Comparison of Eating Habits, Body Composition and Densitometric Parameters between Subjects with Normal Cognitive Function and Mild Cognitive Impairment: An Observational Study.

The role of nutrition in the ageing process of the brain is pivotal. Therefore, the study aimed to compare eating habits, body composition and densitometric parameters between subjects with normal cognitive function (NCF) and mild cognitive impairment (MCI). A total of 95 subjects with NCF (74% of women) and 95 individuals with MCI (77% of women) aged 50-70 years were studied. Densitometric parameters were evaluated using dual-energy X-ray absorptiometry methods. Eating habits were assessed using the food frequency questionnaire and 3-day diary records, and advanced glycation end products (AGEs) intake was calculated. Significant differences between groups were detected for the %fat in the right arm (NCF vs. MCI: 38.4 (30.4-46.8) vs. 43.5 (35.5-49.2)%, p = 0.0407). Moreover, the MCI group had a significantly lower intake of calcium (p = 0.0010), phosphor (p = 0.0411), vitamins B2 (p = 0.0138) and B12 (p = 0.0024) compared to the NCF group, with both groups also differing in the frequency of butter (p = 0.0191) and fermented milk beverages (p = 0.0398) intake. Analysis restricted to women showed significant differences between groups in right arm %fat, VAT mass, calcium, vitamins B2, B12, butter and fermented milk products intake, while in men, differences were detected in the intake of calcium, iodine, vitamin B1, water and AGEs. In conclusion, subjects with NCF and MCI have comparable densitometric variables but differ significantly in some body composition parameters and the intake of some food groups and nutrients.

Expression of miR-223 to predict outcomes after transcatheter aortic valve implantation.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is an established treatment for aortic stenosis (AS) in patients at increased surgical risk. Up to 29% of patients annually experience major adverse cardiac and cerebrovascular events (MACCE) after TAVI. MicroRNAs (miRNA) are currently widely investigated as novel cardiovascular biomarkers. The aim of this study was to determine the influence of TAVI on the expressions of selected miRNAs associated with platelet function (miR-125a-5p, miR-125b and miR-223), and evaluate the predictive value of these miRNAs for MACCE in 65 patients undergoing TAVI. METHODS: Venous blood samples for miRNA expression analysis were collected 1 day before TAVI and at hospital discharge. The expression of miR-223, miR-125a-5p, miR-125b was evaluated in platelet-depleted plasma. RESULTS: The expression of miR-223 and miR-125b increased after TAVI, compared to the measurement before (p = 0.020, p = 0.003, respectively). Among 63 patients discharged from the hospital, 18 patients experienced MACCE (29%) during the median 15 months of observation. Baseline low miR-223 expression was a predictor of MACCE in univariate Cox regression analysis (hazard ratio [HR]: 2.71, 95% confidence interval [CI]: 1.04-7.01; p = 0.041). After inclusion of covariates, age, gender (male), New York Heart Association class and diabetes into the multivariate Cox regression model, miR-223 did not reach statistical significance (HR: 2.56, 95% CI: 0.79-8.33; p = 0.118). CONCLUSIONS: To conclude, miR-223 might improve risk stratification after TAVI. Further studies are required to confirm the clinical applicability of this promising biomarker.

Characterization of the SGLT2 Interaction Network and Its Regulation by SGLT2 Inhibitors: A Bioinformatic Analysis.

Background: Sodium-glucose cotransporter 2 (SGLT2), also known as solute carrier family 5 member 2 (SLC5A2), is a promising target for a new class of drugs primarily established as kidney-targeting, effective glucose-lowering agents used in diabetes mellitus (DM) patients. Increasing evidence indicates that besides renal effects, SGLT2 inhibitors (SGLT2i) have also a systemic impact via indirectly targeting the heart and other tissues. Our hypothesis states that the pleiotropic effects of SGLT2i are associated with their binding force, location of targets in the SGLT2 networks, targets involvement in signaling pathways, and their tissue-specific expression. Methods: Thus, to investigate differences in SGLT2i impact on human organisms, we re-created the SGLT2 interaction network incorporating its inhibitors and metformin and analyzed its tissue-specific expression using publicly available datasets. We analyzed it in the context of the so-called key terms ( autophagy, oxidative stress, aging, senescence, inflammation, AMPK pathways, and mTOR pathways) which seem to be crucial to elucidating the SGLT2 role in a variety of clinical manifestations. Results: Analysis of SGLT2 and its network components' expression confidence identified selected organs in the following order: kidney, liver, adipose tissue, blood, heart, muscle, intestine, brain, and artery according to the TISSUES database. Drug repurposing analysis of known SGLT2i pointed out the influence of SGLT1 regulators on the heart and intestine tissue. Additionally, dapagliflozin seems to also have a stronger impact on brain tissue through the regulation of SGLT3 and SLC5A11. The shortest path analysis identified interaction SIRT1-SGLT2 among the top five interactions across six from seven analyzed networks associated with the key terms. Other top first-level SGLT2 interactors associated with key terms were not only ADIPOQ, INS, GLUT4, ACE, and GLUT1 but also less recognized ILK and ADCY7. Among other interactors which appeared in multiple shortest-path analyses were GPT, COG2, and MGAM. Enrichment analysis of SGLT2 network components showed the highest overrepresentation of hypertensive disease, DM-related diseases for both levels of SGLT2 interactors. Additionally, for the extended SGLT2 network, we observed enrichment in obesity (including SGLT1), cancer-related terms, neuroactive ligand-receptor interaction, and neutrophil-mediated immunity. Conclusion: This study provides comprehensive and ranked information about the SGLT2 interaction network in the context of tissue expression and can help to predict the clinical effects of the SGLT2i.

