final quality check, we included eight articles in the systematic review. A significant difference in richness and diversity in gut microbiota was observed in hypertensive patients compared with healthy controls. There was an increased abundance of many bacteria such as , , , Enterobacteriaceae, , , , , and , while a decreased abundance of , , spp., and . Alteration of the composition also varied based on diet, age, ethnicity, and severity of HTN. Short-chain fatty acids (SCFAs)-producing bacteria are found to be on the lower side in hypertensives owing to the protective property of SCFAs against inflammation, especially butyric acid. From the perspective of metabolomic changes, harmful metabolites for cardiovascular health such as intestinal fatty acid binding protein (I-FABP), lipopolysaccharides (LPSs), zonulin, sphingomyelins, acylcarnitines, and trimethylamine -oxide (TMAO) were found to be increased in hypertensives. Changes in these biomarkers further establish the relation between gut epithelial health and high blood pressure (BP). Participants affected by diseases have an overall lower rate of acquiring new genes, which results in a low richness of genes in them compared with healthy individuals. There is increased expression of the choline utilization () gene and reduced expression of genes associated with biosynthesis and transport of amino acids in high-BP participants. The unique changes in the composition of the microbiota, functional changes in genes, and metabolome collectively help for a better understanding of the pathogenesis of HTN and also suggest the gut as a promising new therapeutic target for HTN. To establish a further causal relationship between the two, more research is required.
PubMed: 36381851
DOI: 10.7759/cureus.29927 -
Neuroscience and Biobehavioral Reviews Sep 2023Recent lifestyle changes have resulted in tremendous peer pressure and mental stress, and increased the incidences of chronic psychological disorders; like addiction,... (Review)
Review
Recent lifestyle changes have resulted in tremendous peer pressure and mental stress, and increased the incidences of chronic psychological disorders; like addiction, depression and anxiety (ADA). In this context, the stress-tolerance levels vary amongst individuals and genetic factors play prominent roles. Vulnerable individuals may often be drawn towards drug-addiction to combat stress. This systematic review critically appraises the relationship of various genetic factors linked with the incidences of ADA development. For coherence, we focused solely on cocaine as a substance of abuse in this study. Online scholarly databases were used to screen pertinent literature using apt keywords; and the final retrieval included 42 primary-research articles. The major conclusion drawn from this systematic analysis states that there are 51 genes linked with the development of ADA; and 3 (BDNF, PERIOD2 and SLC6A4) of them are common to all the three aspects of ADA. Further, inter-connectivity analyses of the 51 genes further endorsed the central presence of BDNF and SLC6A4 genes in the development of ADA disorders. The conclusions derived from this systematic study pave the way for future studies for the identification of diagnostic biomarkers and drug targets; and for the development of novel and effective therapeutic regimens against ADA.
Topics: Humans; Cocaine-Related Disorders; Depression; Brain-Derived Neurotrophic Factor; Anxiety; Anxiety Disorders; Cocaine; Serotonin Plasma Membrane Transport Proteins
PubMed: 37271299
DOI: 10.1016/j.neubiorev.2023.105270 -
European Journal of Clinical... Feb 2024Calprotectin is a calcium-binding-S100-protein synthetized mainly in neutrophils which has been demonstrated to be an accurate biomarker of the presence of these cells.... (Review)
Review
BACKGROUND
Calprotectin is a calcium-binding-S100-protein synthetized mainly in neutrophils which has been demonstrated to be an accurate biomarker of the presence of these cells. Gut barrier dysfunction in patients with advanced chronic liver disease (ACLD), in addition to the lack of noninvasive tools for diagnosis and prognosis of cirrhosis decompensations, has raised interest in this biomarker.
AIMS
Our aim is to summarize the current evidence regarding the role of calprotectin in terms of its diagnostic and prognostic utility in ACLD.
METHODS
We performed a systematic search (PROSPERO registration no. CRD42023389069) of original articles published without any restrictions on the publication date until January 2023 providing information about calprotectin for the prognosis or diagnosis of ACLD and its decompensations in adult patients.
RESULTS
A total 227 articles were identified, and 26 observational studies finally met the inclusion criteria. In 14 studies, calprotectin was measured in ascitic fluid, all of which reported higher calprotectin values in spontaneous bacterial peritonitis, while cut-off points for its diagnosis were proposed in nine studies. Three studies reported higher faecal calprotectin levels in patients with hepatic encephalopathy and portal hypertension. Four studies evaluated faecal calprotectin and one plasma calprotectin as biomarkers for gut barrier integrity and bacterial translocation.
CONCLUSIONS
Calprotectin is emerging as a promising biomarker in ACLD, particularly for the management of bacterial infections and alcohol-related liver disease. Further research with better study designs should help to determine the feasibility of calprotectin measurement in routine clinical practice.
Topics: Adult; Humans; Biomarkers; Hypertension, Portal; Leukocyte L1 Antigen Complex; Liver Cirrhosis; Prognosis
PubMed: 37849372
DOI: 10.1111/eci.14111 -
Molecular Pain 2021Trigeminal neuralgia (TN) is a severe facial pain disease of unknown cause and unclear genetic background. To examine the existing knowledge about genetics in TN, we...
Trigeminal neuralgia (TN) is a severe facial pain disease of unknown cause and unclear genetic background. To examine the existing knowledge about genetics in TN, we performed a systematic study asking about the prevalence of familial trigeminal neuralgia, and which genes that have been identified in human TN studies and in animal models of trigeminal pain. MedLine, Embase, Cochrane Library and Web of Science were searched from inception to January 2021. 71 studies were included in the systematic review. Currently, few studies provide information about the prevalence of familial TN; the available evidence indicates that about 1-2% of TN cases have the familial form. The available human studies propose the following genes to be possible contributors to development of TN: CACNA1A, CACNA1H, CACNA1F, KCNK1, TRAK1, SCN9A, SCN8A, SCN3A, SCN10A, SCN5A, NTRK1, GABRG1, MPZ gene, MAOA gene and SLC6A4. Their role in familial TN still needs to be addressed. The experimental animal studies suggest an emerging role of genetics in trigeminal pain, though the animal models may be more relevant for trigeminal neuropathic pain than TN per se. In summary, this systematic review suggests a more important role of genetic factors in TN pathogenesis than previously assumed.
Topics: Animals; Facial Pain; Humans; NAV1.7 Voltage-Gated Sodium Channel; Serotonin Plasma Membrane Transport Proteins; Trigeminal Neuralgia
PubMed: 34000891
DOI: 10.1177/17448069211016139