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The prediction of the spatiotemporal dynamic evolution of vegetation cover in the Huainan mining area and the quantitative evaluation of its driving factors are of great significance for protecting and restoring the environment in this area. This study uses the Landsat 5 TM and Landsat 8 OLI time-series data to estimate the vegetation cover and uses the transition matrix to analyze the spatiotemporal transfer of vegetation cover from 1989 to 2004, 2004 to 2021, and 2021 to 2030. In addition, a structural equation model (SEM) was established in this study to assess the driving factors of vegetation cover. The quantitative analysis and the cellular automata (CA)-Markov model were performed to predict the future vegetation cover in the Huainan mining area. The results are as follows: (1) In different periods, the vegetation cover types were mainly high cover types transferred to other vegetation cover types; (2) human activities are the key factors affecting the vegetation growth, while topographical factor is the most influential factor promoting the vegetation growth; (3) highly consistent CA-Markov and multi-criteria evaluation (MCE) predicted results of vegetation cover in 2030 compared to that in 2021. The proportion of bare soil and low cover types had increased significantly, mainly concentrated in the internal area of the mines. The prediction of the spatiotemporal evolution of vegetation cover in the Huainan mining area and the quantitative change in driving factors are of significant importance for the restoration of the environment in mining areas.
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Monitoreo del Ambiente , Suelo , Humanos , Monitoreo del Ambiente/métodos , Modelos Teóricos , Minería , ChinaRESUMEN
AIM: Hypertensive nephropathy is embodied by kidney tissue fibrosis and glomerular sclerosis, as well as renal inflammation. The Hippo/YAP (yes-associated protein, YAP) axis has been reported to promote inflammation and fibrosis and may participate in the pathogenesis of heart, vascular and renal injuries. However, the role of the Hippo/YAP pathway in hypertensive renal injury has not been reported so far. We explored the role of the Hippo/YAP signalling pathway in hypertensive renal injury and the effect of peptide 17 on its effects. METHODS: Histopathological analyses were performed based on the Masson and Haematoxylin/eosin (HE) staining approaches. Biochemical indexes were determined and immunofluorescence and western blotting were used to detect protein expression levels. The mRNA expression levels were determined by qRT-PCR. RESULTS: Our results showed that peptide 17 reduced the systolic blood pressure (SBP) and urine protein/creatinine ratio in hypertensive rats. In addition, peptide 17 reduced the histopathological damage of kidneys in spontaneously hypertensive rats (SHRs). Moreover, peptide 17 downregulated genes in the Hippo/Yap pathway in kidney tissue of SHRs and Ang II-treated kidney cells. The expression levels of inflammatory factors TNF-α, IL-1ß and MCP-1 and the pro-fibrotic factors TGF-ß1, fibronectin, and CTGF were increased in the kidney of hypertensive rats, but reversed by peptide 17 treatment. Silencing of YAP had effect similar to that of peptide 17 in vivo and in vitro. CONCLUSION: Peptide 17 alleviates early renal injury in hypertension by regulating the Hippo/YAP signalling pathway. These findings may be useful in the treatment of hypertensive renal injury.
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Hipertensión Renal , Hipertensión , Animales , Fibrosis , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Hipertensión Renal/tratamiento farmacológico , Inflamación/metabolismo , Riñón/patología , RatasRESUMEN
During inflammation or tissue injury, pro-inflammatory mediators attract migratory monocytes to inflammatory sites and monocyte-to-macrophage differentiation occurs to activate macrophages. We report here that PAQR11, a member of the progesterone and AdipoQ receptor family, regulates monocyte-to-macrophage differentiation in vitro and in vivo. Paqr11 gene was highly induced during monocyte-to-macrophage differentiation. Knockdown or deletion of Paqr11 inhibited monocyte differentiation but had little effect on macrophage polarization. Mechanistically, PAQR11 promoted cell survival as apoptosis was increased by Paqr11 knockdown or deletion. Activation of the MAPK signalling pathway was involved in the regulatory role of PAQR11 on monocyte differentiation and cell survival. C/EBPß regulated the expression of Paqr11 at the transcriptional level. In mice, deletion of Paqr11 gene alleviated progression of collagen-induced rheumatoid arthritis. Thus, these results provide strong evidence that PAQR11 has a function in monocyte-to-macrophage differentiation and such function is related to autoimmune disease in vivo.
