Role of miRNA-210, miRNA-21 and miRNA-126 as diagnostic biomarkers in colorectal carcinoma: impact of HIF-1α-VEGF signaling pathway.

Colorectal cancer (CRC) is a major cause of death worldwide. Novel non-invasive, high diagnostic value screening test is urgently needed to improve survival rate, treatment and prognosis. Stable, small, circulating microRNA (miRNA) offers unique opportunities for the early diagnosis of several diseases. It acts as tumor oncogenes or suppressors and involve in cell death, survival, and metastasis. Communication between miRNA and carcinogenesis is critical but it still not clear and needs further investigation. The aim of our study is to evaluate the role of miR-210, miR-21, miR-126, as non-invasive diagnostic biomarkers for screening, early detection of CRC, studying their correlation with prognostic variables, and clarifying the roles of miRNAs on HIF-1α-VEGF signaling pathway. The expression of miR-210, miR-21 and miR-126 was performed using qRT-PCR in adenocarcinoma (no = 35), adenomas (no = 51), and neoplasm free controls (no = 101). Serum levels of VEGF and HIF-1α was determined by ELISA Kit. The results show that the expression of miR-210, miR-21, VEGF, HIF-1α was significantly up-regulated while that miRNA-126 was down-regulated in both adenocarcinoma and adenomas compared with controls (p < 0.001 for each). No significant difference was noted comparing patients with adenocarcinoma and adenomas. The three miRNAs correlated with VEGF, HIF-α. The miR-210 and miR-21 associated with TNM classification and clinical staging of adenocarcinoma (p < 0.001) and they show high diagnostic value with sensitivity and specificity 88.6%, 90.1% and 91.4%, 95.0% respectively. Our study revealed that circulating miR-210, miR-21 were up-regulated while miR-126 was down-regulated in CRC and adenomas patients, they all correlated with TNM staging and they had high diagnostic value. HIF-1α VEGF signaling pathways regulated by miRNAs played a role in colon cancer initiation. To the best of our knowledge, this is the first study of this miRNAs panel in CRC in our community. These data suggested that these biomarkers could be a potential novel, non-invasive marker for early diagnosis, screening and predicting prognosis of CRC. Understanding the molecular functions by which miRNAs affect cancer and understanding its roles in modulating the signaling output of VEGF might be fruitful in reducing the incidence and slowing the progression of this dark malignancy.

Hyperlipidemia Increases Nalbuphine Brain Accumulation with Multiple Dosing without Affecting Its Analgesic Response-Its Respiratory Depression Potential Should Be Investigated in Future Studies.

Nalbuphine is associated with a significant risk of respiratory depression. Its central nervous system entry is hindered by P-glycoproteins, and lower P-glycoprotein activity is a risk factor for respiratory depression. We assessed the effect of hyperlipidemia on nalbuphine pharmacokinetics, brain and liver uptake, and analgesic response following single (2.5 mg/kg) and multiple (2.5 mg/kg/day for three days) doses in normolipidemic and hyperlipidemic rats. Trends of reduction and increase in nalbuphine Cmax and Vdss/F were observed, respectively, in hyperlipidemic rats. Negative correlations were observed between Cmax and serum lipoproteins. Serum-normalized brain and liver levels at 1 h post-dose were lower in hyperlipidemic rats, with brain and liver levels being negatively and positively correlated with TG and HDL, respectively. At steady state, marked nalbuphine accumulation was observed in hyperlipidemic rat brains (R = 1.6) compared with normolipidemic rats (R = 1.1). Nalbuphine analgesic response was not altered by hyperlipidemia at steady state. Caution should be exercised since greater brain accumulation in hyperlipidemic patients treated with nalbuphine could increase their risk of respiratory depression. Our study highlights an unexpected role of lipoproteins in drug absorption and tissue uptake. We also propose a model for reduced nalbuphine absorption based on interaction with intestinal HDL-3.

Corrigendum: BM-MSCs alleviate diabetic nephropathy in male rats by regulating ER stress, oxidative stress, inflammation, and apoptotic pathways.

[This corrects the article DOI: 10.3389/fphar.2023.1265230.].

BM-MSCs alleviate diabetic nephropathy in male rats by regulating ER stress, oxidative stress, inflammation, and apoptotic pathways.

