RESUMO
The regulation of the circadian clock plays an important role in influencing physiological conditions. While it is reported that the timing and quantity of energy intake impact circadian regulation, the underlying mechanisms remain unclear. This study investigated the impact of dietary protein intake on peripheral clocks. Firstly, transcriptomic analysis was conducted to investigate molecular targets of low-protein intake. Secondly, mPer2::Luc knock-in mice, fed with either a low-protein, normal, or high-protein diet for 6 weeks, were analyzed for the oscillation of PER2 expression in peripheral tissues and for the expression profiles of circadian and metabolic genes. Lastly, the candidate pathway identified by the in vivo analysis was validated using AML12 cells. As a result, using transcriptomic analysis, we found that the low-protein diet hardly altered the circadian rhythm in the central clock. In animal experiments, expression levels and period lengths of PER2 were different in peripheral tissues depending on dietary protein intake; moreover, mRNA levels of clock-controlled genes and endoplasmic reticulum (ER) stress genes were affected by dietary protein intake. Induction of ER stress in AML12 cells caused an increased amplitude of Clock and Bmal1 and an advanced peak phase of Per2. This result shows that the intake of different dietary protein ratios causes an alteration of the circadian rhythm, especially in the peripheral clock of mice. Dietary protein intake modifies the oscillation of ER stress genes, which may play key roles in the regulation of the circadian clock.
Assuntos
Ritmo Circadiano , Proteínas Alimentares , Proteínas Circadianas Period , Animais , Camundongos , Ritmo Circadiano/genética , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Proteínas Alimentares/administração & dosagem , Estresse do Retículo Endoplasmático , Relógios Circadianos/genética , Masculino , Camundongos Endogâmicos C57BL , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Perfilação da Expressão Gênica , Linhagem Celular , TranscriptomaRESUMO
We investigated if elevated cardiac troponin I (cTnI) serum levels before non-cardiac surgery were predictors of postoperative cardiac events in patients with end stage renal disease (ESRD) undergoing dialysis. In total, 703 consecutive patients with ESRD undergoing dialysis who underwent non-cardiac surgery were enrolled. Preoperative cTnI serum levels were measured at least once in all patients. The primary endpoint was defined as a composite of cardiac death, myocardial infarction (MI), and pulmonary edema during hospitalization or within 30 days after surgery in patients with a hospitalization longer than 30 days after surgery. Postoperative cardiac events occurred in 48 (6.8%) out of 703 patients (cardiac death 1, MI 18, and pulmonary edema 33). Diabetes mellitus (DM), previous ischemic heart disease, and congestive heart failure were more common in patients with postoperative cardiac events. Peak cTnI serum levels were higher in patients with postoperative cardiac event (180 ± 420 ng/L vs. 80 ± 190 ng/L, p = 0.008), and also elevated peak cTnI levels > 45 ng/L were more common in patients with postoperative cardiac events (66.8% vs. 30.5%, p < 0.001). Multivariate logistic regression analysis showed that DM (odds ratio [OR] 2.509, 95% confidence interval [CI] 1.178-5.345, p = 0.017) and serum peak cTnI levels ≥ 45 ng/L (OR 3.167, 95% CI 1.557-6.444, p = 0.001) were independent predictors for the primary outcome of cardiac death/MI/pulmonary edema. Moreover, cTnI levels ≥ 45 ng/L had an incremental prognostic value to the revised cardiac risk index (RCRI) (Chi-square = 23, p < 0.001), and to the combined RCRI and left ventricular ejection fraction (Chi-square = 12, p = 0.001). Elevated preoperative cTnI levels are predictors of postoperative cardiac events including cardiac death, MI, and pulmonary edema in patients with ESRD undergoing non-cardiac surgery.
