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Archives of Razi Institute Nov 2021Substance P binds to the Neurokinin-1 (NK-1) receptors found in the emetic center of the central nervous system (CNS) to induce emesis. Maropitant is a selective NK-1... (Review)
Review
Substance P binds to the Neurokinin-1 (NK-1) receptors found in the emetic center of the central nervous system (CNS) to induce emesis. Maropitant is a selective NK-1 receptor antagonist that inhibits the binding of substance P to NK-1 receptors and is commonly used to prevent and treat vomiting in dogs. This review study aimed to discuss and analyze the therapeutic potential of substance P (Neurokinin-1 receptor) antagonist with a particular focus on the drug maropitant in canine medicine. A systematic literature review was performed to identify the existing literature on the subject during the past 20 years (2001-2021) using such databases as ScienceDirect, PubMed, Scopus, and Google Scholar. The initial search identified 173 articles; however, 41 articles were selected for further analysis, based on the specific inclusion and exclusion criteria. Studies have already confirmed the role of substance P and NK-1 receptors in central pain processing, intestinal smooth muscle contraction, vasodilation, and neurogenic inflammation. Maropitant is one of the most effective veterinary antiemetic drugs that work well against peripheral and central stimuli that trigger the vomiting center. It has been already demonstrated that the therapeutic efficacy of maropitant for managing acute vomiting in dogs is associated with pancreatitis, gastritis, and parvoviral enteritis. It can also prevent and treat chemotherapy-induced emesis and delay the signs of nausea and adverse gastrointestinal effects. Regarding the broad-spectrum antiemetic activity of maropitant, it can be recommended for managing uremic vomiting in dogs. In addition, it has also exhibited an anesthetic sparing effect since the dogs treated with maropitant require a slightly lower percentage of isoflurane as an inhalational anesthetic. The NK-1 receptors are also identified in different areas of the pain pathways. Therefore, NK-1 receptor antagonists might be effective for managing visceral pain. However, further studies are required to establish the broad therapeutic potential of NK-1 receptor antagonist drugs, such as maropitant in canine medicine. It has been shown that the pain associated with the subcutaneous administration of maropitant is due to metacresol, a preservative used in some formulations. Therefore, the side effects can be eliminated by developing novel maropitant formulations specifically for dogs.
Topics: Animals; Antiemetics; Dogs; Neurokinin-1 Receptor Antagonists; Receptors, Neurokinin-1; Substance P; Vomiting
PubMed: 35355772
DOI: 10.22092/ari.2021.356171.1797 -
Giornale Italiano Di Nefrologia :... 2016Vitamin K-dependent matrix Gla protein (MGP) is a key inhibitor of vascular calcification (VC). MGP is synthesized by chondrocytes and vascular smooth muscle cells... (Review)
Review
Vitamin K-dependent matrix Gla protein (MGP) is a key inhibitor of vascular calcification (VC). MGP is synthesized by chondrocytes and vascular smooth muscle cells (VSMC) and the absence or inactivity of MGP results in excessive calcification of both growth plate and vasculature. Apart from its vitamin K dependency little is known about other factors that influence MGP metabolism. Phosphate, calcium and magnesium are involved in bone mineralization and play an important role in VC. In this review we provide a summary of the effect of phosphate, calcium, and magnesium on MGP metabolism. Elevated phosphate and calcium levels promote VC, in part by increasing the release of matrix vesicles (MV) that under the influence of calcium and phosphate become calcification competent. Phosphate and calcium simultaneously induce an upregulation of MGP protein and gene expression, which possibly inhibits calcification. Elevated phosphate levels did not change MGP protein levels in MV. On the contrary, elevated calcium concentrations caused a decrease of MGPloading in MV, which might in part explainthe calcifying effects of MV. Magnesium is a known inhibitor of VC. However, magnesium has been shown to have an inhibitory effect on MGP synthesis induced through downregulation of the calcium-sensing receptor and hereby causing a decrease in calcium induced MGP upregulation. There might also be stimulatory effect of magnesium on MGP in which the TRPM7 channel is involved. In conclusion there is a clear interaction between MGP and phosphate, calcium and magnesium. The upregulation of MGP by phosphate and calcium might be a cellular response that possibly results in the mitigation of VC.
