How Protein Depletion Balances Thrombosis and Bleeding Risk in the Context of Platelet's Activatory and Negative Signaling.

Platelets are small cell fragments that play a crucial role in hemostasis, requiring fast response times and fine signaling pathway regulation. For this regulation, platelets require a balance between two pathway types: the activatory and negative signaling pathways. Activatory signaling mediators are positive responses that enhance stimuli initiated by a receptor in the platelet membrane. Negative signaling regulates and controls the responses downstream of the same receptors to roll back or even avoid spontaneous thrombotic events. Several blood-related pathologies can be observed when these processes are unregulated, such as massive bleeding in activatory signaling inhibition or thrombotic events for negative signaling inhibition. The study of each protein and metabolite in isolation does not help to understand the role of the protein or how it can be contrasted; however, understanding the balance between active and negative signaling could help develop effective therapies to prevent thrombotic events and bleeding disorders.

Analysis of Scientometric Indicators in Publications Associated with Healthy Aging in the World, Period 2011-2020.

Today, the world population is aging at a fast rate. This scenario of the accelerated aging of human populations entails increased concern for healthy aging that is associated with a rise in scientific production related to the topic. In this study, the Scopus database from Elsevier was used, with a final search carried out on 5 January 2022, and various bibliometric indicators were obtained from SciVal. The study was fundamentally intended to characterize, determine trends, and understand the evolution and current state of research on the concept of "healthy aging" in the last decade. We found that there has been proportionally greater and more accelerated growth in the subject with respect to the general productivity of the world and that countries with high life expectancies tend to have made more effort to investigate this topic. The "hottest" research areas were found to be related to the cognitive aspect and the biological mechanisms involved in aging.

Ancient genomes in South Patagonia reveal population movements associated with technological shifts and geography.

Archaeological research documents major technological shifts among people who have lived in the southern tip of South America (South Patagonia) during the last thirteen millennia, including the development of marine-based economies and changes in tools and raw materials. It has been proposed that movements of people spreading culture and technology propelled some of these shifts, but these hypotheses have not been tested with ancient DNA. Here we report genome-wide data from 20 ancient individuals, and co-analyze it with previously reported data. We reveal that immigration does not explain the appearance of marine adaptations in South Patagonia. We describe partial genetic continuity since ~6600 BP and two later gene flows correlated with technological changes: one between 4700-2000 BP that affected primarily marine-based groups, and a later one impacting all <2000 BP groups. From ~2200-1200 BP, mixture among neighbors resulted in a cline correlated to geographic ordering along the coast.

Older adults with frailty syndrome present an altered platelet function and an increased level of circulating oxidative stress and mitochondrial dysfunction biomarker GDF-15.

INTRODUCTION: The elderly population is increasing worldwide and in Chile, it is expected to grow rapidly. The World Health Organization (WHO) ICOPE guideline (Integrated Care for Older People) emphasizes the importance of frailty diagnosis to prevent dependence. Frailty in older adults is considered an indicator of vulnerability and poor health outcomes, of multifactorial etiology. Our objective was to investigate the association of activation of coagulation and increased risk of thrombosis with frailty in people older than 64 years. A prevalent-case control study was designed with 28 frail older and 27 robust older adults (non-frail, control group) older than 64 years. Frailty was defined by Fried's Phenotype, Platelet aggregation and activation plasma levels of Thromboxane B2 (TXB2), 8-isoprostane and Growth Differentiation Factor-15 (GDF-15) were determined. RESULTS: Compared to healthy controls, frail older adults, had a) higher percentage of platelet aggregation induction with ADP 4 µM (82.85% (3.35) and 73.41% (3.26), p-value = 0.024) and subaggregant dose of ADP (30.83% (7.47) and 13.25% (3.21), p-value = 0.002); b) higher platelet activation: P-selectin exposure (18.23% (4.41) and 6.96% (1.08), p-value = 0.011), and activated GPIIß-IIIα (21.51% (3.41) and 8.26% (1.18), p-value = 0.001), at the baseline level and against a subaggregant dose ADP: P-selectin exposure (46.93% (5.95) and 13.41% (3.35), p-value = 0.002) and activated GPIIß-IIIα (43.29% (6.04) and 26.71% (4.92), p-value = 0.024); c) higher plasma levels of TXB2 (201.8 ng/mL (59.53-236.3) and 45.77 ng/mL (25.14-98.26), p-value<0.0001), d) elevated plasma levels of 8-isoprostane (70.94 pg/mL, IQ: 65.89-99,96 and 56.24 pg/mL, IQ: 42.18-74.81, p-value = 0.001), and e) higher plasma GDF-15 levels (2,379 pg/mL, IQ: 1,845-4,121and 1367 pg/mL, IQ: 1190-1747, p-value = 0.0001). DISCUSSION: Older adults with frailty syndrome have an upregulated platelet activity that may contribute to an increased risk of thrombosis and aspirin resistance. The elevated oxidative stress and increases of GDF-15 levels might be related to altered platelet responsiveness in frail patients. CONCLUSION: The determination of biomarkers of platelet dysfunction, oxidative stress and cell senescence/mitochondrial dysfunction may contribute to frailty diagnosis, and approaches aimed at regulating platelet function in frail older adults could contribute to its prevention and treatment.