Association Between the Expression of MicroRNA-125b and Survival in Patients With Acute Coronary Syndrome and Coronary Multivessel Disease.

Background: MicroRNAs (miRNA, miR) have an undeniable physiological and pathophysiological significance and act as promising novel biomarkers. The aim of the study was to investigate blood-derived miRNAs and their association with long-term all-cause mortality in patients with multivessel disease (MVD) suffering from acute coronary syndrome (ACS). Materials and Methods: This study was an observational prospective study, which included 90 patients with MVD and ACS. Expression of miR-125a, miR-125b, and miR-223 was analysed by polymerase chain reaction (PCR). Patients were followed-up for a median of 7.5 years. All-cause mortality was considered as the primary endpoint. Adjusted Cox-regression analysis was performed for prediction of events. Results: Elevated expression of miR-125b (>4.6) at the time-point of ACS was associated with increased long-term all-cause mortality (adjusted [adj.] hazard ratio [HR] = 11.26, 95% confidence interval [95% CI]: 1.15-110.38; p = 0.038). The receiver operating characteristic (ROC) analysis showed a satisfactory c-statistics for miR-125b for the prediction of long-term all-cause mortality (area under the curve [AUC] = 0.76, 95% CI: 0.61-0.91; p = 0.034; the negative predictive value of 98%). Kaplan-Meier time to event analysis confirmed an early separation of the survival curves between patients with high vs low expression of miR-125b (p = 0.003). An increased expression of miR-125a and miR-223 was found in patients with non-ST-segment elevation ACS (NSTE-ACS) as compared to those with ST-segment elevation myocardial infarction (STEMI) (p = 0.043 and p = 0.049, respectively) with no difference in the expression of miR-125b between the type of ACS. Conclusion: In this hypothesis generating study, lower values of miR-125b were related to improved long-term survival in patients with ACS and MVD. Larger studies are needed to investigate whether miR-125b can be used as a suitable predictor for long-term all-cause mortality.

The role of non-coding RNAs in neuroinflammatory process in multiple sclerosis.

Multiple sclerosis (MS) is a central nervous system chronic neuroinflammatory disease followed by neurodegeneration. The diagnosis is based on clinical presentation, cerebrospinal fluid testing and magnetic resonance imagining. There is still a lack of a diagnostic blood-based biomarker for MS. Due to the cost and difficulty of diagnosis, new and more easily accessible methods are being sought. New biomarkers should also allow for early diagnosis. Additionally, the treatment of MS should lead to the personalization of the therapy. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) as well as their target genes participate in pathophysiology processes in MS. Although the detailed mechanism of action of non-coding RNAs (ncRNAs, including miRNAs and lncRNAs) on neuroinflammation in MS has not been fully explained, several studies were conducted aiming to analyse their impact in MS. In this article, we review up-to-date knowledge on the latest research concerning the ncRNAs in MS and evaluate their role in neuroinflammation. We also point out the most promising ncRNAs which may be promising in MS as diagnostic and prognostic biomarkers.

High concentration of symmetric dimethylarginine is associated with low platelet reactivity and increased bleeding risk in patients with acute coronary syndrome.

