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1.
EMBO Rep ; 25(2): 524-543, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38253688

RESUMEN

Metabolites derived from the intestinal microbiota play an important role in maintaining skeletal muscle growth, function, and metabolism. Here, we found that D-malate (DMA) is produced by mouse intestinal microorganisms and its levels increase during aging. Moreover, we observed that dietary supplementation of 2% DMA inhibits metabolism in mice, resulting in reduced muscle mass, strength, and the number of blood vessels, as well as the skeletal muscle fiber type I/IIb ratio. In vitro assays demonstrate that DMA decreases the proliferation of vascular endothelial cells and suppresses the formation of blood vessels. In vivo, we further demonstrated that boosting angiogenesis by muscular VEGFB injection rescues the inhibitory effects of D-malate on muscle mass and fiber area. By transcriptomics analysis, we identified that the mechanism underlying the effects of DMA depends on the elevated intracellular acetyl-CoA content and increased Cyclin A acetylation rather than redox balance. This study reveals a novel mechanism by which gut microbes impair muscle angiogenesis and may provide a therapeutic target for skeletal muscle dysfunction in cancer or aging.


Asunto(s)
Células Endoteliales , Microbiota , Ratones , Animales , Células Endoteliales/metabolismo , Acetilación , Ciclina A/metabolismo , Angiogénesis , Malatos/metabolismo , Músculo Esquelético/metabolismo , Envejecimiento
2.
EMBO J ; 39(7): e103304, 2020 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-32104923

RESUMEN

Beneficial effects of resistance exercise on metabolic health and particularly muscle hypertrophy and fat loss are well established, but the underlying chemical and physiological mechanisms are not fully understood. Here, we identified a myometabolite-mediated metabolic pathway that is essential for the beneficial metabolic effects of resistance exercise in mice. We showed that substantial accumulation of the tricarboxylic acid cycle intermediate α-ketoglutaric acid (AKG) is a metabolic signature of resistance exercise performance. Interestingly, human plasma AKG level is also negatively correlated with BMI. Pharmacological elevation of circulating AKG induces muscle hypertrophy, brown adipose tissue (BAT) thermogenesis, and white adipose tissue (WAT) lipolysis in vivo. We further found that AKG stimulates the adrenal release of adrenaline through 2-oxoglutarate receptor 1 (OXGR1) expressed in adrenal glands. Finally, by using both loss-of-function and gain-of-function mouse models, we showed that OXGR1 is essential for AKG-mediated exercise-induced beneficial metabolic effects. These findings reveal an unappreciated mechanism for the salutary effects of resistance exercise, using AKG as a systemically derived molecule for adrenal stimulation of muscle hypertrophy and fat loss.


Asunto(s)
Ácidos Cetoglutáricos/sangre , Atrofia Muscular/genética , Receptores Purinérgicos P2/genética , Entrenamiento de Fuerza/métodos , Adulto , Anciano , Animales , Línea Celular , Femenino , Técnicas de Inactivación de Genes , Humanos , Masculino , Ratones , Persona de Mediana Edad , Modelos Animales , Atrofia Muscular/metabolismo , Receptores Purinérgicos P2/metabolismo
3.
BMC Pediatr ; 24(1): 498, 2024 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-39095721

RESUMEN

OBJECTIVE: To determine the prevalence of and risk factors for overweight and obese among Chinese children and adolescents. METHODS: This analytical cross-sectional study included 16,640 children and adolescents aged 6-18 years across four provinces of China in 2016. Physical characteristics and responses to questionnaires were analyzed. Body Mass Index (BMI) and the prevalence of overweight and obesity were calculated. RESULTS: Among children and adolescents, the overall prevalence of overweight and obesity in 2016 in four regions of China was 27.2% and 29.6%, respectively. Among different stages and sexes, the highest prevalence of obesity (15.8%) was observed in adolescent boys. From childhood to adolescence, the obesity rate among boys increased by 0.7% (from 15.1% to 15.8%), while the obesity rate among girls decreased by 0.9% (from 10.8% to 9.9%). Children and adolescents who were overweight or obese had significantly higher systolic blood pressures, larger waist circumferences and larger hip sizes than those with a normal BMI. Logistic regression analyses identified thirteen factors associated with overweight or obesity in children and adolescents. CONCLUSIONS: Our results indicate that the prevalence of overweight and obesity is high among children and adolescents, especially among male adolescents in four regions of China. A suitable intervention program should not only help parents understand the serious risk of childhood obesity but also, more importantly, help to encourage a healthy lifestyle among children and adolescents.