Natural Bioactive Compounds As Protectors Of Mitochondrial Dysfunction In Cardiovascular Diseases And Aging.

Diet, particularly the Mediterranean diet, has been considered as a protective factor against the development of cardiovascular diseases, the main cause of death in the world. Aging is one of the major risk factors for cardiovascular diseases, which have an oxidative pathophysiological component, being the mitochondria one of the key organelles in the regulation of oxidative stress. Certain natural bioactive compounds have the ability to regulate oxidative phosphorylation, the production of reactive oxygen species and the expression of mitochondrial proteins; but their efficacy within the mitochondrial physiopathology of cardiovascular diseases has not been clarified yet. The following review has the purpose of evaluating several natural compounds with evidence of mitochondrial effect in cardiovascular disease models, ascertaining the main cellular mechanisms and their potential use as functional foods for prevention of cardiovascular disease and healthy aging.

Decoding the Role of Platelets and Related MicroRNAs in Aging and Neurodegenerative Disorders.

Platelets are anucleate cells that circulate in blood and are essential components of the hemostatic system. During aging, platelet numbers decrease and their aggregation capacity is reduced. Platelet dysfunctions associated with aging can be linked to molecular alterations affecting several cellular systems that include cytoskeleton rearrangements, signal transduction, vesicular trafficking, and protein degradation. Age platelets may adopt a phenotype characterized by robust secretion of extracellular vesicles that could in turn account for about 70-90% of blood circulating vesicles. Interestingly these extracellular vesicles are loaded with messenger RNAs and microRNAs that may have a profound impact on protein physiology at the systems level. Age platelet dysfunction is also associated with accumulation of reactive oxygen species. Thereby understanding the mechanisms of aging in platelets as well as their age-dependent dysfunctions may be of interest when evaluating the contribution of aging to the onset of age-dependent pathologies, such as those affecting the nervous system. In this review we summarize the findings that link platelet dysfunctions to neurodegenerative diseases including Alzheimer's Disease, Parkinson's Disease, Multiple Sclerosis, Huntington's Disease, and Amyotrophic Lateral Sclerosis. We discuss the role of platelets as drivers of protein dysfunctions observed in these pathologies, their association with aging and the potential clinical significance of platelets, and related miRNAs, as peripheral biomarkers for diagnosis and prognosis of neurodegenerative diseases.

Genetic association of gastric cancer with miRNA clusters including the cancer-related genes MIR29, MIR25, MIR93 and MIR106: results from the EPIC-EURGAST study.

MicroRNAs (miRNAs) are post-transcriptional gene regulators involved in a wide range of biological processes including tumorigenesis. Deregulation of miRNA pathways has been associated with cancer but the contribution of their genetic variability to this disorder is poorly known. We analyzed the genetic association of gastric cancer (GC) and its anatomical and histological subtypes, with 133 single-nucleotide polymorphisms (SNPs) tagging 15 isolated miRNAs and 24 miRNA clusters potentially involved in cancer, in 365 GC cases and 1,284 matched controls within the European Prospective Investigation into Cancer and Nutrition cohort. Various SNPs were associated with GC under the log-additive model. Furthermore, several of these miRNAs passed the gene-based permutation test when analyzed according to GC subtypes: three tagSNPs of the miR-29a/miR-29b-1 cluster were associated with diffuse subtype (minimum p-value = 1.7 × 10(-4) ; odds ratio, OR = 1.72; 95% confidence interval, CI = 1.30-2.28), two tagSNPs of the miR-25/miR-93/miR-106b cluster were associated with cardia GC (minimum p-value = 5.38 × 10(-3) ; OR = 0.56, 95% CI = 0.37-0.86) and one tagSNP of the miR-363/miR-92a-2/miR-19b-2/miR-20b/miR-18b/miR-106a cluster was associated with noncardia GC (minimum p-value = 5.40 × 10(-3) ; OR = 1.41, 95% CI = 1.12-1.78). Some functionally validated target genes of these miRNAs are implicated in cancer-related processes such as methylation (DNMT3A, DNMT3B), cell cycle (E2F1, CDKN1A, CDKN1C), apoptosis (BCL2L11, MCL1), angiogenesis (VEGFA) and progression (PIK3R1, MYCN). Furthermore, we identified genetic interactions between variants tagging these miRNAs and variants in their validated target genes. Deregulation of the expression of these miRNAs in GC also supports our findings, altogether suggesting for the fist time that genetic variation in MIR29, MIR25, MIR93 and MIR106b may have a critical role in genetic susceptibility to GC and could contribute to the molecular mechanisms of gastric carcinogenesis.