scholarly journals MicroRNA-34a: the bad guy in age-related vascular diseases

2021 ◽  
Author(s):  
Angela Raucci ◽  
Federica Macrì ◽  
Stefania Castiglione ◽  
Ileana Badi ◽  
Maria Cristina Vinci ◽  
...  
Keyword(s):  
Risk Factors ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Vascular Diseases ◽  
B Cell Lymphoma ◽  
Sirtuin 1 ◽  
Inflammatory Factors ◽  
Low Grade ◽  
Genetic Ablation ◽  
Age Related

AbstractThe age-related vasculature alteration is the prominent risk factor for vascular diseases (VD), namely, atherosclerosis, abdominal aortic aneurysm, vascular calcification (VC) and pulmonary arterial hypertension (PAH). The chronic sterile low-grade inflammation state, alias inflammaging, characterizes elderly people and participates in VD development. MicroRNA34-a (miR-34a) is emerging as an important mediator of inflammaging and VD. miR-34a increases with aging in vessels and induces senescence and the acquisition of the senescence-associated secretory phenotype (SASP) in vascular smooth muscle (VSMCs) and endothelial (ECs) cells. Similarly, other VD risk factors, including dyslipidemia, hyperglycemia and hypertension, modify miR-34a expression to promote vascular senescence and inflammation. miR-34a upregulation causes endothelial dysfunction by affecting ECs nitric oxide bioavailability, adhesion molecules expression and inflammatory cells recruitment. miR-34a-induced senescence facilitates VSMCs osteoblastic switch and VC development in hyperphosphatemia conditions. Conversely, atherogenic and hypoxic stimuli downregulate miR-34a levels and promote VSMCs proliferation and migration during atherosclerosis and PAH. MiR34a genetic ablation or miR-34a inhibition by anti-miR-34a molecules in different experimental models of VD reduce vascular inflammation, senescence and apoptosis through sirtuin 1 Notch1, and B-cell lymphoma 2 modulation. Notably, pleiotropic drugs, like statins, liraglutide and metformin, affect miR-34a expression. Finally, human studies report that miR-34a levels associate to atherosclerosis and diabetes and correlate with inflammatory factors during aging. Herein, we comprehensively review the current knowledge about miR-34a-dependent molecular and cellular mechanisms activated by VD risk factors and highlight the diagnostic and therapeutic potential of modulating its expression in order to reduce inflammaging and VD burn and extend healthy lifespan.

scholarly journals Allostatic load and ageing: linking the microbiome and nutrition with age-related health

2019 ◽  
Vol 47 (4) ◽  
pp. 1165-1172 ◽  
Author(s):  
Paul G. Shiels ◽  
Sarah Buchanan ◽  
Colin Selman ◽  
Peter Stenvinkel
Keyword(s):  
Allostatic Load ◽  
Nutritional Risk ◽  
Inflammatory Factors ◽  
Low Grade ◽  
Methyl Donors ◽  
Inflammatory Status ◽  
Persistent Inflammation ◽  
Age Related ◽  
Metabolic Capability ◽  
Lifestyle Disease

Abstract Ageing is a process of decline in physiological function and capability over time. It is an anticipated major burden on societal health-care costs due to an increasingly aged global population. Accelerated biological ageing is a feature of age-related morbidities, which also appear to share common underpinning features, including low-grade persistent inflammation, phosphate toxicity, diminished Nrf2 activity, a depleted metabolic capability, depressed mitochondrial biogenesis and a low diversity gut microbiome. Social, psychological, lifestyle and nutritional risk factors can all influence the trajectory of age-related health, as part of an individual's exposome, which reflects the interplay between the genome and the environment. This is manifest as allostatic (over)load reflecting the burden of lifestyle/disease at both a physiological and molecular level. In particular, age-related genomic methylation levels and inflammatory status reflect exposome differences. These features may be mediated by changes in microbial diversity. This can drive the generation of pro-inflammatory factors, such as TMAO, implicated in the ‘diseasome’ of ageing. Additionally, it can be influenced by the ‘foodome’, via nutritional differences affecting the availability of methyl donors required for maintenance of the epigenome and by the provision of nutritionally derived Nrf2 agonists. Both these factors influence age-related physiological resilience and health. This offers novel insights into possible interventions to improve health span, including a rage of emerging senotherapies and simple modifications of the nutritional and environmental exposome. In essence, the emerging strategy is to treat ageing processes common to the diseasome of ageing itself and thus preempt the development or progression of a range of age-related morbidities.