Asunto(s)
Índice de Masa Corporal , Obesidad Infantil , Humanos , Adolescente , China/epidemiología , Estudios Transversales , Masculino , Femenino , Niño , Obesidad Infantil/epidemiología , Prevalencia , Factores de Riesgo , Sobrepeso/epidemiología , Distribución por Sexo
4.
Int J Behav Med ; 2024 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-38658436

RESUMEN

BACKGROUND: Sleep problems are common among nurses and can lead to various health problems. Further, the relationship between multiple sleep problems and memory impairment in clinical nurses remains unknown. Therefore, in this study, we aimed to explore the relationship between sleep problems and memory impairment among nurses. METHODS: Multistage cluster-stratified random sampling was performed from tertiary hospitals in Shandong, China. Overall, a total of 1833 nurses were included in the final analysis. The Chinese version of the Pittsburgh Sleep Quality Index and prospective and retrospective memory questionnaire were administered to the participants. RESULTS: The sleep quality of the nurses decreased during the normal epidemic prevention and control period compared with that before the epidemic in terms of sleep duration, sleep efficiency, and sleep disturbances. Nurses who reported cumulative or specific sleep problems (e.g., high sleep latency, sleep disturbances, and daytime dysfunction) and those in the "daily disturbances" and "poor sleep quality" groups had a higher risk of memory impairment than the others. CONCLUSION: Sleep problems might be important for memory impairment among nurses. These findings may help identify nurses at considerable risk of memory impairment in clinical practice.

5.
J Lipid Res ; 64(5): 100368, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-37028769

RESUMEN

The rising prevalence of obesity has become a worldwide health concern. Obesity usually occurs when there is an imbalance between energy intake and energy expenditure. However, energy expenditure consists of several components, including metabolism, physical activity, and thermogenesis. Toll-like receptor 4 (TLR4) is a transmembrane pattern recognition receptor, and it is abundantly expressed in the brain. Here, we showed that pro-opiomelanocortin (POMC)-specific deficiency of TLR4 directly modulates brown adipose tissue thermogenesis and lipid homeostasis in a sex-dependent manner. Deleting TLR4 in POMC neurons is sufficient to increase energy expenditure and thermogenesis resulting in reduced body weight in male mice. POMC neuron is a subpopulation of tyrosine hydroxylase neurons and projects into brown adipose tissue, which regulates the activity of sympathetic nervous system and contributes to thermogenesis in POMC-TLR4-KO male mice. By contrast, deleting TLR4 in POMC neurons decreases energy expenditure and increases body weight in female mice, which affects lipolysis of white adipose tissue (WAT). Mechanistically, TLR4 KO decreases the expression of the adipose triglyceride lipase and lipolytic enzyme hormone-sensitive lipase in WAT in female mice. Furthermore, the function of immune-related signaling pathway in WAT is inhibited because of obesity, which exacerbates the development of obesity reversely. Together, these results demonstrate that TLR4 in POMC neurons regulates thermogenesis and lipid balance in a sex-dependent manner.


Asunto(s)
Proopiomelanocortina , Receptor Toll-Like 4 , Femenino , Ratones , Masculino , Animales , Proopiomelanocortina/genética , Proopiomelanocortina/metabolismo , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Obesidad/metabolismo , Peso Corporal , Tejido Adiposo Pardo/metabolismo , Termogénesis/genética , Neuronas/metabolismo , Lípidos , Metabolismo Energético
6.
J Biol Chem ; 298(8): 102166, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35750210

RESUMEN

Siderophores are conditionally essential metabolites used by microbes for environmental iron sequestration. Most Streptomyces strains produce hydroxamate-based desferrioxamine (DFO) siderophores composed of repeating units of N1-hydroxy-cadaverine (or N1-hydroxy-putrescine) and succinate. The DFO biosynthetic operon, desABCD, is highly conserved in Streptomyces; however, expression of desABCD alone does not account for the vast structural diversity within this natural product class. Here, we report the in vitro reconstitution and biochemical characterization of four DesD orthologs from Streptomyces strains that produce unique DFO siderophores. Under in vitro conditions, all four DesD orthologs displayed similar saturation steady-state kinetics (Vmax = 0.9-2.5 µM⋅min-1) and produced the macrocyclic trimer DFOE as the favored product, suggesting a conserved role for DesD in the biosynthesis of DFO siderophores. We further synthesized a structural mimic of N1-hydroxy-N1-succinyl-cadaverine (HSC)-acyl-adenylate, the HSC-acyl sulfamoyl adenosine analog (HSC-AMS), and obtained crystal structures of DesD in the ATP-bound, AMP/PPi-bound, and HSC-AMS/Pi-bound forms. We found HSC-AMS inhibited DesD orthologs (IC50 values = 48-53 µM) leading to accumulation of linear trimeric DFOG and di-HSC at the expense of macrocyclic DFOE. Addition of exogenous PPi enhanced DesD inhibition by HSC-AMS, presumably via stabilization of the DesD-HSC-AMS complex, similar to the proposed mode of adenylate stabilization where PPi remains buried in the active site. In conclusion, our data suggest that acyl-AMS derivatives may have utility as chemical probes and bisubstrate inhibitors to reveal valuable mechanistic and structural insight for this unique family of adenylating enzymes.


