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Frontiers in Pharmacology 2022Insulin secretory agents are commonly used to treat type 2 diabetes. However, traditional insulin secretory agents such as sulfonylureas and glinides have side effects...
Insulin secretory agents are commonly used to treat type 2 diabetes. However, traditional insulin secretory agents such as sulfonylureas and glinides have side effects of hypoglycemia. In recent years, researchers have discovered that berberine can inhibit the voltage-gated k channels of pancreatic β cell membrane and promote insulin secretion without causing hypoglycemia, because the glucose-lowering effects of berberine are only under hyperglycemic conditions or in a high-glucose-dependent manner. In order to shed light on the glucose-lowing effects of berberine in type 2 diabetes with different baseline fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c), we conducted a meta-analysis of randomized controlled trials. We searched eight databases, which included PubMed, EMBASE, Web of Science, the Cochrane Library, and the Chinese databases such as Sino-Med, China National Knowledge Infrastructure (CNKI), Wanfang Database, and VIP Database for Chinese Technical Periodicals, for randomized controlled trials, with berberine as the intervention and patients with type 2 diabetes mellitus as subjects, published up until November 2021. We analyzed the glucose-lowing effects of berberine, including its effects on FPG, HbA1c and 2-h plasma blood glucose (2hPBG), by calculating weighted mean differences (WMD) and 95% confidence interval (CI). To assess the safety of berberine, we analyzed the incidence of total adverse events and hypoglycemia by calculating relative risk (RR) and 95% CI. Thirty-seven studies involving 3,048 patients were included in the meta-analysis. The results showed that berberine could reduce FPG (WMD = -0.82 mmol/L, 95% CI (-0.95, -0.70)), HbA1c (WMD = -0.63%, 95% CI (-0.72, -0.53)), and 2hPBG (WMD = -1.16 mmol/L, 95% CI (-1.36, -0.96)), with all results being statistically significant. Subgroup analyses revealed that the glucose-lowering effect of berberine was associated with baseline mean FPG and HbA1c in type 2 diabetes. In addition, berberine alone or in combination with oral hypoglycemic agents (OHAs) in the treatment of T2DM did not significantly increase the incidence of total adverse events (RR = 0.73, 95% CI (0.55, 0.97), = 0.03) and the risk of hypoglycemia (RR = 0.48, 95% CI (0.21, 1.08), = 0.08). Berberine has a glucose-lowering effect, which is related to the baseline FPG and HbA1c levels of patients. Treatment with berberine may be safe since it does not increase the incidence of total adverse events and the risk of hypoglycemia. https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=292975, identifier CRD42021292975.
PubMed: 36467075
DOI: 10.3389/fphar.2022.1015045 -
Acta Histochemica Jan 2023Epithelial membrane protein 2 (EMP2) is a cell surface protein composed of approximately 160 amino acids and encoded by the growth arrest-specific 3 (GAS3)/peripheral... (Review)
Review
OBJECTIVES
Epithelial membrane protein 2 (EMP2) is a cell surface protein composed of approximately 160 amino acids and encoded by the growth arrest-specific 3 (GAS3)/peripheral myelin protein 22 kDa (PMP22) gene family. Although EMP2 expression has been investigated in several diseases, much remains unknown regarding its mechanism of action and the extent of its role in pathogenesis. Our aim was to perform a systematic review on the involvement of EMP2 in disease processes and the current usage of anti-EMP2 therapies.
METHODS
A Boolean search of the English-language medical literature was performed. PubMed, Scopus, Cochrane, and Web of Science were used to identify relevant citations. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
RESULTS
52 studies met the inclusion criteria for qualitative analysis. Of those, 28 (53.8%) were human-only studies, 11 (21.2%) were animal-only studies, and 13 (25%) studies included both human and animal models. Furthermore, 34 (65.4%) studies focused on EMP2's role in neoplasms, while the remaining 18 (34.6%) articles evaluated its role in other pathologies.
CONCLUSION
Overall, the evidence suggests the mechanisms of action of EMP2 are context dependent. Promising results have been produced by utilizing EMP2 as a biomarker and therapeutic target. More studies are warranted to better understand the mechanism and comprehend the role of EMP2 in the pathogenesis of diseases.