Introduction: Diabetic nephropathy (DN), a chronic kidney disease, is a major cause of end-stage kidney disease worldwide. Mesenchymal stem cells (MSCs) have become a promising option to mitigate several diabetic complications. Methods: In this study, we evaluated the therapeutic potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) in a rat model of STZ-induced DN. After the confirmation of diabetes, rats were treated with BM-MSCs and sacrificed at week 12 after treatment. Results: Our results showed that STZ-induced DN rats had extensive histopathological changes, significant upregulation in mRNA expression of renal apoptotic markers, ER stress markers, inflammatory markers, fibronectin, and intermediate filament proteins, and reduction of positive immunostaining of PCNA and elevated P53 in kidney tissue compared to the control group. BM-MSC therapy significantly improved renal histopathological changes, reduced renal apoptosis, ER stress, inflammation, and intermediate filament proteins, as well as increased positive immunostaining of PCNA and reduced P53 in renal tissue compared to the STZ-induced DN group. Conclusion: In conclusion, our study indicates that BM-MSCs may have therapeutic potential for the treatment of DN and provide important insights into their potential use as a novel therapeutic approach for DN.

Apelin Association with Hepatic Fibrosis and Esophageal Varices in Patients with Chronic Hepatitis C Virus.

Portal hypertension and esophageal varices complicating hepatitis C virus (HCV)-related chronic liver diseases are some of the most devastating sequelae. Angiogenesis is the hallmark of their pathogenesis. Apelin is one of the recently identified angiogenic and fibrogenic peptides. We studied apelin gene expression, apelin (rs3761581) single-nucleotide polymorphism (SNP), and serum apelin level in patients with chronic HCV, and their association with liver fibrosis and esophageal varices in 112 patients with HCV-related chronic liver disease (40 with liver cirrhosis [LC]/low-grade varices, 33 with LC/high-grade varices, and 39 with fibrotic non-cirrhotic liver/no varices) and 80 healthy control subjects. Real-time polymerase chain reaction was used for apelin gene expression assay and apelin rs3761581 SNP analysis in peripheral blood samples. The serum apelin level was measured by ELISA. Apelin gene expression was undetectable in the studied samples. The SNP analysis revealed a greater frequency of the C (mutant) allele among patients compared with control subjects (P = 0.012; odds ratio, 3.67). The serum apelin level was significantly greater in patients with LC/varices (median, 31.6 ng/L) compared with patients without LC/varices (median, 2.9 ng/L; P < 0.001). A serum apelin level cutoff value of 16.55 ng/L predicted the presence of varices, with an area under the receiver operating characteristic curve value of 0.786. A positive correlation was found between serum apelin level and grade of liver fibrosis (r = 0.346, P < 0.001) and portal hypertension (r = 0.438, P < 0.001). In conclusion, the apelin rs3761581-C allele may be associated with the progression of HCV-related chronic liver disease and varices formation, and can be considered a potential therapeutic target to control fibrosis progression. The serum apelin level provided an accurate prediction of the presence of esophageal varices.

Antimelanocyte Antibodies: A Possible Role in Patients with Vitiligo.

BACKGROUND: Vitiligo is an acquired depigmenting skin disorder with multifactorial pathogenesis including genetic, autoimmune, and neuronal factors. Both humoral- and cell-mediated immunities are supposed to have a role in the pathogenesis of vitiligo. Patients with vitiligo have an increased concentration of circulating autoantibodies that are specific to melanocyte cytoplasm and surface antigens that related to the extent of the disease. AIMS AND OBJECTIVES: The aim of the present study was to evaluate the role of antimelanocyte antibodies (AMAs), complement 3 and 4 (C3 and C4), and antinuclear antibodies (ANAs) in the pathogenesis of vitiligo. MATERIALS AND METHODS: This study included 49 patients with nonsegmental vitiligo and 36 healthy individuals as a control group. All participants were subjected to detailed history, general examination, and detailed dermatological examination of the skin, hair, nails, and oral mucosa. The severity of vitiligo was assessed according to the Vitiligo Area Scoring Index (VASI). AMA, C3 and C4, and ANA serum levels were measured for patients and controls. RESULTS: ANA, AMA, and C4 levels were significantly higher in the sera of patients than in controls. ANA, AMA, and C4 serum levels showed significant positive correlations with VASI score. CONCLUSION: Our results support the role of AMA in the pathogenesis of nonsegmental vitiligo, correlating with the disease extent and severity. However, a longitudinal study in a large cohort of patients to evaluate the clinical and predictive value of AMA is warranted.

Expression of miRNAs-122, -192 and -499 in end stage renal disease associated with acute myocardial infarction.

