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Brown and beige fat are specialized for energy expenditure by dissipating energy from glucose and fatty acid oxidation as heat. While glucose and fatty acid metabolism have been extensively studied in thermogenic adipose tissues, the involvement of amino acids in regulating adaptive thermogenesis remains little studied. Here, we report that asparagine supplementation in brown and beige adipocytes drastically upregulated the thermogenic transcriptional program and lipogenic gene expression, so that asparagine-fed mice showed better cold tolerance. In mice with diet-induced obesity, the asparagine-fed group was more responsive to ß3-adrenergic receptor agonists, manifesting in blunted body weight gain and improved glucose tolerance. Metabolomics and 13 C-glucose flux analysis revealed that asparagine supplement spurred glycolysis to fuel thermogenesis and lipogenesis in adipocytes. Mechanistically, asparagine stimulated the mTORC1 pathway, which promoted expression of thermogenic genes and key enzymes in glycolysis. These findings show that asparagine bioavailability affects glycolytic and thermogenic activities in adipose tissues, providing a possible nutritional strategy for improving systemic energy homeostasis.
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Asparagina/farmacologia , Glicólise/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Termogênese/efeitos dos fármacos , Animais , Células Cultivadas , Temperatura Baixa , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Metabolômica , CamundongosRESUMO
OBJECTIVES: This retrospective study was conducted to assess the efficacy and safety of high intensity focused ultrasound (HIFU) in combination with chemotherapy compared with chemotherapy alone in treating patients with unresectable locally advanced pancreatic cancer (LAPC). METHODS: The data of unresectable LAPC patients who received chemotherapy with or without HIFU ablation were retrieved retrospectively. The overall survival (OS), objective response rate (ORR), cancer antigen 19-9 response rate, and safety were compared between these two groups before and after propensity score matching (PSM). RESULTS: Overall, 254 patients with LAPC were included, of whom 92 underwent HIFU ablation. After PSM to control for potential biases, HIFU was associated with improved OS (12.8 versus 12.2 months, log-rank P = .046), as compared to patients without HIFU ablation. Patients with numeric rating scale (NRS) less than 4, and receiving HIFU ablation were significantly associated with improved OS (adjusted hazard ratio [aHR] = 0.365 [95% confidence interval (CI) = 0.148-0.655], P = .002; aHR = 0.490 [95% CI = 0.250-0.961], P = .038; respectively) by multivariate analyses with the adjustment of age, NRS, and tumor size. ORR was also observed to be higher in HIFU group of 30.0% than in the chemotherapy group of 13.3% (P = .039). No severe adverse events of special interest or HIFU-caused deaths were observed. CONCLUSIONS: Patients with unresectable LAPC who received gemcitabine-based chemotherapy might benefit from additional HIFU ablation.
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Adenocarcinoma , Ablação por Ultrassom Focalizado de Alta Intensidade , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/terapia , Estudos Retrospectivos , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/cirurgia , Pontuação de Propensão , Ablação por Ultrassom Focalizado de Alta Intensidade/efeitos adversos , Resultado do Tratamento , Neoplasias PancreáticasRESUMO
Brown and beige adipocytes harbor the thermogenic capacity to adapt to environmental thermal or nutritional changes. Histone methylation is an essential epigenetic modification involved in the modulation of nonshivering thermogenesis in adipocytes. Here, we describe a molecular network leading by KMT5c, a H4K20 methyltransferase, that regulates adipocyte thermogenesis and systemic energy expenditure. The expression of Kmt5c is dramatically induced by a ß3-adrenergic signaling cascade in both brown and beige fat cells. Depleting Kmt5c in adipocytes in vivo leads to a decreased expression of thermogenic genes in both brown and subcutaneous (s.c.) fat tissues. These mice are prone to high-fat-diet-induced obesity and develop glucose intolerance. Enhanced transformation related protein 53 (Trp53) expression in Kmt5c knockout (KO) mice, that is due to the decreased repressive mark H4K20me3 on its proximal promoter, is responsible for the metabolic phenotypes. Together, these findings reveal the physiological role for KMT5c-mediated H4K20 methylation in the maintenance and activation of the thermogenic program in adipocytes.
