Search

Metabolic remodeling in heart failure (HF) is a type of overload cardiomyopathy caused by insufficient energy supply or an imbalance of glucose and lipid metabolism. Therefore, metabolic pathways may serve as potential targets for HF treatment. BRM-associated factor (BAF) 60c (also known as smarcd3) promotes the transformation of oxidative muscle fibers to glycolytic muscle fibers. Our study aimed to test whether BAF60c and the PGC1[alpha]--PPAR[alpha]--mTOR pathway interact to affect myocardial metabolism in HF rats. Established rat models of HF were injected with BAF60c low or overexpression plasmids to assess cardiac contractile proteins, energy metabolism, oxidative metabolism, glycolysis, high-energy phosphate content, mitochondrial function, and apoptosis. BAF60c overexpression/siRNA plasmid was transfected into H9C2 cells. These results suggest that HF rats present decreased levels of BAF60c, increased glycolysis, and reduced levels of cardiac contractile proteins, PGC1[alpha], PPAR[alpha], and oxidative metabolism. Overexpression of BAF60c maintained the balance between oxidative metabolism and glycolysis and activated the PGC1[alpha]-PPAR[alpha]-mTOR pathway. PGC1[alpha] interacted with BAF60c, and overexpression of PGC1[alpha] decreased BAF60c knockdown, damaging H9C2 cells. Collectively, overexpression of BAF60c activated the PGC1[alpha]-PPAR[alpha]-mTOR pathway, maintained the oxidative metabolism/glycolysis balance, and improved mitochondrial function in HF rats. This study offers novel insights into HF treatment. Key words: heart failure, oxidative metabolism/glycolysis equilibrium, mitochondrial function, BAF60c, PGC1[alpha]-PPARa-mTOR pathway, myocardial hypertrophy. BAF60c (BRM-associated factor 60c) favorise la glycolyse dans le muscle et ameliore l'homeostasie du glucose. Cette etude a explore le mecanisme d'action de BAF60c dans l'insuffisance cardiaque (IC). Des modeles d'insuffisance cardiaque chez le rat foetal/adulte ont ete etablis, et les niveaux de proteines contractiles cardiaques et de facteurs lies au metabolisme energetique, au metabolisme oxydatif et a la glycolyse ont ete detectes. Un plasmide de surexpression ou un petit ARNi de BAF60c ont ete injectes a des rats adultes atteints d'IC pour evaluer le captage de glucose par le myocarde, le contenu en phosphate a haute energie, la fonction mitochondriale, la proliferation cellulaire et l'apoptose. Le plasmide de surexpression ou le petit ARNi de BAF60c ont ete transfectes dans des cellules hypertrophiques cardiaques H9C2 afin d'en explorer les effets in vitro. L'interaction entre BAF60c et PGC1[alpha] a ete examinee. Les resultats suggeraient que les rats adultes atteints d'IC presentent des niveaux accrus de proteines foetales (ssTnI et fTnT), de BAF60c et de facteurs lies a la glycolyse, et des niveaux reduits de proteines contractiles cardiaques, de PGC1[alpha], de PPAR[alpha] et de facteurs lies au metabolisme oxydatif. La suppression de BAF60c ameliorait le captage du glucose, maintenait l'equilibre entre le metabolisme oxydatif et la glycolyse, favorisait la proliferation des cellules H9C2 et inhibait l'apoptose. PGC1[alpha] interagissait avec BAF60c. La suppression de BAF60c activait egalement la voie PGC1[alpha]/PPAR[alpha]/mTOR. La surexpression de PGC1[alpha] diminuait les dommages causes aux cellules H9C2 par BAF60c. Dans l'ensemble, la regulation a la baisse de BAF60c activait la voie PGC1[alpha]/PPAR[alpha]/mTOR, maintenait l'equilibre entre le metabolisme oxydatif et la glycolyse et ameliorait la fonction mitochondriale dans des modeles d'IC chez le rat. Cette etude peut offrir de nouvelles perspectives pour le traitement de l'IC. [Traduit par la Redaction] Mots-cles : insuffisance cardiaque, equilibre metabolisme oxydatif/glycolyse, fonction mitochondriale, BAF60c, voie PGC1[alpha]/PPAR[alpha]/mTOR, hypertrophie myocardique., Introduction Although 'energy deficiency' is considered a factor in the transition from functional compensatory hypertrophy to heart failure (HF), the details of the metabolic reconstruction and the determination of the [...]