INTRODUCTION: New diagnostic tools are needed to accurately detect acute myocardial infarction (AMI) in patients with end stage renal disease (ESRD) presenting with ischemic chest pain. We aimed in this study to investigate circulating miR-122, -192 and -499 expression levels in patients with AMI on top of ESRD and evaluate the potential of these miRNAs as blood-based biomarkers for AMI in patients with ESRD. MATERIAL AND METHODS: The study included 80 ESRD patients without AMI, 80 patients with ESRD associated with AMI and 60 healthy subjects. Assessment of microRNAs was done using SYBR Green based real-time PCR. RESULTS: Levels of miR-122 were 28-fold and 20-fold higher in controls than in ESRD patients with or without AMI respectively (p < 0.001), while no differences were detected between the two patient groups (p = 0.9). Levels of miR-192 showed a marked increase in ESRD patients with and without AMI compared to the control group (> 500-fold, > 8000-fold respectively, p ≤ 0.001). Patients who developed AMI had lower expression than ESRD patients without AMI (p < 0.001). Non-significant miR-499 elevation was found in ESRD patients without cardiac disease compared to the control group, while highly significant elevation of miR- 499 was demonstrated in ESRD patients who developed AMI compared to other ESRD patients and the control group (> 100-fold, > 350-fold respectively, p = 0.001). CONCLUSIONS: Altered expression of miR-122 and -192 may contribute in pathogenesis of ESRD. MiR-192 and -499 may serve as potential biomarkers for AMI in ESRD. Further studies are needed to correlate these miRNAs with disease progression and outcome.

Thrombo-hemorrhagic liability in children with congenital heart diseases.

BACKGROUND: The precise mechanisms of the increased incidence of hemostatic abnormalities in congenital heart disease (CHD) have not been determined. The aim of the study was to evaluate some indicators of activation of platelets and vascular endothelial cells in patients with CHD, evaluation of bleeding liability of these patients, and correlation with the clinical presentation of these patients. METHODS: This work was carried out on 20 patients with cyanotic congenital heart diseases (CCHD), 20 patients with acyanotic congenital heart diseases (ACHD), and 20 healthy children who served as the control group, aged between 1 and 10years. All were subjected to full clinical examination, complete blood count, oxygen saturation, echocardiography, bleeding and coagulation times, PT, PTT, FDPs, plasma soluble P-selectin, E-selectin, and platelet factor 4 (PF4). RESULTS: There was significant prolongation of PT and PTT, and there was a significant lowering of platelet counts. These results were obtained in CCHD and ACHD, but were more significant in CCHD patients. There was a significant elevation in PF4 (55.0±25.5ng/mL), P-selectin (128.9±42.44ng/dL), and E-selectin (9461.5±1701.24pg/mL) levels in children with CCHD as compared to those with ACHD (PF4, 21±7.94ng/mL; P-selectin, 80.1±13.2ng/mL; E-selectin, 7969.6±2127.5pg/mL), and significant increase in both groups when compared to the control group (PF4, 8.1±4.7ng/mL; P-selectin, 27.83±9.73ng/mL; E-selectin, 6750.00±3204.00pg/mL). There was a significant negative correlation between oxygen saturation, plasma P-selectin (r=-0.865), E-selectin (r=-0.401), and PF4 (r=-0.792) in patients with CCHD. CONCLUSION: Patients with CHD-both cyanotic and acyanotic-have variable degrees of increased liability for both thrombosis and hemorrhage that represents some sort of adaptation to preserve hemostasis and to protect these patients against the clinical presentation of both thrombosis and bleeding. This is to say that CHD patients have their own point of balance between thrombogenicity and bleeding liability. Wide-scale studies are needed to detect the normal levels of different thrombohemorrhagic parameters of these patients.

Clinical significance of SNP (rs2596542) in histocompatibility complex class I-related gene A promoter region among hepatitis C virus related hepatocellular carcinoma cases.

The major histocompatibility complex class I-related gene A (MICA) is an antigen induced by stress and performs an integral role in immune responses as an anti-infectious and antitumor agent. This work was designed to investigate whether (SNP) rs2596542C/T in MICA promoter region is predictive of liver cirrhosis (LC) and hepatocellular carcinoma (HCC) or not. Forty-seven healthy controls and 94 HCV-infected patients, subdivided into 47 LC and 47 HCC subjects were enrolled in this study. SNP association was studied using real time PCR and soluble serum MICA concentration was measured using ELISA. Results showed that heterozygous genotype rs2596542CT was significantly (P = 0.022) distributed between HCC and LC related CHC patients. The sMICA was significantly higher (P = 0.0001) among HCC and LC. No significant association (P = 0.56) between rs2596542CT genotypes and sMICA levels was observed. Studying SNP rs2596542C/T association with HCC and LC susceptibility revealed that statistical significant differences (P = 0.013, P = 0.027) were only observed between SNP rs2596542C/T and each of HCC and LC, respectively, versus healthy controls, indicating that the rs2596542C/T genetic variation is not a significant contributor to HCC development in LC patients. Moreover, the T allele was considered a risk factor for HCC and LC vulnerability in HCV patients (OR = 1.93 and 2.1, respectively), while the C allele contributes to decreasing HCC risk. Therefore, SNP (rs2596542C/T) in MICA promoter region and sMICA levels might be potential useful markers in the assessment of liver disease progression to LC and HCC.