Topics: Calcium; Calcium-Binding Proteins; Extracellular Matrix Proteins; Humans; Magnesium; Phosphates; Vascular Calcification; Matrix Gla Protein
PubMed: 28134400
DOI: No ID Found -
Modern Pathology : An Official Journal... Oct 2022Mucoepidermoid carcinoma (MEC) and adenosquamous carcinoma (ASC) have overlapping histopathological appearances and sites of occurrence, which may cause diagnostic...
Mucoepidermoid carcinoma (MEC) and adenosquamous carcinoma (ASC) have overlapping histopathological appearances and sites of occurrence, which may cause diagnostic difficulty impacting subsequent treatment. We conducted a systematic review of the scientific literature to determine whether molecular alterations were sufficiently different in MEC and ASC to aid in classifying the two entities. We searched Medline, Embase and Web of Science for studies reporting molecular determinations of ASC and/or MEC and screened retrieved records for eligibility. Two independent researchers reviewed included studies, assessed methodological quality and extracted data. Of 8623 identified records, 128 articles were included for analysis: 5 which compared the two tumors in the same investigation using the same methods and 123 which examined the tumors separately. All articles, except one were case series of moderate to poor methodological quality. The 5 publications examining both tumors showed that 52/88 (59%) MEC and 0% of 110 ASC had rearrangement of the MAML2 gene as detected by FISH and/or RT-PCR, but did not investigate other genes. In the entire series MEC had MAML2 gene rearrangement in 1337/2009 (66.6%) of tumors studied. The articles examining tumors separately found that MEC had mutations in EGFR (11/329 cases, 3.3%), KRAS (11/266, 4.1%) and ERBB2 (9/126, 7.1%) compared with ASC that had mutations in EGFR (660/1705, 38.7%), KRAS (143/625, 22.9%) and ERBB2 (6/196, 3.1%). The highest level of recurrent mutations was in pancreatic ASC where (108/126, 85.7%) reported mutations in KRAS. The EGFR mutations in ASC were similar in number and kind to those in lung adenocarcinoma. By standards of systematic review methodology and despite the large number of retrieved studies, we did not find adequate evidence for a distinctive molecular profile of either MEC or ASC that could definitively aid in its classification, especially in histologically difficult cases that are negative for MAML2 rearrangement. The case series included in this review indicate the relevance of MAML2 rearrangement to support the diagnosis of MEC, findings that should be confirmed by additional research with adequate study design.
Topics: Carcinoma, Adenosquamous; Carcinoma, Mucoepidermoid; DNA-Binding Proteins; ErbB Receptors; Humans; In Situ Hybridization, Fluorescence; Nuclear Proteins; Proto-Oncogene Proteins p21(ras); Salivary Gland Neoplasms; Trans-Activators; Transcription Factors
PubMed: 35871081
DOI: 10.1038/s41379-022-01100-z -
Pain Physician Sep 2023Responsiveness to opioid analgesics differs among patients with acute postoperative pain. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Responsiveness to opioid analgesics differs among patients with acute postoperative pain.
OBJECTIVE
Our study presents the most recent evidence on the effect of genetic variations on postoperative pain, opioid consumption, nausea, and vomiting in patients treated with opioids.
STUDY DESIGN
An updated systematic review and meta-analysis on the association between single-nucleotide polymorphisms and opioids administered to patients with acute postoperative pain.
METHODS
PubMed, Embase, ISI Web of Science, and the Cochrane Library databases were searched for articles published from February 1, 2014, through December 31, 2021.
