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1.
Biosci Biotechnol Biochem ; 88(2): 168-176, 2024 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-38093456

RESUMO

Among the branched-chain amino acids, leucine and isoleucine have been well studied for their roles in improving mitochondrial function and reducing oxidative stress. However, role of valine in mitochondrial function regulation and oxidative stress management remains elusive. This study investigated valine effect on mitochondrial function and oxidative stress in vitro. Valine increased expression of genes involved in mitochondrial biogenesis and dynamics. It upregulates mitochondrial function at complexes I, II, and IV levels of electron transport chain. Flow cytometry studies revealed, valine reduced oxidative stress by significantly lowering mitochondrial reactive oxygen species and protein expression of 4-hydroxynonenal. Functional role of valine against oxidative stress was analyzed by XFe96 Analyzer. Valine sustained oxidative phosphorylation and improved ATP generation rates during oxidative stress. In conclusion, our findings shed more light on the critical function of valine in protecting mitochondrial function thereby preventing mitochondrial/cellular damage induced by oxidative stress.


Assuntos
Aminoácidos de Cadeia Ramificada , Valina , Valina/farmacologia , Valina/metabolismo , Aminoácidos de Cadeia Ramificada/metabolismo , Isoleucina/metabolismo , Isoleucina/farmacologia , Leucina/metabolismo , Estresse Oxidativo , Mitocôndrias/metabolismo
2.
Int J Mol Sci ; 24(2)2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36674463

RESUMO

Porphyromonas gingivalis (P. gingivalis), a key pathogen in periodontitis, is associated with neuroinflammation. Periodontal disease increases with age; 70.1% of adults 65 years and older have periodontal problems. However, the P. gingivalis- lipopolysaccharide (LPS)induced mitochondrial dysfunction in neurodegenerative diseases remains elusive. In this study, we investigated the possible role of P. gingivalis-LPS in mitochondrial dysfunction during neurodegeneration. We found that P. gingivalis-LPS treatment activated toll-like receptor (TLR) 4 signaling and upregulated the expression of Alzheimer's disease-related dementia and neuroinflammatory markers. Furthermore, the LPS treatment significantly exacerbated the production of reactive oxygen species and reduced the mitochondrial membrane potential. Our study highlighted the pivotal role of P. gingivalis-LPS in the repression of serum response factor (SRF) and its co-factor p49/STRAP that regulate the actin cytoskeleton. The LPS treatment repressed the genes involved in mitochondrial function and biogenesis. P. gingivalis-LPS negatively altered oxidative phosphorylation and glycolysis and reduced total adenosine triphosphate (ATP) production. Additionally, it specifically altered the mitochondrial functions in complexes I, II, and IV of the mitochondrial electron transport chain. Thus, it is conceivable that P. gingivalis-LPS causes mitochondrial dysfunction through oxidative stress and inflammatory events in neurodegenerative diseases.


Assuntos
Lipopolissacarídeos , Doenças Neuroinflamatórias , Humanos , Adulto , Lipopolissacarídeos/farmacologia , Transdução de Sinais , Porphyromonas gingivalis/metabolismo , Estresse Oxidativo , Mitocôndrias/metabolismo
3.
Int J Mol Sci ; 23(19)2022 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-36232837

RESUMO

CCG-1423 is a Rho A pathway inhibitor that has been reported to inhibit Rho/SRF-mediated transcriptional regulation. Serum response factor and its cofactors, which include ternary complex factors and myocardin-related transcription factors, regulate various cellular functions. In this study, we observed that CCG-1423 modulates the mitochondrial functions. The effect of this small molecule drug was determined by measuring mitochondrial function using an XFe96 Analyzer and an Oxygraph 2k (O2k) high-resolution respirometer. CCG-1423 treatment significantly reduced oxidative phosphorylation in a dose-dependent manner. However, CCG-1423 increased the glycolytic rate. We also observed that histone 4 at lysine-16 underwent hyperacetylation with the treatment of this drug. Immunolabeling with F-actin and MitoTracker revealed the alteration in the actin cytoskeleton and mitochondria. Taken together, our findings highlight a critical role of CCG-1423 in inhibiting the transcription of SRF/p49 and PGC-1α, ß, resulting in the downregulation of mitochondrial genes, leading to the repression of mitochondrial oxidative phosphorylation and overall ATP reduction. This study provides a better understanding of the effects of CCG-1423 on mitochondria, which may be useful for the assessment of the potential clinical application of CCG-1423 and its derivatives.


