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ß-Glucosidase is a crucial cellulase, as its activity determines the efficiency of cellulose hydrolysis into glucose. This study addresses the functional and structural characteristics of Thermotoga profunda ß-glucosidase (Tp-BGL). Tp-BGL exhibited a Km of 0.3798 mM for p-nitrophenyl-ß-d-glucopyranoside (pNPGlc) and 4.44 mM for cellobiose, with kcat/Km of 1211.16 and 4.18 s-1 mM-1, respectively. In addition, Tp-BGL showed significant pH adaptability and thermal stability, with a Tm of 85.7 °C and retaining >90 % of its activity after incubation at 80 °C for 90 min. The crystal structure of Tp-BGL was resolved at 1.95 Å resolution, and reveals a typical TIM barrel structure. Comparative structural analysis highlighted that the major distinction between Tp-BGL and the other glucosidases lies in their loop regions.
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BACKGROUND AND OBJECTIVES: Malnutrition, mainly caused by inadequate energy intake, predicts poor prognostic outcome in chronic kidney disease (CKD) patients. In this study, we aim to explore the effect of non-protein energy supplement in CKD stage 3b-5 (CKD3b-5) malnourished patients with or without receiving continuous peritoneal dialysis (PD). METHODS AND STUDY DESIGN: 30 patients with CKD3b-5 and 20 patients who received PD were identified as malnourished according to Subjective Global Assessment (SGA), and enrolled into this clinical study. Compared with the control group which just received regular nutrition counseling, an additional non-protein energy supplement (600 kcal) was given to the participants for 12 weeks in the intervention group. Before and after study, the nutritional status of patients was judged by human body composition measurement, anthropometric parameters, physical fitness test, and quality of life survey. Other biochemical indexes relating to nutrition, renal function and inflammatory response were also included for disease evaluation. RESULTS: After 12 weeks of oral non-protein energy supplementation, the body weight, body fat and associated anthropometric parameters significantly increased upon intervention. Also, the participants showed enhanced physical fitness and better life quality in the intervention group. Consistently, the improved nutritional status was further confirmed by biochemical examinations. However, we did not observe a perceptible change of renal function, measured residual renal function, or general inflammatory response indices after intervention. CONCLUSIONS: 12 weeks of oral non-protein energy supplement could efficiently improve the nutritional status of CKD3b-5 patients and those who receive peritoneal dialysis; meanwhile, it has little effect on renal function and inflammatory response.
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Desnutrición , Diálisis Peritoneal , Insuficiencia Renal Crónica , Humanos , Desnutrición/etiología , Desnutrición/terapia , Estado Nutricional , Diálisis Peritoneal/efectos adversos , Diálisis Peritoneal/métodos , Calidad de Vida , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/terapiaRESUMEN
BACKGROUND: Gastrointestinal (GI) diseases are known to be largely influenced by one's lifestyle and dietary uptake. A high-salt diet (HSD) is well recognized as a risk factor for cardiovascular complications, hypertension, and metabolic syndromes. However, the relationship between an HSD and the GI system, which is the compartment that comes in direct contact with exogenous stimulants, has not been fully explored. AIMS: We seek to better understand the complexity of the pathogenic effects of an HSD in the context of GI disorders. METHODS: By searching the PubMed and Web of science, the review of literature was performed using keywords: high-salt and GI, high-salt and immunity, salt and microbiota, salt and hormone. RESULTS: In this review, we concluded that high-salt intake potentially perturbs the local immune homeostasis, alters the gut microbiota composition and function, and affects the endocrine hormone profiling in the GI system. CONCLUSION: HSD might get involved in GI diseases through the reshaping of gastroenterological milieu, which could help to better understand the complexity of the pathogenic effects of an HSD in the context of GI disorders.