Topics: Animals; Humans; Membrane Glycoproteins; Membrane Proteins
PubMed: 36455339
DOI: 10.1016/j.acthis.2022.151976 -
Clinical Genitourinary Cancer Feb 2023Numerous studies suggested methylation modifications play an important role in upper tract urothelial carcinoma (UTUC), but few have depicted DNA methylation... (Meta-Analysis)
Meta-Analysis
PURPOSE
Numerous studies suggested methylation modifications play an important role in upper tract urothelial carcinoma (UTUC), but few have depicted DNA methylation architecture on the pathological process of UTUC. We aimed to better understand the pathogenesis of UTUC and provide precision medicine references when managing UTUC patients.
METHODS
PubMed, Cochrane Library, EMBASE, and Scopus were searched for UTUC until December 31, 2020. Methodological quality assessment was conducted according to NIH recommendations. Meta-analysis was conducted to assess the prognostic effect of methylated genes. Kaplan-Meier survival analyses were performed to validate methylated genes and cytosine-phosphate-guanine (CpG) sites.
RESULTS
Eleven studies (3619 patients) were eligible to investigate 12 methylated genes and 10 CpGs. The quality of all the studies was fair to good. Meta-analysis found the pooled effect of eligible methylated genes had a low risk of tumor recurrence (HR = 0·67; 95% CI: 0·51-0·87; P = ·003), but a high risk of tumor progression (HR = 1·60; 95% CI: 1·17-2·18; P = ·003) and cancer-specific mortality (HR = 1·35; 95% CI: 1·06-1·72; P = ·01). For individual methylation status of GDF15, HSPA2, RASSF1A, TMEFF2, and VIM, the pooled effect of each gene was found pleiotropic on both diagnosis and prognosis. Survival analysis suggested higher methylation of SPARCL1 had a better disease-specific survival (P = ·048).
CONCLUSION
We combined meta-analysis and Kaplan-Meier survival analysis using the most updated evidence on the methylation of UTUC. Candidate biomarkers with essential diagnosis and prognosis function might provide precision medicine references for personalized therapies.
Topics: Humans; Carcinoma, Transitional Cell; Urinary Bladder Neoplasms; DNA Methylation; Neoplasm Recurrence, Local; Prognosis; Urologic Neoplasms; Membrane Proteins; Neoplasm Proteins
PubMed: 36376170
DOI: 10.1016/j.clgc.2022.10.008 -
Frontiers in Pharmacology 2022The nine membrane-delimited eukaryotic adenylyl cyclases are pseudoheterodimers with an identical domain order of seven (nine) distinct subdomains. Bioinformatics show...
The nine membrane-delimited eukaryotic adenylyl cyclases are pseudoheterodimers with an identical domain order of seven (nine) distinct subdomains. Bioinformatics show that the protein evolved from a monomeric bacterial progenitor by gene duplication and fusion probably in a primordial eukaryotic cell around 1.5 billion years ago. Over a timespan of about 1 billion years, the first fusion product diverged into nine highly distinct pseudoheterodimeric isoforms. The evolutionary diversification ended approximately 0.5 billion years ago because the present isoforms are found in the living fossil coelacanth, a fish. Except for the two catalytic domains, C1 and C2, the mAC isoforms are fully diverged. Yet, within each isoform a high extent of conservation of respective subdomains is found. This applies to the C- and N-termini, a long linker region between the protein halves (C1b), two short cyclase-transducing-elements (CTE) and notably to the two hexahelical membrane domains TM1 and TM2. Except for the membrane anchor all subdomains were previously implicated in regulatory modalities. The bioinformatic results unequivocally indicate that the membrane anchors must possess an important regulatory function specifically tailored for each mAC isoform.