Assuntos
Falência Renal Crônica , Infarto do Miocárdio , Edema Pulmonar , Humanos , Troponina I , Edema Pulmonar/diagnóstico , Edema Pulmonar/etiologia , Volume Sistólico , Função Ventricular Esquerda , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/etiologia , Falência Renal Crônica/complicações , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/terapia , Morte , BiomarcadoresRESUMO
BACKGROUND: Anticoagulant therapy has been important for stroke prevention in patients with atrial fibrillation (AF). However, it was not recommended due to its relatively higher risk of bleeding than its lower risk of stroke in patients with a CHA2 DS2 -VASc score of 0. HYPOTHESIS: This study aimed to evaluate the predictors of stroke in AF patients with very low risk of stroke. METHODS: Between 1990 and 2020, 542 patients with non-valvular AF (NVAF) with a CHA2 DS2 -VASc score of 0 followed up for at least 6 months were enrolled. Patients with only being woman as a risk factor were included as a CHA2 DS2 -VASc score of 0 in this study. The primary outcome was stroke or systemic embolism. RESULTS: The primary outcome rate was 0.78%/year. In Cox hazard model, age of ≥50 years at diagnosis (hazard ratio [HR] 6.710, 95% confidence interval [CI] 1.811-24.860, p = .004), LVEDD of ≥46 mm (HR 4.513, 95% CI 1.038-19.626, p = .045), and non-paroxysmal AF (HR 5.575, 95% CI 1.621-19.175, p = .006) were identified as independent predictors of stroke or systemic embolism. Patients with all three independent predictors had a higher risk of stroke or systemic embolism (4.21%/year), whereas those without did not have a stroke or systemic embolism. CONCLUSION: The annual stroke or systemic embolism rate in NVAF patients with CHA2 DS2 -VASc score of 0 was 0.78%/year, and age at AF diagnosis, LVEDD, and non-paroxysmal AF were independent predictors of stroke or systemic embolism in patients considered to have a very low risk of stroke.
Assuntos
Fibrilação Atrial , Embolia , Acidente Vascular Cerebral , Feminino , Humanos , Pessoa de Meia-Idade , Fibrilação Atrial/complicações , Fibrilação Atrial/diagnóstico , Medição de Risco , Eletrocardiografia/efeitos adversos , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/diagnóstico , Fatores de Risco , Embolia/complicações , Embolia/epidemiologia , Anticoagulantes/uso terapêuticoRESUMO
BACKGROUND: Positron emission tomography (PET) viability scan is used to determine whether patients with a myocardial scar on single-photon emission computed tomography (SPECT) may need revascularization. However, the clinical utility of revascularization decision-making guided by PET viability imaging has not been proven yet. The purpose of this study was to investigate the impact of PET to determine revascularization on clinical outcomes. METHODS: Between September 2012 and May 2021, 53 patients (37 males; mean age = 64 ± 11 years) with a myocardial scar on MIBI SPECT who underwent PET viability test were analyzed in this study. The primary outcome was a temporal change in echocardiographic findings. The secondary outcome was all-cause mortality. RESULTS: Viable myocardium was presented by PET imaging in 29 (54.7%) patients. Revascularization was performed in 26 (49.1%) patients, including 18 (34.0%) with percutaneous coronary intervention (PCI) and 8 (15.1%) with coronary artery bypass grafting. There were significant improvements in echocardiographic findings in the revascularization group and the viable myocardium group. All-cause mortality was significantly lower in the revascularization group than in the medical therapy-alone group (19.2% vs. 44.4%, log-rank P = 0.002) irrespective of viable (21.4% vs. 46.7%, log-rank P = 0.025) or non-viable myocardium (16.7% vs. 41.7%, log-rank P = 0.046). All-cause mortality was significantly lower in the PCI group than in the medical therapy-alone group (11.1% vs. 44.4%, log-rank P < 0.001). CONCLUSION: Revascularization improved left ventricular systolic function and survival of patients with a myocardial scar on SPECT scans, irrespective of myocardial viability on PET scans.