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Artritis Experimental/metabolismo , Artritis Reumatoide/metabolismo , Diferenciación Celular , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Macrófagos/metabolismo , Proteínas de la Membrana/metabolismo , Monocitos/metabolismo , Animales , Apoptosis , Artritis Experimental/genética , Artritis Experimental/inmunología , Artritis Experimental/patología , Artritis Reumatoide/genética , Artritis Reumatoide/inmunología , Artritis Reumatoide/patología , Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Progresión de la Enfermedad , Regulación de la Expresión Génica , Células HEK293 , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Macrófagos/inmunología , Macrófagos/patología , Proteínas de la Membrana/genética , Ratones , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Monocitos/inmunología , Monocitos/patología , Fosforilación , Transducción de Señal , Células THP-1RESUMEN
Adenosylmethionine decarboxylase 1 (AMD1) is a key enzyme involved in biosynthesis of polyamines including spermidine and spermine. The potential function of AMD1 in human gastric cancers is unknown. We analyzed AMD1 expression level in 319 human gastric cancer samples together with the adjacent normal tissues. The protein expression level of AMD1 was significantly increased in human gastric cancer samples compared with their corresponding para-cancerous histological normal tissues (P < 0.0001). The expression level of AMD1 was positively associated with Helicobactor pylori 16sRNA (P < 0.0001), tumor size (P < 0.0001), tumor differentiation (P < 0.05), tumor venous invasion (P < 0.0001), tumor lymphatic invasion (P < 0.0001), blood vessel invasion (P < 0.0001), and tumor lymph node metastasis (TNM) stage (P < 0.0001). Patients with high expression of AMD1 had a much shorter overall survival than those with normal/low expression of AMD1. Knockdown of AMD1 in human gastric cancer cells suppressed cell proliferation, colony formation and cell migration. In a tumor xenograft model, knockdown of AMD1 suppressed the tumor growth in vivo. Inhibition of AMD1 by an inhibitor SAM486A in human gastric cancer cells arrested cell cycle progression during G1-to-S transition. Collectively, our studies at the cellular, animal and human levels indicate that AMD1 has a tumorigenic effect on human gastric cancers and affect the prognosis of the patients.
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Adenocarcinoma/patología , Adenosilmetionina Descarboxilasa/metabolismo , Carcinogénesis/patología , Infecciones por Helicobacter/patología , Neoplasias Gástricas/patología , Adenocarcinoma/microbiología , Adenocarcinoma/mortalidad , Adenosilmetionina Descarboxilasa/antagonistas & inhibidores , Adenosilmetionina Descarboxilasa/genética , Adulto , Anciano , Anciano de 80 o más Años , Amidinas/farmacología , Animales , Diferenciación Celular , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Femenino , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Infecciones por Helicobacter/microbiología , Helicobacter pylori/genética , Helicobacter pylori/aislamiento & purificación , Humanos , Indanos/farmacología , Metástasis Linfática/patología , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Poliaminas/metabolismo , Pronóstico , Estómago/patología , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/mortalidad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Progestin and adipoQ receptor 4 (PAQR4) is a member of the PAQR family, and the members within this family are involved in the regulation of a number of biological processes including metabolism and cancer development. The potential function of PAQR4 in human cancers is unknown. Analysis of ONCOMINE database reveals that PAQR4 is highly expressed in human breast cancers. We confirmed this finding by analyzing 82 human breast cancers samples. PAQR4 mRNA level was significantly upregulated in human breast cancer samples compared with their corresponding para-cancerous histological normal tissues (P < 0.0001). The mRNA level of PAQR4 was negatively correlated with disease-free survival (P < 0.0001) and overall survival of the patients (P = 0.001). Knockdown of PAQR4 in human breast cancer cells SUM159 and MCF7 suppressed cell proliferation. In contrast, overexpression of PAQR4 in SUM159 cells enhanced cell proliferation and colony formation. In a tumor xenograft model, overexpression of PAQR4 promoted tumor growth of SUM159 cells in vivo, while PAQR4 knockdown suppressed the tumor growth. PAQR4 was able to negatively regulate cyclin-dependent kinases 4 (CDK4) protein level in the breast cancer cells. Knockdown of PAQR4 accelerated degradation of CDK4 together with upregulation of CDK4 polyubiquitination. On the other hand, overexpression of PAQR4 slowed down CDK4 protein degradation and reduced CDK4 polyubiquitination. Collectively, these data at the cellular, animal and human levels indicate that PAQR4 has a tumorigenic effect on human breast cancers, and such effect is associated with a modulatory activity of PAQR4 on protein degradation of CDK4.
