INTRODUCTION: Cardiovascular diseases and diabetes mellitus (DM) are two disease entities that commonly coexist in a single patient. Ranolazine is an active piperazine derivative approved by FDA in 2006 as an anti-anginal medication. It was noted to have HbA1c lowering effects in the trials on angina. The proposed mechanism of action is the inhibition of glucagon secretion by blocking the Na v1.3 isoform of sodium channels in pancreatic alpha cells leading to glucagon- and glucose-lowering effects. HbA1c lowering to a target of 6.5% in type 2 diabetes patients has been shown to reduce risk of microvascular complications. The objective of this study is to determine the efficacy and safety of Ranolazine in HbA1c lowering as an add-on therapy to existing anti-diabetic regimen.

METHODS: A comprehensive literature search in PubMed, The Cochrane Central Register of Controlled Trials, the ClinicalTrials.gov website, Google Scholar databases and EMBASE databases were made using the search terms "Randomized controlled trial", "Ranolazine," "HbA1c," and "glycosylated hemoglobin", as well as various combinations of these, was done to identify randomized control trials. No restriction on language and time were done. The authors extracted data for characteristics, quality assessment and mean change in HbA1c after at least eight weeks of treatment with ranolazine. The program RevMan 5.3 was used to generate the statistical analysis of the data.

RESULTS: Six RCTs were included to make up a total of 1,650 diabetic patients. Five studies had moderate risk of bias assessment while one had low risk of bias assessment and hence was not included in the analysis. The overall analysis showed an HbA1c reduction of 0.35% 0.68 to -0.03, p-value=0.03) however, the population was heterogenous (I2=100%). The heterogeneity was not eliminated by sensitivity analysis.

DISCUSSION: The results showed a statistically significant lowering of HbA1c with ranolazine. However, the population was heterogenous. The sources of heterogeneity could be the (1) differences in the level of glycemic control among subjects as indicated by baseline HbA1c levels, (2) the current anti-diabetic regimen of the study patients, i.e. whether or not they are on insulin therapy, (3) the presence or absence of ischemic heart disease and (5) duration of ranolazine therapy, and (4) the presence or absence of chronic kidney disease. When the analysis excluded the population with combination insulin therapy and ranolazine, the effect becomes non-significant. Thus, the HbA1c lowering effect may have been from the insulin therapy rather than the ranolazine.

CONCLUSION: Ranolazine as anti-diabetic therapy shows statistically significant HbA1c lowering effect. It can be a potential treatment option for patients with both DM and angina pectoris. However, well-designed, prospective trials are still recommended to determine the effect on a less heterogenous population. Likewise, more studies are needed to determine its safety.

Human ; Hemoglobin A, Glycosylated ; Glucagon ; Glucagon-secreting Cells ; Diabetes Mellitus, Type 2 ; Ranolazine ; Insulin ; Language ; Prospective Studies ; Blood Glucose ; Angina Pectoris ; Coronary Artery Disease ; Myocardial Ischemia ; Renal Insufficiency, Chronic ; Pubmed ; Sodium Channels ; Protein Isoforms

Serum prostate-specific antigen (PSA) is composed of the PSA precursor protein (proPSA) in the absence of the leader peptide induced by human kallikrein 2 (hK2). There are many forms of PSA in the blood, including free PSA and bound PSA. Serum proPSA, as a free PSA, has many isoforms, among which, [-2]proPSA (p2PSA) cannot be activated by hK2 and therefore exists stably in the blood. Serum p2PSA is a homologous isomer of PSA. Serum prostate health index and % p2PSA, as the derivative indexes of p2PSA and molecular markers associated with the development and progression of prostate cancer, can reduce serum PSA test-induced excessive diagnosis and treatment of the malignancy and improve the accuracy of its prediction. This review summarizes recent progress in the studies of serum p2PSA and its derivative indexes in prostate cancer.
Humans ; Male ; Prostate-Specific Antigen ; blood ; Prostatic Neoplasms ; blood ; immunology ; Protein Isoforms ; blood

OBJECTIVETo investigate the impact of androgen receptor splice variant 7 (AR-V7) expression on overall survival for patients with metastatic prostate cancer.