Assuntos
Cicatriz , Intervenção Coronária Percutânea , Masculino , Humanos , Pessoa de Meia-Idade , Idoso , Tomografia Computadorizada por Raios X , Tomografia Computadorizada de Emissão de Fóton Único , Miocárdio , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada de EmissãoRESUMO
The last decade's progress unraveling the mutational landscape of all age groups of cancer has uncovered mutations in histones as vital contributors of tumorigenesis. Here we review three new aspects of oncogenic histones: first, the identification of additional histone mutations potentially contributing to cancer formation; second, tumors expressing histone mutations to study the crosstalk of post-translational modifications, and; third, development of sophisticated biological model systems to reproduce tumorigenesis. At the outset, we recapitulate the firstly discovered histone mutations in pediatric and adolescent tumors of the brain and bone, which still remain the most pronounced histone alterations in cancer. We branch out to discuss the ramifications of histone mutations, including novel ones, that stem from altered protein-protein interactions of cognate histone modifiers as well as the stability of the nucleosome. We close by discussing animal models of oncogenic histones that reproduce tumor formation molecularly and morphologically and the prospect of utilizing them for drug testing, leading to efficient treatment and cure of deadly cancers with histone mutations.
Assuntos
Modelos Animais de Doenças , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Histonas/genética , Mutação , Neoplasias/genética , Nucleossomos/genética , Animais , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , CamundongosRESUMO
DNA methylation is a dynamic and reversible process that governs gene expression during development and disease. Several examples of active DNA demethylation have been documented, involving genome-wide and gene-specific DNA demethylation. How demethylating enzymes are targeted to specific genomic loci remains largely unknown. We show that an antisense lncRNA, termed TARID (for TCF21 antisense RNA inducing demethylation), activates TCF21 expression by inducing promoter demethylation. TARID interacts with both the TCF21 promoter and GADD45A (growth arrest and DNA-damage-inducible, alpha), a regulator of DNA demethylation. GADD45A in turn recruits thymine-DNA glycosylase for base excision repair-mediated demethylation involving oxidation of 5-methylcytosine to 5-hydroxymethylcytosine in the TCF21 promoter by ten-eleven translocation methylcytosine dioxygenase proteins. The results reveal a function of lncRNAs, serving as a genomic address label for GADD45A-mediated demethylation of specific target genes.
Assuntos
5-Metilcitosina/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proteínas de Ciclo Celular/metabolismo , Citosina/análogos & derivados , Metilação de DNA/fisiologia , Neoplasias/genética , Proteínas Nucleares/metabolismo , RNA Longo não Codificante/fisiologia , Timina DNA Glicosilase/fisiologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Ilhas de CpG/fisiologia , Citosina/metabolismo , Metilação de DNA/genética , Reparo do DNA/genética , Regulação Neoplásica da Expressão Gênica , Genoma Humano , Células HEK293 , Humanos , Dados de Sequência Molecular , Proteínas Nucleares/genética , Regiões Promotoras Genéticas/fisiologia , RNA Longo não Codificante/genéticaRESUMO
Isoquinoline alkaloids-enriched herbal plants have been used as traditional folk medicine for their anti-inflammatory, antimicrobial, and analgesic effects. They induce cell cycle arrest, apoptosis, and autophagy, leading to cell death. While the molecular mechanisms of these effects are not fully understood, it has been suggested that binding to nucleic acids or proteins, enzyme inhibition, and epigenetic modulation by isoquinoline alkaloids may play a role in the effects. This review discusses recent evidence on the molecular mechanisms by which the isoquinoline alkaloids can be a therapeutic target of cancer treatment.
Assuntos
Alcaloides/farmacologia , Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Isoquinolinas/farmacologia , Neoplasias/tratamento farmacológico , Analgésicos/farmacologia , Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Medicina Tradicional , Ácidos Nucleicos/químicaRESUMO
BACKGROUND: This study investigates the impact of the occurrence of Osborn waves during therapeutic hypothermia (TH) on the recurrence of future fatal arrhythmias in patients resuscitated after sudden cardiac arrest (SCA). METHODS: Of all survivors of out-of-hospital SCA, 100 consecutive patients (mean age, 52 ± 15 years; 80% men) who received TH were included in this study. RESULTS: The most common first documented arrhythmia was ventricular fibrillation (VF) (77%), and ischemic heart disease (44%) and idiopathic VF (22%) were the most common causes of SCA in resuscitated patients. During TH, Osborn waves developed in 29 patients (29%). Osborn waves occurred more frequently in patients with Brugada syndrome. Patients with Osborn waves had lower in-hospital (10.3% vs 26.8%; P = .072) and 1-year death rates (20.7% vs 39.4%; P = .073) and better cerebral function (cerebral performance category scale, 2.0 ± 1.5 vs 2.7 ± 1.8; P = .053) than those without Osborn waves, although there was no statistical significance. Among 78 in-hospital survivors, 31 (40%) underwent implantable cardioverter-defibrillator (ICD) implantation. Appropriate ICD shocks from fatal arrhythmias were more frequent in patients who had Osborn waves than in those without Osborn waves (43% vs 6%; P = .032). CONCLUSIONS: Osborn waves during TH had no significant effect on the survival and cerebral function of patients resuscitated SCA. However, appropriate ICD shocks due to the recurrence of VF were more frequent in patients with Osborn waves during long-term follow-up.
