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1.
Cell Mol Life Sci ; 79(8): 410, 2022 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-35821533

RESUMO

Beyond well-assessed risk factors, cardiovascular events could be also associated with the presence of epigenetic and genetic alterations, such as the methylenetetrahydrofolate-reductase (MTHFR) C677T polymorphism. This gene variant is related to increased circulating levels of homocysteine (Hcy) and cardiovascular risk. However, heterozygous carriers have an augmented risk of cardiovascular accidents independently from normal Hcy levels, suggesting the presence of additional deregulated processes in MTHFR C677T carriers. Here, we hypothesize that targeting Sirtuin 1 (SIRT1) could be an alternative mechanism to control the cardiovascular risk associated to MTHFR deficiency condition. Flow Mediated Dilatation (FMD) and light transmission aggregometry assay were performed in subjects carrying MTHFR C677T allele after administration of resveratrol, the most powerful natural clinical usable compound that owns SIRT1 activating properties. MTHFR C677T carriers with normal Hcy levels revealed endothelial dysfunction and enhanced platelet aggregation associated with SIRT1 downregulation. SIRT1 activity stimulation by resveratrol intake was able to override these abnormalities without affecting Hcy levels. Impaired endothelial function, bleeding time, and wire-induced thrombus formation were rescued in a heterozygous Mthfr-deficient (Mthfr+/-) mouse model after resveratrol treatment. Using a cell-based high-throughput multiplexed screening (HTS) assay, a novel selective synthetic SIRT1 activator, namely ISIDE11, was identified. Ex vivo and in vivo treatment of Mthfr+/- mice with ISIDE11 rescues endothelial vasorelaxation and reduces wire-induced thrombus formation, effects that were abolished by SIRT1 inhibitor. Moreover, platelets from MTHFR C677T allele carriers treated with ISIDE11 showed normalization of their typical hyper-reactivity. These results candidate SIRT1 activation as a new therapeutic strategy to contain cardio and cerebrovascular events in MTHFR carriers.


Assuntos
Homocistinúria , Metilenotetra-Hidrofolato Redutase (NADPH2) , Sirtuína 1 , Trombose , Animais , Genótipo , Homocistinúria/tratamento farmacológico , Homocistinúria/metabolismo , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Camundongos , Espasticidade Muscular , Transtornos Psicóticos/metabolismo , Resveratrol/farmacologia , Sirtuína 1/genética , Sirtuína 1/metabolismo , Trombose/tratamento farmacológico , Trombose/genética , Trombose/metabolismo , Trombose/prevenção & controle
2.
Int J Mol Sci ; 24(17)2023 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-37685989

RESUMO

The global population is experiencing an increase in ageing and life expectancy [...].


Assuntos
Centenários , Longevidade , Idoso de 80 Anos ou mais , Humanos , Longevidade/genética , Envelhecimento/genética , Expectativa de Vida
3.
Int J Mol Sci ; 24(5)2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36902151

RESUMO

SARS-CoV-2 infection causes a considerable inflammatory response coupled with impaired platelet reactivity, which can lead to platelet disorders recognized as negative prognostic factors in COVID-19 patients. The virus may cause thrombocytopenia or thrombocytosis during the different disease stages by destroying or activating platelets and influencing platelet production. While it is known that several viruses can impair megakaryopoiesis by generating an improper production and activation of platelets, the potential involvement of SARS-CoV-2 in affecting megakaryopoiesis is poorly understood. To this purpose, we explored, in vitro, the impact of SARS-CoV-2 stimulation in the MEG-01 cell line, a human megakaryoblastic leukemia cell line, considering its spontaneous capacity of releasing platelet-like particles (PLPs). We interrogated the effect of heat-inactivated SARS-CoV-2 lysate in the release of PLPs and activation from MEG-01, the signaling pathway influenced by SARS-CoV-2, and the functional effect on macrophagic skewing. The results highlight the potential influence of SARS-CoV-2 in the early stages of megakaryopoiesis by enhancing the production and activation of platelets, very likely due to the impairment of STATs signaling and AMPK activity. Overall, these findings provide new insight into the role of SARS-CoV-2 in affecting megakaryocyte-platelet compartment, possibly unlocking another avenue by which SARS-CoV-2 moves.


