Abordagem de Bioinformática e Biologia de Sistemas para Identificar a Ligação Patogenética entre Insuficiência Cardíaca e Sarcopenia / Bioinformatics and Systems Biology Approach to Identify the Pathogenetic Link between Heart Failure and Sarcopenia

Resumo Fundamento Apesar das evidências crescentes de que pacientes com insuficiência cardíaca (IC) são suscetíveis à sarcopenia, o motivo da associação não é bem compreendido. Objetivo O objetivo deste estudo é explorar ainda mais o mecanismo molecular de ocorrência desta complicação. Métodos Conjuntos de dados de expressão gênica para HF (GSE57345) e Sarcopenia (GSE1428) foram obtidos do banco de dados Gene Expression Omnibus (GEO). Genes diferencialmente expressos (DEGs) foram identificados usando pacotes 'edgeR' e "limma" de R, e suas funções foram analisadas usando Gene Ontology (GO) e a Enciclopédia de Genes e Genomas de Kyoto (KEGG). Redes de interação proteína-proteína (PPI) foram construídas e visualizadas usando Search Tool for the Retrieval of Interacting Genes (STRING) e Cytoscape. Os genes hub foram selecionados usando o plugin cytoHubba e validados com GSE76701 para IC e GSE136344 para Sarcopenia. As vias relacionadas e os mecanismos moleculares dos genes hub foram realizados pela análise de enriquecimento de genes (GSEA). As análises estatísticas foram realizadas no software R. P < 0,05 foi considerado estatisticamente significativo. Resultados Foram encontrados 114 DEGs comuns. As vias relacionadas ao fator de crescimento, secreção de insulina e cGMP-PKG estavam enriquecidas tanto na IC quanto na sarcopenia. Descobriu-se que CYP27A1, KCNJ8, PIK3R5, TIMP2, CXCL12, KIT e VCAM1 são genes hub significativos após validação com GSEA enfatizando a importância dos genes hub na regulação da resposta inflamatória. Conclusão Nosso estudo revela que a IC e a Sarcopenia compartilham vias e mecanismos patogênicos comuns. Estes achados podem sugerir novas direções para pesquisas futuras sobre a patogênese subjacente.

Abstract Background Despite increasing evidence that patients with heart failure (HF) are susceptible to sarcopenia, the reason for the association is not well understood. Objective The purpose of this study is to explore further the molecular mechanism of the occurrence of this complication. Methods Gene expression datasets for HF (GSE57345) and Sarcopenia (GSE1428) were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified using 'edgeR' and "limma" packages of R, and their functions were analyzed using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Protein-protein interaction (PPI) networks were constructed and visualized using Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape. Hub genes were selected using the plugin cytoHubba and validation with GSE76701 for HF and GSE136344 for Sarcopenia. The related pathways and molecular mechanisms of the hub genes were performed by Gene set enrichment analysis (GSEA). The statistical analyses were performed using R software. P < 0.05 was considered statistically significant. Results A total of 114 common DEGs were found. Pathways related to growth factor, Insulin secretion and cGMP-PKG were enriched in both HF and Sarcopenia. CYP27A1, KCNJ8, PIK3R5, TIMP2, CXCL12, KIT, and VCAM1 were found to be significant hub genes after validation, with GSEA emphasizing the importance of the hub genes in the regulation of the inflammatory response. Conclusion Our study reveals that HF and Sarcopenia share common pathways and pathogenic mechanisms. These findings may suggest new directions for future research into the underlying pathogenesis.

Circulating miRNA-1-3p as Biomarker of Accelerated Sarcopenia in Patients Diagnosed with Chronic Heart Failure