Assuntos
Arritmias Cardíacas/etiologia , Arritmias Cardíacas/mortalidade , Arritmias Cardíacas/fisiopatologia , Hipotermia Induzida , Parada Cardíaca Extra-Hospitalar/mortalidade , Parada Cardíaca Extra-Hospitalar/terapia , Adulto , Ecocardiografia , Eletrocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RecidivaRESUMO
BACKGROUND: The association of N-terminal pro-B type natriuretic peptide (NT-proBNP) and plasma renin activity (PRA) for the prognosis of the patients with acute heart failure (HF) has not been fully investigated. This study aimed to determine the association between NT-proBNP and PRA and to investigate the incremental value of PRA to NT-proBNP for predicting long term prognosis in patients with acute HF. METHODS: Three hundred and ninety-six patients (mean age, 64.7 ± 15.9 years; 46.5% female) presenting with acute HF were enrolled between December 2004 and July 2013. Patients with newly diagnosed HF as well as patients with acute exacerbated chronic HF were included. The prognosis was assessed with the composite event of all-cause mortality and readmission for HF during a 2-year follow-up period. RESULTS: The etiology of HF was ischemic in 116 (29.3%) patients. In a Cox proportional hazards model, log-transformed PRA (hazard ratio [HR], 1.205; P = 0.007) was an independent predictor of the composite outcome of all-cause mortality and readmission for HF in addition to age (HR, 1.032; P = 0.001), white blood cell (WBC) count (HR, 1.103; P < 0.001), and left ventricular ejection fraction (LVEF) (HR, 0.978; P = 0.013). Adding PRA to age, sex, LVEF, and NT-proBNP significantly improved the prediction for the composite outcome of all-cause mortality and readmission for HF, as shown by the net reclassification improvement (0.47; P < 0.001) and integrated discrimination improvement (0.10; P < 0.001). CONCLUSION: PRA could provide incremental predictive value to NT-proBNP for predicting long term prognosis in patients with acute HF.
Assuntos
Biomarcadores/sangue , Insuficiência Cardíaca/diagnóstico , Renina/sangue , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Feminino , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/patologia , Humanos , Estimativa de Kaplan-Meier , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Readmissão do Paciente , Fragmentos de Peptídeos/sangue , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Estudos Retrospectivos , Função Ventricular Esquerda/fisiologiaRESUMO
Non-small cell lung cancer (NSCLC) is a major subtype of lung cancer. Besides genetic and environmental factors, epigenetic alterations contribute to the tumorigenesis of NSCLC. Epigenetic changes are considered key drivers of cancer initiation and progression, and altered expression and activity of epigenetic modifiers reshape the epigenetic landscape in cancer cells. Euchromatic histone-lysine N-methyltransferase 2 (EHMT2) is a histone methyltransferase and catalyzes mono- and di-methylation at histone H3 lysine 9 (H3K9me1 and H3K9me2, respectively), leading to gene silencing. EHMT2 overexpression has been reported in various types of cancer, including ovarian cancer and neuroblastoma, in relation to cell proliferation and metastasis. However, its role in NSCLC is not fully understood. In this study, we showed that EHMT2 gene expression was higher in NSCLC than normal lung tissue based on publicly available data. Inhibition of EHMT2 by BIX01294 (BIX) reduced cell viability of NSCLC cell lines via induction of autophagy. Through RNA sequencing analysis, we found that EHMT2 inhibition significantly affected the cholesterol biosynthesis pathway. BIX treatment directly induced the expression of SREBF2, which is a master regulator of cholesterol biosynthesis, by lowering H3K9me1 and H3K9me2 at the promoter. Treatment of a cholesterol biosynthesis inhibitor, 25-hydroxycholesterol (25-HC), partially recovered BIX-induced cell death by attenuating autophagy. Our data demonstrated that EHMT2 inhibition effectively induced cell death in NSCLC cells through altering cholesterol metabolism-dependent autophagy.