Assuntos
Plaquetas , COVID-19 , Humanos , Plaquetas/metabolismo , SARS-CoV-2 , COVID-19/metabolismo , Megacariócitos/metabolismo , Linhagem Celular
4.
Int J Mol Sci ; 24(7)2023 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-37047437

RESUMO

The homozygous genotype of the Longevity-Associated Variant (LAV) in Bactericidal/Permeability-Increasing Fold-Containing Family B member 4 (BPIFB4) is enriched in long-living individuals of three independent populations and its genetic transfer in C57BL/6J mice showed a delay in frailty progression and improvement of several biomarkers of aging and multiple aspects of health. The C57BL/6J strain is a suitable model for studying therapies aimed at extending healthy aging and longevity due to its relatively short lifespan and the availability of aging biomarkers. Epigenetic clocks based on DNA methylation profiles are reliable molecular biomarkers of aging, while frailty measurement tools are used to evaluate overall health during aging. In this study, we show that the systemic gene transfer of LAV-BPIFB4 in aged C57BL/6J mice was associated with a significant reduction in the epigenetic clock-based biological age, as measured by a three CpG clock method. Furthermore, LAV-BPIFB4 gene transfer resulted in an improvement of the Vitality Score with a reduction in the Frailty Index. These findings further support the use of LAV-BPIFB4 gene therapy to induce beneficial effects on epigenetic mechanisms associated with aging and frailty in aged mice, with potential implications for future therapies to prevent frailty in humans.


Assuntos
Fragilidade , Longevidade , Humanos , Camundongos , Animais , Idoso , Longevidade/genética , Fragilidade/genética , Camundongos Endogâmicos C57BL , Epigênese Genética , Biomarcadores , Terapia Genética , Metilação de DNA , Peptídeos e Proteínas de Sinalização Intercelular/genética
5.
Eur Heart J ; 42(28): 2780-2792, 2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34104945

RESUMO

AIMS: Increased shedding of extracellular vesicles (EVs)-small, lipid bilayer-delimited particles with a role in paracrine signalling-has been associated with human pathologies, e.g. atherosclerosis, but whether this is true for cardiac diseases is unknown. METHODS AND RESULTS: Here, we used the surface antigen CD172a as a specific marker of cardiomyocyte (CM)-derived EVs; the CM origin of CD172a+ EVs was supported by their content of cardiac-specific proteins and heart-enriched microRNAs. We found that patients with aortic stenosis, ischaemic heart disease, or cardiomyopathy had higher circulating CD172a+ cardiac EV counts than did healthy subjects. Cellular stress was a major determinant of EV release from CMs, with hypoxia increasing shedding in in vitro and in vivo experiments. At the functional level, EVs isolated from the supernatant of CMs derived from human-induced pluripotent stem cells and cultured in a hypoxic atmosphere elicited a positive inotropic response in unstressed CMs, an effect we found to be dependent on an increase in the number of EVs expressing ceramide on their surface. Of potential clinical relevance, aortic stenosis patients with the highest counts of circulating cardiac CD172a+ EVs had a more favourable prognosis for transcatheter aortic valve replacement than those with lower counts. CONCLUSION: We identified circulating CD172a+ EVs as cardiac derived, showing their release and function and providing evidence for their prognostic potential in aortic stenosis patients.


