Magnoflorine from Berberis vulgaris Roots-Impact on Hippocampal Neurons in Mice after Short-Term Exposure.

In search of novel potential drug candidates that could be used as treatments or prophylactics for memory impairment, an aporphine alkaloid magnoflorine (MAG) isolated from the root of Berberis vulgaris was proven to exhibit beneficial anti-amnestic properties. Its effects on immunoreactivity to parvalbumin in the mouse hippocampus were assessed together with a study on its safety and concentration in the brain and plasma. For this purpose, four experimental groups were created: the MAG10 group-treated with 10 mg MAG/kg b.w. i.p., the MAG20 group-treated with 20 mg MAG/kg b.w. i.p., the MAG50 group-treated with 50 mg MAG/kg b.w. i.p., and a control group-injected with saline i.p. at a volume corresponding to their weight. Our results indicated that the hippocampal fields CA1-CA3 were characterized by an elevated number of parvalbumin-immunoreactive neurons (PV-IR) and nerve fibers in mice at the doses of 10 and 20 mg/kg b.w. (i.p.). No significant changes to the levels of IL-1ß, IL-6 or TNF-α were observed for the above two doses; however, the administration of 50 mg/kg b.w. i.p. caused a statistically significant elevation of IL-6, IL-1beta plasma levels and an insignificant raise in the TNF-alpha value. The HPLC-MS analysis showed that the alkaloid's content in the brain structures in the group treated with 50 mg/kg b.w. did not increase proportionally with the administered dose. The obtained results show that MAG is able to influence the immunoreactivity to PV-IR in hippocampal neurons and might act as a neuroprotective compound.

Investigation of relationship between precursor of miRNA-944 and its mature form in lung squamous-cell carcinoma - the diagnostic value.

INTRODUCTION: MicroRNA (miRNA) are attractive markers of lung cancer, due to their regulatory role in cell cycle. However, we know more about function of miRNA in cancer development, there is still little known about role of their precursors (primary miRNA; pri-miRNA) in tumorgenesis. In present study we investigated potential role of miRNA-944 and its precursor pri-miRNA-944 in development of squamous-cell lung cancer (SCC) and explored interdependence between miRNA precursor and its mature form. This is a first available literature report analyzing pri-miRNA as a cancer diagnostic marker. MATERIAL AND METHODS: Expression of miRNA-944 and its precursor was analyzed in 58 fresh-frozen tissues of non-small cell lung cancer and corresponding adjacent non-cancerous tissues using qRT-PCR. Expression of pri-miRNA-944 was correlated with TP63 and miRNA-944. Using ROC analysis diagnostic accuracy of studied markers was evaluated. RESULTS: miRNA-944 and its precursor were significantly overexspressed in SCC compared to adenocarcinoma (AC) and non-cancerous tissue. pri-miRNA-944 strongly and positively correlated with TP63 (r = 0.739, p < 0.001) and with mature miRNA-944 expression (r = 0.691, p < 0.001). Also, TP63 expression significantly correlated with mature miRNA (r = 0.785, p < 0.001). Combined analysis of pri-miRNA-944 and mature miRNA-944 allowed to distinguish SCC tissue form AC with sensitivity of 93.3% and specificity of 100% (AUC = 0.978), and SCC from non-cancerous tissue with 92.9% sensitivity and 100% specificity (AUC = 0.992). CONCLUSION: We assumed that pri-miRNA-944 and miRNA-944 may be involved in early squamous-type differentiation of lung tumors. Moreover, analysis of both markers provided high diagnostic accuracy for SCC detection.

The diagnostic role of plasma circulating precursors of miRNA-944 and miRNA-3662 for non-small cell lung cancer detection.