PubMed: 36238545
DOI: 10.3389/fphar.2022.1009797 -
Antibiotics (Basel, Switzerland) Aug 2022The challenging severity of some infections, especially in critically ill patients, makes the diffusion of antimicrobial drugs within tissues one of the cornerstones of... (Review)
Review
The challenging severity of some infections, especially in critically ill patients, makes the diffusion of antimicrobial drugs within tissues one of the cornerstones of chemotherapy. The knowledge of how antibacterial agents penetrate tissues may come from different sources: preclinical studies in animal models, phase I-III clinical trials and post-registration studies. However, the particular physiopathology of critically ill patients may significantly alter drug pharmacokinetics. Indeed, changes in interstitial volumes (the ) and/or in glomerular filtration ratio may influence the achievement of bactericidal concentrations in peripheral compartments, while inflammation can alter the systemic distribution of some drugs. On the contrary, other antibacterial agents may reach high and effective concentrations thanks to the increased tissue accumulation of macrophages and neutrophils. Therefore, the present review explores the tissue distribution of beta-lactams and other antimicrobials acting on the cell wall and cytoplasmic membrane of bacteria in critically ill patients. A systematic search of articles was performed according to PRISMA guidelines, and tissue/plasma penetration ratios were collected. Results showed a highly variable passage of drugs within tissues, while large interindividual variability may represent a hurdle which must be overcome to achieve therapeutic concentrations in some compartments. To solve that issue, off-label dosing regimens could represent an effective solution in particular conditions.
PubMed: 36139944
DOI: 10.3390/antibiotics11091164 -
Biomolecules Aug 2022α-synuclein is a core component of Lewy bodies, one of the pathological hallmarks of Parkinson's disease. Aggregated α-synuclein can impair both synaptic functioning... (Review)
Review
α-synuclein is a core component of Lewy bodies, one of the pathological hallmarks of Parkinson's disease. Aggregated α-synuclein can impair both synaptic functioning and axonal transport. However, understanding the pathological role that α-synuclein plays at a cellular level is complicated as existing findings are multifaceted and dependent on the mutation, the species, and the quantity of the protein that is involved. This systematic review aims to stratify the research findings to develop a more comprehensive understanding of the role of aggregated α-synuclein on synaptic and axonal proteins in Parkinson's disease models. A literature search of the PubMed, Scopus, and Web of Science databases was conducted and a total of 39 studies were included for analysis. The review provides evidence for the dysregulation or redistribution of synaptic and axonal proteins due to α-synuclein toxicity. However, due to the high quantity of variables that were used in the research investigations, it was challenging to ascertain exactly what effect α-synuclein has on the expression of the proteins. A more standardized experimental approach regarding the variables that are employed in future studies is crucial so that existing literature can be consolidated. New research involving aggregated α-synuclein at the synapse and regarding axonal transport could be advantageous in guiding new treatment solutions.
Topics: Axons; Humans; Lewy Bodies; Parkinson Disease; Synapses; alpha-Synuclein
PubMed: 36139038
DOI: 10.3390/biom12091199 -
Frontiers in Oncology 2022Cancer is a leading cause of death worldwide and novel prognostic factors are reported with increasing numbers. Systematic reviews and meta-analyses on cumulative...
Cancer is a leading cause of death worldwide and novel prognostic factors are reported with increasing numbers. Systematic reviews and meta-analyses on cumulative research data are crucial in estimating the true prognostic value of proposed factors. Dysadherin (FXYD Domain Containing Ion Transport Regulator 5; FXYD5) is a cell membrane glycoprotein that modulates Na+, K+-ATPase activity and cell-cell adhesion. It is abundantly expressed in a variety of cancer cells, but only in a limited number of normal cells and its levels are increased in many different tumor types. The expression or level of dysadherin has been suggested as an independent predictor for metastasis and poor prognosis by number of studies, yet we lack a definitive answer. In this study, we systematically evaluated the prognostic value of dysadherin in cancer and summarized the current knowledge on the subject. PubMed, Scopus, Web of Science and relevant clinical trial and preprint databases were searched for relevant publications and PRISMA and REMARK guidelines were applied in the process. After a careful review, a total of 23 original research articles were included. In each study, dysadherin was pointed as a marker for poor prognosis. Meta-analyses revealed 3- and 1.5-fold increases in the risk of death (fixed effects HR 3.08, 95% CI 1.88-5.06, RR 1.47, 95% CI 1.06-2.05 on overall survival, respectively) for patients with high (>50%) tumoral FXYD5 level. In many studies, a connection between dysadherin expression or level and metastatic behavior of the cancer as well as inverse correlation with E-cadherin level were reported. Thus, we conclude that dysadherin might be a useful prognostic biomarker in the assessment of disease survival of patients with solid tumors.