scholarly journals Retinoid analogs and polyphenols as potential therapeutics for age-related macular degeneration

2020 ◽  
Vol 245 (17) ◽  
pp. 1615-1625 ◽  
Author(s):  
Tanu Parmar ◽  
Joseph T Ortega ◽  
Beata Jastrzebska
Keyword(s):  
Animal Models ◽  
Macular Degeneration ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Developed Countries ◽  
Natural Compounds ◽  
Scientific Data ◽  
Age Related Macular Degeneration ◽  
Positive Effects ◽  
Age Related

Progressive retinal degeneration manifesting as age-related macular degeneration (AMD) in the elderly affects millions of individuals worldwide. Among various blinding diseases, AMD is the leading cause of central vision impairment in developed countries. Poor understanding of AMD etiology hampers the development of therapeutics against this devastating ocular disease. Currently, daily intravitreal injections of anti-angiogenic drugs, preventing abnormal vessel growth are the only treatment option for wet AMD. However, for dry AMD associated with retinal atrophy, at present there is no cure available. Recent clinical research has demonstrated beneficial effects of plant-derived compounds for various eye disorders. Thus, the ongoing efforts toward discovering efficient treatments preventing or delaying AMD progression focus on implementing a healthy diet rich in vitamins, including vitamin A, E, and C, minerals and carotenoids, in particular lutein and zeaxanthin, to reduce the disease burden. In addition, studies in cell culture and animal models indicated therapeutic potential of dietary polyphenolic compounds present in fruits and vegetables. These natural compounds protect visual function and retinal morphology likely due to their anti-oxidant and anti-inflammatory properties. Although understanding of the exact mechanism of these compounds’ positive effects requires further investigation, they provide non-invasive alternative to battle AMD-like condition. Additionally, studies carried in animal models mimicking AMD-like pathology, examining the pharmacological potential of particular retinoid analogs, demonstrated promising results for their use, and thus they should be considered as an option in developing therapies for AMD. In here, we summarize the most current knowledge regarding developments of therapeutic options to maintain ocular health and prevent vision loss associated with aging. Impact statement Age-related macular degeneration (AMD) is a devastating retinal degenerative disease. Epidemiological reports showed an expected increasing prevalence of AMD in the near future. The only one existing FDA-approved pharmacological treatment involves an anti-vascular endothelial growth factor (VEGF) therapy with serious disadvantages. This limitation emphasizes an alarming need to develop new therapeutic approaches to prevent and treat AMD. In this review, we summarize scientific data unraveling the therapeutic potential of the specific retinoid and natural compounds. The experimental results reported by us and other research groups demonstrated that retinoid analogs and compounds with natural product scaffolds could serve as lead compounds for the development of new therapeutic agents with potential to prevent or slow down the pathogenesis of AMD.

scholarly journals Elucidation of the Mechanism Underlying the Anti-Inflammatory Properties of (S)-(+)-Carvone Identifies a Novel Class of Sirtuin-1 Activators in a Murine Macrophage Cell Line

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 777
Author(s):  
Cátia Sousa ◽  
Bruno Miguel Neves ◽  
Alcino Jorge Leitão ◽  
Alexandrina Ferreira Mendes
Keyword(s):  
Cell Line ◽  
Sirtuin 1 ◽  
Low Grade ◽  
Murine Macrophage ◽  
Macrophage Cell Line ◽  
Macrophage Cell ◽  
Murine Macrophage Cell Line ◽  
Protein Levels ◽  
Age Related ◽  
Anti Inflammatory