Assuntos
Vesículas Extracelulares , MicroRNAs , Infarto do Miocárdio , Humanos , Hipóxia , Miocárdio , Miócitos Cardíacos
6.
Int J Mol Sci ; 23(23)2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36499641

RESUMO

Huntington's disease (HD) is caused by the production of mutant Huntingtin (mHTT), characterized by long polyglutamine repeats with toxic effects. There are currently no clinically validated therapeutic agents that slow or halt HD progression, resulting in a significant clinical unmet need. The striatum-derived STHdh cell line, generated from mHTT knock-in mouse embryos (STHdhQ111/Q111), represents a useful model to study mechanisms behind pathogenesis of HD and to investigate potential new therapeutic targets. Indeed, these cells show susceptibility to nucleolar stress, activated DNA damage response and apoptotic signals, and elevated levels of H3K9me3 that all together concur in the progressive HD pathogenesis. We have previously shown that the adeno-associated viral vector-mediated delivery of the longevity-associated variant (LAV) of BPIFB4 prevents HD progression in a mouse model of HD. Here, we show that LAV-BPIFB4 stably infected in STHdhQ111/Q111 cells reduces (i) nucleolar stress and DNA damage through the improvement of DNA repair machinery, (ii) apoptosis, through the inhibition of the caspase 3 death signaling, and (iii) the levels of H3K9me3, by accelerating the histone clearance, via the ubiquitin-proteasome pathway. These findings pave the way to propose LAV-BPIFB4 as a promising target for innovative therapeutic strategies in HD.


Assuntos
Doença de Huntington , Animais , Camundongos , Apoptose/genética , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Doença de Huntington/metabolismo , Neostriado/metabolismo , Neuroproteção/genética , Variação Genética
7.
Cytokine ; 137: 155305, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33002742

RESUMO

A way to delay aging and the related low-grade chronic inflammatory state is to study the model of positive physiology such as the Long-Living Individuals (LLIs). Our recent studies have shown higher levels of the host defense BPI Fold-Containing Family B Member 4 (BPIFB4) protein in the LLIs' blood. Notably, BPIFB4 has been shown to influence monocytes typesetting and M2 anti-inflammatory phenotype (CD206+CD163++) macrophages skewing. According to the role of a complex cytokine milieu in guiding the macrophage polarization, here we found that circulating concentrations of thymus and activation regulated chemokine (TARC)/CCL17 and small-inducible cytokine B10 (IP-10)/CXCL10) cytokines, were additionally associated with the LLIs' state. In a differentiation process in vitro, the addition of LLIs' plasma to the cell culture medium, enhanced the ability of monocytes, either from LLIs or controls, to acquire a M2 phenotype. Interestingly, a neutralizing antibody against TARC blunted the M2 skewing effect of the LLIs' plasma. Collectively, these data indicate that exceptional longevity may associate with a peculiar anti-inflammatory myeloid profile responsible for improved reparative processes and reduced inflammatory status mediated in part by TARC and M2 generation.


Assuntos
Envelhecimento/sangue , Quimiocina CCL17/sangue , Longevidade , Macrófagos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimiocina CXCL10/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Ativação de Macrófagos , Macrófagos/classificação , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade
8.
Eur Heart J ; 41(26): 2487-2497, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-31289820

RESUMO

AIMS: Here, we aimed to determine the therapeutic effect of longevity-associated variant (LAV)-BPIFB4 gene therapy on atherosclerosis. METHODS AND RESULTS: ApoE knockout mice (ApoE-/-) fed a high-fat diet were randomly allocated to receive LAV-BPIFB4, wild-type (WT)-BPIFB4, or empty vector via adeno-associated viral vector injection. The primary endpoints of the study were to assess (i) vascular reactivity and (ii) atherosclerotic disease severity, by Echo-Doppler imaging, histology and ultrastructural analysis. Moreover, we assessed the capacity of the LAV-BPIFB4 protein to shift monocyte-derived macrophages of atherosclerotic mice and patients towards an anti-inflammatory phenotype. LAV-BPIFB4 gene therapy rescued endothelial function of mesenteric and femoral arteries from ApoE-/- mice; this effect was blunted by AMD3100, a CXC chemokine receptor type 4 (CXCR4) inhibitor. LAV-BPIFB4-treated mice showed a CXCR4-mediated shift in the balance between Ly6Chigh/Ly6Clow monocytes and M2/M1 macrophages, along with decreased T cell proliferation and elevated circulating levels of interleukins IL-23 and IL-27. In vitro conditioning with LAV-BPIFB4 protein of macrophages from atherosclerotic patients resulted in a CXCR4-dependent M2 polarization phenotype. Furthermore, LAV-BPIFB4 treatment of arteries explanted from atherosclerotic patients increased the release of atheroprotective IL-33, while inhibiting the release of pro-inflammatory IL-1ß, inducing endothelial nitric oxide synthase phosphorylation and restoring endothelial function. Finally, significantly lower plasma BPIFB4 was detected in patients with pathological carotid stenosis (>25%) and intima media thickness >2 mm. CONCLUSION: Transfer of the LAV of BPIFB4 reduces the atherogenic process and skews macrophages towards an M2-resolving phenotype through modulation of CXCR4, thus opening up novel therapeutic possibilities in cardiovascular disease.