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Conducta Alimentaria/fisiología , Enfermedades Gastrointestinales/epidemiología , Microbioma Gastrointestinal/efectos de los fármacos , Tracto Gastrointestinal/efectos de los fármacos , Sodio en la Dieta/efectos adversos , Enfermedades Gastrointestinales/etiología , Microbioma Gastrointestinal/fisiología , Tracto Gastrointestinal/microbiología , Tracto Gastrointestinal/fisiología , Humanos , Incidencia , Factores de RiesgoRESUMEN
Lymphangiogenesis occurs during renal fibrosis in patients with chronic kidney diseases and vascular endothelial growth factor (VEGF)-C is required for the formation of lymphatic vessels; however, the underlying mechanisms remain unclear. We demonstrate that macrophages can regulate unilateral ureteral obstruction (UUO)-induced renal lymphangiogenesis by expressing high levels of VEGF-C by C-C motif chemokine receptor 2 (CCR2)-mediated signaling. Mice deficient in Ccr2 manifested repressed lymphangiogenesis along with attenuated renal injury and fibrosis after UUO induction. The infiltrated macrophages after UUO induction generated a microenvironment in favor of lymphangiogenesis, which likely depended on Ccr2 expression. Mechanistic studies revealed that CCR2 is required for macrophages to activate phosphatidylinositol 3-kinase (PI3K)-AKT-mechanistic target of rapamycin (mTOR) signaling in response to its ligand monocyte chemoattractant protein 1 stimulation, whereas hypoxia-inducible factor (HIF)-1α is downstream of PI3K-AKT-mTOR signaling. HIF-1α directly bound to the VEGF-C promoter to drive its expression to enhance lymphangiogenesis. Collectively, we characterized a novel regulatory network in macrophages, in which CCR2 activates PI3K-AKT-mTOR signaling to mediate HIF-1α expression, which then drives VEGF-C expression to promote lymphangiogenesis.
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Riñón/metabolismo , Linfangiogénesis/fisiología , Macrófagos/metabolismo , Receptores CCR2/metabolismo , Transducción de Señal/fisiología , Obstrucción Ureteral/metabolismo , Animales , Fibrosis/genética , Fibrosis/metabolismo , Fibrosis/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Riñón/patología , Ratones , Ratones Noqueados , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores CCR2/genética , Serina-Treonina Quinasas TOR/metabolismo , Obstrucción Ureteral/patología , Factor C de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Aloperine is a quinolizidine alkaloid extracted from the leaves of Sophora plants. It has been recognized with the potential to treat inflammatory and allergic diseases as well as tumors. In this report, we demonstrate that pretreatment with aloperine provided protection for mice against ischemia-reperfusion (IR)-induced acute renal injury as manifested by the attenuated inflammatory infiltration, reduced tubular apoptosis, and well-preserved renal function. Mechanistic studies revealed that aloperine selectively repressed IL-1ß and IFN-γ expression by regulating PI3K/Akt/mTOR signaling and NF-κB transcriptional activity. However, aloperine did not show a perceptible impact on IL-6 and TGF-ß expression and the related Jak2/Stat3 signaling. It was also noted that aloperine regulates AP-1 activity, through which it not only enhances SOD expression to increase reactive oxygen species (ROS) detoxification but also promotes the expression of antiapoptotic Bcl-2, thereby preventing tubular cells from IR-induced apoptosis. Collectively, our data suggest that administration of aloperine prior to IR insults, such as renal transplantation, could be a viable approach to prevent IR-induced injuries.
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Three ultraviolet light-emitting organic acids of 3,3'-(4-phenyl-4H-1,2,4-triazole-3,5-diyl)dibenzoic acid (Tz-1), 4,4',4â³-(4H-1,2,4-triazole-3,4,5-triyl)tribenzoic acid (Tz-2), and 4,4'-(4-(4'-carboxy-[1,1'-biphenyl]-4-yl)-4H-1,2,4-triazole-3,5-diyl)dibenzoic acid (Tz-3) were successfully synthesized and fully characterized by the (1)H NMR, the IR absorption spectra, and the X-ray single crystal diffraction. It was found that Tz-1, Tz-2, and Tz-3 could give out the ultraviolet photoluminescent spectra centered at 369 nm, 365 nm and 350 nm, respectively. The luminescence quantum yields of Tz-1 and Tz-2 were measured to be 0.20 and 0.14, respectively. Additionally, the density functional theory (DFT) and the time-dependent DFT calculations were also carried out for Tz-1, Tz-2, and Tz-3.