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Adipócitos Bege/fisiologia , Adipócitos Marrons/fisiologia , Histona-Lisina N-Metiltransferase , Termogênese/fisiologia , Proteína Supressora de Tumor p53/metabolismo , Adipócitos Bege/metabolismo , Adipócitos Marrons/metabolismo , Animais , Dieta Hiperlipídica , Feminino , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Masculino , Camundongos , Camundongos Knockout , Proteína Supressora de Tumor p53/genéticaRESUMO
Mutations in IDH1 (isocitrate dehydrogenases) such as R132H/Q/C, are frequently found in intrahepatic cholangiocarcinoma (IHCC). Mutant IDH1 proteins obtain an abnormal activity converting α-ketoglutarate (αKG) to 2-hydroxyglutarate (2-HG), inhibiting the activity of multiple αKG-dependent dioxygenases, leading to metabolism disorder. Here, we depict a molecular network leading by mutant IDH1, that regulates hepatic lipid embolism using mouse model (KI) with IDH1 R132Q specifically knocked in liver. KI mice appear small and have notably reduced hepatic TG and FFA levels. Technically, mutant IDH1-mediated 2-HG can stabilize PTEN mRNA level probably depending on miR-32, activate Akt-SEBP1c signaling, leading to lipogenesis defect. Our study identifies a new role of oncometabolite 2-HG in inhibiting hepatic lipid metabolism.
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Neoplasias dos Ductos Biliares , Lipogênese , Camundongos , Animais , Fígado , Proteínas Mutantes , Ductos Biliares Intra-HepáticosRESUMO
The activation of brown adipose tissues and beige adipose tissues can utilize more substrates, including glucose and fatty acids, regulate the energy balance of the whole body and improve metabolic diseases such as obesity and type â ¡ diabetes. Elucidating the regulatory mechanisms underlying the thermogenic adipose program may provide excellent targets for therapeutics against metabolic diseases. The current studies have indicated that epigenetic modifications are vital for regulating differentiation and thermogenesis of adipose tissues. In this review, we summarize the recent progress of epigenetic modifications in adipose tissue development and thermogenesis from the aspects of DNA methylation, histone modification, chromatin remodeling, and non-coding RNAs in order to provide new ideas for further studying the activation of adipose tissues.
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Diabetes Mellitus Tipo 2 , Doenças Metabólicas , Humanos , Epigênese Genética , Termogênese/genética , Tecido Adiposo Marrom/metabolismo , Doenças Metabólicas/metabolismoRESUMO
The global incidence of metabolic dysfunction-associated fatty liver disease (MAFLD) has been steadily increasing, making it a leading chronic liver disease. MAFLD refers to a metabolic syndrome linked with type 2 diabetes mellitus, obesity. However, its pathophysiology is complex, there are currently no effective and approved medicines for therapy. Rutin, a naturally occurring polyphenolic flavonoid, is widely distributed in fruits, vegetables, and other plants. It exhibits a plethora of bioactive properties, such as antioxidant, anticancer, and anti-inflammatory and neuroprotective activities, making it an extremely promising phytochemical. Rutin has shown great potential in the treatment of a wide variety of metabolic diseases and received considerable attention in recent years. Fortuitously, various research studies have validated rutin's extensive biological functions in treating metabolic disorders. Despite the fact that the exact pathophysiological mechanisms through which rutin has a hepatoprotective effect on MAFLD are still not fully elucidated. This review comprehensively outlines rutin's multifaceted preventive and therapeutic effects in MAFLD, including the modulation of lipid metabolism, reduction of insulin resistance, diminution of inflammation and oxidative stress, combatting of obesity, and influence on intestinal flora. This paper details the known molecular targets and pathways of rutin in MAFLD pathogenesis. It endeavored to provide new ideas for treating MAFLD and accelerating its translation from bench to bedside.