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Biomarcadores de Tumor/análisis , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Quinasa 4 Dependiente de la Ciclina/metabolismo , Receptores de Progesterona/metabolismo , Adulto , Anciano , Animales , Neoplasias de la Mama/mortalidad , Carcinogénesis/metabolismo , Supervivencia sin Enfermedad , Femenino , Xenoinjertos , Humanos , Ratones , Persona de Mediana EdadRESUMEN
Land use demand change in the Huaihe River basin (HRB) and ecosystem service values (ESVs) in watersheds are important for the sustainable development and use of land resources. This paper takes the HRB as the research object, and using remote sensing images of land use as the data source adopts the comprehensive evaluation analysis method of ESVs based on equivalent factors and sensitivity analysis of the performance characteristics of ESV changes of different land use types. The PLUS model is used to predict spatiotemporal land use change characteristics to 2030 combining inertial development, ecological development, and cultivated land development. The spatial distribution and aggregation of ESVs at each scale were also explored by analyzing ESVs at municipal, county, and grid scales. Considering also hotspots, the contribution of land use conversion to ESVs was quantified. The results showed that (1) from 2000 to 2020, cultivated land decreased sharply to 28,344.6875 km2, while construction land increased sharply to 26,914.563 km2, and the change of other land types was small. (2) The ESVs in the HRB were 222,019 × 1012 CNY in 2000, 235,015 × 1012 CNY in 2005, 234,419 × 1012 CNY in 2010, 229,885 × 1012 CNY in 2015, and 224,759 × 1012 CNY in 2020, with an overall fluctuation, first increasing and then decreasing. (3) The ESVs were 219,977 × 1012 CNY, 218,098 × 1012 CNY, 219,757 × 1012 CNY, and 213,985 × 1012 CNY under the four simulation scenarios of inertial development, ecological development, cultivated land development, and urban development, respectively. At different scales, the high-value areas decreased, and the low-value areas increased. (4) The hot and cold spots of ESV values were relatively clustered, with the former mainly clustered in the southeast region and the latter mainly clustered in the northwest region. The sensitivity of ecological value was lower than 1, while the ESV was inelastic to the ecological coefficient, and the results were plausible. The mutual conversion of cultivated land to water contributed the most to ESVs. Based on the multi-scenario simulation of land use in the HRB by the PLUS model, we identified the spatial distribution characteristics of ESVs at different scales, which can provide a scientific basis and multiple perspectives for the optimization of land use structure and socio-economic development decisions.
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Ecosistema , Ríos , Conservación de los Recursos Naturales , China , Desarrollo SostenibleRESUMEN
Numerous studies have shown that changes in environmental factors can significantly impact and shift the structure of phytoplankton communities in marine ecosystems. However, little is known about the association between the ecological stoichiometry of seawater nutrients and phytoplankton community diversity and stability in subtropical bays. Therefore, we investigated the relationship between the phytoplankton community assemblage and seasonal variation in the Beibu Gulf, South China Sea. In this study, we found that the abundance of Bacillariophyceae in spring was relatively greater than in other seasons, whereas the abundance of Coscinodiscophyceae was relatively low in spring and winter but greatly increased in summer and autumn. Values of the alpha diversity indices gradually increased from spring to winter, revealing that seasonal variations shifted the phytoplankton community structure. The regression lines between the average variation degree and the Shannon index and Bray-Curtis dissimilarity values showed significantly positive correlations, indicating that high diversity was beneficial to maintaining community stability. In addition, the ecological stoichiometry of nutrients exhibited significantly positive associations with Shannon index and Bray-Curtis dissimilarity, demonstrating that ecological stoichiometry can significantly influence the alpha and beta diversity of phytoplankton communities. The C:N:P ratio was not statistically significantly correlated with average variation degree, suggesting that ecological stoichiometry rarely impacted the community stability. Temperature, nitrate, dissolved inorganic phosphorous, and total dissolved phosphorus were the main drivers of the phytoplankton community assemblage. The results of this study provide new perspectives about what influences phytoplankton community structure and the association between ecological stoichiometry, community diversity, and stability in response to environmental changes.