INTRODUCTION: microRNA (miRNA) seem to be most attractive cancer markers due their crucial role in tumor development and possibility of their analysis using liquid biopsy. To date there is little known about role of miRNA precursors (pri-miRNA) in carcinogenesis and their utility as tumor markers. MATERIAL AND METHODS: miRNA-944 and miRNA-3662 precursors as potential non-small cell lung cancer (NSCLC) markers were analyzed in plasma samples of 56 patients in an early stage of NSCLC and 100 healthy individuals. RESULTS: Diagnostic test based on two studied markers for stage I-IIIA of the disease allowed to distinguish NSCLC from healthy individuals with 75.7% sensitivity and 82.3% specificity (AUC=0.898). pri-miRNA-944 distinguished SCC from AC with sensitivity of 78.6% and specificity of 91.7% (AUC=0.771), and pri-miRNA-3662 distinguished AC from SCC with 57.1% sensitivity and 90% specificity (AUC=0.845). CONCLUSION: Circulating pri-miRNA-944 and 3662 can improve non-invasive NSCLC detection of operable stages of SCC and AC. miRNA precursors could be considered as novel potential lung cancer biomarkers.

Levels of renalase and advanced oxidation protein products with regard to catecholamines in haemodialysed patients.

INTRODUCTION: The main mediators of the sympathetic nervous system in the effectors part are catecholamines (CA). An increased sympathetic nerve activity observed in chronic kidney disease (CKD), is due to a raised level of CA in plasma. Renalase is a protein secreted by the kidneys, composed of 342 amino acids, which is able to metabolize the circulating CA and possibly play an important role in the regulation of sympathetic tone and blood pressure. Also, oxidative stress, defined as a disruption of the equilibrium between the generation of oxidants, is a crucial factor in the development of the inflammatory syndrome associated with CKD. The advanced oxidation protein products (AOPP) represent exquisite markers of phagocyte-derived oxidative stress. OBJECTIVE: The aim of the study was to investigate the concentration of renalase and explore the associations between AOPP with regards to CA in haemodialysis (HD) patients. MATERIAL AND METHODS: The study was conducted among 50 residents of the municipality and neighbouring villages in the province of Lublin, central-eastern Poland. RESULTS: In the studied patients, it was found that an average concentration of renalase was 44.8 ± 6.5 µg/mL, whereas of AOPP plasma levels - 57.5 ± 21.5 µmol/L. The results demonstrated the correlation between levels of renalase and AOPP in the HD patients. Indeed, elevated levels of renalase and AOPP in HD may be due to the presence of uremic toxins in blood. The concentration of urea affects the plasma concentrations of AOPP and renalase causing a direct relationship between renalase and AOPP. However, there is no clear relationship between renalase and circulating catecholamines in HD patients.

Relationship between microRNA-146a expression and plasma renalase levels in hemodialyzed patients.

BACKGROUND: microRNA (miRNA) belongs to the non-coding RNAs family responsible for the regulation of gene expression. Renalase is a protein composed of 342 amino acids, secreted by the kidneys and possibly plays an important role in the regulation of sympathetic tone and blood pressure. The aim of the present study was to investigate plasma renalase concentration, and explore the relationship between miRNA-146a-5p expression and plasma renalase levels in hemodialyzed patients. METHODS: The study population comprised 55 subjects who succumbed to various cardiac events, 27 women and 28 men, aged 65-70 years. The total RNA including miRNA fraction was isolated using QiagenmiRNEasy Serum/Plasma kit according to the manufacturer's protocol. The isolated miRNAs were analyzed using a quantitative polymerase chain reaction (qRT-PCR) technique. The plasma renalase levels were measured using a commercial ELISA kit. RESULTS: In the group of patients with high levels of renalase, higher miRNA-146a expression was found, compared with those with low concentration of renalase. Patients with simultaneous low miRNA-146a expression and high level of renalase were confirmed to deliver a significantly longer survival time compared with other patients. CONCLUSIONS: miRNA-146a and plasma renalase levels were estimated as independent prognostic factors of hemodialyzed patients' survival time. Patients with low miRNA-146a expression demonstrated a significantly longer survival time in contrast to the patients with a high expression level of miRNA-146a. Moreover, a significantly longer survival time was found in patients with high renalase activity compared with patients with low activity of the enzyme.

Analysis of primary-miRNA-3662 and its mature form may improve detection of the lung adenocarcinoma.