Asunto(s)
Sideróforos , Streptomyces , Adenosina Monofosfato/metabolismo , Cadaverina/metabolismo , Deferoxamina , Ligasas/metabolismo , Streptomyces/metabolismo
7.
Dig Dis ; 41(2): 187-197, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36063795

RESUMEN

BACKGROUND AND AIMS: The objective of this study was to compare the safety and efficacy of endoscopic resection with surgical resection in the treatment of intermediate-risk gastric gastrointestinal stromal tumors (GISTs) and to further evaluate whether imatinib adjuvant treatment is necessary for resected intermediate-risk gastric GIST by ER. METHODS: We retrospectively studied 128 cases for intermediate-risk gastric GISTs that were distributed in endoscopic (n = 33) and surgical groups (n = 95) at our center between December 2009 to July 2020. We statistically compared the clinical features, pathological reports, perioperative data, and long-term follow-up outcomes. RESULTS: Compared with the surgery group, the endoscopy group was associated with smaller tumor size (2.4 ± 1.0 vs. 6.0 ± 1.7 cm, p < 0.001), shorter operating time (67.3 ± 36.5 vs. 145.9 ± 74.8 min, p < 0.001), fewer incidence of short-term postoperative complications (3% vs. 32.6%, p = 0.002). Shorter postoperative hospital days (4.5 ± 1.4 vs. 8.5 ± 2.4 days, p < 0.001), shorter gastric functional recovery time (p < 0.001), and a lower overall medical cost of hospitalization (p < 0.001) was detected in the endoscopy group. During the median 44.5 months follow-up period, there were no cases of recurrence, metastasis, and death in the endoscopy group. Among 128 patients, 68 accepted adjuvant therapy with imatinib after resection. It was observed that the OS of the adjuvant treatment group with imatinib was lower than that of the group without imatinib (p = 0.033). CONCLUSION: Endoscopic resection for intermediate-risk gastric GIST is a feasible and safe method, and there is no significant benefit for patients with intermediate-risk gastric GIST to accept imatinib adjuvant treatment after ER.


Asunto(s)
Tumores del Estroma Gastrointestinal , Neoplasias Gástricas , Humanos , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/cirugía , Tumores del Estroma Gastrointestinal/patología , Mesilato de Imatinib/efectos adversos , Resultado del Tratamiento , Estudios Retrospectivos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/cirugía , Neoplasias Gástricas/patología , Endoscopía Gastrointestinal
8.
Gastric Cancer ; 26(4): 590-603, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37061602

RESUMEN

BACKGROUND AND AIMS: Perforation is a common complication during endoscopic resection (ER) of gastric gastrointestinal stromal tumors (gGISTs) associated with secondary infections, sepsis, hospitalization time and cost. However, the risk factors of perforation remain controversial. This study aimed to investigate the risk factors for perforation during ER of gGISTs. METHODS: This retrospective case-control study included consecutive patients with gGISTs who underwent ER between June 2009 and November 2021 at the Nanjing Drum Tower Hospital. Univariate and multivariate analyses were performed to investigate the risk factors for perforation. Sensitivity analyses with propensity scoring (PS) were performed to evaluate the stability of the independent effects. RESULTS: In total, 422 patients with gGISTs were included. The following factors were associated with perforation during ER: in the non-intraluminal growth patterns (all confounders adjusted odds ratio [aOR]: 5.39, 95% CI 2.99-9.72, P < 0.001), in the gastric fundus (aOR 2.25, 95% CI 1.40-3.60, P = 0.007), sized ≥ 2 cm (aOR 1.70, 95% CI 1.04-2.77, P = 0.035), in the lesser curvature (aOR 0.12, 95% CI 0.05-0.27, P < 0.001), and in the gastric cardia (aOR 0.13, 95% CI 0.04-0.50, P = 0.003). The PS analysis confirmed the stable independent effects of these identified risk factors. CONCLUSIONS: ERs of gGISTs in non-intraluminal growth patterns, in the gastric fundus, and with larger tumor size were independent risk factors for perforation. While tumors in the lesser curvature or gastric cardia were independent protective factor for perforation.