Circulating tumor DNA (ctDNA) has been widely used as a minimally invasive biomarker in clinical routine. However, a number of factors such as panel design, sample quality, patients' disease stages are known to influence ctDNA detection sensitivity. In this study, we systematically evaluated common factors associated with the variability of ctDNA detection in plasma and investigated ctDNA abundance in bronchoalveolar lavage (BAL). Whole exome profiling was conducted on 61 tumor tissue samples to identify tumor‐specific variants, which were then used to design personalized assay MarRyDa® for ctDNA detection. DNA extracted from BAL fluid and plasma were genotyped using MarRyDa® platform. Our analysis showed that histological subtypes and disease stages had significant differences in ctDNA detection rate. Furthermore, we found that DNA purified from BAL supernatants contains the highest levels of ctDNA compared with BAL precipitates and plasma; therefore, utilizing BAL supernatants for tumor detection might provide additional benefits. Finally, we demonstrated that tumor cellularity played significant roles in the design of personalized ctDNA panel which eventually impacts ctDNA detection sensitivity. We suggest setting a flexible criteria for sample quality control and utilization of BAL might benefit more patients in clinics. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to evaluate the effect and related mechanisms of Mesenchymal stem cells (MSCs) and Angiotensin converting enzyme II (ACE II) on acute lung injury (ALI). Methods: MSCs were separated from umbilical cord cells, and the changes of phenotype before and after ACE II silence were observed using Flow Cytometer. ALI model was induced by 10 mg/mL bleomycin in 60 Balb/c mice, and the rest 8 mice were regarded as the baseline group. The mice were randomly divided into four groups ( n = 15): control, ACE II, stem, and stem + ACE II. The apoptotic index (AI) was calculated using TUNEL, and the detection of protein and mRNA of Bax, Bak and p53, Bcl-2, Grp78, CHOP and Caspase 12 were used by western-blot and RT-PCR, respectively. Results: The umbilical cord cells differentiated into stable MSCs about 14 days, and ACE II transfection reached a peak at the 5th day after transfection. ACE II silence did not affect the phenotype of MSCs. All the proteins and mRNAs expression except Bcl-2 in the stem and stem + ACE II were significantly lower than those in control from 8 h ( p < 0.05, p < 0.01), while Bcl-2 exhibited an opposite trend. Stem + ACE II performed a better effect than single stem in most indexes, including AI ( p < 0.05, p < 0.01). Conclusions: The co-administration of MSCs and ACE II can significantly suppress apoptosis in ALI mice, and may be an effective clinical treatment for ALI. [ABSTRACT FROM AUTHOR]

Ionizing radiation (IR) resistance and toxicity to normal cells are the main problems in radiotherapy for cancer. In this study, we demonstrated that epigallocatechin gallate (EGCG) could inhibit effectively IR-induced damage to mouse normal hepatic cells AML-12, and improve dramatically the radiosensitivity of mouse hepatoma cells H22 to 60 Coγ. In addition, the different effects of EGCG and underlying molecular mechanisms based on microRNA-34a (miR-34a) and apoptosis-related proteins were investigated by cells viability analysis, quantitative realtime PCR (qRT-PCR), Western blot and cells transfection. The results indicated EGCG played the key role of radiosensitization on H22 cells by activating the miR-34a/Sirt1/p53 signaling pathway. Besides, EGCG could down-regulate the expression of anti-apoptotic protein Bcl-2, and up-regulate the expression of pro-apoptotic proteins Bax and Caspase-3 in H22 cells. Interestingly, EGCG showed contrary results on AML-12 cells. Therefore, radiation protection and radiosensitization of EGCG were associated with apoptosis regulated by miR-34a/Sirt1/p53 signaling pathway., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Multiple Sclerosis (MS), an autoimmune and demyelinating disease, is one the most prevalent neurological disabilities in young adults. It results in damage of the central nervous system, disrupting communication between the patient's brain, spinal cord and body. Mobility limitations is one of the earliest symptoms and affects a majority of persons with Multiple Sclerosis. We are working towards an effort to characterize individuals with MS, from those without, on the basis of variations in the gait patterns. In the proposed work, statistical methods were used to identify differentiating gait data features for MS characterization. The prediction algorithms built upon these characteristic features will help clinicians develop effective and early cure and therapy designs for persons with Multiple Sclerosis.