RESULTS
Added to the previous meta-analysis, 39 studies (a total of 7,455 patients) were included in the final meta-analysis. Highlights of the findings include: 1) human μ-opioid receptor gene 118G allele carriers required more opioids during the first postoperative 24 hours (standard mean difference [SMD] = -0.27; 95% CI,-0.40 to -0.14; P < 0.0001) and 48 hours (SMD = -0.52; 95% CI, -0.83 to -0.20; P = 0.001), and reported higher pain scores during the first 24 hours but not at the 48-hour postoperative period (SMD = -0.09, 95% CI, -0.15 to -0.03; P = 0.002) compared to homozygous 118AA patients. 2) patients with the CYP3A4 *1G allele required fewer opioids during the first 24-hour postoperative period (SMD = 0.59; 95% CI, 0.05 to 1.14; P = 0.03) compared to patients with the homozygous CYP3A4*1/*1 allele. 3) Adenosine triphosphate-binding cassette subfamily B member-1 (ABCB1) 3435T allele carriers required more opioids during the 48-hour postoperative period (SMD = -0.21; 95% CI, -0.38 to -0.04; P = 0.02) compared to homozygous CC carriers. 4) Catechol-O-methyl transferase 158A allele carriers required fewer opioids during the first 24-hour postoperative period (SMD = 0.33; 95% CI, 0.15 to 0.51; P = 0.0004) compared to homozygous GG carriers. No significant differences were observed in patients with CYP2D6*10 and ABCB1 G2677A/T genetic polymorphisms.
LIMITATIONS
Several loci were not analyzed in detail due to insufficient clinical data. Furthermore, nongenetic factors that affected analgesic efficacy and the clinical outcome of postoperative pain were not discussed and were not the aim of this meta-analysis.
CONCLUSIONS
In combination with previous systematic reviews and meta-analyses, our results indicate that the A118G allele variant of OPRM1 and the *1*1G allele variant of CYP3A4 have a profound influence on individual differences in opioid reactivity in patients with postoperative pain. Our results, together with the identification of additional single nucleotide polymorphisms in future studies, may provide a theoretical basis for precise clinical analgesia.
KEY WORDS
Single nucleotide polymorphism, postoperative pain, opioid, meta-analysis.
Topics: Humans; Analgesics, Opioid; Catechol O-Methyltransferase; Cytochrome P-450 CYP3A; Pain, Postoperative; Polymorphism, Single Nucleotide
PubMed: 37774182
DOI: No ID Found -
Translational Psychiatry Jan 2017Disrupted-in-Schizophrenia 1 (DISC1) is a gene known as a risk factor for mental illnesses possibly associated with dopamine impairments. DISC1 is a scaffold protein... (Review)
Review
Disrupted-in-Schizophrenia 1 (DISC1) is a gene known as a risk factor for mental illnesses possibly associated with dopamine impairments. DISC1 is a scaffold protein interacting with proteins involved in the dopamine system. Here we summarise the impact of DISC1 disruption on the dopamine system in animal models, considering its effects on presynaptic dopaminergic function (tyrosine hydroxylase levels, dopamine transporter levels, dopamine levels at baseline and after amphetamine administration) and postsynaptic dopaminergic function (dopamine D1 and D2 receptor levels, dopamine receptor-binding potential and locomotor activity after amphetamine administration). Our findings show that many but not all DISC1 models display (1) increased locomotion after amphetamine administration, (2) increased dopamine levels after amphetamine administration in the nucleus accumbens, and (3) inconsistent basal dopamine levels, dopamine receptor levels and binding potentials. There is also limited evidence for decreased tyrosine hydroxylase levels in the frontal cortex and increased dopamine transporter levels in the striatum but not nucleus accumbens, but these conclusions warrant further replication. The main dopaminergic findings are seen across different DISC1 models, providing convergent evidence that DISC1 has a role in regulating dopaminergic function. These results implicate dopaminergic dysregulation as a mechanism underlying the increased rate of schizophrenia seen in DISC1 variant carriers, and provide insights into how DISC1, and potentially DISC1-interacting proteins such as AKT and GSK-3, could be used as novel therapeutic targets for schizophrenia.