ABSTRACT Background: While sarcopenia is an important clinical finding in individuals diagnosed with chronic heart failure (CHF), efforts to identify a reliable biomarker capable of predicting the overall muscular and functional decline in CHF patients have been unsuccessful to date. Objectives: The objectives of this study were to study the diagnostic utility of MicroRNA (miRNA)-1-3p as a predictor of sarcopenia status in individuals diagnosed with CHF. Methods: In total, 80 individuals with heart failure exhibiting a left ventricular ejection fraction < 50% were enrolled in this study. All patients were analyzed to assess miR-1-3p expression levels, with body composition being evaluated through dual-energy X-ray absorptiometry and sarcopenia being defined based on the sum of appendicular lean muscle mass (ALM) divided by height in meters squared and handgrip strength (HGS). In addition, the activation of the Akt/mTOR signaling pathway was evaluated in these individuals. Results: In total, 40 of the enrolled patients (50%) exhibited sarcopenia. Sarcopenic patients presented with increased miR-1-3p expression levels as compared to non-sarcopenic individuals (1.69 ± 0.132 vs. 1.22 ± 0.106; p < 0.05). With respect to sarcopenic indices, appendicular skeletal mass index was most strongly correlated with miR-1-3p expression, which was also strongly correlated with HGS. High levels of Akt/mTOR signaling pathway components were expressed in sarcopenic individuals, highlighting a significant relationship between miR-1-3p activity and signaling through this pathway. Moreover, miR-1-3p was identified as a specific marker for sarcopenia in individuals with CHF. Conclusion: These results suggest that circulating miR-1-3p levels are related to Akt/mTOR pathway activation and can offer valuable insight into the overall physical capacity and muscular integrity of CHF patients as a predictor of sarcopenia.

Association of bone mineral density with chronic obstructive pulmonary disease in postmenopausal women

Abstract Background Osteoporosis (OP) is common in patients with chronic obstructive pulmonary disease (COPD). The relationship between OP and COPD has been primarily studied in male patients, and few reports are available in postmenopausal women. Objective The purpose of this study was to investigate the association between bone mineral density (BMD) and COPD in postmenopausal women. Methods This cross-sectional study included 133 clinically stable female ex-smokers with confirmed COPD, and 31 age-matched “ex-smoker” female controls. We analyzed groups according to their airway obstruction category. BMD was measured on dual-energy X-ray absorptiometry images of the left femoral neck. Results Patients with COPD had lower T-scores and higher prevalence of osteopenia/OP than the control group. In the COPD group, the airway obstruction category was significantly associated with the T-score after adjustment for confounders. Multivariate logistic regression analysis showed COPD was an independent marker for increased risk of osteopenia/OP in postmenopausal women. Conclusions COPD and airway obstruction category were strongly related to BMD. Postmenopausal women with COPD, especially those with severe airway obstruction, had a higher prevalence rate and a higher risk of osteopenia and OP than female controls without COPD.

MicroRNA-383-5p inhibits the progression of gastric carcinoma via targeting HDAC9 expression

MicroRNAs (miRNAs), as post-transcriptional regulators, have been reported to be involved in the initiation and progression of various types of cancer, including gastric cancer (GC). The present study aimed to investigate the role of miR-383-5p in gastric carcinogenesis. Cell viability was analyzed using CCK-8 kit. Annexin V-fluorescein isothiocyanate/propidium iodide double staining was used to evaluate cell apoptosis. The expression levels of miR-383-5p and histone deacetylase 9 (HDAC9) mRNA in GC tissues and cell lines were analyzed using RT-qPCR. The protein expression of HDAC9 was detected by western blotting. We found that HDAC9 was up-regulated and miR-383-5p was down-regulated in GC tissues and cell lines. High HDAC9 expression or low miR-383-5p expression was closely related to poor prognosis and metastasis in GC patients. HDAC9 knockout or miR-383-5p mimics led to growth inhibition and increased apoptosis in AGS and SGC-7901 cells. More importantly, we validated that miR-383-5p as a post-transcriptional regulator inhibited HDAC9 expression and was inversely correlated with HDAC9 expression in GC tissues. miR-383-5p had the opposite effects to HDAC9 in gastric carcinogenesis. miR-383-5p played an important role in gastric carcinogenesis, and it is one of the important mechanisms to regulate oncogenic HDAC9 in GC, which might be helpful in the development of novel therapeutic strategies for the treatment of GC.