BACKGROUND: Dual antiplatelet therapy (DAPT) prevents ischemic events in patients with acute coronary syndrome (ACS), but is associated with increased risk of bleeding events. Symmetric dimethylarginine (SDMA) is one of nitric oxide (NO)-related pathway metabolites and stands as a promising biomarker of early chronic kidney disease (CKD) and cardiovascular diseases (CVDs). OBJECTIVES: Our study evaluated the role of SDMA in predicting bleeding events in patients after ACS treated with DAPT. METHODS: We compared plasma concentrations of NO-related pathway metabolites in patients with ACS (n = 291) and investigated the prognostic value of SDMA as a bleeding predictor during 1-year follow-up. We measured the metabolites concentration using ultra performance liquid chromatography. Platelet reactivity was determined using impedance aggregometry. RESULTS: Patients with the highest quartile (4th) of SDMA concentration had significantly lower platelet aggregation compared to those in the 1st-3rd quartiles of SDMA, based on ADP + PGE1-, AA-, and ADP-induced platelet reactivity tests (p = 0.0004, p = 0.002, p = 0.014, respectively). Patients with major or minor bleeding events had significantly higher concentrations of SDMA as compared to those without bleeding events or to those with minimal bleeding events (p = 0.019, p = 0.019, respectively). CONCLUSION: Higher SDMA concentration is associated with lower platelet reactivity and is associated with major and minor bleeding events in patients with ACS on DAPT. Therefore, SDMA stands as a potential biomarker for individualization of duration and potency of antiplatelet therapies in the ACS population at high risk of bleeding complications.

Plasma Trimethylamine-N-Oxide Is an Independent Predictor of Long-Term Cardiovascular Mortality in Patients Undergoing Percutaneous Coronary Intervention for Acute Coronary Syndrome.

To investigate the association of liver metabolite trimethylamine N-oxide (TMAO) with cardiovascular disease (CV)-related and all-cause mortality in patients with acute coronary syndrome (ACS) who underwent percutaneous coronary intervention. Our prospective observational study enrolled 292 patients with ACS. Plasma concentrations of TMAO were measured during the hospitalization for ACS. Observation period lasted seven yr in median. Adjusted Cox-regression analysis was used for prediction of mortality. ROC curve analysis revealed that increasing concentrations of TMAO levels assessed at the time point of ACS significantly predicted the risk of CV mortality (c-index=0.78, p < 0.001). The cut-off value of >4 µmol/L, labeled as high TMAO level (23% of study population), provided the greatest sum of sensitivity (85%) and specificity (80%) for the prediction of CV mortality and was associated with a positive predictive value of 16% and a negative predictive value of 99%. A multivariate Cox regression model revealed that high TMAO level was a strong and independent predictor of CV death (HR = 11.62, 95% CI: 2.26-59.67; p = 0.003). High TMAO levels as compared with low TMAO levels were associated with the highest risk of CV death in a subpopulation of patients with diabetes mellitus (27.3 vs. 2.6%; p = 0.004). Although increasing TMAO levels were also significantly associated with all-cause mortality, their estimates for diagnostic accuracy were low. High TMAO level is a strong and independent predictor of long-term CV mortality among patients presenting with ACS.

MicroRNAs and long non-coding RNAs in the pathophysiological processes of diabetic cardiomyopathy: emerging biomarkers and potential therapeutics.

The epidemic of diabetes mellitus (DM) necessitates the development of novel therapeutic and preventative strategies to attenuate complications of this debilitating disease. Diabetic cardiomyopathy (DCM) is a frequent disorder affecting individuals diagnosed with DM characterized by left ventricular hypertrophy, diastolic and systolic dysfunction and myocardial fibrosis in the absence of other heart diseases. Progression of DCM is associated with impaired cardiac insulin metabolic signaling, increased oxidative stress, impaired mitochondrial and cardiomyocyte calcium metabolism, and inflammation. Various non-coding RNAs, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), as well as their target genes are implicated in the complex pathophysiology of DCM. It has been demonstrated that miRNAs and lncRNAs play an important role in maintaining homeostasis through regulation of multiple genes, thus they attract substantial scientific interest as biomarkers for diagnosis, prognosis and as a potential therapeutic strategy in DM complications. This article will review the different miRNAs and lncRNA studied in the context of DM, including type 1 and type 2 diabetes and the contribution of pathophysiological mechanisms including inflammatory response, oxidative stress, apoptosis, hypertrophy and fibrosis to the development of DCM .

The Relation of the Brain-Derived Neurotrophic Factor with MicroRNAs in Neurodegenerative Diseases and Ischemic Stroke.