Topics: Amphetamine; Animals; Dopamine; Dopamine Plasma Membrane Transport Proteins; Dopamine Uptake Inhibitors; Locomotion; Mice; Nerve Tissue Proteins; Nucleus Accumbens; Rats; Receptors, Dopamine D1; Receptors, Dopamine D2; Tyrosine 3-Monooxygenase
PubMed: 28140405
DOI: 10.1038/tp.2016.282 -
CNS Neuroscience & Therapeutics Apr 2024Alzheimer's disease (AD) is a neurodegenerative disorder distinguished by a swift cognitive deterioration accompanied by distinctive pathological hallmarks such as... (Review)
Review
BACKGROUND
Alzheimer's disease (AD) is a neurodegenerative disorder distinguished by a swift cognitive deterioration accompanied by distinctive pathological hallmarks such as extracellular Aβ (β-amyloid) peptides, neuronal neurofibrillary tangles (NFTs), sustained neuroinflammation, and synaptic degeneration. The elevated frequency of AD cases and its proclivity to manifest at a younger age present a pressing challenge in the quest for novel therapeutic interventions. Numerous investigations have substantiated the involvement of C/EBPβ in the progression of AD pathology, thus indicating its potential as a therapeutic target for AD treatment.
AIMS
Several studies have demonstrated an elevation in the expression level of C/EBPβ among individuals afflicted with AD. Consequently, this review predominantly delves into the association between C/EBPβ expression and the pathological progression of Alzheimer's disease, elucidating its underlying molecular mechanism, and pointing out the possibility that C/EBPβ can be a new therapeutic target for AD.
METHODS
A systematic literature search was performed across multiple databases, including PubMed, Google Scholar, and so on, utilizing predetermined keywords and MeSH terms, without temporal constraints. The inclusion criteria encompassed diverse study designs, such as experimental, case-control, and cohort studies, restricted to publications in the English language, while conference abstracts and unpublished sources were excluded.
RESULTS
Overexpression of C/EBPβ exacerbates the pathological features of AD, primarily by promoting neuroinflammation and mediating the transcriptional regulation of key molecular pathways, including δ-secretase, apolipoprotein E4 (APOE4), acidic leucine-rich nuclear phosphoprotein-32A (ANP32A), transient receptor potential channel 1 (TRPC1), and Forkhead BoxO (FOXO).
DISCUSSION
The correlation between overexpression of C/EBPβ and the pathological development of AD, along with its molecular mechanisms, is evident. Investigating the pathways through which C/EBPβ regulates the development of AD reveals numerous multiple vicious cycle pathways exacerbating the pathological progression of the disease. Furthermore, the exacerbation of pathological progression due to C/EBPβ overexpression and its molecular mechanism is not limited to AD but also extends to other neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and multiple sclerosis (MS).
CONCLUSION
The overexpression of C/EBPβ accelerates the irreversible progression of AD pathophysiology. Additionally, C/EBPβ plays a crucial role in mediating multiple pathways linked to AD pathology, some of which engender vicious cycles, leading to the establishment of feedback mechanisms. To sum up, targeting C/EBPβ could hold promise as a therapeutic strategy not only for AD but also for other degenerative diseases.
Topics: Humans; Alzheimer Disease; CCAAT-Enhancer-Binding Protein-beta; Disease Progression; Animals; Amyloid beta-Peptides
PubMed: 38644578
DOI: 10.1111/cns.14721 -
Biomedical Reports Mar 2024Thrombopoietin receptor agonists (TPO-RAs) have a role in second-line immune thrombocytopenic purpura (ITP) treatment, binding to and activating thrombopoietin receptors...
Thrombopoietin receptor agonists use and risk of thrombotic events in patients with immune thrombocytopenic purpura: A systematic review and meta‑analysis of randomized controlled trials.