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Rapid review (RR) could accelerate the traditional systematic review (SR) process by simplifying or omitting steps using various shortcuts. With the increasing popularity of RR, numerous shortcuts had emerged, but there was no consensus on how to choose the most appropriate ones. This study conducted a literature search in PubMed from inception to December 21, 2023, using terms such as "rapid review" "rapid assessment" "rapid systematic review" and "rapid evaluation". We also scanned the reference lists and performed citation tracking of included impact studies to obtain more included studies. We conducted a narrative synthesis of all RR approaches, shortcuts and studies assessing their effectiveness at each stage of RRs. Based on the current evidence, we provided recommendations on utilizing certain shortcuts in RRs. Ultimately, we identified 185 studies focusing on summarizing RR approaches and shortcuts, or evaluating their impact. There was relatively sufficient evidence to support the use of the following shortcuts in RRs: limiting studies to those published in English-language; conducting abbreviated database searches (e.g., only searching PubMed/MEDLINE, Embase, and CENTRAL); omitting retrieval of grey literature; restricting the search timeframe to the recent 20 years for medical intervention and the recent 15 years for reviewing diagnostic test accuracy; conducting a single screening by an experienced screener. To some extent, the above shortcuts were also applicable to SRs. This study provided a reference for future RR researchers in selecting shortcuts, and it also presented a potential research topic for methodologists.
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Medicina Baseada em Evidências , Humanos , Medicina Baseada em Evidências/normas , Medicina Baseada em Evidências/métodos , Projetos de Pesquisa/normas , Revisões Sistemáticas como Assunto/métodosRESUMO
Y-box binding protein 2 (YBX2) is an essential modulator of brown adipose tissue activation, yet the regulation on its own expression and the involved mechanism remains largely unknown. Herein, we report the YBX2 protein level, but not mRNA level, is induced in response to acute ß-adrenergic signaling. In this context, YBX2 is a dual substrate for both AMPK and Akt2. The phosphorylation at Thr115 by AMPK or at Ser137 by Akt2 facilitates YBX2 accumulation in brown adipocytes by decreasing ubiquitination-mediated degradation. Beyond stabilizing PGC1α mRNA, increased YBX2 upon thermogenic activation assists the expression of glycolytic enzymes, promotes glucose utilization and lactate production. Mechanistically, YBX2 modulates translation of glycolytic genes via direct binding to 5'-UTRs of these genes. Together these findings suggest YBX2 is responsive to thermogenic stimuli by phosphorylation modification, and stabilized YBX2 helps to boost glycolysis and thermogenesis in brown adipocytes.
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Mitochondria are the pivot organelles to control metabolism and energy homeostasis. The capacity of mitochondrial metabolic adaptions to cold stress is essential for adipocyte thermogenesis. How brown adipocytes keep mitochondrial fitness upon a challenge of cold-induced oxidative stress has not been well characterized. This manuscript shows that IFI27 plays an important role in cristae morphogenesis, keeping intact succinate dehydrogenase (SDH) function and active fatty acid oxidation to sustain thermogenesis in brown adipocytes. IFI27 protein interaction map identifies SDHB and HADHA as its binding partners. IFI27 physically links SDHB to chaperone TNF receptor associated protein 1 (TRAP1), which shields SDHB from oxidative damage-triggered degradation. Moreover, IFI27 increases hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA) catalytic activity in ß-oxidation pathway. The reduced SDH level and fatty acid oxidation in Ifi27-knockout brown fat results in impaired oxygen consumption and defective thermogenesis. Thus, IFI27 is a novel regulator of mitochondrial metabolism and thermogenesis.