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors that plays a crucial role in the development of the nervous system while supporting the survival of existing neurons and instigating neurogenesis. Altered levels of BDNF, both in the circulation and in the central nervous system (CNS), have been reported to be involved in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), multiple sclerosis (MS), and ischemic stroke. MicroRNAs (miRNAs) are a class of non-coding RNAs found in body fluids such as peripheral blood and cerebrospinal fluid. Several different miRNAs, and their target genes, are recognized to be involved in the pathophysiology of neurodegenerative and neurovascular diseases. Thus, they present as promising biomarkers and a novel treatment approach for CNS disorders. Currently, limited studies provide viable evidence of miRNA-mediated post-transcriptional regulation of BDNF. The aim of this review is to provide a comprehensive assessment of the current knowledge regarding the potential diagnostic and prognostic values of miRNAs affecting BDNF expression and its role as a CNS disorders and neurovascular disease biomarker. Moreover, a novel therapeutic approach in neurodegenerative diseases and ischemic stroke targeting miRNAs associated with BDNF will be discussed.

Long Non-coding RNAs as Promising Therapeutic Approach in Ischemic Stroke: a Comprehensive Review.

In recent years, ischemic stroke (IS) has been one of the major causes of disability and mortality worldwide. The general mechanism of IS is based on reduced blood supply to neuronal tissue, resulting in neuronal cell damage by various pathological reactions. One of the main techniques for acute IS treatment entails advanced surgical approaches for restoration of cerebral blood supply but this is often associated with secondary brain injury, also known as ischemic reperfusion injury (I/R injury). Many researches have come to emphasize the significant role of long non-coding RNAs (lncRNAs) in IS, especially in I/R injury and their potential as therapeutic approaches. LncRNAs are non-protein transcripts that are able to regulate cellular processes and gene expression. Further, lncRNAs have been shown to be involved in neuronal signaling pathways. Several lncRNAs are recognized as key factors in the physiological and pathological processes of IS. In this review, we discuss the role of lncRNAs in neuronal injury mechanisms and their association with brain neuroprotection. Moreover, we identify the lncRNAs that show the greatest potential as novel therapeutic approaches in IS, which therefore merit further investigation in preclinical research. Graphical Abstract.

The Importance of Non-Coding RNAs in Neurodegenerative Processes of Diabetes-Related Molecular Pathways.

Diabetes mellitus (DM) is a complex condition and serious health problem, with growing occurrence of DM-associated complications occurring globally. Persistent hyperglycemia is confirmed as promoting neurovascular dysfunction leading to irreversible endothelial cell dysfunction, increased neuronal cell apoptosis, oxidative stress and inflammation. These collaboratively and individually result in micro- and macroangiopathy as well as neuropathy demonstrated by progressive neuronal loss. Recently, major efforts have been pursued to select not only useful diagnostic and prognostic biomarkers, but also novel therapeutic approaches. Both microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) belong to a class of non-coding RNAs identified in most of the body fluids i.e., peripheral blood, cerebrospinal fluid, brain tissue and neurons. Numerous miRNAs, lncRNAs and their target genes are able to modulate signaling pathways known to play a role in the pathophysiology of progressive neuronal dysfunction. Therefore, they pose as promising biomarkers and treatment for the vast majority of neurodegenerative disorders. This review provides an overall assessment of both miRNAs' and lncRNAs' utility in decelerating progressive nervous system impairment, including neurodegeneration in diabetic pathways.

Significance of circulating microRNAs in diabetes mellitus type 2 and platelet reactivity: bioinformatic analysis and review.

In the light of growing global epidemic of type 2 diabetes mellitus (T2DM), significant efforts are made to discover next-generation biomarkers for early detection of the disease. Multiple mechanisms including inflammatory response, abnormal insulin secretion and glucose metabolism contribute to the development of T2DM. Platelet activation, on the other hand, is known to be one of the underlying mechanisms of atherosclerosis, which is a common T2DM complication that frequently results in ischemic events at later stages of the disease. Available data suggest that platelets contain large amounts of microRNAs (miRNAs) that are found in circulating body fluids, including the blood. Since miRNAs have been illustrated to play an important role in metabolic homeostasis through regulation of multiple genes, they attracted substantial scientific interest as diagnostic and prognostic biomarkers in T2DM. Various miRNAs, as well as their target genes are implicated in the complex pathophysiology of T2DM. This article will first review the different miRNAs studied in the context of T2DM and platelet reactivity, and subsequently present original results from bioinformatic analyses of published reports, identifying a common gene (PRKAR1A) linked to glucose metabolism, blood coagulation and insulin signalling and targeted by miRNAs in T2DM. Moreover, miRNA-target gene interaction networks built upon Gene Ontology information from electronic databases were developed. According to our results, miR-30a-5p, miR-30d-5p and miR-30c-5p are the most widely regulated miRNAs across all specified ontologies, hence they are the most promising biomarkers of T2DM to be investigated in future clinical studies.