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INTRODUCTION: Peanuts are widely consumed as a meal ingredient and a snack, and are commonly considered as a healthy food based on their nutrient profile. Peanut consumption has been associated with a lower risk of metabolic syndrome (MetS) in epidemiological studies. This study aims to investigate whether consuming peanuts affects the gut microbiota in adults with risk of MetS and whether the intervention effect of peanuts is associated with gut microbiota composition. METHODS AND RESULTS: This study analyzes the gut microbiota of subjects from a 12-week randomized clinical trial comparing consumption of either peanuts or isocaloric carbohydrate bars. It is observed that there is high inter-individual variability on multiple clinical and anthropometrical parameters in response to peanut consumption. Meanwhile, the gut microbiota composition is also highly person-specific and have minor changes when compared laterally or longitudinally. This study employs a machine-learning algorithm and establishes prediction models using the microbiome data and the responsiveness data of different parameters in subjects with peanut intervention. As a result, it is found that the improvement of MetS risk and numerous parameters, including diastolic blood pressure, body weight, waist circumference, and fasting blood glucose level can be predicted for responsiveness with high accuracy that has a value of area under curve over 0.70 by receiver operating characteristic analysis. CONCLUSION: Together, the findings of this study suggest that individual gut microbiota configuration may modulate host metabolism and alter an individual's response to peanut intervention, thus highlighting the importance of personalized nutrition.
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Arachis , Microbioma Gastrointestinal/fisiología , Síndrome Metabólico/microbiología , Adulto , Anciano , Glucemia/análisis , Presión Sanguínea , Peso Corporal , Femenino , Microbioma Gastrointestinal/genética , Humanos , Masculino , Síndrome Metabólico/prevención & control , Persona de Mediana Edad , Resultado del Tratamiento , Circunferencia de la Cintura , Adulto JovenRESUMEN
Among adult-onset motor neuron diseases, amyotrophic lateral sclerosis (ALS) is the most common. ALS involves the increasing loss of lower and upper motor neurons. Within a few years of onset, ALS causes patient death via progressive paralysis of respiratory muscles. However, the current drugs used to treat ALS, riluzole, edaravone, and dextromethorphan/quinidine, can only delay the progression of the disease and alleviate a small number of symptoms in some patients, and no completely effective treatment is available. Traditional Chinese medicine (TCM) has shown significant advantages in the treatment of ALS in China and Asia; however, the mechanism of its efficacy is unclear. This review discusses the pathogenetic hypothesis of ALS in detail from the level of neurons and glial cells and uses two current experimental animal models of ALS to design experimental strategies to study TCM treatment. We aim to provide a scientific explanation of the mechanism of the effect of TCM in the treatment of ALS, which will help clinicians and research scientists to accept the theory of TCM to treat ALS and promote the development of TCM modernization.
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Fat storage and mobilization in adipose tissue play a central role in energy metabolism and are directly linked to the development of obesity. Upon starvation, fat is mobilized from adipose tissue by lipolysis, a process by which triglycerides are hydrolyzed to free fatty acids to be used as an energy source in skeletal muscles and other tissues. However, how lipolysis is activated by starvation is not fully known. In this study, we demonstrate that PAQR11, a member of the progesterone and AdipoQ receptor family, regulates starvation-mediated lipolysis. Paqr11-deleted mice are resistant to high-fat diet-induced obesity. Paqr11 deletion promotes lipolysis in white adipose tissue, characterized by increased phosphorylations of hormone-sensitive lipase (HSL) and perilipin 1 (PLIN1) and elevated serum levels of glycerol and free fatty acids. PKA activity and cAMP levels in white adipose tissue are also increased by Paqr11 deletion, accompanied by accelerated protein degradation of phosphodiesterase 4D (PDE4D). Mechanistically, PAQR11 decreases the interaction of PDE4D with SKP1-CUL1-FBXO2 E3 ligase complex, thus modulating the polyubiquitination/degradation of PDE4D. Fasting decreases the expression of the Paqr11 gene, and starvation-induced lipolysis in white adipose tissue is enhanced by Paqr11 deletion, while insulin-mediated suppression of lipolysis is not affected. Collectively, these results reveal that PAQR11 regulates lipolysis of adipose tissue and affects high-fat diet-induced obesity.