INTRODUCTION: Because of the alarming data concerning lung cancer morbidity and mortality, investigation of new molecular markers allowing early cancer detection is desirable. In the present study, we investigated the potential role of miRNA-3662 precursor (pri-miRNA-3662) as potential novel diagnostic marker of lung adenocarcinoma (AC). MATERIALS AND METHODS: Expression of miRNA-3662 and pri-miRNA-3662 was analyzed in 56 fresh-frozen tissues of non-small cell lung cancer and corresponding adjacent non-cancerous tissues using (NCT) qRT-PCR. Using receiver operating curves (ROC) analysis, the diagnostic accuracy of both studied markers for AC detection was assessed. RESULTS: miRNA-3662 and its precursor were significantly overexpressed in AC compared to squamous-cell carcinoma (SCC) and NCT. Combined analysis of pri-miRNA-3662 and mature miRNA-3662 allowed to distinguish AC tissue from SCC with sensitivity of 96% and specificity of 85.7% (AUC = 0.963), and SCC from non-cancerous tissue with 92% sensitivity and 92% specificity (AUC = 0.979). CONCLUSIONS: miRNA-3662 and its precursor are potentially involved in AC development. pri-miRNA seem to be novel interesting group of potential cancer biomarkers, because they demonstrate high diagnostic accuracy for tumor detection.

Cholinergic activation affects the acute and chronic antinociceptive effects of morphine.

Current studies indicate that the cholinergic and opioid systems interact to modulate pain. In the present work, we investigated the influence of the cholinesterase inhibitors, donepezil (0.5; 1 or 3mg/kg, i.p.) and rivastigmine (0.03; 0.5 or 1mg/kg, i.p.), on the acute antinociceptive effects of morphine (5mg/kg, i.p.) in the hot plate test in mice. Herein, both inhibitors were found to enhance and prolong the analgesic effects of morphine without affecting latencies themselves. In an extension of this work, we determined which cholinergic receptors subtype mediates the enhancement of analgesic effects of morphine, following inhibition of cholinesterases. In this part of the study, scopolamine (0.5mg/kg, i.p.), a muscarinic cholinergic receptors antagonist, but not mecamylamine (3mg/kg, i.p.), a nicotinic cholinergic receptors antagonist, reversed the enhancing effects of donepezil (3mg/kg, i.p.) and rivastigmine (1mg/kg, i.p.) on the morphine antinociception. Moreover, both cholinesterase inhibitors attenuated the development of tolerance to the antinociceptive effects of morphine. In contrast, acute administration of donepezil (3mg/kg, i.p.) or rivastigmine (1mg/kg, i.p.) on the day of expression of tolerance, had no effect on the already developed morphine tolerance. What is more, in both set of experiments, rivastigmine was slightly more potent than donepezil due to the broader inhibitory spectrum of this drug on acetylcholine degradation. Thus, our results suggest that the cholinesterase inhibitors, donepezil and rivastigmine, may be administered with morphine in order to enhance the latter's analgesic effects for the treatment of acute and chronic pain.

Fibroblast growth factor 21 - a key player in cardiovascular disorders?

Fibroblast growth factor 21 (FGF21) is a newly discovered adipokine, synthesized by several organs, mostly by the liver, which was introduced as a potent metabolic regulator and insulin-sensitizing factor. Numerous animal studies have demonstrated that FGF21 improves glucose and lipids metabolism and exerts anti-inflammatory effects. However, data obtained from human studies have shown contradictory results, in which circulating FGF21 levels were often elevated in obesity, dyslipidemia, type 2 diabetes (DM2) and other conditions connected with insulin resistance. This increase in basal FGF21 concentrations observed in patients with obesity and other conditions related to insulin resistance was being explained as a compensatory response to the underlying metabolic disturbances or tissue resistance to FGF21 action. Furthermore, the results of clinical trials have shown that increased FGF21 concentrations were associated with increased cardiovascular (CV) risk and had a prognostic value in CV outcomes. In recent years, it has been reported that FGF21 may exert cardioprotective effects. This mini-review aims to summarize the current state of knowledge about the role of FGF21 in CV disorders, and discuss the molecular mechanism underlying the anti-atherogenic properties of this compound.