Thrombopoietin receptor agonists (TPO-RAs) have a role in second-line immune thrombocytopenic purpura (ITP) treatment, binding to and activating thrombopoietin receptors on megakaryocyte membranes in the bone marrow. This promotes megakaryocyte maturation and increases platelet production. Despite a 2-6% incidence of thrombotic events during TPO-RA treatment, it remains uncertain whether TPO-RAs elevate thrombosis rates. A comprehensive search of electronic databases was conducted using the relevant search criteria. To assess the risk of bias, the included studies were assessed using the revised Cochrane Risk of Bias Assessment Tool 2.0, and a meta-analysis was performed using RevMan 5.4.1. A total of 1,698 patients with ITP were included from randomized controlled trials (RCTs). There were 26 thromboembolic events in the TPO-RAs group and 4 in the control group. However, there was no significant difference in the incidence of thrombotic events between the two groups [odds ratio (OR)=1.76, 95% confidence interval (CI): 0.78-4.00, P=0.18], even if the duration of treatment was >12 weeks (OR=2.46, 95% CI: 0.81-7.43, P=0.11). Subgroup analysis showed that none of the four drugs significantly increased the incidence of thrombotic events (romiplostim: OR=0.92, 95% CI: 0.14-6.13, P=0.93; eltrombopag: OR=2.32, 95% CI: 0.64-8.47, P=0.20; avatrombopag: OR=4.15, 95% CI: 0.20-85.23, P=0.36; and hetrombopag: OR=0.76, 95% CI: 0.03-18.76, P=0.87). There was also no significant difference in the results of the double-blinded placebo-controlled RCTs (OR=1.21, 95% CI: 0.41-3.58, P=0.73). Compared to patients with ITP who did not receive TPO-RA treatment, those receiving TPO-RA treatment did not exhibit a significantly increased risk of thrombotic events.
PubMed: 38357229
DOI: 10.3892/br.2024.1732 -
Nutrients Nov 2021Several observational studies have examined vitamin D pathway polymorphisms and their association with type 1 diabetes (T1D) susceptibility, with inconclusive results.... (Meta-Analysis)
Meta-Analysis
Several observational studies have examined vitamin D pathway polymorphisms and their association with type 1 diabetes (T1D) susceptibility, with inconclusive results. We aimed to perform a systematic review and meta-analysis assessing associations between selected variants affecting 25-hydroxyvitamin D [25(OH)D] and T1D risk. We conducted a systematic search of Medline, Embase, Web of Science and OpenGWAS updated in April 2021. The following keywords "vitamin D" and/or "single nucleotide polymorphisms (SNPs)" and "T1D" were selected to identify relevant articles. Seven SNPs (or their proxies) in six genes were analysed: rs10741657, (low frequency) rs117913124, rs12785878, rs3755967, rs17216707, rs10745742 and rs8018720. Seven case-control and three cohort studies were eligible for quantitative synthesis ( = 10). Meta-analysis results suggested no association with T1D (range of pooled ORs for all SNPs: 0.97-1.02; > 0.01). Heterogeneity was found in rs12785878 (I: 64.8%, = 0.02). Sensitivity analysis showed exclusion of any single study did not alter the overall pooled effect. No association with T1D was observed among a Caucasian subgroup. In conclusion, the evidence from the meta-analysis indicates a null association between selected variants affecting serum 25(OH)D concentrations and T1D.