Assuntos
Actinas , Fator de Resposta Sérica , Actinas/metabolismo , Trifosfato de Adenosina , Anilidas , Benzamidas , Histonas , Lisina , Mitocôndrias/metabolismo , Fatores de Complexo Ternário/metabolismo , Fatores de Transcrição/metabolismo
4.
Int J Mol Sci ; 22(2)2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33418837

RESUMO

Alternative splicing generates multiple distinct isoforms that increase transcriptome and proteome diversity. There are seven sirtuin genes in humans, each consists of multiple exons that are likely to undergo alternative splicing. Our aim was to characterize the effect of alternative splicing on the sirtuin genes. Here, we report the identification of 23 human sirtuin isoforms, most of which were not previously reported. Five of the sirtuin genes had more than one isoform, whereas sirtuin-6 had nine isoforms. Exon skipping was the main event. Most of the sirtuin isoforms were deficient in parts of the protein domains, including the catalytic domain, the N- or C-terminus, nuclear localization signal or mitochondrial targeting signal. The domain loss caused potential structural changes. Three SIRT1 isoforms had a differential effect on the mitochondrial oxygen consumption rate. Age-related changes in the expression of SIRT1 isoforms were observed in the human heart in fetus, adults, and very old individuals. We also identified 15 sirtuin isoforms in mice. Our data indicate that alternative splicing increases sirtuin gene diversity and may modulate subcellular localization and function, thereby adding complexity to the gene regulation of mitochondrial respiration, metabolism, and cardiac function during maturation and aging.


Assuntos
Variação Genética , Sirtuínas/genética , Processamento Alternativo , Animais , Éxons , Loci Gênicos , Genoma , Humanos , Camundongos , Mitocôndrias/metabolismo , Miocárdio/metabolismo , Domínios Proteicos , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Estrutura Terciária de Proteína , RNA Mensageiro/metabolismo , Sirtuínas/química , Sirtuínas/metabolismo , Zinco/química , Zinco/metabolismo
5.
BMC Cell Biol ; 15: 32, 2014 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-25183317

RESUMO

BACKGROUND: The protein p49/STRAP (SRFBP1) is a transcription cofactor of serum response factor (SRF) which regulates cytoskeletal and muscle-specific genes. RESULTS: Two conserved domains were found in the p49/STRAP protein. The SRF-binding domain was at its N-terminus and was highly conserved among mammalian species, xenopus and zebrafish. A BUD22 domain was found at its C-terminus in three sequence databases. The BUD22 domain was conserved among mammalian p49/STRAP proteins, and yeast cellular morphogenesis proteins, which is involved in ribosome biogenesis that affects growth rate and cell size. The endogenous p49/SRAP protein was localized mainly in the nucleus but also widely distributed in the cytoplasm, and was in close proximity to the actin. Transfected GFP-p49/STRAP protein co-localized with nucleolin within the nucleolus. Overexpression of p49/STRAP reduced actin content in cultured cells and resulted in smaller cell size versus control cells. Increased expression of p49/STRAP in transgenic mice resulted in newborns with malformations, which included asymmetric abdominal and thoracic cavities, and substantial changes in cardiac morphology. p49/STRAP altered the expression of certain muscle-specific genes, including that of the SRF gene, which is a key regulator of cardiac genes at the developmental, structural and maintenance level and has two SRE binding sites. CONCLUSIONS: Since p49/STRAP is a co-factor of SRF, our data suggest that p49/STRAP likely regulates cell size and morphology through SRF target genes. The function of its BUD22 domain warrants further investigation. The observed increase in p49/STRAP expression during cellular aging may contribute to observed morphological changes in senescence.