Assuntos
Aterosclerose , Placa Aterosclerótica , Idoso , Animais , Apolipoproteínas E , Aterosclerose/genética , Espessura Intima-Media Carotídea , Feminino , Humanos , Inflamação , Peptídeos e Proteínas de Sinalização Intercelular , Longevidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Knockout para ApoE , Pessoa de Meia-Idade , Fosfoproteínas , Receptores CXCR4
9.
Int J Mol Sci ; 22(4)2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33669501

RESUMO

People are living longer, not, as was previously the case, due to reduced child mortality, but because we are postponing the ill-health of old age [...].


Assuntos
Longevidade/fisiologia , Modelos Biológicos , Idoso de 80 Anos ou mais , Ensaios Clínicos como Assunto , Dieta , Epigênese Genética , Saúde , Humanos , Longevidade/genética , Probióticos/farmacologia
10.
Int J Mol Sci ; 22(19)2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34639203

RESUMO

In severe muscle injury, skeletal muscle tissue structure and functionality can be repaired through the involvement of several cell types, such as muscle stem cells, and innate immune responses. However, the exact mechanisms behind muscle tissue regeneration, homeostasis, and plasticity are still under investigation, and the discovery of pathways and cell types involved in muscle repair can open the way for novel therapeutic approaches, such as cell-based therapies involving stem cells and peripheral blood mononucleate cells. Indeed, peripheral cell infusions are a new therapy for muscle healing, likely because autologous peripheral blood infusion at the site of injury might enhance innate immune responses, especially those driven by macrophages. In this review, we summarize current knowledge on functions of stem cells and macrophages in skeletal muscle repairs and their roles as components of a promising cell-based therapies for muscle repair and regeneration.


Assuntos
Macrófagos/citologia , Músculo Esquelético/citologia , Doenças Musculares/terapia , Medicina Regenerativa , Células-Tronco/citologia , Animais , Humanos , Imunidade Inata , Macrófagos/fisiologia , Músculo Esquelético/fisiologia , Células-Tronco/fisiologia
11.
Int J Mol Sci ; 21(19)2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-32998388

RESUMO

Aging is the most relevant risk factor for cardiovascular diseases which are the main cause of mortality in industrialized countries. In this context, there is a progressive loss of cardiovascular homeostasis that translates in illness and death. The study of long living individuals (LLIs), which show compression of morbidity toward the end of their life, is a valuable approach to find the key to delay aging and postpone associate cardiovascular events. A contribution to the age-related decline of cardiovascular system (CVS) comes from the immune system; indeed, it is dysfunctional during aging, a process described as immunosenescence and comprises the combination of several processes overpowering both innate and adaptative immune system. We have recently discovered a longevity-associated variant (LAV) in bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4), which is a secreted protein able to enhance endothelial function through endothelial nitric oxide synthase (eNOS) activation and capable to protect from hypertension, atherosclerosis, diabetic cardiopathy, frailty, and inflammaging. Here, we sum up the state of the art of the mechanisms involved in the main pathological processes related to CVD (atherosclerosis, aging, diabetic cardiopathy, and frailty) and shed light on the therapeutic effects of LAV-BPIFB4 in these contexts.