METHODSThe data of 113 diagnosed metastatic prostate cancer patients from January 2002 to June 2010 were collected retrospectively, including patient's age at diagnosis, prostate-specific antigen (PSA) level at diagnosis,Gleason score, clinical stage, PSA nadir during hormonal therapy, the time to PSA nadir, vital status, survival time and cause of death. The expression of AR-V7 in prostate cancer tissue was detected by using immunohistochemical staining. The correlation of AR-V7 expression and patient clinicopathological characteristics in all patients were analysed using Student t-test or Chi-square test. Cox proportional hazards regression models were used to evaluate the predictive role of AR-V7 expression and patient characteristics for overall survival.

RESULTSThe median PSA nadir was 0.7 µg/L (ranged from 0.0 to 143.0 µg/L). The median time to PSA nadir was 8.1 months (ranged from 0.9 to 71.0 months). The follow-up was performed until March 12, 2014. During the follow-up period, 67 of 113 metastatic prostate cancer patients (59.3%) died and the median overall survival was 96 months (ranged from 5 to 135 months). The AR-V7 detection rate was 20.4% (23/113). The serum PSA level in patients with positively expression of AR-V7 was significantly higher than that without AR-V7 expression (t = 2.521, P = 0.013). Multivariate Cox regression analysis indicated that the expression of AR-V7 (HR = 2.421, P = 0.002) and time to PSA nadir (HR = 1.019, P = 0.022) were independent prognostic factors of overall survival for metastatic prostate cancer patients.

CONCLUSIONSThe expression of AR-V7 in prostate cancer tissues and time to PSA nadir during hormonal therapy are independent prognostic factors of overall survival for metastatic prostate cancer patients. Therapy targeting AR-V7 may improve prognosis of metastatic prostate cancer patients.

Adult ; Aged ; Aged, 80 and over ; Humans ; Male ; Middle Aged ; Neoplasm Metastasis ; Prognosis ; Proportional Hazards Models ; Prostate-Specific Antigen ; blood ; Prostatic Neoplasms ; diagnosis ; metabolism ; pathology ; Protein Isoforms ; metabolism ; Receptors, Androgen ; metabolism ; Retrospective Studies

Prostate-specific antigen (PSA) is recognized as an organ-specific marker with low specificity and sensitivity in discriminating prostate cancer (PCa) from other benign conditions, such as prostatic hyperplasia or chronic prostatitis. Thus, in the case of clinical suspicion, a PCa diagnosis cannot be made without a prostate biopsy. [-2]proPSA (p2PSA), a precursor of PSA, has been investigated as a new marker to accurately detect PCa. The aim of this systematic review was to discuss the available literature regarding the clinical validity and utility of p2PSA and its derivatives, p2PSA/fPSA (%p2PSA) and the Prostate Health Index (PHI). A systematic search of the PubMed and Scopus electronic databases was performed in accordance with the PRISMA statement (http://www.prisma-statement.org), considering the time period from January 1990 to January 2014 and using the following search terms: proprostate specific antigen, proenzyme PSA, proPSA, [-2]proPSA, p2PSA, Prostate Health Index, and PHI. To date, 115 studies have been published, but only 35 were considered for the qualitative analysis. These studies suggested that p2PSA is the most cancer-specific form of PSA, being preferentially expressed in PCa tissue and being significantly elevated in the serum of men with PCa. It is now evident that p2PSA, %p2PSA, and PHI measurements improve the specificity of the available tests (PSA and derivatives) in detecting PCa. Moreover, increasing PHI values seem to correlate with more aggressive disease. Some studies have compared p2PSA and its derivatives with other new biomarkers and found p2PSA to be significantly more accurate. Indeed, the implementation of these tests in clinical practice has the potential to significantly increase the physician's ability to detect PCa and avoid unnecessary biopsies, while also having an effective impact on costs. Further studies in large, multicenter, prospective trials are required to confirm these encouraging results on the clinical utility of these new biomarkers.
Humans ; Male ; Prostate-Specific Antigen/*blood ; Prostatectomy ; Prostatic Neoplasms/*diagnosis/pathology/surgery ; Protein Isoforms/blood ; Protein Precursors/*blood ; Sensitivity and Specificity ; Severity of Illness Index ; Tumor Markers, Biological/blood