Assuntos
Camundongos/anatomia & histologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Citoesqueleto de Actina/metabolismo , Animais , Animais Recém-Nascidos , Linhagem Celular , Tamanho Celular , Regulação da Expressão Gênica , Camundongos/embriologia , Camundongos/genética , Camundongos Transgênicos , Estrutura Terciária de Proteína , Fator de Resposta Sérica/genética , Fatores de Transcrição/análise , Regulação para Cima
6.
J Ark Med Soc ; 110(8): 160-3, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24511859

RESUMO

Alzheimer's disease (AD) affects approximately 5.3 million Americans. Recently, new diagnostic criteria advanced by the National Institute of Aging have significantly improved our understanding of the AD continuum across several stages and is more scientifically based compared to the previously formulated criteria in 1984. Use by primary care physicians of these new clinical criteria coupled with the understanding of the role of biomarkers will help you to make accurate diagnoses earlier in the disease process when intervention can be most beneficial.


Assuntos
Doença de Alzheimer/diagnóstico , Disfunção Cognitiva/diagnóstico , Médicos de Atenção Primária , Atenção Primária à Saúde/métodos , Idoso , Diagnóstico Diferencial , Feminino , Humanos , Masculino
7.
Cells ; 13(5)2024 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-38474356

RESUMO

RhoA-regulated gene transcription by serum response factor (SRF) and its transcriptional cofactor myocardin-related transcription factors (MRTFs) signaling pathway has emerged as a promising therapeutic target for pharmacological intervention in multiple diseases. Altered mitochondrial metabolism is one of the major hallmarks of cancer, therefore, this upregulation is a vulnerability that can be targeted with Rho/MRTF/SRF inhibitors. Recent advances identified a novel series of oxadiazole-thioether compounds that disrupt the SRF transcription, however, the direct molecular target of these compounds is unclear. Herein, we demonstrate the Rho/MRTF/SRF inhibition mechanism of CCG-203971 and CCG-232601 in normal cell lines of human lung fibroblasts and mouse myoblasts. Further studies investigated the role of these molecules in targeting mitochondrial function. We have shown that these molecules hyperacetylate histone H4K12 and H4K16 and regulate the genes involved in mitochondrial function and dynamics. These small molecule inhibitors regulate mitochondrial function as a compensatory mechanism by repressing oxidative phosphorylation and increasing glycolysis. Our data suggest that these CCG molecules are effective in inhibiting all the complexes of mitochondrial electron transport chains and further inducing oxidative stress. Therefore, our present findings highlight the therapeutic potential of CCG-203971 and CCG-232601, which may prove to be a promising approach to target aberrant bioenergetics.


Assuntos
Fator de Resposta Sérica , Fatores de Transcrição , Camundongos , Humanos , Animais , Fator de Resposta Sérica/metabolismo , Fatores de Transcrição/metabolismo , Transdução de Sinais , Linhagem Celular , Mitocôndrias/metabolismo
8.
Pathol Res Pract ; 257: 155309, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38678848

RESUMO

Gene expression of formalin-fixed paraffin-embedded (FFPE) tissue may serve for molecular studies on cardiovascular diseases. Chemotherapeutics, such as doxorubicin (DOX) may cause heart injury, but the mechanisms of these side effects of DOX are not well understood. This study aimed to investigate whether DOX-induced gene expression in archival FFPE heart tissue in experimental rats would correlate with the gene expression in fresh-frozen heart tissue by applying RNA sequencing technology. The results showed RNA from FFPE samples was degraded, resulting in a lower number of uniquely mapped reads. However, DOX-induced differentially expressed genes in FFPE were related to molecular mechanisms of DOX-induced cardiotoxicity, such as inflammation, calcium binding, endothelial dysfunction, senescence, and cardiac hypertrophy signaling. Our data suggest that, despite the limitations, RNA sequencing of archival FFPE heart tissue supports utilizing FFPE tissues from retrospective studies on cardiovascular disorders, including DOX-induced cardiotoxicity.