The signaling pathways involved in age-related inflammation are increasingly recognized as targets for the development of preventive and therapeutic strategies. Our previous study elucidated the structure–activity relationship of monoterpene compounds derived from p-menthane as potential anti-inflammatory drugs and identified (S)-(+)-carvone as the most potent among the compounds tested. This study aims at identifying the molecular mechanism underlying the anti-inflammatory properties of (S)-(+)-carvone. The murine macrophage cell line, Raw 264.7, was stimulated with bacterial lipopolysaccharide (LPS) to simulate inflammation. Western blot was used to assess protein levels and post-translational modifications. The subcellular localization of NF-κB/p65 was visualized by immunocytochemistry. An in vitro fluorometric assay was used to measure Sirtuin-1 (SIRT1) activity. (S)-(+)-carvone inhibited LPS-induced JNK1 phosphorylation, but not that of p38 and ERK1/2 and also did not affect the phosphorylation and degradation of the NF-κB inhibitor, IκB-α. Accordingly, (S)-(+)-carvone did not affect LPS-induced phosphorylation of NF-κB/p65 on Ser536 and its nuclear translocation, but it significantly decreased LPS-induced IκB-α resynthesis, a NF-κB-dependent process, and NF-κB/p65 acetylation on lysine (Lys) 310. Deacetylation of that Lys residue is dependent on the activity of SIRT1, which was found to be increased by (S)-(+)-carvone, while its protein levels were unaffected. Taken together, these results show that (S)-(+)-carvone is a new SIRT1 activator with the potential to counteract the chronic low-grade inflammation characteristic of age-related diseases.

scholarly journals Targeting Platelet in Atherosclerosis Plaque Formation: Current Knowledge and Future Perspectives

2020 ◽  
Vol 21 (24) ◽  
pp. 9760
Author(s):  
Lei Wang ◽  
Chaojun Tang
Keyword(s):  
Risk Factors ◽  
Molecular Mechanisms ◽  
Vascular System ◽  
Current Knowledge ◽  
Vascular Inflammation ◽  
Plaque Formation ◽  
Inflammatory Factors ◽  
Future Perspectives ◽  
Atherosclerotic Plaque Formation

Besides their role in hemostasis and thrombosis, it has become increasingly clear that platelets are also involved in many other pathological processes of the vascular system, such as atherosclerotic plaque formation. Atherosclerosis is a chronic vascular inflammatory disease, which preferentially develops at sites under disturbed blood flow with low speeds and chaotic directions. Hyperglycemia, hyperlipidemia, and hypertension are all risk factors for atherosclerosis. When the vascular microenvironment changes, platelets can respond quickly to interact with endothelial cells and leukocytes, participating in atherosclerosis. This review discusses the important roles of platelets in the plaque formation under pro-atherogenic factors. Specifically, we discussed the platelet behaviors under disturbed flow, hyperglycemia, and hyperlipidemia conditions. We also summarized the molecular mechanisms involved in vascular inflammation during atherogenesis based on platelet receptors and secretion of inflammatory factors. Finally, we highlighted the studies of platelet migration in atherogenesis. In general, we elaborated an atherogenic role of platelets and the aspects that should be further studied in the future.

scholarly journals Periodontitis, Low-Grade Inflammation and Systemic Health: A Scoping Review

Medicina ◽  
2020 ◽  
Vol 56 (6) ◽  
pp. 272
Author(s):  
Gennaro Cecoro ◽  
Marco Annunziata ◽  
Morena Tina Iuorio ◽  
Livia Nastri ◽  
Luigi Guida
Keyword(s):  
Scoping Review ◽  
Current Knowledge ◽  
Inflammatory Factors ◽  
Cochrane Library ◽  
Low Grade ◽  
Eligibility Criteria ◽  
Hand Search ◽  
Scoping Reviews ◽  
Systemic Health ◽  
Low Grade Inflammation

Background and objectives: Periodontitis is a multifactorial chronic inflammatory infectious disease in which an infection is necessary, but not sufficient, for development of the condition. Individual susceptibility strictly linked to the immune and inflammatory response of the organism must also be present. Low-grade inflammation (LGI) is a systemic status of chronic sub-clinical production of inflammatory factors. This condition represents a risk factor for many chronic diseases including diabetes, cardiovascular disease, cerebrovascular disease, neurodegenerative disease and cancer. This scoping review aims to clarify, summarize and disseminate current knowledge on the possible link between periodontitis, LGI and systemic health. Materials and Methods: PRISMA Extension for Scoping Reviews guidelines were followed. An ad-hoc created keyword string was used to search the electronic databases of PubMed/Medline, Embase, The Cochrane Library and ClinicalTrials.gov. A hand search of specialized journals and their reference lists was also performed. Results: 14 studies that respected eligibility criteria were selected and analyzed. There is emerging evidence of strong links between periodontitis, LGI and systemic health. On the one hand, periodontitis influences the systemic status of LGI and on the other hand, the systemic production of inflammatory factors affects periodontitis with a bidirectional connection. Conclusions: LGI and the subsequent onset of a systemic inflammatory phenotype can be considered the common substrate of many chronic inflammatory diseases including periodontitis, with multiple mutual connections between them. Understanding of the biological principles and mechanisms underlying such a complex interrelationship could lead to significant improvements in the field of personalized diagnostics and therapeutic protocols.