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Morte Celular , Colesterol/biossíntese , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Neoplasias Pulmonares/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proliferação de Células , Antígenos de Histocompatibilidade/genética , Antígenos de Histocompatibilidade/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Células Tumorais CultivadasRESUMO
A new sensitive analytical method using capillary electrophoresis with laser induced fluorescence (CE-LIF) was applied for the simultaneous detection of DNA methylation and hydroxymethylation levels in human cancers of different origin. DNA hydroxymethylation, measured as 5-hydroxymethylcytosine (5hmC) levels, was decreased in gliomas with mutation in the isocitrate dehydrogenase 1 (IDH1) gene when compared to IDH1-wildtype gliomas. Independent from IDH1 mutation, 5hmC levels were decreased in lung carcinomas when compared to normal lung tissue. Reduced DNA hydroxymethylation was also observed upon dedifferentiation in cultured murine embryonic fibroblasts. Our data show that reduced DNA hydroxymethylation is related to cellular dedifferentiation and can be detected in various types of cancers, independent from the IDH1 mutation status. Quantitative determination of altered 5hmC levels may therefore have potential as a biomarker linked to cellular differentiation and tumorigenesis.
Assuntos
5-Metilcitosina/análogos & derivados , Neoplasias/química , 5-Metilcitosina/análise , Animais , Desdiferenciação Celular , Metilação de DNA , Eletroforese Capilar/métodos , Fluorescência , Glioma/química , Humanos , Neoplasias Pulmonares/química , Camundongos , Neoplasias/patologiaRESUMO
Ovarian cancer is the gynecological malignancy with the poorest prognosis, in part due to its high incidence of recurrence. Platinum agents are widely used as a first-line treatment against ovarian cancer. Recurrent tumors, however, frequently demonstrate acquired chemo-resistance to platinum agent toxicity. To improve chemo-sensitivity, combination chemotherapy regimens have been investigated. This study examined anti-tumor effects and molecular mechanisms of cytotoxicity of Oldenlandia diffusa (OD) extracts on ovarian cancer cells, in particular, cells resistant to cisplatin. Six ovarian cancer cells including A2780 and cisplatin-resistant A2780 (A2780cis) as representative cell models were used. OD was extracted with water (WOD) or 50% methanol (MOD). MOD significantly induced cell death in both cisplatin-sensitive cells and cisplatin-resistant cells. The combination treatment of MOD with cisplatin reduced viability in A2780cis cells more effectively than treatment with cisplatin alone. MOD in A2780cis cells resulted in downregulation of the epigenetic modulator KDM1B and the DNA repair gene DCLRE1B. Transcriptional suppression of KDM1B and DCLRE1B induced cisplatin sensitivity. Knockdown of KDM1B led to downregulation of DCLRE1B expression, suggesting that DCLRE1B was a KDM1B downstream target. Taken together, OD extract effectively promoted cell death in cisplatin-resistant ovarian cancer cells under cisplatin treatment through modulating KDM1B and DCLRE1B.