Assuntos
Cardiotoxicidade , Doxorrubicina , Formaldeído , Inclusão em Parafina , Análise de Sequência de RNA , Transcriptoma , Animais , Cardiotoxicidade/genética , Formaldeído/toxicidade , Doxorrubicina/efeitos adversos , Análise de Sequência de RNA/métodos , Ratos , Masculino , Fixação de Tecidos/métodos , Miocárdio/patologia , Miocárdio/metabolismo , Perfilação da Expressão Gênica/métodos , Ratos Sprague-Dawley
9.
Geroscience ; 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38507186

RESUMO

Chronic periodontitis and its keystone pathogen, Porphyromonas gingivalis, have increasingly been linked with Alzheimer's disease (AD). However, P.gingivalis-lipopolysaccharide (LPS) mediated release of neuroinflammatory proteins contributes to AD remains underexplored. In this study, we utilized data-independent acquisition mass spectrometry to characterize P.gingivalis-LPS induced profile of differentially expressed proteins associated with the neuroinflammatory response in human neuroblastoma (SH-SY5Y) and human microglial (HMC3) cells. We reported a set of 124 proteins in SH-SY5Y cells and 96 proteins in HMC3 cells whose levels were significantly upregulated or downregulated by exposure to P. gingivalis-LPS. Our findings demonstrate that P. gingivalis-LPS contributed to the elevated expressions of dementia biomarkers and pro-inflammatory cytokines that include APP, Aß1-42, Aß1-40, T-Tau, p-Tau, VEGF, TGF-ß, IL-1ß, IL-6 and TNF-α through 2 distinct pathways of extracellular sensing by cell surface receptors and intracellular cytosolic receptors. Interestingly, intracellular signaling proteins activated with P. gingivalis-LPS transfection using Lipofectamine™ 2000 had significantly higher fold change protein expression compared to the extracellular signaling with P. gingivalis-LPS treatment. Additionally, we also explored P. gingivalis-LPS mediated activation of caspase-4 dependent non canonical inflammasome pathway in both SH-SY5Y and HMC3 cells. In summary, P. gingivalis-LPS induced neuroinflammatory protein expression in SH-SY5Y and HMC3 cells, provided insights into the specific inflammatory pathways underlying the potential link between P. gingivalis-LPS infection and the pathogenesis of Alzheimer's disease and related dementias.

10.
Biology (Basel) ; 13(3)2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38534442

RESUMO

Interleukin-1ß converting enzyme (ICE, caspase-1) is a thiol protease that cleaves the pro-inflammatory cytokine precursors of IL-1ß and IL-18 into active forms. Given the association between caspase-1 and cardiovascular pathology, we analyzed the hearts of ICE knockout (ICE KO) mice to test the hypothesis that caspase-1 plays a significant role in cardiac morphology and function. We characterized the histological and functional changes in the hearts of ICE KO mice compared to the Wild type. The cardiomyocytes from the neonatal ICE KO mice showed an impaired response to oxidative stress. Subsequently, the hearts from the ICE KO mice were hypertrophied, with a significant increase in the left ventricular and septal wall thickness and a greater LV mass/body weight ratio. The ICE KO mice hearts exhibited irregular myofibril arrangements and disruption of the cristae in the mitochondrial structure. Proapoptotic proteins that were significantly increased in the hearts of ICE KO versus the Wild type included pErk, pJNK, p53, Fas, Bax, and caspase 3. Further, the antiapoptotic proteins Bag-1 and Bcl-2 are activated in ICE KO hearts. Functionally, there was an increase in the left ventricular epicardial diameter and volume in ICE KO. In conclusion, our findings support the important role of caspase-1 in maintaining cardiac health; specifically, a significant decrease in caspase-1 is detrimental to the cardiovascular system.