Management of cardiovascular disease in aging persons with haemophilia

2017 ◽  
Vol 37 (03) ◽  
pp. 196-201 ◽  
Author(s):  
Michiel Voskuil ◽  
Evelien Mauser-Bunschoten ◽  
Roger Schutgens
Keyword(s):  
Risk Factors ◽  
Atrial Fibrillation ◽  
Cardiovascular Disease ◽  
Current Knowledge ◽  
Anticoagulation Management ◽  
General Overview ◽  
Age Related ◽  
Aging Persons

SummaryWith the aging of the haemophilia population, age related comorbidities become more and more a medical issue. Managing haemophilia patients with cardiovascular disease is a difficult task for many haemophilia-treating physicians. Over the years, insights on prevalence, risk factors and management of cardiovascular disease in haemophilia have improved substantially. It is now recognised that many risk factors, such as hypertension and overweight, occur quite frequently in patients with haemophilia. Several new insights in anticoagulation management of atrial fibrillation and coronary ischaemia in haemophilia have been suggested. This review provides an general overview of the current knowledge of these topics in literature.

Abstract 13080: Clinical Significance of Clonal Hematopoiesis With JAK2V617F in Patients With Cardiovascular Diseases

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Kento Wada ◽  
Tomofumi Misaka ◽  
Tetsuro Yokokawa ◽  
Yusuke KIMISHIMA ◽  
Keiji Minakawa ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cardiovascular Diseases ◽  
Multivariable Analysis ◽  
Myeloproliferative Neoplasm ◽  
Vascular Diseases ◽  
Interleukin 1Β ◽  
Clonal Hematopoiesis ◽  
Age Related ◽  
Artery Disease ◽  
Atherosclerotic Risk Factors

Background: It becomes increasingly clear that age-related clonal hematopoiesis (CH) is associated with cardiovascular diseases. However, CH with a driver mutation that causes myeloproliferative neoplasm (MPN) is not fully understood. Objective: To determine the clinical relevance of CH with MPN-driving mutations on cardiovascular diseases. Methods: This study prospectively enrolled 832 patients with cardiovascular diseases who did not show any hematological disorders. We examined the presence of the known MPN-driving mutations including JAK2V617F, CALRdel52, CALRins5, MPLW515L, and MPLW515K by an allele-specific polymerase chain reaction. Results: Out of 832 patients, 16 patients (1.9%) exhibited MPN-driving mutations including 15 patients with JAK2V617F (1.8%) and 1 patient with CALRins5 (0.1%). We divided the patients into two groups: vascular diseases including coronary artery disease, stroke, aortic aneurysm, aortic dissection, peripheral artery disease, deep vein thrombosis, and pulmonary thromboembolism (n=462, 55%) and non-vascular diseases (n=370, 45%). The prevalence of JAK2V617F-positive CH was significantly higher in patients with vascular diseases than in those with non-vascular diseases (2.8% vs. 0.5%, P = 0.014). In a multivariable analysis adjusted for known classic-atherosclerotic risk factors (age, male, obesity, smoking, hypertension, diabetes mellitus, dyslipidemia), the presence of JAK2V617F-positive CH was independently associated with vascular diseases (odds ratio, 5.448; P = 0.043). Additionally, peripheral leukocyte IL1B mRNA expressions as well as plasma interleukin-1β concentrations were significantly increased in patients with JAK2V617F-positive CH compared to those without JAK2V617F (P = 0.040 and P = 0.030, respectively). Conclusions: CH with JAK2V617F, but not CALR or MPL mutations, was significantly associated with vascular diseases independently on classic-atherosclerotic risk factors, in relation to interleukin-1β-related inflammatory mechanisms. JAK2V617F is a potential diagnostic and therapeutic target for vascular diseases.

scholarly journals Neurovascular Inflammaging in Health and Disease

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1614 ◽  
Author(s):  
Ádám Mészáros ◽  
Kinga Molnár ◽  
Bernát Nógrádi ◽  
Zsófia Hernádi ◽  
Ádám Nyúl-Tóth ◽  
...  
Keyword(s):  
Tissue Injury ◽  
Current Knowledge ◽  
Neurovascular Unit ◽  
Sterile Inflammation ◽  
Inflammasome Activation ◽  
Low Grade ◽  
Intrinsic Factors ◽  
Age Related ◽  
Cellular Debris ◽  
The Central Nervous System