Assuntos
Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Oldenlandia/química , Neoplasias Ovarianas/genética , Extratos Vegetais/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Enzimas Reparadoras do DNA/genética , Sinergismo Farmacológico , Exodesoxirribonucleases , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Nucleares/genética , Neoplasias Ovarianas/tratamento farmacológico , Oxirredutases N-Desmetilantes/genéticaRESUMO
Cordyceps is a genus of ascomycete fungi that has been used for traditional herbal remedies. It contains various bioactive ingredients including cordycepin. Cordycepin, also known as 3-deoxyadenosine, is a major compound and has been suggested to have anticancer potential. The treatment of various cancer cells with cordycepin in effectively induces cell death and retards their cancerous properties. However, the underlying mechanism is not fully understood. Recent evidence has shed light on the molecular pathways involving cysteine-aspartic proteases (caspases), mitogen-activated protein kinases (MAPKs), and glycogen synthase kinase 3 beta (GSK-3ß). Furthermore, the pathways are mediated by putative receptors, such as adenosine receptors (ADORAs), death receptors (DRs), and the epidermal growth factor receptor (EGFR). This review provides the molecular mechanisms by which cordycepin functions as a singular or combinational anticancer therapeutic agent.
Assuntos
Antineoplásicos/farmacologia , Desoxiadenosinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Cordyceps/química , Humanos , Sistema de Sinalização das MAP QuinasesRESUMO
BACKGROUND: Ovarian cancer is one of the major causes of death among females in worldwide. Cisplatin is a primary anti-cancer drug against ovarian cancer, but the recurrent tumors after treatment frequently show acquired chemoresistance. Extract of Scutellaria baicalensis (SbE) has been reported to have functional compounds including baicalin, which has anti-cancer effects. However, the anti-cancer effects of SbE in ovarian cancer and its underlying mechanisms are elusive. METHODS: We investigated that the effects of SbE and/or cisplatin on cell death in the cisplatin sensitive ovarian cancer cell line A2780 (CSC) and the counterpart cell line that has cisplatin resistance (CRC). Molecular mechanisms of the effects, focusing on apoptosis and autophagy, were examined. RESULTS: Treatment of cisplatin or SbE reduced cell viability significantly in CSC and too much lesser extent in CRC. Cisplatin-induced cell death in CSC was mediated by p53-induced apoptosis acompanied by expresson of damage-regulated autophagy modulator (DRAM). In CRC, decreased DRAM expression (p < 0.01) hindered p21-mediated cell death and contributed to cisplatin resistance. Treatment of SbE also induced cell death in CSC by p53-dependent apoptosis, not in CRC. Autophagy was not induced by neither cisplatin nor SbE. Intriguingly, the combinational treatment of SbE and cisplatin significantly decreased cell viability in CRC. The cell death was mediated by autophagy with increased expression of Atg5 and Atg12 (p < 0.05), rather than p53-dependent pathway with repressed expression of p21 (p < 0.001) through HDAC1 activation. CONCLUSIONS: The combined treatment of SbE with cisplatin was effective in CRC, leading to cell death via Beclin1-independent autophagy, suggesting that SbE treatment in combination with cisplatin has a potential as a chemotherapeutic agent in cisplatin-resistant ovarian cancer.
Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Extratos Vegetais/farmacologia , Scutellaria baicalensis/química , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quimioterapia Combinada , Feminino , Humanos , Neoplasias Ovarianas/fisiopatologiaRESUMO
Neuroblastoma (NB) is childhood malignancy that retains characteristics of cancer stem cells (CSCs). Targeting the CSCs is one of the therapeutic strategies proposed to achieve complete remission of NB. ß-carotene (BC), an active precursor of retinoids, is a well-known antioxidant reported to possess anti-CSCs effects. Here, we investigated the involvement of retinoic acid receptors (RARs) in the anti-CSCs effects of BC. Treatment with BC or retinoic acid (RA) upregulated RARß mRNA expression in two NB cell lines. Inhibition of RARß using siRNA up-regulated gene expression of delta-like 1 homologue (DLK1), a marker of CSCs. To understand the molecular mechanisms of RARß-mediated inhibition of DLK1, four retinoic acid receptor elements (RAREs) were identified in the promoter of DLK1. Chromatin immunoprecipitation assays indicated that RARß bound directly to a RARE in the DLK1 promoter region. Knock-down of RARß also increased the self-renewal capacity of NB cells, which was suppressed by BC. Taken together, this study provided evidence that the therapeutic anti-CSC effects of BC depend on RARß and its ability to interact with and down-regulate the CSCs marker, DLK1.