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Adipócitos Marrons , Ácido Succínico , Ácido Succínico/metabolismo , Adipócitos Marrons/metabolismo , Tecido Adiposo Marrom/metabolismo , Ácidos Graxos/metabolismo , Termogênese/fisiologiaRESUMO
Histone deacetylases (HDACs) are widely involved in many biological processes, as well as in control of brown and beige adipose physiology, but the precise molecular mechanisms by which HDACs are assembled into transcriptional machinery to fine-tune thermogenic program remain ill-defined. PWWP domain containing 2b (PWWP2B), which is identified as a component of the nucleosome remodeling and deacetylation complex (NuRD), interacts and stabilizes HDAC1/2 at the thermogenic gene promoters to suppress their expression. Ablation of Pwwp2b promotes adipocyte thermogenesis and ameliorates diet-induced obesity in vivo. Intriguingly, Pwwp2b is not only a brown fat-enriched gene but also dramatically induced by cold and sympathetic stimulation, which may serve as a physiological brake to avoid over-activation of thermogenesis in brown and beige fat cells.
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OBJECTIVE: The outbreak of COVID-19 pandemic has greatly impacted on radiotherapy (RT) strategy for breast cancer patients, which might lead to increased distressing psychological symptoms. We performed a multi-center cross-section survey to investigate prevalence of fear of cancer recurrence (FCR) and predictors for FCR in patients referred to RT during pandemic. METHODS: 542 patients were consecutively enrolled from three regions in China including Yangtze Delta River Region, Guangdong and Shanxi province. Patients' characteristics were collected using an information sheet, Fear of progression questionnaire-short form, Hospital Anxiety/Depression Scale and EORTC QLQ-C30. The hierarchical multiple regression models were performed. RESULTS: 488 patients with complete data were eligible. The RT strategy was affected in 265 (54.3%) patients, including 143 with delayed RT initiation, 66 believing to have delayed RT initiation but actually not, 24 with RT interruptions, 19 shifting to local hospitals for RT and the remaining 13 influenced on both RT schedule and hospital level. The model explained 59.7% of observed variances in FCR (p<0.001) and showed that influence of RT strategy had significantly impacted on FCR (â³R2 = 0.01, â³F=2.966, p=0.019). Hospitals in Shanxi province (ß=-0.117, p=0.001), emotional function (ß=-0.19, p<0.001), social function (ß=-0.111, p=0.006), anxiety (ß=0.434, p<0.001) and RT interruption (ß=0.071, p=0.035) were independent predictors. CONCLUSIONS: RT strategy for breast cancer patients was greatly influenced during pandemic. RT interruption is an independent predictor for high FCR. Our findings emphasize the necessity to ensure continuum of RT, and efforts should be taken to alleviate FCR through psychological interventions.
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UNLABELLED: Using data from a randomized placebo-controlled trial of 10,101 postmenopausal women not selected on the basis of osteoporosis, we examined whether the effect of raloxifene treatment on fractures was consistent across categories of fracture risk. Treatment with raloxifene for 5 yr reduced the risk of clinical vertebral fractures, but not nonvertebral fractures, irrespective of the presence or absence of risk factors for fracture. INTRODUCTION: In The Raloxifene Use for The Heart (RUTH) trial, women assigned to raloxifene had a lower risk of clinical vertebral fractures but not nonvertebral fractures. However, it is uncertain whether the effect of raloxifene on fractures in this population not selected for low BMD differs according to risk factors for fractures. MATERIALS AND METHODS: We randomly assigned 10,101 postmenopausal women >or=55 yr of age with documented coronary heart disease or at high risk for coronary events to 60 mg raloxifene daily or placebo and followed them for a median of 5.6 yr. Fractures (nonvertebral and clinical vertebral) were prespecified secondary endpoints that were reported at semiannual visits. Fractures were adjudicated and confirmed using X-ray reports or medical records. RESULTS: There was no difference between raloxifene and placebo groups in risk of nonvertebral fractures (428 versus 438 events; hazard ratio [HR], 0.96; 95% CI, 0.84-1.10), including hip/femur (89 versus 103 events; HR, 0.85; 95% CI, 0.64-1.13) and wrist (107 versus 111 events; HR, 0.95; 95% CI, 0.73-1.24) fractures. Women treated with raloxifene had a lower risk of clinical vertebral fractures (64 versus 97 events; HR, 0.65; 95% CI, 0.47-0.89). The effect of treatment with raloxifene on risk of nonvertebral and clinical vertebral fractures was consistent across fracture risk categories defined at baseline by age, smoking status, physical activity level, prior history of fracture, family history of hip fracture, diabetes mellitus, previous use of hormone therapy, thyroid hormone use, statin use, weight loss, body mass index, or fracture specific summary risk score. CONCLUSIONS: In older women with or at high risk of coronary heart disease not selected on the basis of osteoporosis or increased fracture risk, treatment with raloxifene for 5 yr reduced the risk of clinical vertebral fractures, but not nonvertebral fractures, irrespective of presence or absence of risk factors for fracture.