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Tejido Adiposo/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Lipólisis/fisiología , Proteínas de la Membrana/metabolismo , Adipocitos/metabolismo , Tejido Adiposo Blanco/metabolismo , Animales , Dieta Alta en Grasa/efectos adversos , Metabolismo Energético , Ácidos Grasos no Esterificados/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Lipasa/metabolismo , Metabolismo de los Lípidos , Masculino , Proteínas de la Membrana/genética , Ratones , Obesidad/metabolismo , Perilipina-1/metabolismo , Estabilidad Proteica , Esterol Esterasa/metabolismo , Transcriptoma , Triglicéridos/metabolismo , UbiquitinaciónRESUMEN
Dietary interventions such as fasting have been proved to be effective in the prevention of metabolic and autoimmune diseases as well as aging-related conditions. The complicated interaction between nutrition and immunity has drawn wide attention in recent years. In this study, we investigated the therapeutic effect of intermittent caloric restriction on autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, in mice. EAE was induced by immunization of C57BL/6 mice with myelin oligodendrocyte glycoprotein 35-55 peptide. After the EAE symptoms became obvious at the 4th week post-immunization, the mice were administered with a modified fasting-mimicking diet (FMD) at 1/3 cal of control for 3 days, followed by ad libitum with normal chow for 4 days. A total of two cycles of FMD was applied. Compared with the mice without receiving caloric restriction, the mice using FMD had significant decreases in EAE severity, immune cell infiltration in spinal cord and CNS demyelination. FMD administration also reversed EAE-mediated CNS accumulation of total CD4+ T cells and in particular, IFN-γ-producing CD4+ T cells. Moreover, FMD application elevated the cell proliferation rate in CNS and enhanced expression of brain-derived neurotrophic factor (BDNF) and remyelination markers. In conclusion, our results indicate that intermittent caloric restriction using the modified FMD was effective in the treatment of EAE through ameliorating inflammatory response and promoting recovery of the damaged tissue.
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Restricción Calórica , Ayuno , Esclerosis Múltiple/dietoterapia , Animales , Autoinmunidad , Restricción Calórica/métodos , Modelos Animales de Enfermedad , Femenino , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patologíaRESUMEN
OBJECTIVE: Low-density lipoprotein cholesterol (LDL-C) is the hallmark of atherosclerotic cardiovascular diseases. The hepatic LDL receptor (LDLR) plays an important role in clearance of circulating LDL-C. PCSK9 facilitates degradation of LDLR in the lysosome and antagonizing PCSK9 has been successfully used in the clinic to reduce blood LDL-C level. Here we identify a new player that modulates LDLR interaction with PCSK9, thus controlling LDLR degradation and cholesterol homeostasis. METHODS: The blood LDL-C and cholesterol levels were analyzed in mice with hepatic deletion of Paqr3 gene. The half-life of LDLR was analyzed in HepG2 cells. The interaction of PAQR3 with LDLR and PCSK9 was analyzed by co-immunoprecipitation and immunofluorescent staining. RESULTS: The blood LDL-C and total cholesterol levels in the mice with hepatic deletion of Paqr3 gene were significantly lower than the control mice after feeding with high-fat diet (pâ¯<â¯0.001 and pâ¯<â¯0.05 respectively). The steady-state level of LDLR protein is elevated by Paqr3 knockdown/deletion and reduced by PAQR3 overexpression. The half-life of LDLR protein is increased by Paqr3 knockdown and accelerated by PAQR3 overexpression. PAQR3 interacts with the ß-sheet domain of LDLR and the P-domain of PCSK9 respectively. In addition, PAQR3 can be localized in early endosomes and colocalized with LDLR, PCSK9 and LDL. Mechanistically, PAQR3 enhances the interaction between LDLR and PCSK9. CONCLUSION: Our study reveals that PAQR3 plays a pivotal role in controlling hepatic LDLR degradation and blood LDL-C level via modulating LDLR-PCSK9 interaction.