Impact of I/D polymorphism of ACE gene on risk of development and course of chronic obstructive pulmonary disease.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) affects more than 10% of the world's population over 40 years of age. The main exogenous risk factor is cigarette smoking; however, only 20% of smokers develop COPD, indicating that some other factors, e.g. genetic, may play an important role in the disease pathogenesis. Recent research indicates that ACE (angiotensin-converting enzyme) may be a susceptibility gene for asthma or COPD. The aim of our study was to determine the influence of I/D (insertion/deletion) polymorphism of the ACE gene (AluYa5, rs4646994) on the risk and course of COPD. MATERIAL AND METHODS: We investigated ACE I/D polymorphism in 206 COPD and 165 healthy Caucasian subjects. RESULTS: In the generalized linear model (GLZ) analysis of the influence of selected factors on presence of COPD we found a significant independent effect for male sex (repeatedly increases the risk of COPD, OR = 7.7, p = 0.049), as well as smoking or lower body mass index, but only in combination with older age (OR = 0.96, p = 0.003 and OR = 1.005, p = 0.04 respectively). Interestingly, analysis of factors which may influence the risk of a higher number of exacerbations demonstrated that occurrence of DD genotype, but only in men, is associated with a lower risk (OR = 0.7, p = 0.03) of this complication. CONCLUSIONS: We suggest that ACE may not be a susceptibility gene for the origin of COPD but a disease-modifying gene. Since the impact of I/D polymorphism of the ACE gene on COPD risk is moderate or negligible, other molecular changes, that will help predict the development of this disease, should still be sought.

Role of circulating microRNA in hemodialyzed patients.

MicroRNA (miRNA) belongs to the family of non-coding RNAs, which posttranscriptionally regulate gene function. Moreover, accumulating evidence points to an essential role of miRNAs in development and monitoring of kidney disease, though the role of particular miRNAs in patients undergoing hemodialysis is still unclear. This might have consequences. It is possible that measuring a single miRNA in hemodialyzed patients may not provide adequate information about development of many pathological processes. The goal of this review is to highlight the current knowledge in the field of miRNAs, with a special emphasis on their circulation in hemodialyzed patients.

Influence of Thermal Processing and in vitro Digestion on the Antioxidant Potential of Ginger and Ginger Containing Products.

Zingiber officinale (Zingiberaceae) is a common spice and a medicine widely cultivated in tropical and subtropical climate around the globe, which contains both precious polyphenols and terpenes in its extracts. The ubiquity of ginger in a variety of foods encouraged the authors to assess the influence of thermal processing and digestion of the plant material on its antioxidant capacity. The obtained results of DPPH assay showed marked differences in the antioxidant potential of the processed samples, in comparison with fresh ginger rhizomes. Autoclave and microwave heating procedures were found to evoke the-mildest decomposition of the antioxidants and increase the antioxidant capacity of the plant (from IC50 of 210±10 for a fresh rhizome to ca 160±16 gg/mL for the former, and to 150±18 for the latter technique), whereas frying and boiling for different durations significantly deteriorated the antiradical potential up to IC5o= 940±36 pg/mL. Mouth and stomach digestion decreased the antioxidant potential of the extracts even to ca. 1000i47 µg/mL. A protective role of saliva towards the antioxidant compounds against hydrochloric acid and pepsin activities has been proven. A marked deterioration in antioxidant capacity in digested rhizomes may shed new light on the actual absorption of consumed polyphenols with food products.

Plasma and erythrocyte relationship of catecholamines in hemodialysis patients.

The function of the autonomic nervous system is based on reciprocal interaction between the sympathetic and parasympathetic parts, most frequently in the form of antagonistic action on target organs. The main mediators of the sympathetic nervous system in the effectors part are catecholamines (CA), which are involved in various physiological processes. Moreover, CA also has a profound effect on the kidneys, being factors that impact on renal haemodynamics, and have been reported to be altered in pathological disorders, e.g. extracellular volume expression, hypertension and cardiovascular complications. The increased sympathetic nerve activity, at least in part, can explain the raised in plasma CA observed in chronic kidney diseases. Furthermore, plasma CA levels in ureamic patients cannot be considered a reliable index of sympathetic activity, due to existence of many factors which may affect their values. In addition, CA released into the circulation, as one of many substances, may penetrate across the cellular membranes of erytrocytes (RBC). Taking these observations together, the aim of the presented study was to investigate for the first time the plasma and erythrocyte relationship of catecholamines in haemodialysis. The studies were performed among 37 haemodialysed patients who were inhabitants of the Lublin commune. Plasma and intracellular concentration of CA were measured prior to and following haemodialysis by high performance liquid chromatography with electrochemical detection. The results suggest that RBC are able to accumulate CA at the stage of terminal renal failure; in addition, the levels of adrenaline and dopamine in RBC depend on the accumulation of urea in plasma. It was also found that the dynamic changes in concentration of RBC adrenaline are an independent predictor of mortality in haemodialysis patients.