11.
Mol Nutr Food Res ; 68(6): e2300716, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38426663

RESUMO

SCOPE: Dietary proteins and essential amino acids (EAAs) are the major nutritional supplements that support the growth and activity of gut microbes contributing to the wellbeing of their host. This study hypothesizes that daily supplementation of the diet with either EAAs or whey protein for 12 weeks would improve the gut microbiome of older adults. METHODS AND RESULTS: The stool samples are processed and subjected to Illumina-based 16S ribosomal ribonucleic acid (rRNA) gene amplicon sequencing. In both groups, the most abundant families are found in order of relative abundance included: Bacteroidaceae, Lachnospiraceae, Ruminococcaceae, Prevotellaceae, Rikenellaceae, Enterobacteriaceae, Oscillospiraceae, Tannerellaceae, and Akkermansiaceae, which indicate that these subjects are able to maintain a same healthy microbial diversity in their guts. A significant finding is a reduction of proinflammatory cytokine, interleukin-18 (IL-18) in the EAAs group. It also uses the standard 6-min walking test (6MWT) as a measure of cardiopulmonary fitness. At the end of the study, the subjects in the EAAs group perform significantly better in the 6MWT as compared to the whey group. CONCLUSION: It seems plausible that the improved physical performance and reduced proinflammatory cytokine, IL-18 seen in the EAAs group, are independent of changes in gut microbiota.


Assuntos
Microbioma Gastrointestinal , Humanos , Idoso , Proteínas do Soro do Leite , Interleucina-18 , Suplementos Nutricionais , Aminoácidos Essenciais , Ingestão de Alimentos , RNA Ribossômico 16S
12.
Am J Case Rep ; 24: e938344, 2023 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-37016564

RESUMO

BACKGROUND Dementia with Lewy bodies (DLB) is a common cause of dementia. Given the similarities between the symptoms of DLB and non-DLB Alzheimer disease (AD) and related dementias, patients can sometimes be misdiagnosed with AD. To increase the sensitivity of current DLB guidelines, the DLB Consortium published its fourth revised report in 2017 with increased diagnostic weight given to dopamine transporter (DAT) uptake in the basal ganglia, demonstrated by single-photon emission computed tomography or positron emission tomography imaging. We aimed to describe the role of DAT scans in evaluating dopamine deficiency in patients with overlapping symptoms of AD and DLB. CASE REPORT We present case studies of 3 patients with memory impairment who had a diagnosis of probable AD and were being treated with cholinesterase inhibitors. During treatment, dopamine deficiency was suspected and DAT scans were performed. All 3 patients revealed severe DAT deficits in the bilateral corpus striatum. These results were consistent with probable DLB as per the current revised DLB Consortium report. All patients received treatment with carbidopa/levodopa and demonstrated improved overall function. CONCLUSIONS All 3 of our cases demonstrated the role of DAT scans in evaluating dopamine deficiency syndromes in patients with overlapping symptoms of neurocognitive disorders. Thus, a DAT scan is critical for establishing an earlier and more definitive diagnosis of DLB, which provides treatment options for dopamine replacement. It also assists providers with prognostication of dopamine deficiency syndromes and is therefore beneficial in counseling patients and caregivers.