Assuntos
Aterosclerose/genética , Cardiomiopatias Diabéticas/genética , Fragilidade/genética , Hipertensão/genética , Imunossenescência/genética , Longevidade/genética , Fosfoproteínas/genética , Imunidade Adaptativa , Fatores Etários , Animais , Aterosclerose/imunologia , Aterosclerose/prevenção & controle , Cardiomiopatias Diabéticas/imunologia , Cardiomiopatias Diabéticas/prevenção & controle , Fragilidade/imunologia , Fragilidade/prevenção & controle , Regulação da Expressão Gênica no Desenvolvimento/imunologia , Terapia Genética/métodos , Humanos , Hipertensão/imunologia , Hipertensão/prevenção & controle , Imunidade Inata , Peptídeos e Proteínas de Sinalização Intercelular , Longevidade/imunologia , Camundongos , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/imunologia , Fosfoproteínas/imunologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Fatores de Risco
12.
Int J Mol Sci ; 19(10)2018 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-30347645

RESUMO

Evolutionary forces select genetic variants that allow adaptation to environmental stresses. The genomes of centenarian populations could recapitulate the evolutionary adaptation model and reveal the secrets of disease resistance shown by these individuals. Indeed, longevity phenotype is supposed to have a genetic background able to survive or escape to age-related diseases. Among these, cardiovascular diseases (CVDs) are the most lethal and their major risk factor is aging and the associated frailty status. One example of genetic evolution revealed by the study of centenarians genome is the four missense Single Nucleotide Polymorphisms (SNPs) haplotype in bactericidal/permeability-increasing fold-containing family B, member 4 (BPIFB4) locus that is enriched in long living individuals: the longevity associated variant (LAV). Indeed, LAV-BPIFB4 is able to improve endothelial function and revascularization through the increase of endothelial nitric oxide synthase (eNOS) dependent nitric oxide production. This review recapitulates the beneficial effects of LAV-BPIFB4 and its therapeutic potential for the treatment of CVDs.


Assuntos
Doenças Cardiovasculares/genética , Longevidade/genética , Fosfoproteínas/genética , Polimorfismo de Nucleotídeo Único , Seleção Genética , Evolução Molecular , Humanos , Peptídeos e Proteínas de Sinalização Intercelular
13.
BMC Med Genet ; 18(1): 147, 2017 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-29237418

RESUMO

BACKGROUND: Mutations in the gene that encodes CDGSH iron sulfur domain 2 (CISD2) are causative of Wolfram syndrome type 2 (WFS2), a rare autosomal recessive neurodegenerative disorder mainly characterized by diabetes mellitus, optic atrophy, peptic ulcer bleeding and defective platelet aggregation. Four mutations in the CISD2 gene have been reported. Among these mutations, the homozygous c.103 + 1G > A substitution was identified in the donor splice site of intron 1 in two Italian sisters and was predicted to cause a exon 1 to be skipped. METHODS: Here, we employed molecular assays to characterize the c.103 + 1G > A mutation using the patient's peripheral blood mononuclear cells (PBMCs). 5'-RACE coupled with RT-PCR were used to analyse the effect of the c.103 + 1G > A mutation on mRNA splicing. Western blot analysis was used to analyse the consequences of the CISD2 mutation on the encoded protein. RESULTS: We demonstrated that the c.103 + 1G > A mutation functionally impaired mRNA splicing, producing multiple splice variants characterized by the whole or partial absence of exon 1, which introduced amino acid changes and a premature stop. The affected mRNAs resulted in either predicted targets for nonsense mRNA decay (NMD) or non-functional isoforms. CONCLUSIONS: We concluded that the c.103 + 1G > A mutation resulted in the loss of functional CISD2 protein in the two Italian WFS2 patients.