PubMed: 36119538
DOI: 10.3389/fonc.2022.945992 -
Frontiers in Pharmacology 2022The Na/K-ATPase is an integral membrane ion pump, essential to maintaining osmotic balance in cells in the presence of cardiotonic steroids; more specifically, ouabain...
The Na/K-ATPase is an integral membrane ion pump, essential to maintaining osmotic balance in cells in the presence of cardiotonic steroids; more specifically, ouabain can be an endogenous modulator of the Na/K-ATPase. Here, we conducted a systematic review of the effects of cardiotonic steroids on Ca in the brain of rats and mice. Methods: The review was carried out using the PubMed, Virtual Health Library, and EMBASE databases (between 12 June 2020 and 30 June 2020) and followed the guidelines described in the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). Results: in total, 829 references were identified in the electronic databases; however, only 20 articles were considered, on the basis of the inclusion criteria. The studies demonstrated the effects of ouabain on Ca signaling in synaptosomes, brain slices, and cultures of rat and mouse cells. In addition to the well-known cytotoxic effects of high doses of ouabain, resulting from indirect stimulation of the reverse mode of the Na/Ca exchanger and increased intracellular Ca, other effects have been reported. Ouabain-mediated Ca signaling was able to act increasing cholinergic, noradrenergic and glutamatergic neurotransmission. Furthermore, ouabain significantly increased intracellular signaling molecules such as InsPs, IP3 and cAMP. Moreover treatment with low doses of ouabain stimulated myelin basic protein synthesis. Ouabain-induced intracellular Ca increase may promote the activation of important cell signaling pathways involved in cellular homeostasis and function. Thus, the study of the application of ouabain in low doses being promising for application in neurological diseases. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020204498, identifier CRD42020204498.
PubMed: 36105192
DOI: 10.3389/fphar.2022.916312 -
Frontiers in Genetics 2022Exosomes are nano-extracellular vesicles secreted by a variety of cells. They are composed of a double-layer membrane that can transport a variety of proteins, coding...
Exosomes are nano-extracellular vesicles secreted by a variety of cells. They are composed of a double-layer membrane that can transport a variety of proteins, coding and non-coding genes, and bioactive substances. Exosomes participate in information transmission between cells and regulate processes such as cell proliferation, migration, angiogenesis, and phenotypic transformation. They have broad prospects in the occurrence, development, and treatment of many diseases including orthopedics. Exosomes derived from different types of bone cells such as mesenchymal stem cells, osteoblasts, osteoclasts, and their precursors are recognized to play pivotal roles in bone remodeling processes including osteogenesis, osteoclastogenesis, and angiogenesis. This articlesummarizes the characteristics of exosomes and their research progress in bone remodeling, bone tumors, vascular skeletal muscle injury, spinal cord injury, degenerative disc diseases, cartilage degeneration, osteoarthritis, necrosis of the femoral head, and osteoporosis.
PubMed: 36081990
DOI: 10.3389/fgene.2022.915141 -
The Cochrane Database of Systematic... Sep 2022Ocular surface burns can be caused by chemicals (alkalis and acids) or direct heat. One effect of the burn is damage to the limbal epithelial stem cells of the ocular... (Review)
Review
BACKGROUND
Ocular surface burns can be caused by chemicals (alkalis and acids) or direct heat. One effect of the burn is damage to the limbal epithelial stem cells of the ocular surface with delayed re-epithelialisation, stem cell failure, and conjunctivalisation of the cornea. Amniotic membrane transplantation (AMT) performed in the acute phase (day 0 to day 7) following an ocular surface burn is claimed to reduce pain and accelerate healing. The surgery involves securing a layer of amniotic membrane (AM) to the eyelid margins as a patch to cover the entire ocular surface. However, there is debate about the severity of an ocular burn that may benefit from AMT and uncertainty of whether AMT improves outcomes.