Assuntos
Doença de Alzheimer , Doença por Corpos de Lewy , Humanos , Doença por Corpos de Lewy/diagnóstico por imagem , Doença por Corpos de Lewy/tratamento farmacológico , Dopamina , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/tratamento farmacológico , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Tomografia por Emissão de Pósitrons
13.
Geroscience ; 45(3): 1729-1743, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36720768

RESUMO

In a recent randomized, double-blind, placebo-controlled trial, we were able to demonstrate the superiority of a dietary supplement composed of essential amino acids (EAAs) over whey protein, in older adults with low physical function. In this paper, we describe the comparative plasma protein expression in the same subject groups of EAAs vs whey. The plasma proteomics data was generated using SOMA scan assay. A total of twenty proteins were found to be differentially expressed in both groups with a 1.5-fold change. Notably, five proteins showed a significantly higher fold change expression in the EAA group which included adenylate kinase isoenzyme 1, casein kinase II 2-alpha, Nascent polypeptide-associated complex subunit alpha, peroxiredoxin-1, and peroxiredoxin-6. These five proteins might have played a significant role in providing energy for the improved cardiac and muscle strength of older adults with LPF. On the other hand, fifteen proteins showed slightly lower fold change expression in the EAA group. Some of these 15 proteins regulate metabolism and were found to be associated with inflammation or other comorbidities. Gene Ontology (GO) enrichment analysis showed the association of these proteins with several biological processes. Furthermore, protein-protein interaction network analysis also showed distinct networks between upregulated and downregulated proteins. In conclusion, the important biological roles of the upregulated proteins plus better physical function of participants in the EAAs vs whey group demonstrated that EAAs have the potential to improve muscle strength and physical function in older adults. This study was registered with ClinicalTrials.gov: NCT03424265 "Nutritional interventions in heart failure."


Assuntos
Aminoácidos Essenciais , Suplementos Nutricionais , Humanos , Idoso , Proteínas do Soro do Leite , Proteínas Sanguíneas , Ingestão de Alimentos
14.
J Biomed Sci ; 18: 15, 2011 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-21303526

RESUMO

Serum response factor (SRF) regulates certain microRNAs that play a role in cardiac and skeletal muscle development. However, the role of SRF in the regulation of microRNA expression and microRNA biogenesis in cardiac hypertrophy has not been well established. In this report, we employed two distinct transgenic mouse models to study the impact of SRF on cardiac microRNA expression and microRNA biogenesis. Cardiac-specific overexpression of SRF (SRF-Tg) led to altered expression of a number of microRNAs. Interestingly, downregulation of miR-1, miR-133a and upregulation of miR-21 occurred by 7 days of age in these mice, long before the onset of cardiac hypertrophy, suggesting that SRF overexpression impacted the expression of microRNAs which contribute to cardiac hypertrophy. Reducing cardiac SRF level using the antisense-SRF transgenic approach (Anti-SRF-Tg) resulted in the expression of miR-1, miR-133a and miR-21 in the opposite direction. Furthermore, we observed that SRF regulates microRNA biogenesis, specifically the transcription of pri-microRNA, thereby affecting the mature microRNA level. The mir-21 promoter sequence is conserved among mouse, rat and human; one SRF binding site was found to be in the mir-21 proximal promoter region of all three species. The mir-21 gene is regulated by SRF and its cofactors, including myocardin and p49/Strap. Our study demonstrates that the downregulation of miR-1, miR-133a, and upregulation of miR-21 can be reversed by one single upstream regulator, SRF. These results may help to develop novel therapeutic interventions targeting microRNA biogenesis.


Assuntos
Cardiomegalia/metabolismo , MicroRNAs/metabolismo , Miocárdio/metabolismo , Fator de Resposta Sérica/metabolismo , Sequência de Aminoácidos , Animais , Cardiomegalia/genética , Sequência Conservada , Regulação para Baixo , Regulação da Expressão Gênica , Humanos , Camundongos , Camundongos Transgênicos , MicroRNAs/genética , Miocárdio/patologia , Proteínas Nucleares/metabolismo , Ratos , Fator de Resposta Sérica/genética , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Regulação para Cima
15.
Am J Cancer Res ; 11(9): 4070-4091, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34659877