Assuntos
Senilidade Prematura/genética , Perda Auditiva Neurossensorial/genética , Proteínas de Membrana/genética , Doenças Mitocondriais/genética , Mutação , Atrofia Óptica/genética , Sítios de Splice de RNA/genética , Sequência de Bases , Células Sanguíneas , Códon sem Sentido , Éxons/genética , Feminino , Humanos , Íntrons/genética , Leucócitos Mononucleares , Proteínas de Membrana/química , Isoformas de Proteínas/genética , Sítios de Splice de RNA/fisiologia , Splicing de RNA , RNA Mensageiro/genética , Análise de Sequência , Deleção de Sequência
14.
BMC Genet ; 16: 15, 2015 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-25888430

RESUMO

BACKGROUND: Lone atrial flutter (AFL) and atrial fibrillation (AF) are common and sometimes consequential cardiac conduction disorders with a strong heritability, as underlined by recent genome-wide association studies that identified genetic modifiers. Follow-up family-based genetic analysis also identified Mendelian transmission of disease alleles. Three affected members were exome-sequenced for the identification of potential causative mutations, which were subsequently validated by direct sequencing in the other 3 affected members. Taqman assay was then used to confirm the role of any mutation in an independent population of sporadic lone AFL/AF cases. RESULTS: The family cluster analysis provided evidence of genetic inheritance of AFL in the family via autosomal dominant transmission. The exome-sequencing of 3 family members identified 7 potential mutations: of these, rs58238559, a rare missense genetic variant in the ATP-binding cassette sub-family B, member 4 (ABCB4) gene was carried by all affected members. Further analysis of 82 subjects with sporadic lone AF, 63 subjects with sporadic lone AFL, and 673 controls revealed that the allele frequency for this variation was significantly higher in cases than in the controls (0.05 vs. 0.01; OR = 3.73; 95% CI = 1.16-11.49; P = 0.013). CONCLUSIONS: rs58238559 in ABCB4 is a rare missense variant with a significant effect on the development of AFL/AF.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Fibrilação Atrial/genética , Flutter Atrial/genética , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Exoma , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Linhagem
15.
Heliyon ; 10(8): e29017, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38644830

RESUMO

The programmed cell death pathways of apoptosis are important in mammalian cellular protection from infections. The activation of these pathways depends on the presence of membrane receptors that bind bacterial components to activate the transduction mechanism. In addition to bacteria, these mechanisms can be activated by outer membrane vesicles (OMVs). OMVs are spherical vesicles of 20-250 nm diameter, constitutively released by Gram-negative bacteria. They contain several bacterial determinants including proteins, DNA/RNA and proteins, that activate different cellular processes in host cells. This study focused on Klebsiella pneumoniae-OMVs in activating death mechanisms in human bronchial epithelial cells (BEAS-2B). Characterization of purified OMVs was achieved by scanning electron microscopy, nanoparticle tracking analysis and protein profiling. Cell viability was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay while apoptotic induction was measured by flow cytometry and confirmed by western blotting. The OMVs produced showed a spherical morphology, with a diameter of 137.2 ± 41 nm and a vesicular density of 7.8 × 109 particles/mL Exposure of cell monolayers to 50 µg of K. pneumoniae-OMV for 14 h resulted in approximately 25 % cytotoxicity and 41.15-41.14 % of cells undergoing early and late apoptosis. Fluorescence microscopy revealed reduced cellular density, the presence of apoptotic bodies, chromatin condensation, and nuclear membrane blebbing in residual cells. Activation of caspases -3 and -9 and dysregulation of BAX, BIM and Bcl-xL indicated the activation of mitochondria-dependent apoptosis. Furthermore, a decrease in the antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase involved endoplasmic reticulum stress with the potential formation of reactive oxygen species. These findings provide evidence for the role of OMVs in apoptosis and involvement in the pathogenesis of K. pneumoniae infections.