Adiponectin ; blood ; metabolism ; Cytokines ; blood ; Female ; Humans ; Male ; Oxidation-Reduction ; Protein Isoforms ; blood ; metabolism ; Pulmonary Disease, Chronic Obstructive ; blood

Adult ; Asian Continental Ancestry Group ; DNA, Viral ; blood ; Female ; Genes, Viral ; genetics ; Hepatitis B virus ; genetics ; Humans ; Male ; Middle Aged ; Mutation ; Protein Isoforms ; genetics ; Viral Core Proteins ; genetics

BACKGROUND: The leukocyte common antigen (CD45) is a transmembrane-type protein tyrosine phosphatase that has five isoforms. METHODS: We generated seven murine mAbs against human CD45 by injecting cells from different origins, such as human thymocytes, PBMCs, and leukemic cell lines. By using various immunological methods including flow cytometry, immunohistochemistry, and immunoprecipitation, we evaluated the reactivity of those mAbs to CD45 of thymus as well as tonsil lysates. Furthermore, we transiently transfected COS-7 cells with each of gene constructs that express five human CD45 isoforms respectively, and examined the specificities of the mAbs against the transfected isoforms. RESULTS: In case of thymocytes, lymphocytes, and monocytes, all the seven mAbs demonstrated positive reactivities whereas none was reactive to erythrocytes and platelets. The majority of immune cells in formalin-fixed paraffin-embedded thymus and tonsil tissues displayed strong membranous immunoreactivity, and the main antigen was detected near 220 kDa in all cases. Among the mAbs, four mAbs (AP4, DN11, SHL-1, and P6) recognized a region commonly present in all the five isoforms. One mAb, YG27, recognized four isoforms (ABC, AB, BC, and O). Two mAbs, P1 and P14, recognized the isoforms that contain exon A encoded regions (ABC and AB). CONCLUSION: In this study, we confirmed that AP4, DN11, SHL-1, YG27 and P6, are mAbs reactive with the CD45 antigen whereas P1 and P14 are reactive with the CD45RA antigen.
Animals ; Antibodies, Monoclonal ; Antigens, CD45 ; Blood Platelets ; Cell Line ; COS Cells ; Erythrocytes ; Exons ; Flow Cytometry ; Humans ; Immunohistochemistry ; Immunoprecipitation ; Leukocytes ; Lymphocytes ; Monocytes ; Palatine Tonsil ; Protein Isoforms ; Protein Tyrosine Phosphatases ; Thymocytes ; Thymus Gland

Chronic and heavy alcohol consumption is one of the causes of heart diseases. However, the effects of ethanol on insulin sensitivity in myocardium has been unclear. To investigate the effects of ethanol on the expression of AMP-activated protein kinase (AMPK), myocyte enhancer factor 2 (MEF2) and glucose transporter 4 (GLUT4), all of which are involved in the regulation of insulin sensitivity, in the myocardium, we performed three parts of experiments in vivo and in vitro. I: Rats were injected with 5-amino-4-imidazolecarboxamide ribonucleotide (AICAR, 0.8 mg.kg(-1)) for 2 h. II: Rats received different dose (0.5, 2.5 or 5 g.kg(-1).d(-1)) of ethanol for 22-week. III: Primary neonatal rat cardiomyocytes were isolated and treated with or without 100 mM ethanol or 1 mM AICAR for 4 h. The cardiac protein and mRNA expression of AMPKalpha subunits, MEF2 and GLUT4 were observed by western-blotting and RT-PCR, respectively. Serum TNFalpha levels were assessed by ELISA. The results showed chronic ethanol exposure induced insulin resistance. Ethanol decreased the mRNA levels of AMPKalpha1 and alpha2, the protein levels of total- and phospho-AMPKalpha in cardiomyocytes. Similarly, ethanol showed inhibitory effects on both the mRNA and protein levels of MEF2A and 2D, and GLUT4 in a dose-response-like fashion. Correlation analysis implied an association between phospho-AMPKalpha and MEF2A or MEF2D, and between the levels of MEF2 protein and GLUT4 transcription. In addition, ethanol elevated serum TNFalpha level. Taken together, chronic ethanol exposure decreases the expression of AMPKalpha and MEF2, and is associated with GLUT4 decline in rat myocardium.
AMP-Activated Protein Kinases/genetics/*metabolism ; Aminoimidazole Carboxamide/analogs & derivatives/pharmacology ; Animals ; Enzyme Activation/drug effects ; Ethanol/*administration & dosage/*pharmacology ; Feeding Behavior/*drug effects ; Gene Expression Regulation/drug effects ; Glucose Transporter Type 4/genetics/*metabolism ; Insulin/pharmacology ; Insulin Resistance ; Male ; Myocardium/*enzymology ; Myogenic Regulatory Factors/antagonists & inhibitors/genetics/*metabolism ; Protein Isoforms/antagonists & inhibitors/genetics/metabolism ; RNA, Messenger/genetics/metabolism ; Rats ; Rats, Wistar ; Ribonucleotides/pharmacology ; Time Factors ; Tumor Necrosis Factor-alpha/blood