RESUMO

Doxorubicin (DOX) is a highly effective chemotherapy agent that often causes cardiotoxicity. Despite a number of extensive studies, the risk for DOX cardiotoxicity remains unpredictable. The majority of the studies on DOX-induced cardiotoxicity have been focused on the effects on cardiomyocytes that lead to contractile dysfunction. The roles of systemic inflammation, endothelial injury and neutrophil recruitment, all induced by the DOX, are increasingly recognized as the mechanisms that trigger the development and progression of DOX-induced cardiomyopathy. This review explores recent data regarding the possible mechanisms and biomarkers of early subclinical DOX-associated cardiotoxicity.

16.
Gerontol Geriatr Med ; 7: 23337214211018933, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34104686

RESUMO

Cardiovascular disease is a common comorbidity associated with an aging population. However, there is a unique group of individuals whose age-defying qualities are still being investigated. This retrospective chart review analyzed various cardiac and metabolic health parameters to characterize the prevalence of heart failure and metabolic derangements in individuals aged 90 years old or older in central Arkansas. Only 236 of the 291 patients in our study cohort had blood pressures recorded. Of these, 50% had systolic blood pressures ≥140 mmHg. Additionally, 77% had pulse pressures ≥50 mmHg. Of the 96 patients with BNP data, 44% had values ≥300 pg/mL. There was a slight positive correlation between aging and HDL cholesterol, while there was a negative correlation between aging and both total cholesterol and LDL cholesterol. A majority of our patients had both elevated systolic blood pressures and elevated pulse pressures. A majority also had high BNP values, indicative of some degree of heart failure. Additionally, atrial fibrillation was a common arrhythmia identified on EKG. However, these oldest of the old patients had fewer documented metabolic derangements. These findings lay important groundwork for further investigation into lifestyle and genetic components that allow them to live exceptionally long with such comorbidities.

17.
Geriatr Orthop Surg Rehabil ; 12: 21514593211036231, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34395047

RESUMO

INTRODUCTION: Public health achievements throughout the last century have resulted in a steady increase in life expectancy. An emergent subset has distinguished themselves, living well beyond the ninth decade by avoiding or delaying the onset of most age-related diseases, including bone diseases and fractures. In this study, we evaluated the bone health of the oldest community-dwelling individuals living in rural Arkansas. METHODS: 299 patients aged ≥90 years were retrospectively reviewed for recorded fractures within 12 years prior to the investigation period. Records were also examined for medications and test results pertinent to bone health, including thyroid stimulating hormone, vitamin D levels, hematocrit, hemoglobin, body mass index, and bone densitometric values. RESULTS: 68 patients (23%) had at least one fracture documented, and 15 had >1 fracture. 40% of patients with fractures had osteoporosis and 28% had osteopenia, respectively. 232 patients (78%) had no documented fractures, and of these, only 18% had osteoporosis and 16% had osteopenia. No significant clinical markers were found among the very old to explain the relatively low occurrence of fractures. CONCLUSIONS: Patients over 90 years of age had an overall low prevalence of fractures and relative preservation of bone health, suggesting a preserved bone molecular profile in these individuals. Epigenetic factors and activity levels might also have favorably affected bone health. The low percentage of osteoporosis and fractures likely reduced the morbidity and mortality in this population, potentially contributing to their overall longevity.