16.
Geroscience ; 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38884925

RESUMO

Beyond their activity in hemostasis and thrombosis, recent advances attribute platelets a pro-youthful role capable to attenuate immune senescence and age-related neuroinflammation. Previous studies from our group associated a polymorphic haplotype variant in the BPIFB4 gene (LAV-BPIFB4) with exceptional longevity. Transfer of the LAV-BPIFB4 in preclinical models has proved strategic to cope with frailty conditions, aging-related events, e.g., cardiovascular ones, and immune dysfunction mainly through a favorable conditioning of the immune system. However, whether platelets participate in LAV-BPIFB4 therapeutic action is currently unknown. Herein, we discovered that platelets were instrumental in boosting the favorable health outcomes of the systemic AAV-LAV-BPIFB4 gene transfer in vivo, as the α-CD42b platelet depletion completely abolished the vascular protective action of LAV-BPIFB4 and suppressed its pro-resolutive CD206 + anti-/CD86 + pro-inflammatory Ly6C + monocyte skewing to LPS stimulation. Of note, this is associated with a huge drop in the protective levels of BPIFB4 in the plasma of AAV-LAV-BPIFB4-injected C57BL/6 mice, indicating that plasma circulating platelets may be a reservoir of the BPIFB4 protein. Indeed, we noticed that BPIFB4 was released by human platelets, a process that is amplified in LAV-allele carrier donors. Accordingly, lentivirus-mediated overexpression of human LAV-BPIFB4 isoform, but not WT-BPIFB4 isoform was able in leading differentiated megakaryocytes to release more platelet-like-particles enriched for BPIFB4. In addition, in vitro, the M2 macrophage polarization increased when releasate from platelets, and even more from LAV pre-stimulated once, was added in monocyte cell culture. Our data suggest that platelet release of BPIFB4 and of yet-to-be-determined unidentified factors mediates the therapeutic efficacy of LAV-BPIFB4 treatment.

17.
Nutrients ; 15(1)2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36615875

RESUMO

Longevity, as a complex life-history trait, shares an ontogenetic relationship with other quantitative traits, such as epigenetic and environmental factors. Therefore, it is important to identify environmental factors that may modify the epigenome to establish healthy aging. This study explored the association between tap drinking water and longevity in Cilento, Italy, to understand whether trace elements in local drinking water may have an influence on old, nonagenarian, and centenarian people and promote their health and longevity. Data on population and water sources were collected through the National Demographic Statistics, the Cilento Municipal Archives, and the Cilento Integrated Water Service. Ordinary least squares (OLS) regression and a geographically weight regression (GWR) model were used to study the spatial relationship between the explanatory and outcome variables of longevity. The results of the study showed that the prevalence of longevity is concentrated in the central, northern and southeastern areas of the territory and that some trace elements present in tap water may contribute to local longevity in Cilento. Specifically, all Cilento municipalities had alkaline tap water, and the municipalities with the highest longevity concentrations had higher alkalinity levels than the other municipalities, soft to medium-hard water hardness, an amount of total dissolved solids equivalent to the level of excellent water, lower amounts of sodium, adequate iron concentration, and adequate dietary intake of manganese per day.


Assuntos
Água Potável , Oligoelementos , Idoso de 80 Anos ou mais , Humanos , Longevidade , Água Potável/análise , Oligoelementos/análise , Nonagenários , Centenários , Itália/epidemiologia
18.
Cell Death Dis ; 14(8): 523, 2023 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-37582912

RESUMO

Long-living individuals (LLIs) escape age-related cardiovascular complications until the very last stage of life. Previous studies have shown that a Longevity-Associated Variant (LAV) of the BPI Fold Containing Family B Member 4 (BPIFB4) gene correlates with an extraordinarily prolonged life span. Moreover, delivery of the LAV-BPIFB4 gene exerted therapeutic action in murine models of atherosclerosis, limb ischemia, diabetic cardiomyopathy, and aging. We hypothesize that downregulation of BPIFB4 expression marks the severity of coronary artery disease (CAD) in human subjects, and supplementation of the LAV-BPIFB4 protects the heart from ischemia. In an elderly cohort with acute myocardial infarction (MI), patients with three-vessel CAD were characterized by lower levels of the natural logarithm (Ln) of peripheral blood BPIFB4 (p = 0.0077). The inverse association between Ln BPIFB4 and three-vessel CAD was confirmed by logistic regression adjusting for confounders (Odds Ratio = 0.81, p = 0.0054). Moreover, in infarcted mice, a single administration of LAV-BPIFB4 rescued cardiac function and vascularization. In vitro studies showed that LAV-BPIFB4 protein supplementation exerted chronotropic and inotropic actions on induced pluripotent stem cell (iPSC)-derived cardiomyocytes. In addition, LAV-BPIFB4 inhibited the pro-fibrotic phenotype in human cardiac fibroblasts. These findings provide a strong rationale and proof of concept evidence for treating CAD with the longevity BPIFB4 gene/protein.