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Colesterol/sangre , Péptidos y Proteínas de Señalización Intracelular/farmacología , Proproteína Convertasa 9/metabolismo , Receptores de LDL/metabolismo , Animales , LDL-Colesterol/sangre , Células Hep G2 , Humanos , Péptidos y Proteínas de Señalización Intracelular/deficiencia , Péptidos y Proteínas de Señalización Intracelular/genética , Hígado/metabolismo , Proteínas de la Membrana , Ratones , Unión Proteica/efectos de los fármacosRESUMEN
Continuous deficiency of leucine, a member of branched chain amino acids, is able to reduce obesity and improve insulin sensitivity in mice. Intermittent fasting has been shown to be effective in intervention of metabolic disorders including diabetes. However, it is unknown whether intermittent leucine deprivation can intervene in type 2 diabetes progression. We administered leucine-deprived food every other day in db/db mice, a type 2 diabetes model, for a total of eight weeks to investigate the interventional effect of intermittent leucine deprivation. Intermittent leucine deprivation significantly reduces hyperglycemia in db/db mice independent of body weight change, together with improvement in glucose tolerance and insulin sensitivity. The total area of pancreatic islets and ß cell number are increased by intermittent leucine deprivation, accompanied by elevated proliferation of ß cells. The expression level of Ngn3, a ß cell progenitor marker, is also increased by leucine-deleted diet. However, leucine deficiency engenders an increase in fat mass and a decrease in lean mass. Lipid accumulation in the liver is elevated and liver function is compromised by leucine deprivation. In addition, leucine deficiency alters the composition of gut microbiota. Leucine deprivation increases the genera of Bacteroides, Alloprevotella, Rikenellaceae while reduces Lachnospiraceae and these changes are correlated with fasting blood glucose levels of the mice. Collectively, our data demonstrated that intermittent leucine deprivation can intervene in the progression of type 2 diabetes in db/db mice. However, leucine deficiency reduces lean mass and aggravates hepatic steatosis in the mouse.
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Calorie restriction (CR) extends lifespan and elicits numerous effects beneficial to health and metabolism in various model organisms, but the underlying mechanisms are not completely understood. Gut microbiota has been reported to be associated with the beneficial effects of CR; however, it is unknown whether these effects of CR are causally mediated by gut microbiota. In this study, we employed an antibiotic-induced microbiota-depleted mouse model to investigate the functional role of gut microbiota in CR. Depletion of gut microbiota rendered mice resistant to CR-induced loss of body weight, accompanied by the increase in fat mass, the reduction in lean mass and the decline in metabolic rate. Depletion of gut microbiota led to increases in fasting blood glucose and cholesterol levels independent of CR. A few metabolism-modulating hormones including leptin and insulin were altered by CR and/or gut microbiota depletion. In addition, CR altered the composition of gut microbiota with significant increases in major probiotic genera such as Lactobacillus and Bifidobacterium, together with the decrease of Helicobacter. In addition, we performed fecal microbiota transplantation in mice fed with high-fat diet. Mice with transferred microbiota from calorie-restricted mice resisted high fat diet-induced obesity and exhibited metabolic improvement such as alleviated hepatic lipid accumulation. Collectively, these data indicate that CR-induced metabolic improvement especially in body weight reduction is mediated by intestinal microbiota to a certain extent.