Topics: Adolescent; Adult; Amidohydrolases; Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor; Child; Child, Preschool; Cholestanetriol 26-Monooxygenase; Cohort Studies; Cytochrome P450 Family 2; Diabetes Mellitus, Type 1; Female; Genetic Predisposition to Disease; Humans; Male; Oxidoreductases Acting on CH-CH Group Donors; Polymorphism, Single Nucleotide; Receptors, Calcitriol; Vesicular Transport Proteins; Vitamin D; Vitamin D Deficiency; Vitamin D-Binding Protein; Vitamin D3 24-Hydroxylase; Young Adult
PubMed: 34959812
DOI: 10.3390/nu13124260 -
Tropical Medicine and Infectious Disease Sep 2023The Duffy protein, a transmembrane molecule, functions as a receptor for various chemokines and facilitates attachment between the reticulocyte and the Duffy... (Review)
Review
The Duffy protein, a transmembrane molecule, functions as a receptor for various chemokines and facilitates attachment between the reticulocyte and the Duffy antigen-binding protein. Duffy expression correlates with the Duffy receptor gene for the chemokine, located on chromosome 1, and exhibits geographical variability worldwide. Traditionally, researchers have described the Duffy negative genotype as a protective factor against infection. However, recent studies suggest that this microorganism's evolution could potentially diminish this protective effect. Nevertheless, there is currently insufficient global data to demonstrate this phenomenon. This study aimed to evaluate the relationship between the Duffy genotype/phenotype and the prevalence of infection. The protocol for the systematic review was registered in PROSPERO as CRD42022353427 and involved reviewing published studies from 2012 to 2022. The Medline/PubMed, Web of Science, Scopus, and SciELO databases were consulted. Assessments of study quality were conducted using the STROBE and GRADE tools. A total of 34 studies were included, with Africa accounting for the majority of recorded studies. The results varied significantly regarding the relationship between the Duffy genotype/phenotype and invasion. Some studies predominantly featured the negative Duffy genotype yet reported no malaria cases. Other studies identified minor percentages of infections. Conversely, certain studies observed a higher prevalence (99%) of Duffy-negative individuals infected with In conclusion, this systematic review found that the homozygous Duffy genotype positive for the A allele (FY*A/*A) is associated with a higher incidence of infection. Furthermore, the negative Duffy genotype does not confer protection against vivax malaria.
PubMed: 37888591
DOI: 10.3390/tropicalmed8100463 -
International Journal of Cardiology Mar 2017Despite advances in therapeutic interventions AF remains a progressive and symptomatic disease. Therefore, novel therapeutic interventions targeting the underlying... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Despite advances in therapeutic interventions AF remains a progressive and symptomatic disease. Therefore, novel therapeutic interventions targeting the underlying arrhythmogenic substrate for AF is needed. Atrial fibrosis is an important component of the arrhythmogenic substrate of AF and may be initiated by aldosterone binding to the mineralocorticoid receptor. We hypothesized that aldosterone pathway blockade with mineralocorticoid receptor antagonists (MRA) reduces atrial fibrosis, and thus AF.
METHODS
We searched OVID MEDLINE, OVID EMBASE and the Cochrane Central Register of Controlled Trials from inception to June 10th, 2016 for randomized controlled trials (RCT) and observational studies addressing MRA and providing information on AF occurrence. Two independent reviewers selected and appraised the data. We performed random-effects meta-analyses. Summary odds ratios (OR) with 95% confidence intervals (CI) were calculated.
RESULTS
We included 14 studies, 5 RCT and 9 observational cohorts, with a cumulative number of 5332 patients (male: 74.9%, age: 65.3years); 2397 (45.0%) received an MRA (spironolactone or eplerenone). During follow-up, 204 (8.5%) patients treated with MRAs, developed AF, compared to 547 (18.6%) patients, without MRA treatment. Meta-analyses showed a significant overall reduction of AF risk in MRA treated patients (OR: 0.48 CI: 0.38-0.60 p<0.001), including a reduction of new-onset AF (OR: 0.52 CI: 0.37-0.74 p<0.001) and recurrent AF (OR: 0.37 CI: 0.24-0.57 p<0.001), but not post-operative AF (POAF) (OR: 0.60 CI: 0.33-1.09 p=0.09).
CONCLUSIONS
MRAs significantly reduce new-onset AF and recurrent AF, but not POAF. MRA treatment can be considered an additive therapeutic strategy in AF.
Topics: Aldosterone; Atrial Fibrillation; Humans; Mineralocorticoid Receptor Antagonists
PubMed: 28062142
DOI: 10.1016/j.ijcard.2016.12.029