Assuntos
Doença da Artéria Coronariana , Peptídeos e Proteínas de Sinalização Intercelular , Longevidade , Idoso , Animais , Humanos , Camundongos , Envelhecimento/genética , Haplótipos/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Isquemia , Longevidade/genética
19.
Immun Ageing ; 9(1): 26, 2012 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-23153280

RESUMO

Aging is the sum of the deleterious changes that occur as time goes by. It is the main risk factor for the development of cardiovascular disease, and aging of the vasculature is the event that most often impacts on the health of elderly people. The "free-radical theory of aging" was proposed to explain aging as a consequence of the accumulation of reactive oxygen species (ROS). However, recent findings contradict this theory, and it now seems that mechanisms mediating longevity act through induction of oxidative stress. In fact, calorie restriction - a powerful way of delaying aging - increases ROS accumulation due to stimulation of the basal metabolic rate; moreover, reports show that antioxidant therapy is detrimental to healthy aging. We also now know that genetic manipulation of the insulin-like-growth-factor-1/insulin signal (IIS) has a profound impact on the rate of aging and that the IIS is modulated by calorie restriction and physical exercise. The IIS regulates activation of nitric oxide synthase (eNOS), the activity of which is essential to improving lifespan through calorie restriction, as demonstrated by experiments on eNOS knockout mice. Indeed, eNOS has a key role in maintaining vascular integrity during aging by activating vasorelaxation and allowing migration and angiogenesis. In this review, we will overview current literature on these topics and we will try to convince the reader of the importance of vascular integrity and nitric oxide production in determining healthy aging.

20.
Nutrients ; 14(17)2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36079922

RESUMO

Longevity is rightly considered one of the greatest achievements of modern society. Biomedical research has shown that aging is the major risk factor for many diseases, so to find the right answers to aging it is necessary to identify factors that can positively influence longevity. This study investigated the clinical status, nutritional behavior, lifestyle, and social and community determinants of the well-being of young older adults and nonagenarians/centenarians in Salerno and province through the judgment of their physicians. Data were collected through an online survey. Multivariate Poisson and logistic regression models were used to calculate significant predictors of the outcomes of interest. The interesting finding was that cardiovascular disease was a risk factor for young older adults, while it was a protective factor for nonagenarians/centenarians, meaning that as age increased, heart problems tended to decrease. Certain foods were found to be a significant protective factor for both young older adult and nonagenarian-centenarian patients. In addition, psychosomatic disorders were found to be determinant for the young older adults, while depression was a risk factor for the nonagenarians/centenarians because they were not always gratified by their long lives and often felt like a burden on the family. The protective significant variable among the determinants of community well-being for both young older adults and nonagenarians/centenarians was the retention of honorary achievement. Based on our results, we are able to support the hypothesis of a difference between the young older adults and the nonagenarians/centenarians in clinical status, nutritional behaviors, lifestyle, and determinants of community well-being. However, societies need more social and educational programs that are able to build "a new idea of old age" by improving and supporting the young older adults and the nonagenarians/centenarians, with the goal of intergenerational solidarity, well-being, and social inclusion, as well as preventive interventions on lifestyles and nutrition, which will allow us to provide a new key to understanding aging.


Assuntos
Estado Nutricional , Médicos , Idoso , Idoso de 80 Anos ou mais , Centenários , Estudos Transversais , Humanos , Estilo de Vida , Nonagenários
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