Assuntos
Células-Tronco Neoplásicas/efeitos dos fármacos , Neuroblastoma/tratamento farmacológico , Receptores do Ácido Retinoico/metabolismo , beta Caroteno/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Proteínas de Ligação ao Cálcio , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Células-Tronco Neoplásicas/patologia , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Regiões Promotoras GenéticasRESUMO
BACKGROUND: The Paeonia lactiflora extract (PLE) has been reported to have neuroprotective effect against neurodegeneration that are induced by cellular stress such as oxidative stress. Its underlying mechanisms, however, remain unclear. In latest decades, emerging evidence has suggested that epigenetic mechanisms play a key role in gene regulation in response to the cellular stress. We investigated whether epigenetic modulation was involved in neuronal cell death by the neurotoxicant, 1-Methyl-4-phenylpyridinium (MPP(+)), and the neuroprotective effect of PLE. METHODS: Differentiated SH-SY5Y, which is a well-established dopaminergic cell line model, was treated with 0 ~ 200 µg/ml PLE for 4 h prior to MPP(+) treatment. The effect of PLE on cell viability was determined by MTT assays. Gene expression levels of oxidative stress responsive genes, such as Heme oxygenase 1 (HMOX1), and histone modifiers, such as histone acetyltransferases (HATs) and deacetylases (HDACs) were measured by quantitative RT PCR. In order to investigate the changes in epigenetic modifications, the acetylated lysine 9 (H3K9ac) and lysine 27 (H3K27ac) of Histone H3 were measured by western blot using histones extracted from the cells. RESULTS: MPP(+)-induced cell death in SH-SY5Y cells was significantly reduced by PLE pretreatment in a dose-dependent manner, indicating the potent neuroprotective effects of PLE. It was accompanied by induced expression of HMOX1. MPP(+) treatment increased the expression of HATs and consistently increased H3K9ac and H3K27ac of Histone H3. PLE pretreatment impeded the changes in H3K9ac and H3K27ac, coincided with increased expression of HDAC5 without changes in HAT expression. CONCLUSIONS: The results suggested that MPP(+)-induced cell death in the dopaminergic SH-SY5Y cells was related with transcriptional induction of HATs and increased histone H3 acetylation and that PLE might prevent the cells from MPP(+)-induced cell death via tempering histone H3 acetylation.
Assuntos
Apoptose/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Paeonia/química , Extratos Vegetais/farmacologia , Acetilação , Linhagem Celular Tumoral , Heme Oxigenase-1/metabolismo , Histonas/metabolismo , Humanos , Fármacos Neuroprotetores/química , Extratos Vegetais/químicaRESUMO
Consumption of protein-rich diets and supplements has been increasingly advocated by individuals seeking to optimize metabolic health and mitigate the effects of aging. Protein intake is postulated to support muscle mass retention and enhance longevity, underscoring its perceived benefits in age-related metabolic regulation. However, emerging evidence presents a paradox; while moderate protein consumption contributes to health maintenance, an excessive intake is associated with an elevated risk of chronic diseases, notably obesity and diabetes. Furthermore, recent studies suggest that reducing the ratio of protein intake to macronutrients improves metabolic parameters and extends lifespan. The aim of this study is to review the current evidence concerning the metabolic effects of protein-restricted diets and their potential mechanisms. Utilizing rodent models, investigations have revealed that protein-restricted diets exert a notable influence over food intake and energy consumption, ultimately leading to body weight loss, depending on the degree of dietary protein restriction. These phenotypic alterations are primarily mediated by the FGF21 signaling pathway, whose activation is likely regulated by ATF4 and the circadian clock. The evidence suggests that protein-restricted diets as an alternative approach to calorie-restricted regimes, particularly in overweight or obese adults. However, more research is needed to determine the optimal level of restriction, duration, and long-term effects of such interventions.
