RESUMEN
BACKGROUND: The aim of the study was to investigate the association between human immunodeficiency virus (HIV)-related gut microbiota changes, alterations in the kynurenine (Kyn) pathway of tryptophan (Trp) metabolism, and visceral adipose tissue in the context of HIV infection. METHODS: Three hundred eighty-three people with HIV (PWH) were included from the Copenhagen comorbidity in HIV infection (COCOMO) study. Gut microbiota composition was analyzed by 16S ribosomal ribonucleic acid sequencing. Plasma metabolites were analyzed by liquid chromatography-tandem mass spectrometry. Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) areas were measured by single-slice computed tomography (CT) scan (4th lumbar vertebra). RESULTS: The HIV-related gut microbiota alterations were associated with lower Trp (ß -.01; 95% confidence interval [CI], -0.03 to -0.00) and higher Kyn-to-Trp ratio (ß 0.03; 95% CI, 0.01-0.05), which in turn was associated with higher VAT-to-SAT ratio (ß 0.50; 95% CI, 0.10-0.90) and larger VAT area (ß 30.85; 95% CI, 4.43-57.28). In mediation analysis, the Kyn-to-Trp ratio mediated 10% (P = .023) of the association between the VAT-to-SAT ratio and HIV-related gut microbiota. CONCLUSIONS: Our data suggest HIV-related gut microbiota compositional changes and gut microbial translocation as potential drivers of high Kyn-to-Trp ratio in PWH. In turn, increased activity in the Kyn pathway of Trp metabolism was associated with larger visceral adipose tissue area. Taken together, our findings suggest a possible role for this pathway in the gut-adipose tissue axis in the context of HIV infection.
Asunto(s)
Microbioma Gastrointestinal , Infecciones por VIH , VIH/metabolismo , Infecciones por VIH/complicaciones , Humanos , Grasa Intraabdominal/metabolismo , Quinurenina/metabolismo , Triptófano/metabolismoRESUMEN
The design of more effective therapies for metastatic disease involves development of new compounds able to specifically block the malignant process. We demonstrated previously that a new synthetic nitrogenated compound 3'-1-chloroethyl-2,3-dihydro-1H-imidazo-(2, 1-i)-purine-4-ium-7-yl-3'-deoxy-1',5', 6'-tri-O-(methylsulfonyl)-muco-inositol chloride (DIC) had an anti-proliferative activity on tumor cells in vitro. In the present work we demonstrate that DIC induces apoptosis on the LM3 murine mammary adenocarcinoma cell line in vitro and has anti-angiogenic activity in vivo. We also evaluated toxicity, biodistribution and anti-neoplastic properties of DIC in vivo. Toxicity studies allowed us to establish the LD50 (750 mg/kg body weight). Administration of 250 mg/kg/day (LD10) for 6 days did not cause overt toxic effects. Biodistribution assays revealed that DIC was rapidly eliminated (60% at t=10 min), although it accumulated in tumor tissue at higher concentrations than in other tissues. Daily s.c. treatment with DIC (LD10) for 24 days significantly reduced the number of spontaneous lung metastases. These results suggest that DIC has the ability of impairing the metastatic development by inhibiting angiogenesis and inducing apoptosis on tumor cells.
Asunto(s)
Antineoplásicos/farmacología , Inositol/análogos & derivados , Purinas/farmacología , Adenocarcinoma/patología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Antineoplásicos/toxicidad , División Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Inositol/síntesis química , Inositol/farmacología , Inositol/toxicidad , Radioisótopos de Yodo , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos BALB C , Metástasis de la Neoplasia/prevención & control , Neovascularización Patológica/prevención & control , Purinas/síntesis química , Purinas/toxicidad , Distribución Tisular , Células Tumorales CultivadasRESUMEN
The reaction of 16 alpha,17 alpha-epoxy-3 beta-hydroxy-5-pregnen-20-one with 6-methyl thiopurine activated with sodium hydride leads to the coupling of the purine base with the carbonyl group at C-20 to give a steroidal nucleoside analog, which is termed "nucleosteroid." In the presence of an excess of purine, a parallel reaction occurs in which the oxirane ring is opened, presumably by nucleophilic attack of an intermediate C-20 oxyanion, and yields as the main product of reaction an oligomeric mixture of nucleosteroid units linked together by ether linkages. Analogous reactions conducted with 3 beta-hydroxy-5-pregnen-20-one and with 3 beta,17 alpha-dihydroxy-5-pregnen-20-one gave minor amounts or only traces of the corresponding coupling adduct, and oligomerization did not occur. This behavior is interpreted in terms of the conformational differences showed by the different steroids to the attack by the purine.
Asunto(s)
Purinas/química , Esteroides/química , Acetilación , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Mercaptopurina/análogos & derivados , Mercaptopurina/química , Estructura Molecular , Pregnenos/químicaAsunto(s)
Computadores , Servicio de Alimentación en Hospital , Alimentos , Fenómenos Fisiológicos de la Nutrición , Comportamiento del Consumidor , Costos y Análisis de Costo , Dietoterapia , Dieta para Diabéticos , Dieta Reductora , Dietética , Estudios de Evaluación como Asunto , Humanos , Estaciones del AñoAsunto(s)
Nitrilos/síntesis química , Anhídridos , Cromatografía en Capa Delgada , Cristalización , Hidroxilaminas , MaltosaRESUMEN
Consumer confidence is at its lowest ebb since 1980. Economic growth is at a standstill & unemployment & inflation are both rising. Here's a front-line report from more than three dozen operators who are fending off the recession's dual pressures of slow sales & rising costs. They are using discount pricing, partnering with vendors, setting pay for performance standards & a variety of other recession-beating practices.