Aging is characterized by a chronic low-grade sterile inflammation dubbed as inflammaging, which in part originates from accumulating cellular debris. These, acting as danger signals with many intrinsic factors such as cytokines, are sensed by a network of pattern recognition receptors and other cognate receptors, leading to the activation of inflammasomes. Due to the inflammasome activity-dependent increase in the levels of pro-inflammatory interleukins (IL-1β, IL-18), inflammation is initiated, resulting in tissue injury in various organs, the brain and the spinal cord included. Similarly, in age-related diseases of the central nervous system (CNS), inflammasome activation is a prominent moment, in which cells of the neurovascular unit occupy a significant position. In this review, we discuss the inflammatory changes in normal aging and summarize the current knowledge on the role of inflammasomes and contributing mechanisms in common CNS diseases, namely Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and stroke, all of which occur more frequently with aging.

scholarly journals Macrophage function in the elderly and impact on injury repair and cancer

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
L Duong ◽  
HG Radley ◽  
B Lee ◽  
DE Dye ◽  
FJ Pixley ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Transforming Growth Factor ◽  
Healthy Ageing ◽  
Inflammatory Factors ◽  
Low Grade ◽  
Macrophage Function ◽  
Injury Repair ◽  
Age Related ◽  
Anti Inflammatory ◽  
Age Related Changes

AbstractOlder age is associated with deteriorating health, including escalating risk of diseases such as cancer, and a diminished ability to repair following injury. This rise in age-related diseases/co-morbidities is associated with changes to immune function, including in myeloid cells, and is related to immunosenescence. Immunosenescence reflects age-related changes associated with immune dysfunction and is accompanied by low-grade chronic inflammation or inflammageing. This is characterised by increased levels of circulating pro-inflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-1β and IL-6. However, in healthy ageing, there is a concomitant age-related escalation in anti-inflammatory cytokines such as transforming growth factor-β1 (TGF-β1) and IL-10, which may overcompensate to regulate the pro-inflammatory state. Key inflammatory cells, macrophages, play a role in cancer development and injury repair in young hosts, and we propose that their role in ageing in these scenarios may be more profound. Imbalanced pro- and anti-inflammatory factors during ageing may also have a significant influence on macrophage function and further impact the severity of age-related diseases in which macrophages are known to play a key role. In this brief review we summarise studies describing changes to inflammatory function of macrophages (from various tissues and across sexes) during healthy ageing. We also describe age-related diseases/co-morbidities where macrophages are known to play a key role, focussed on injury repair processes and cancer, plus comment briefly on strategies to correct for these age-related changes.

scholarly journals Interlink between Inflammation and Oxidative Stress in Age-Related Macular Degeneration: Role of Complement Factor H

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 763
Author(s):  
Sara Romero-Vazquez ◽  
Víctor Llorens ◽  
Alba Soler-Boronat ◽  
Marc Figueras-Roca ◽  
Alfredo Adan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Risk Factors ◽  
Macular Degeneration ◽  
Factor H ◽  
Age Related Macular Degeneration ◽  
Complement Factor H ◽  
Low Grade ◽  
Complement Factor ◽  
Age Related ◽  
And Oxidative Stress

Age-related macular degeneration (AMD) heads the list of legal blindness among the elderly population in developed countries. Due to the complex nature of the retina and the variety of risk factors and mechanisms involved, the molecular pathways underlying AMD are not yet fully defined. Persistent low-grade inflammation and oxidative stress eventually lead to retinal pigment epithelium dysfunction and outer blood–retinal barrier (oBRB) breakdown. The identification of AMD susceptibility genes encoding complement factors, and the presence of inflammatory mediators in drusen, the hallmark deposits of AMD, supports the notion that immune-mediated processes are major drivers of AMD pathobiology. Complement factor H (FH), the main regulator of the alternative pathway of the complement system, may have a key contribution in the pathogenesis of AMD as it is able to regulate both inflammatory and oxidative stress responses in the oBRB. Indeed, genetic variants in the CFH gene account for the strongest genetic risk factors for AMD. In this review, we focus on the roles of inflammation and oxidative stress and their connection with FH and related proteins as regulators of both phenomena in the context of AMD.

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