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Benzoatos/síntesis química , Luz , Teoría Cuántica , Triazoles/síntesis química , Rayos Ultravioleta , Benzoatos/química , Luminiscencia , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , Espectrofotometría Infrarroja , Espectrofotometría Ultravioleta , Triazoles/químicaRESUMEN
RATIONALE: Intramural pregnancy is a rare ectopic pregnancy in which the gestational sac is implanted between the muscle walls. Due to the lack of specific clinical manifestations, it is easy to misdiagnose or miss them. If it is allowed to get worse, the uterus will burst, and there will be a lot of bleeding in the later stages, which could lead to the death of the patient. PATIENT CONCERNS: The patient had no history of uterine surgery, embryo transplantation, or any other operations. She complained of having abdominal distention and swelling of the waist but no vaginal bleeding or lower abdomen discomfort. DIAGNOSES: According to her transvaginal ultrasonography, we highly suspected ectopic pregnancy. Hysteroscopy combined with laparoscopy is an effective treatment option that can prevent life-threatening problems. During the surgery, pituitrin helped find the gestational sac, and the pathology report confirmed that it was an intramural pregnancy. INTERVENTIONS: Hysteroscopy combined with laparoscopy is an effective treatment option that can prevent life-threatening problems. During the surgery, we used pituitrin to help find the gestational sac. The use of pituitrin can minimize bleeding during a uterine operation and indicate the location of an intramural pregnancy, helping surgeons to complete the operation successfully. OUTCOMES: The patient recovered quickly and was discharged on the 4th day after surgery, with a significant decrease in human chorionic gonadotrophin (HCG) levels from 14,792.26 mIU/mL before surgery to 1071.40 mIU/mL at discharge. During the follow up, her HCG level dropped to 50.90 mIU/mL on the 14th day after the surgery. She monitored the HCG levels intermittently until they fell within the normal range. LESSONS: Intramural pregnancy is a rare form of ectopic pregnancy, and it is difficult to diagnose early on. This may result in uterine rupture or even life-threatening hemorrhage. If an intramural pregnancy is suspected in early pregnancy, hysteroscopy combined with laparoscopy is advised, and if necessary, low-dose posterior pituitary hormone can enhance uterine contractions and better reveal the position of the gestational sac within the uterine wall.
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Laparoscopía , Hormonas Neurohipofisarias , Embarazo Ectópico , Humanos , Embarazo , Femenino , Histeroscopía , Embarazo Ectópico/diagnóstico , Embarazo Ectópico/cirugía , ÚteroRESUMEN
Body composition measurement plays an important role in the nutritional diagnosis and treatment of diseases. In the past 30 years, the detection of body composition based on bioelectrical impedance analysis (BIA) has been widely used and explored in a variety of diseases. With the development of technology, bioelectrical impedance analysis has gradually developed from single-frequency BIA (SF-BIA) to multi-frequency BIA (multi-frequency BIA, MF-BIA) and over a range of frequencies (bioimpedance spectroscopy, BIS). As the clinical significance of nutrition management in chronic kidney disease has gradually become prominent, body composition measurement by BIA has been favored by nephrologists and nutritionists. In the past 20 years, there have been many studies on the application of BIA in patients with CKD. This review describes and summarizes the latest research results of BIA in nutritional management of patients with CKD including pre-dialysis, hemodialysis, peritoneal dialysis and kidney transplantation, in order to provide reference for the application and research of BIA in nutritional management of chronic kidney disease in the future.
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The pathogenesis of inflammatory bowel disease (IBD) is related to genetic susceptibility, enteric dysbiosis, and uncontrolled, chronic inflammatory responses that lead to colonic tissue damage and impaired intestinal absorption. As a consequence, patients with IBD are prone to nutrition deficits after each episode of disease resurgence. Nutritional supplementation, especially for protein components, is often implemented during the remission phase of IBD. Notably, ingested nutrients could affect the progression of IBD and the prognostic outcome of patients; therefore, they should be cautiously evaluated prior to being used for IBD intervention. Arginine (Arg) is a semi-essential amino acid required for protein synthesis and intimately associated with gut pathophysiology. To help optimize arginine-based nutritional intervention strategies, the present work summarizes that during the process of IBD, patients manifest colonic Arg deficiency and the turbulence of Arg metabolic pathways. The roles of Arg-nitric oxide (catalyzed by inducible nitric oxide synthase) and Arg-urea (catalyzed by arginases) pathways in IBD are debatable; the Arg-polyamine and Arg-creatine pathways are mainly protective. Overall, supplementation with Arg is a promising therapeutic strategy for IBD; however, the dosage of Arg may need to be carefully tailored for different individuals at different disease stages. Additionally, the combination of Arg supplementation with inhibitors of Arg metabolic pathways as well as other treatment options is worthy of further exploration.