Assuntos
Dieta com Restrição de Proteínas , Nutrientes , Humanos , Transdução de Sinais , Longevidade , ObesidadeRESUMO
Nicotinamide Adenine Dinucleotide (NAD) is an endogenous substance in redox reactions and regulates various functions in metabolism. NAD and its precursors are known for their anti-ageing and anti-obesity properties and are mainly active in the liver and muscle. Boosting NAD+ through supplementation with the precursors, such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), enhances insulin sensitivity and circadian rhythm in the liver, and improves mitochondrial function in the muscle. Recent evidence has revealed that the adipose tissue could be another direct target of NAD supplementation by attenuating inflammation and fat accumulation. Moreover, murine studies with genetically modified models demonstrated that nicotinamide phosphoribosyltransferase (NAMPT), a NAD regulatory enzyme that synthesizes NMN, played a critical role in lipogenesis and lipolysis in an adipocyte-specific manner. The tissue-specific effects of NAD+ metabolic pathways indicate a potential of the NAD precursors to control metabolic stress particularly via focusing on adipose tissue. Therefore, this narrative review raises an importance of NAD metabolism in white adipose tissue (WAT) through a variety of studies using different mouse models.
Assuntos
NAD , Mononucleotídeo de Nicotinamida , Camundongos , Animais , NAD/metabolismo , Mononucleotídeo de Nicotinamida/metabolismo , Mononucleotídeo de Nicotinamida/farmacologia , Tecido Adiposo/metabolismo , Fígado/metabolismo , ObesidadeRESUMO
PURPOSE: Nurses have been reported to be at an increased risk for miscarriage and preterm labor. However, there is limited knowledge regarding nurses' preconception health behaviors. Therefore, this study aimed to identify factors influencing these behaviors. METHODS: One hundred sixty nurses, who were planning their first pregnancy within the upcoming year, participated in an online survey from August 11 to October 31, 2021. Data on preconception health behavior, perceived health status, pregnancy anxiety, nursing practice environment, and social support were analyzed using the t-test, Pearson correlation coefficients, and multiple regression analysis. RESULTS: Age (Ñ=.024), educational level (Ñ=.010), marital status (Ñ=.003), work experience (Ñ=.003), satisfaction with the work department (Ñ<.001), smoking status (Ñ=. 039), and previous health problems related to pregnancy outcomes (Ñ=.004) were significantly associated with nurses' preconception health behaviors. Furthermore, perceived health status (Ñ<.001), pregnancy anxiety (Ñ=.011), nursing practice environment (Ñ=.003), and social support (Ñ<.001) showed significant correlations with preconception health behaviors. Social support (ß=. 28, Ñ=.001), satisfaction with the work department (ß=.23, Ñ=.032), marital status (ß=.22, Ñ=.002), and perceived health status (ß=.23, Ñ=.002) were confirmed as factors associated with preconception health behaviors. These factors explained 40.9% of the variance in preconception health behaviors (F=6.64, Ñ<.001). CONCLUSION: Clinical nurses' preconception health behaviors were influenced by social support, perceived health status, satisfaction with the work department, and marital status. Interventions to improve clinical nurses' preconception health behaviors should target social support and perceived health status. A preconception health behavior education program considering clinical nurses' marital status and satisfaction with the workplace can also be implemented.
Assuntos
Comportamentos Relacionados com a Saúde , Enfermeiras e Enfermeiros , Cuidado Pré-Concepcional , Apoio Social , Humanos , Feminino , Adulto , Estudos Transversais , República da Coreia/epidemiologia , Inquéritos e Questionários , Enfermeiras e Enfermeiros/psicologia , Gravidez , Pessoa de Meia-IdadeRESUMO
In recent years, the development and use of various devices for the screening of atrial fibrillation (AF) have significantly increased. Such devices include 12-lead electrocardiogram (ECG), photoplethysmography systems, and single-lead ECG and ECG patches. This review outlines several studies that have focused on the feasibility and efficacy of such devices for AF screening, and summarizes the risks and benefits involved in the initiation of anticoagulant therapy after early detection of AF. We also describe several ongoing trials on unresolved issues associated with AF screening. Overall, this review provides a comprehensive summary of the current state of AF screening and its implications for patient care.