Association of Severity of Coronary Lesions with Bone Mineral Density in Postmenopausal Women / Associação entre Gravidade das Lesões Coronarianas e Densidade Mineral Óssea em Mulheres Pós-Menopausa

Abstract Background: Coronary artery disease (CAD) and osteoporosis (OP) are common diseases in postmenopausal women. In both cross-sectional and longitudinal epidemiologic studies, low bone mass has been related to increased frequency of CAD. However, available data on the relationship between bone mineral density (BMD) and severity of coronary lesions is limited. Objective: To investigate association between the BMD and severity of coronary lesions assessed by Gensini score in postmenopausal women. Methods: This study included 122 postmenopausal women who were diagnosed with CAD. These patients were divided into two groups according to the severity of coronary lesions assessed by the Gensini score - patients with mild coronary lesions (Gensini score < 25) and patients with severe coronary lesions (Gensini score ≥ 25). Femoral neck mineral density was measured with dual energy X-ray absorptiometry (DXA). Results: The study included postmenopausal women aged 64.31 ± 4.71 years, 85 of whom (69.7%) exhibited severe coronary lesions. Participants with severe coronary lesions had a significantly higher T score than did those with mild coronary lesions at the femoral neck (p < 0.05). The mean T-score was −0.84 ± 1.01 in mild coronary lesions group, −1.42 ± 1.39 in severe coronary lesions group (p < 0.05). Multivariable logistic regression analysis showed that osteopenia-osteoporosis at the Femoral neck (odds ratio 2.73; 95% confidence interval 1.06 to 6.13) was associated with an increased risk of developing severe coronary lesions. The multiple regression model showed that T-scores (b = −0.407, SE = 0.151, p=0.007) were the independent predictors of Gensini score. Conclusion: The relationship between severity of coronary lesions and BMD was significant in postmenopausal women. BMD, a low-cost technique involving minimal radiation exposure, widely used for osteoporosis screening, is a promising marker of severity of coronary lesions.

Resumo Fundamento: A doença arterial coronariana (DAC) e a osteoporose são doenças comuns em mulheres pós-menopausa. Tanto em estudos transversais como em estudos epidemiológicos longitudinais, a massa óssea diminuída foi relacionada à frequência aumentada de DAC. No entanto, dados disponíveis sobre a relação entre densidade mineral óssea (DMO) e gravidade das lesões coronarianas são limitados. Objetivo: Investigar a associação entre DMO e gravidade das lesões coronarianas avaliadas pelo escore de Gensini em mulheres pós-menopausa. Métodos: Este estudo incluiu 122 mulheres pós-menopausa diagnosticadas com DAC. As pacientes foram divididas em dois grupos de acordo com a gravidade das lesões coronarianas avaliada pelo escore de Gensini - pacientes com lesões coronarianas leves (escore de Gensini < 25) e pacientes com lesões coronarianas graves (escore de Gensini ≥ 25). A densidade mineral do colo femoral foi medida por absorção de raios-X de dupla energia (DXA). Resultados: O estudo incluiu mulheres pós-menopausa com idade de 64,31 ± 4,71 anos, 85 delas (69,7%) com lesões coronarianas graves. Pacientes com lesões coronarianas graves apresentaram um escore T mais elevado que aquelas com lesões coronarianas leves no colo femoral (p < 0,05). O escore T médio foi -0,84 ± 1,01 no grupo com lesões leves, e -1,42 ± 1,39 no grupo com lesões graves (p < 0,05). A análise de regressão logística multivariada mostrou que a osteopenia-osteoporose no colo femoral (odds ratio 2,73; intervalo de confiança de 95% 1,06 - 6,13) esteve associada com um risco aumentado de se desenvolver lesões coronarianas graves. O modelo de regressão múltipla mostrou que os escores T (b = -0,407; EP= 0,151; p = 0,007) foram preditores independentes do escore de Gensini. Conclusão: Encontrou-se uma relação significativa entre a gravidade das lesões coronarianas e a DMO em mulheres pós-menopausa. DMO, uma técnica de baixo custo que envolve mínima exposição à radiação, e amplamente utilizada no rastreamento de osteoporose, é um marcador promissor da gravidade de lesões coronarianas graves.