Relationship between renalase and N-terminal pro-B-type natriuretic peptide (NT pro-BNP) in haemodialysis patients.

INTRODUCTION: Our knowledge in the field of cause of deaths in dialysis patients is rapidly expanding, yet we still do not fully understand how renalase regulates the processes of cardiovascular disease developing in end-stage renal disease. Increased sympathetic nerve activity observed in chronic kidney diseases due to raised catecholamines in plasma results from the absence of renalase. Renalase synthesized and secreted by the kidneys participate in the regulation of sympathetic tone and blood pressure. A family of natriuretic peptides has been identified - NT pro-BNP - which seems to be the best predictor of clinical outcome and marker of extracellular fluid overload, as well as predicting mortality, irrespective of renal function. OBJECTIVE: The aim of the presented study was to investigate renalase concentration and investigate associations between NT-proBNP, as well as analyzed parameters in haemodialysis patients. MATERIALS AND METHOD: The study was conducted among residents of the municipality and neighbouring villages in the province of Lublin, central-eastern Poland. 49 male subjects on haemodialysis, aged 65.3 ± 14.2 years, median time on haemodialysis: 37.5 months, were included. All study subjects underwent haemodialysis 3 times a week. The mean concentration of renalase in the entire study population was 126.59 ± 32.63 ng/mL. The circulating levels of NT-proBNP was 813.64 ± 706.96 pg/mL. A significant inverse correlation was found between NT-proBNP and renalase plasma levels (R = -0.3, P = 0.03). CONCLUSIONS: Inverse correlation between NT-proBNP and renalase plasma levels in haemodialysis patients were due to impaired kidney function, accompanied by increased sympathetic nerve activity, which have an impact on the development of hypertension and cardiovascular complications.

Level of glycation gap in a healthy subject.

INTRODUCTION: The discordance between glycated hemoglobin (HbA(1C)) and fructosamine (FA) estimations in the assessment of glycemia is often encountered. A number of mechanisms might explain such discordance, but whether or not they are consistent is uncertain. Nevertheless, the fact that there is a discrepancy in HbA(1C) and mean blood glucose cannot be ignored in the monitoring of glycemic control. To address the discrepancy between HbA(1C) and mean blood glucose, Robert Cohen proposed the measurement of glycation gap (GG). Recently, the 'Glycation Gap' (GG) has been defined as the difference between the measured HbA(1C). GG has improved the quality of the monitoring of glycemic control, especially for those patients whose HbA(1C) levels do not truly reflect the mean blood glucose levels. OBJECTIVE: The aims of the statistical analyses were to estimate GG values in a healthy subject. The research was conducted among the inhabitants of the Zwierzyniec commune and nearby villages. MATERIAL AND METHODS: The study population consisted of 93 subjects: 63 women and 30 men, between the ages of 18-79. Measurements of HbA(1C) and FA in the 93 people were used to calculate GG, defined as the difference between measured HbA(1C) and HbA(1C) predicted from FA, based on the population regression of HbA(1C) on FA. CONCLUSIONS: In considering the values GG in the study group, particular significance should be attributed to a progressive increase of GG with advancing age. Elderly people who are at risk of developing diabetes, or who have already developed the disease, may not exhibit the classic symptoms expected. Age-related changes can mean that some symptoms will be masked, or more dificult to spot. It is worth pointing out that HbA(1C) together with GG must be taken into account in the correct interpretation of the glycation processes.