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Enfermedades Inflamatorias del Intestino , Humanos , Suplementos Dietéticos , Arginina , Inflamación , NutrientesRESUMEN
Ribonucleases (RNases) are responsible for RNA metabolism. RNase J, the core enzyme of the RNA degradosome, plays an essential role in global mRNA decay. Emerging evidence showed that the RNase J of Mycobacterium tuberculosis (Mtb-RNase J) could be an excellent target for treating Mtb infection. Here, crystal structures of Mtb-RNase J in apo-state and complex with the single-strand RNA reveal the conformational change upon RNA binding and hydrolysis. Mtb-RNase J forms an active homodimer through the interactions between the ß-CASP and the ß-lactamase domain. Knockout of RNase J slows the growth rate and changes the colony morphologies and cell length in Mycobacterium smegmatis, which is restored by RNase J complementation. Finally, RNA-seq analysis shows that the knockout strain significantly changes the expression levels of 49 genes in metabolic pathways. Thus, our current study explores the structural basis of Mtb-RNase J and might provide a promising candidate in pharmacological treatment for tuberculosis.
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Mycobacterium tuberculosis , Ribonucleasas , Ribonucleasas/metabolismo , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/metabolismo , ARN/metabolismo , Ribonucleasa Pancreática/metabolismo , HidrólisisRESUMEN
Saccharomyces boulardii (S. boulardii) is a probiotic yeast that is widely used to treat gastrointestinal disorders. The present study is aimed to explore the therapeutic effects of S. boulardii on dextran sulfate sodium- (DSS-) induced murine ulcerative colitis (UC) and illustrate the mechanisms of action. C57BL/6 mice were administered S. boulardii (105 and 107 CFU/ml, p.o.) for 3 weeks and then given DSS [2.5% (w/v)] for one week. Administration of S. boulardii prevented DSS-induced reduction in body weight, diarrhea, bloody feces, decreased colon length, and loss of histological structure. Moreover, S. boulardii protected the intestinal barrier by increasing the levels of tight junction proteins zona occludens-1 and Occludin and exerted immunomodulatory effects in DSS-induced mice. Furthermore, S. boulardii suppressed the colonic inflammation by reducing the levels of Interleukin-1ß, Interleukin-6, and Tumor necrosis factor alpha and restored myeloperoxidase activity in mice exposed to DSS. S. boulardii also mitigated colonic oxidative damage by increasing the levels of antioxidant enzymes (superoxide dismutase, catalase, and heme oxygenase 1) and glutathione and decreasing malondialdehyde accumulation. Further studies identified that S. boulardii suppressed the nuclear translocation of nuclear factor kappa B (NF-κB) p65 subunit by decreasing IκKα/ß levels, while promoted the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) in DSS-exposed mice. Collectively, S. boulardii possessed an appreciable therapeutic effect against the experimental mice model of UC. The protective mechanism of S. boulardii may involve inhibition of NF-κB-mediated proinflammatory signaling and activation of Nrf2-modulated antioxidant defense in addition to intestinal barrier protective and immunomodulatory effects.
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Colitis Ulcerosa/prevención & control , Sulfato de Dextran/toxicidad , Regulación de la Expresión Génica , Inflamación/prevención & control , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Saccharomyces boulardii/fisiología , Animales , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/patología , Femenino , Inflamación/inducido químicamente , Inflamación/metabolismo , Inflamación/patología , Ratones , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/genética , FN-kappa B/genética , Saccharomyces boulardii/química , Transducción de SeñalRESUMEN
The functional state of T cells is diverse and under dynamic control for adapting to the changes of microenvironment. Reversible protein phosphorylation represents an important post-translational modification that not only involves in the immediate early response of T cells, but also affects their functionality in the long run. Perturbation of global phosphorylation profile and/or phosphorylation of specific signaling nodes result in aberrant T cell activity. Dual specific phosphatases (DUSPs), which target MAPKs and beyond, have increasingly been emerged as a versatile regulator in T cell biology. Herein in this mini review, we sought to summarize and discuss the impact of DUSP proteins on the regulation of effector T cell activity, T cell polarization, regulatory T cell development and T cell senescence/exhaustion. Given the distinctive engagement of each DUSP member under various disease settings such as chronic infection, autoimmune disorders, cancer and age-related diseases, DUSP proteins likely hold the promise to become a druggable target other than the existing therapeutics that are predominantly by manipulating protein kinase activity.