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Fraturas Ósseas/prevenção & controle , Cloridrato de Raloxifeno/uso terapêutico , Idoso , Doença das Coronárias/prevenção & controle , Método Duplo-Cego , Feminino , Fraturas Ósseas/epidemiologia , Humanos , Incidência , Pessoa de Meia-Idade , Pós-Menopausa , Risco , Fraturas da Coluna Vertebral/epidemiologia , Fraturas da Coluna Vertebral/prevenção & controleRESUMO
Two hallmarks of cancer cells are their resistance to apoptosis and ability to thrive despite reduced levels of vital serum components. c-jun N-terminal kinase (JNK) activation is crucial for apoptosis triggered by serum starvation (SS), and isocitrate dehydrogenase 1 (IDH1) mutations are tumorigenic, in part, because they produce the abnormal metabolite 2-hydroxyglutarate (2-HG). However, it is unknown whether 2-HG-induced tumorigenesis is partially due to JNK inhibition and thus defective SS-induced apoptosis. We show here, using IDH1-R132Q knockin mutant mouse cells, that 2-HG inhibits JNK activation induced only by SS and not by UV or doxorubicin, and thus can block apoptosis. Upon SS, Cdc42 normally disrupts mixed lineage kinase 3's (MLK3's) auto-inhibition, triggering the MLK3-MKK4/7-JNK-Bim apoptotic cascade. 2-HG binds to Cdc42 and abolishes its association with MLK3, inactivating MLK3 and apoptosis. Allograft tumor assays in mice demonstrate that this mechanism contributes to tumorigenesis driven by mutant IDH1, a result confirmed by detection of JNK inactivation in human gliomas harboring IDH1-R132H mutations.
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Apoptose/genética , Carcinogênese/genética , Glioma/genética , Isocitrato Desidrogenase/genética , MAP Quinase Quinase 4/biossíntese , Animais , Linhagem Celular Tumoral , Meios de Cultura Livres de Soro , Regulação Neoplásica da Expressão Gênica , Glioma/metabolismo , Glioma/patologia , Glutaratos/metabolismo , Humanos , MAP Quinase Quinase 4/genética , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
It is well known that c-Src has important roles in tumorigenesis. However, it remains unclear whether c-Src contributes to metabolic reprogramming. Here we find that c-Src can interact with and phosphorylate hexokinases HK1 and HK2, the rate-limiting enzymes in glycolysis. Tyrosine phosphorylation dramatically increases their catalytic activity and thus enhances glycolysis. Mechanistically, c-Src phosphorylation of HK1 at Tyr732 robustly decreases its Km and increases its Vmax by disrupting its dimer formation. Mutation in c-Src phosphorylation site of either HK1 or HK2 remarkably abrogates the stimulating effects of c-Src on glycolysis, cell proliferation, migration, invasion, tumorigenesis and metastasis. Due to its lower Km for glucose, HK1 rather than HK2 is required for tumour cell survival when glucose is scarce. Importantly, HK1-Y732 phosphorylation level remarkably correlates with the incidence and metastasis of various clinical cancers and may serve as a marker to predict metastasis risk of primary cancers.