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Restricción Calórica , Microbioma Gastrointestinal , Pérdida de Peso , Animales , Metabolismo , RatonesRESUMEN
Fasting and especially intermittent fasting have been shown to be an effective intervention in many diseases, such as obesity and diabetes. The fasting-mimicking diet (FMD) has recently been found to ameliorate metabolic disorders. To investigate the effect of a new type of low-protein low-carbohydrate FMD on diabetes, we tested an FMD in db/db mice, a genetic model of type 2 diabetes. The diet was administered every other week for a total of 8 weeks. The intermittent FMD normalized blood glucose levels in db/db mice, with significant improvements in insulin sensitivity and ß cell function. The FMD also reduced hepatic steatosis in the mice. Deterioration of pancreatic islets and the loss of ß cells in the diabetic mice were prevented by the FMD. The expression of ß cell progenitor marker Ngn3 was increased by the FMD. In addition, the FMD led to the reconstruction of gut microbiota. Intermittent application of the FMD increased the genera of Parabacteroides and Blautia while reducing Prevotellaceae, Alistipes and Ruminococcaceae. The changes in these bacteria were also correlated with the fasting blood glucose levels of the mice. Furthermore, intermittent FMD was able to reduce fasting blood glucose level and increase ß cells in STZ-induced type 1 diabetic mouse model. In conclusion, our study provides evidence that the intermittent application of an FMD is able to effectively intervene in the progression of diabetes in mice.
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Amino acids are the key activators of the mTOR complex 1 (mTORC1, mainly composed of mTOR, Raptor and mLST8) required for cell growth and proliferation. On the other hand, deprivation of amino acids induces autophagy via inhibition of mTORC1 signaling. We report here that amino acid-induced mTORC1 activity and amino acid deprivation-induced autophagy are regulated by PAQR3, a newly found tumor suppressor. At the cellular level, PAQR3 negatively regulates amino acid-induced activation of mTORC1. The N-terminal end of PAQR3 interacts with the WD domains of Raptor and mLST8 directly. PAQR3 reduces the interaction of mTOR with Raptor and mLST8, thus disrupts formation of intact mTORC1 complex. PAQR3 modulates leucine-induced alteration in cell size. In addition, PAQR3 knockdown reduces amino acid deprivation-induced autophagy. The inhibitory effect of PAQR3 knockdown on autophagy is abrogated by rapamycin treatment, indicating that PAQR3 modulates autophagy via its regulation on mTORC1 signaling. In conclusion, our finding reveals a new mode of regulation of mTORC1 signaling and autophagy by PAQR3 in response to alterations of amino acids.
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Aminoácidos/deficiencia , Autofagia , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Proteínas de la Membrana/metabolismo , Transducción de Señal , Animales , Autofagosomas/metabolismo , Autofagosomas/ultraestructura , Línea Celular , Tamaño de la Célula , Humanos , Ratones , Unión Proteica , Proteína Reguladora Asociada a mTOR/metabolismo , Homóloga LST8 de la Proteína Asociada al mTOR/metabolismoRESUMEN
The RAD23B-XPC complex in the nucleus plays a key role in the initial damage recognition during global genome nucleotide excision repair (NER). Within the complex, XPC, a product of Xeroderma pigmentosum C, recognizes and interacts with the unpaired bases in the undamaged DNA strand, while RAD23B stabilizes XPC. However, how RAD23B is regulated by other factors is not well known. We report here a mode of spatial regulation of RAD23B that controls XPC stability and DNA damage repair. We first identified that RAD23B was able to directly associate with PAQR3, a newly-discovered tumor suppressor implicated in many types of human cancers. PAQR3 reduced the protein level of XPC, together with accelerated degradation and enhanced polyubiquitination of XPC. Mechanistically, PAQR3 reduces nucleic distribution of RAD23B by tethering it to the Golgi apparatus, thus diminishing the amount of RAD23B proteins available to interact with XPC in the nucleus. The viability of gastric cancer cells upon treatment with chemotherapy drugs including etoposide, cisplatin and doxorubicin was reduced by PAQR3 overexpression, but enhanced by PAQR3 knockdown. The degree of DNA damage induced by these drugs, as measured by immunoblotting with γ-H2AX, was elevated by PAQR3 overexpression and lessened by PAQR3 knockdown. Furthermore, a synthetic peptide comprising the N-terminus of PAQR3 was able to recapitulate the activity of PAQR3 in reducing XPC stability and enhancing chemotherapy drug-induced DNA damage. In conclusion, our study reveals that RAD23B is controlled by subcellular compartmentation, thus affecting XPC-mediated DNA damage repair in cancer cells.