OBJECTIVES
To compare the effect of AMT with medical therapy in the first seven days after an ocular surface burn, compared to medical therapy alone.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL; which contains the Cochrane Eyes and Vision Trials Register; 2021, Issue 9); Ovid MEDLINE; Ovid Embase; LILACS; the ISRCTN registry; ClinicalTrials.gov and the WHO ICTRP. We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 29 September 2021.
SELECTION CRITERIA
We included randomised trials that compared an AMT applied in the first seven days following an ocular surface burn in addition to medical therapy with medical therapy alone. The outcome measures were failure of re-epithelialisation by day 21 post injury, visual acuity at final follow-up, corneal neovascularisation, symblepharon, time to re-epithelialisation and adverse effects.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened search results, assessed the included studies for risk of bias and extracted relevant data. We contacted trial investigators for missing information. We summarised data using risk ratios (RRs) and mean differences (MDs) as appropriate.
MAIN RESULTS
We analysed two RCTs, but excluded individual patients who had been treated outside the acute phase in one of the studies (data provided by study authors). In total, 36 moderate burns from one RCT and 92 severe burns from two RCTs were evaluated separately. For both categories, the certainty of the evidence was downgraded principally as a result of high risks of performance and detection biases, and because of imprecision indicated by very wide confidence intervals. In addition, follow-up was insufficiently frequent to calculate time-to-epithelialisation precisely. Moderate severity ocular burns (Roper-Hall classification II-III) The relative risk of AMT on failure of epithelialisation by day 21 was 0.18 (0.02 to 1.31), and LogMAR visual acuity was 0.32 lower (0.55 to 0.09 lower) in the treatment group (i.e. better), suggesting a possible benefit of AMT. The GRADE assessment for failure of epithelialisation by day 21 was downgraded to very low due to the risk of bias and imprecision (very wide confidence intervals including no effect). The GRADE assessment for visual acuity at final follow-up was downgraded to low due to the risk of bias and imprecision (optimal information size not met). The relative effects of AMT on corneal neovascularisation (RR 0.56; 0.21 to 1.48), symblepharon (RR 0.41; 0.02 to 9.48) and time-to-epithelialisation (13 days lower; 26.30 lower to 0.30 higher) suggest possible benefit of AMT, but the wide confidence intervals indicate that both harm and benefit are possible. GRADE assessments for these outcomes were once again downgraded to very low due to the risk of bias and imprecision. Since adverse effects are rare, the small sample would have fewer occurrences of rare but potentially important adverse effects. The GRADE assessment for adverse effects was therefore considered to be low. Severe ocular burns (Roper-Hall classification IV) The relative risk of AMT on failure of epithelialisation by day 21 was 1.03 (0.94 to 1.12), and LogMAR visual acuity was 0.01 higher (0.29 lower to 0.31 higher) in the treatment group (i.e, worse), indicating no benefit of AMT. GRADE assessments for failure of epithelialisation by day 21 and final outcomes were downgraded to low. The relative effects of AMT on corneal neovascularisation (RR 0.84; 0.66 to 1.06), symblepharon (RR 0.89; 0.56 to 1.42) and time-to-epithelialisation (1.66 days lower; 11.09 lower to 7.77 higher) may include both benefit and harm. GRADE assessments for corneal neovascularisation, symblepharon and time-to-epithelialisation were downgraded to low due to risk of bias and imprecision. For adverse effects, the GRADE assessment was downgraded to low, reflecting the small sample sizes in the RCTs.
AUTHORS' CONCLUSIONS
There is uncertain evidence to support the treatment of moderate acute ocular surface burns with AMT in addition to standard medical therapy as a means of preventing failure of epithelialisation by day 21, improving visual outcome and reducing corneal neovascularisation, symblepharon formation and time-to-epithelialisation. For severe burns, the available evidence does not indicate any significant benefit of treatment with AMT.
Topics: Amnion; Corneal Neovascularization; Eye Burns; Humans; Visual Acuity; Wound Healing
PubMed: 36047788
DOI: 10.1002/14651858.CD009379.pub3