Asunto(s)
Resección Endoscópica de la Mucosa , Tumores del Estroma Gastrointestinal , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patología , Estudios Retrospectivos , Estudios de Casos y Controles , Cardias/patología , Tumores del Estroma Gastrointestinal/cirugía , Tumores del Estroma Gastrointestinal/patología , Factores de Riesgo , Resultado del Tratamiento , Gastroscopía
9.
J Immunol ; 206(12): 2909-2923, 2021 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-34127522

RESUMEN

Porcine epidemic diarrhea virus (PEDV) is a highly pathogenic porcine enteropathogenic coronavirus causing severe enteritis and lethal watery diarrhea in piglets. PEDV infection suppresses the synthesis of type I IFN, and multiple viral proteins of PEDV have been shown to target the adaptors of innate immune pathways to inhibit type I IFN production. In this study, we identified PEDV membrane (M) protein as a new antagonist of type I IFN production in both human embryonic kidney HEK293T cells and porcine kidney PK-15 cells and determined the antagonistic mechanism used by M protein to target IFN regulatory factor 7 (IRF7), an important regulator of type I IFN production. IRF7 is phosphorylated and activated by TBK1 and IKKε in response to viral infection. We found that PEDV M protein interacted with the inhibitory domain of IRF7 and significantly suppressed TBK1/IKKε-induced IRF7 phosphorylation and dimerization of IRF7, leading to the decreased expression of type I IFN, although it did not affect the interaction between TBK1/IKKε and IRF7. As expected, overexpression of M protein significantly increased PEDV replication in porcine cells. The M proteins of both epidemic PEDV strains and vaccine strain showed similar antagonistic effect on type I IFN production, and the 1-55 region of M protein was essential for disruption of IRF7 function by interacting with IRF7. Taken together, our data identified a new, to our knowledge, IFN antagonist of PEDV, as well as a novel, to our knowledge, antagonistic mechanism evolved by PEDV to inhibit type I IFN production.


Asunto(s)
Infecciones por Coronavirus/inmunología , Factor 7 Regulador del Interferón/inmunología , Interferón Tipo I/biosíntesis , Proteínas de la Membrana/inmunología , Virus de la Diarrea Epidémica Porcina/inmunología , Enfermedades de los Porcinos/inmunología , Animales , Línea Celular , Humanos , Interferón Tipo I/inmunología , Porcinos
10.
Gastrointest Endosc ; 95(4): 660-670.e2, 2022 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-34736933

RESUMEN

BACKGROUND AND AIMS: With the increasing incidence of small GI stromal tumors (GISTs), endoscopic full-thickness resection (EFTR) and cap-assisted EFTR (EFTR-C) have been suggested as 2 effective resection methods. We aimed to compare the outcomes of EFTR and EFTR-C for the treatment of small (≤1.5 cm) gastric GISTs. METHODS: This retrospective study included 67 patients who underwent EFTR and 46 patients who underwent EFTR-C at Nanjing Drum Tower Hospital. Clinicopathologic features, adverse events (AEs), and outcomes were compared between the 2 groups. Univariate and multivariate linear and logistic regressions were used to analyze the effects of the procedure on the therapeutic outcomes of patients and adjusted for covariates in the multivariate analysis. RESULTS: The tumor size in the EFTR group tended to be larger (P = .005). The resection time in the EFTR-C group was shorter than that in the EFTR group (38.3 ± 20.7 minutes vs 15.0 ± 11.8 minutes, P < .001), which retained statistical significance with adjustment for the covariates (adjusted mean difference, 22.2; 95% confidence interval, 15.0-29.4; P < .001). The R0 resection rate of the EFTR group was 94.0% and of the EFTR-C group 97.8% (P = .355). The EFTR-C group was superior to the EFTR group in terms of perioperative therapeutic outcomes, AEs, and postoperative recovery. No recurrence occurred in the EFTR and EFTR-C groups. CONCLUSIONS: EFTR-C was found to be the preferable technique for small (≤1.5 cm) gastric GISTs with shorter operation times, lower AEs, faster postoperative recovery, and shorter hospitalization times as compared with EFTR.


Asunto(s)
Resección Endoscópica de la Mucosa , Tumores del Estroma Gastrointestinal , Neoplasias Gástricas , Resección Endoscópica de la Mucosa/métodos , Tumores del Estroma Gastrointestinal/cirugía , Humanos , Estudios Retrospectivos , Neoplasias Gástricas/patología , Resultado del Tratamiento
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