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Fosfatasas de Especificidad Dual/metabolismo , Sistema de Señalización de MAP Quinasas/inmunología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Reguladores/inmunología , Animales , Senescencia Celular/inmunología , Humanos , Activación de Linfocitos , Fosforilación/inmunología , Linfocitos T Citotóxicos/metabolismo , Linfocitos T Reguladores/metabolismoRESUMEN
Kdm2a catalyzes H3K36me2 demethylation to play an intriguing epigenetic regulatory role in cell proliferation, differentiation, and apoptosis. Herein we found that myeloid-specific knockout of Kdm2a (LysM-Cre-Kdm2af/f, Kdm2a-/-) promoted macrophage M2 program by reprograming metabolic homeostasis through enhancing fatty acid uptake and lipolysis. Kdm2a-/- increased H3K36me2 levels at the Pparg locus along with augmented chromatin accessibility and Stat6 recruitment, which rendered macrophages with preferential M2 polarization. Therefore, the Kdm2a-/- mice were highly protected from high-fat diet (HFD)-induced obesity, insulin resistance, and hepatic steatosis, and featured by the reduced accumulation of adipose tissue macrophages and repressed chronic inflammation following HFD challenge. Particularly, Kdm2a-/- macrophages provided a microenvironment in favor of thermogenesis. Upon HFD or cold challenge, the Kdm2a-/- mice manifested higher capacity for inducing adipose browning and beiging to promote energy expenditure. Collectively, our findings demonstrate the importance of Kdm2a-mediated H3K36 demethylation in orchestrating macrophage polarization, providing novel insight that targeting Kdm2a in macrophages could be a viable therapeutic approach against obesity and insulin resistance.
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Histona Demetilasas con Dominio de Jumonji/deficiencia , Macrófagos/metabolismo , Obesidad/genética , PPAR gamma/metabolismo , Animales , Dieta Alta en Grasa , Humanos , Masculino , Ratones , Obesidad/patología , Termogénesis , TransfecciónRESUMEN
Melatonin (N-acetyl-5-methoxytryptamine), a circadian-regulating hormone, has been reported to exert a protective role during acute kidney injury (AKI) induced by renal ischemia-reperfusion injury (I/R). High-mobility group box 1 (HMGB1) is a novel member of the damage-associated molecular pattern (DAMP) family, and has been verified to be an inflammatory cytokine mediating AKI induced by I/R and cisplatin. However, the effect of melatonin on HMGB1, as well as the relationship of these two with folic acid induced AKI are elusive. In this study, we sought to identify the role of melatonin on folic acid induced AKI and its association with HMGB1. Pretreatment with melatonin significantly attenuated folic acid-induced increase in serum creatinine and BUN levels, renal tubular epithelial cell (TEC) apoptosis, and the infiltration of inflammatory cells and secretion of cytokines. Moreover, melatonin pretreatment promoted renal tubular proliferation and improved cell cycle arrest of TECs after folic acid-induced renal damage. This protective role of melatonin was closely related to the inhibition of nucleocytoplasmic translocation of HMGB1 in TECs. These data provide a strong proof that administering melatonin prior to folic acid insult may shed light on a potential treatment for AKI.
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A 5/6 nephrectomized (Nx) rat model was employed to address the impact of telmisartan on CKD related renal injury and the underlying molecular mechanisms. It was noted that telmisartan provided protection for rats against 5/6 Nx induced lethality. Telmisartan treated 5/6 Nx rats manifested improved renal function as characterized by the higher GFR but lower urinary albumin, BUN and Scr as compared with that of control rats. Telmisartan treatment also significantly decreased systolic blood pressure and alleviated glomerulosclerosis and interstitial fibrosis. Mechanistic studies revealed that telmisartan possesses the capability to increase NO generation in the kidney. Further studies demonstrated that telmisartan promotes PPARγ expression, by which it specifically enhances nNOS expression in the kidneys after 5/6 Nx insult. Particularly, blockade of PPARγ signaling by GW9662 abolished the protective effect conferred by telmisartan, indicating that telmisartan induction of renal nNOS expression along with NO generation is dependent on PPARγ signaling. Together, our data support that telmisartan could be a promising drug for treatment of chronic kidney diseases in diverse clinical settings.