5'-AMP-activated protein kinase (AMPK) is a heterotrimeric complex consisting of a catalytic (alpha) and two regulatory (beta and gamma) subunits. Two isoforms are known for catalytic subunit (alpha1, alpha2) and are encoded by different genes. To assess the metabolic effects of AMPKalpha1, we examined the effects of overexpression of adenoviral-mediated AMPKalpha1 in hyperlipidemic type 2 diabetic rats. The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an established animal model of type 2 diabetes that exhibits chronic and slowly progressive hyperglycemia and hyperlipidemia. Thirty five-week-old overt type 2 diabetic rats (n=10) were administered intravenously with Ad.AMPKalpha1. AMPK activity was measured by phosphorylation of acetyl CoA carboxlyase (ACC). To investigate the changes of gene expression related glucose and lipid metabolism, quantitative real-time PCR was performed with liver tissues. Overexpression of AMPKalpha1 showed that blood glucose concentration was decreased but that glucose tolerance was not completely recovered on 7th day after treatment. Plasma triglyceride concentration was decreased slightly, and hepatic triglyceride content was markedly reduced by decreasing expression of hepatic lipogenic genes. Overexpression of AMPKalpha1 markedly improved hepatic steatosis and it may have effective role for improving hepatic lipid metabolism in hyperlipidemic state.
Acetyl Coenzyme A ; Adenoviridae ; AMP-Activated Protein Kinases ; Animals ; Blood Glucose ; Catalytic Domain ; Fatty Liver ; Gene Expression ; Glucose ; Hyperglycemia ; Hyperlipidemias ; Lipid Metabolism ; Liver ; Models, Animal ; Phosphorylation ; Plasma ; Protein Isoforms ; Rats ; Real-Time Polymerase Chain Reaction

BACKGROUND: Increased prevalence of diabetes in recent years is linked with increased cardiovascular morbidity and mortality. Apolipoprotein E (apo E) polymorphism is well known to be related to hyperlipidemia and coronary heart disease, but only a few studies investigated the association between apo E polymorphism and diabetes or insulin resistance. In Korea, two studies with relatively small subjects reported controversial results. Therefore, we investigated the association between apo E polymorphism and diabetes in elderly community population. METHODS: 982 elderly people aged 65 or over in Seongnam city were enrolled. We measured anthropometric variables and blood pressure and performed biochemical tests including fasting glucose, fasting insulin, HbA1c, and lipid profiles. Apo E polymorphism was determined by PCR-RFLP method. RESULTS: Frequencies of apo E isoforms and alleles were similar to those of other reports. Subjects with e4 allele had significantly higher total and LDL-cholesterol levels. However, there were no differences in cholesterol levels between normal subjects and diabetes. Diabetes was not related to apo E polymorphism. CONCLUSION: In Korean aged 65 or over, subjects with diabetes didn't have increased total or LDL-cholesterol, triglyceride, and decreased HDL-cholesterol levels. Diabetes and apo E polymorphism were not related.
Aged ; Alleles ; Apolipoproteins ; Apolipoproteins E ; Blood Pressure ; Cholesterol ; Coronary Disease ; Fasting ; Glucose ; Humans ; Hyperlipidemias ; Insulin ; Insulin Resistance ; Korea ; Prevalence ; Protein Isoforms