Development of a novel compound microbial agent for degradation of kitchen waste

Abstract Large quantities of kitchen waste are produced in modern society and its disposal poses serious environmental and social problems. The aim of this study was to isolate degradative strains from kitchen waste and to develop a novel and effective microbial agent. One hundred and four strains were isolated from kitchen waste and the 84 dominant strains were used to inoculate protein-, starch-, fat- and cellulose-containing media for detecting their degradability. Twelve dominant strains of various species with high degradability (eight bacteria, one actinomycetes and three fungi) were selected to develop a compound microbial agent "YH" and five strains of these species including H7 (Brevibacterium epidermidis), A3 (Paenibacillus polymyxa), E3 (Aspergillus japonicus), F9 (Aspergillus versicolor) and A5 (Penicillium digitatum), were new for kitchen waste degradation. YH was compared with three commercial microbial agents-"Tiangeng" (TG), "Yilezai" (YLZ) and Effective Microorganisms (EM), by their effects on reduction, maturity and deodorization. The results showed that YH exerted the greatest efficacy on mass loss which decreased about 65.87% after 14 days. The agent inhibited NH3 and H2S emissions significantly during composting process. The concentration of NH3 decreased from 7.1 to 3.2 ppm and that of H2S reduced from 0.7 to 0.2 ppm. Moreover, E4/E6 (Extinction value460nm/Extinction value665nm) of YH decreased from 2.51 to 1.31, which meant YH had an obvious maturity effect. These results highlighted the potential application of YH in composting kitchen waste.

Increased red cell distribution width in patients with slow coronary flow syndrome

OBJECTIVE: An elevated red cell distribution width has been recognized as a predictor of various cardiovascular diseases. Slow coronary flow syndrome is an important angiographic clinical entity with an unknown etiology. This study aimed to examine the relationship between red cell distribution width and the presence of slow coronary flow syndrome. METHODS: In total, 185 patients with slow coronary flow syndrome and 183 age- and gender-matched subjects with normal coronary flow (controls) were prospectively enrolled in this study. Red cell distribution width and C-reactive protein were measured upon admission, and the results were compared between the patients with slow coronary flow syndrome and normal controls. RESULTS: Red cell distribution width levels were significantly higher in the patients with slow coronary flow syndrome than the normal controls. Moreover, the data showed that the plasma C-reactive protein levels were also higher in the patients with slow coronary flow syndrome than in the normal controls. In addition, a multivariate analysis indicated that C-reactive protein and red cell distribution width were the independent variables most strongly associated with slow coronary flow syndrome. Finally, the red cell distribution width was positively correlated with C-reactive protein and mean thrombosis in the myocardial infarction frame counts of the patients with slow coronary flow syndrome. CONCLUSION: The data demonstrated that red cell distribution width levels are significantly higher and strongly positively correlated with both C-reactive protein and thrombosis in the myocardial infarction frame counts of patients with slow coronary flow syndrome. These findings suggest that red cell distribution width may be a useful marker for patients with slow coronary flow syndrome. .

TNNI3K is a novel mediator of myofilament function and phosphorylates cardiac troponin I

The phosphorylation of cardiac troponin I (cTnI) plays an important role in the contractile dysfunction associated with heart failure. Human cardiac troponin I-interacting kinase (TNNI3K) is a novel cardiac-specific functional kinase that can bind to cTnI in a yeast two-hybrid screen. The purpose of this study was to investigate whether TNNI3K can phosphorylate cTnI at specific sites and to examine whether the phosphorylation of cTnI caused by TNNI3K can regulate cardiac myofilament contractile function. Co-immunoprecipitation was performed to confirm that TNNI3K could interact with cTnI. Kinase assays further indicated that TNNI3K did not phosphorylate cTnI at Ser23/24 and Ser44, but directly phosphorylated Ser43 and Thr143 in vitro. The results obtained for adult rat cardiomyocytes also indicated that enhanced phosphorylation of cTnI at Ser43 and Thr143 correlated with rTNNI3K (rat TNNI3K) overexpression, and phosphorylation was reduced when rTNNI3K was knocked down. To determine the contractile function modulated by TNNI3K-mediated phosphorylation of cTnI, cardiomyocyte contraction was studied in adult rat ventricular myocytes. The contraction of cardiomyocytes increased with rTNNI3K overexpression and decreased with rTNNI3K knockdown. We conclude that TNNI3K may be a novel mediator of cTnI phosphorylation and contribute to the regulation of cardiac myofilament contraction function.