18.
J Gerontol A Biol Sci Med Sci ; 76(7): 1184-1191, 2021 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-33475727

RESUMO

We have investigated the hypothesis that nutritional supplementation of the diet in low-physical-functioning older individuals with a specially formulated composition based on essential amino acids (EAAs) would improve physical function as compared to supplementation with the same amount of whey protein. A third group of comparable volunteers were given nutrition education but no supplementation of the diet. After 6 weeks of whey protein supplementation (n = 32), there was no effect on the distance walked in 6 minutes, but the distance walked improved significantly from the pre-value after 12 weeks of whey supplementation. EAA consumption (n = 28) significantly improved walking distance at both 6 and 12 weeks. The distance walked at 12 weeks (419.0 ± 25.0 m) was 35.4 m greater than the pre-value of 384.0 ± 23.0 m (p < .001). The increase in distance walked by the EAA group was also significantly greater than that in the whey group at both 6 and 12 weeks (p < .01). In contrast, a decrease in distance walked was observed in the control group (n = 32) (not statistically significant, NS). EAA supplementation also improved grip strength and leg strength, and decreased body weight and fat mass. Plasma low-density lipoprotein concentration was significantly reduced in the EAA group, as well as the concentration of macrophage migration inhibitory factor. There were no adverse responses in any groups, and compliance was greater than 95% in all individuals consuming supplements. We conclude that dietary supplementation with an EAA-based composition may be a beneficial therapy in older individuals with low physical functional capacity. Clinical Trials Registration Number: This study was registered with ClinicalTrials.gov: NCT03424265-"Nutritional interventions in heart failure."


Assuntos
Aminoácidos Essenciais/administração & dosagem , Doenças Cardiovasculares/fisiopatologia , Desempenho Físico Funcional , Proteínas do Soro do Leite/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Suplementos Nutricionais , Método Duplo-Cego , Feminino , Avaliação Geriátrica , Humanos , Masculino
19.
Cancers (Basel) ; 13(24)2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34944912

RESUMO

Chemotherapy with doxorubicin (DOX) may cause unpredictable cardiotoxicity. This study aimed to determine whether the methylation signature of peripheral blood mononuclear cells (PBMCs) prior to and after the first cycle of DOX-based chemotherapy could predict the risk of cardiotoxicity in breast cancer patients. Cardiotoxicity was defined as a decrease in left ventricular ejection fraction (LVEF) by >10%. DNA methylation of PBMCs from 9 patients with abnormal LVEF and 10 patients with normal LVEF were examined using Infinium HumanMethylation450 BeadChip. We have identified 14,883 differentially methylated CpGs at baseline and 18,718 CpGs after the first cycle of chemotherapy, which significantly correlated with LVEF status. Significant differentially methylated regions (DMRs) were found in the promoter and the gene body of SLFN12, IRF6 and RNF39 in patients with abnormal LVEF. The pathway analysis found enrichment for regulation of transcription, mRNA splicing, pathways in cancer and ErbB2/4 signaling. The preliminary results from this study showed that the DNA methylation profile of PBMCs may predict the risk of DOX-induced cardiotoxicity prior to chemotherapy. Further studies with larger cohorts of patients are needed to confirm these findings.

20.
Gerontol Geriatr Med ; 6: 2333721420982808, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33426179

RESUMO

Approximately half of heart failure patients in the US have heart failure with preserved ejection fraction (HFpEF). HFpEF impairs physical performance and thus reduces quality of life. Increasing dietary protein intake can increase lean body mass and physical performance in healthy elderly individuals, but the effect of a high-quality protein supplement, with or without a structured exercise program, has not been investigated in HFpEF patients. Twenty-three obese elderly HFpEF patients with grade 1 or 2 diastolic dysfunction were randomized into three groups: control, protein supplementation alone, and protein plus exercise. Protein supplementation involved providing sufficient whey protein so that total intake was 1.2 g protein/kg/day. The exercise intervention was 2 days of hydrotherapy and 1 day of gym sessions per week under supervision of a fitness expert. Physical parameters and functional tests were performed at baseline and at 12 weeks. Protein supplementation alone failed to improve physical performance. However, when combined with light exercise, there was significant improvement in some (6-minute walk, 10 m walking speed, quadriceps strength), but not all, physical function measurements. The results of this pilot study suggest that further exploration of potential interactive effects between protein supplementation and light exercise in individuals with HFpEF is warranted.

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