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1.
Nat Commun ; 15(1): 2226, 2024 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-38472276

RESUMEN

Hepatic encephalopathy is a neuropsychiatric complication of liver disease which is partly associated with elevated ammonemia. Urea hydrolysis by urease-producing bacteria in the colon is often mentioned as one of the main routes of ammonia production in the body, yet research on treatments targeting bacterial ureases in hepatic encephalopathy is limited. Herein we report a hydroxamate-based urease inhibitor, 2-octynohydroxamic acid, exhibiting improved in vitro potency compared to hydroxamic acids that were previously investigated for hepatic encephalopathy. 2-octynohydroxamic acid shows low cytotoxic and mutagenic potential within a micromolar concentration range as well as reduces ammonemia in rodent models of liver disease. Furthermore, 2-octynohydroxamic acid treatment decreases cerebellar glutamine, a product of ammonia metabolism, in male bile duct ligated rats. A prototype colonic formulation enables reduced systemic exposure to 2-octynohydroxamic acid in male dogs. Overall, this work suggests that urease inhibitors delivered to the colon by means of colonic formulations represent a prospective approach for the treatment of hepatic encephalopathy.


Asunto(s)
Encefalopatía Hepática , Hepatopatías , Perros , Masculino , Ratas , Animales , Encefalopatía Hepática/metabolismo , Ureasa/metabolismo , Amoníaco/metabolismo , Glutamina , Bacterias/metabolismo
2.
Metab Brain Dis ; 38(6): 1999-2012, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37148431

RESUMEN

Chronic liver disease (CLD) is a serious condition where various toxins present in the blood affect the brain leading to type C hepatic encephalopathy (HE). Both adults and children are impacted, while children may display unique vulnerabilities depending on the affected window of brain development.We aimed to use the advantages of high field proton Magnetic Resonance Spectroscopy (1H MRS) to study longitudinally the neurometabolic and behavioural effects of Bile Duct Ligation (animal model of CLD-induced type C HE) on rats at post-natal day 15 (p15) to get closer to neonatal onset liver disease. Furthermore, we compared two sets of animals (p15 and p21-previously published) to evaluate whether the brain responds differently to CLD according to age onset.We showed for the first time that when CLD was acquired at p15, the rats presented the typical signs of CLD, i.e. rise in plasma bilirubin and ammonium, and developed the characteristic brain metabolic changes associated with type C HE (e.g. glutamine increase and osmolytes decrease). When compared to rats that acquired CLD at p21, p15 rats did not show any significant difference in plasma biochemistry, but displayed a delayed increase in brain glutamine and decrease in total-choline. The changes in neurotransmitters were milder than in p21 rats. Moreover, p15 rats showed an earlier increase in brain lactate and a different antioxidant response. These findings offer tentative pointers as to which neurodevelopmental processes may be impacted and raise the question of whether similar changes might exist in humans but are missed owing to 1H MRS methodological limitations in field strength of clinical magnet.


Asunto(s)
Encefalopatía Hepática , Hepatopatías , Humanos , Adulto , Niño , Ratas , Animales , Encefalopatía Hepática/metabolismo , Glutamina/metabolismo , Espectroscopía de Resonancia Magnética , Hepatopatías/metabolismo , Encéfalo/metabolismo , Ácido Láctico/metabolismo
3.
Urol Oncol ; 41(4): 210.e1-210.e8, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36868883

RESUMEN

INTRODUCTION: To evaluate the role of unilateral inguinal lymph-node dissection (ILND) plus contralateral dynamic sentinel node biopsy (DSNB) vs. bilateral ILND in clinical N1 (cN1) penile squamous cell carcinoma (peSCC) patients. MATERIAL AND METHODS: Within our institutional database (1980-2020, included), we identified 61 consecutive cT1-4 cN1 cM0 patients with histological confirmed peSCC who underwent either unilateral ILND plus DSNB (26) or bilateral ILND (35). RESULTS: Median age was 54 years (Interquartile range [IQR]: 48-60 years). Median follow-up was 68 months (IQR 21-105 months). Most patients had pT1 (23 %) or pT2 (54.1%), as well as G2 (47.5%) or G3 (23%) tumors, while lymphovascular invasion (LVI) was present in 67.1% of cases. Considering a cN1 and a cN0 groin, overall 57 out of 61 patients (93.5%) had nodal disease in the cN1 groin. Conversely, only 14 out of 61 patients (22.9%) had nodal disease in the cN0 groin. 5-year IR-free survival was 91% (Confidence interval [CI] 80%-100%) for bilateral ILND group and 88% (CI 73%-100%) for the ipsilateral ILND plus DSNB group (P-value 0.8). Conversely, 5-year CSS was 76% (CI 62%-92%) for bilateral ILND group and 78% (CI 63%-97%) for the ipsilateral ILND plus contralateral DSNB group (P-value 0.9). CONCLUSIONS: In patients with cN1 peSCC the risk of occult contralateral nodal disease is comparable to cN0 high risk peSCC and the gold standard, namely bilateral ILND, may be replaced by unilateral ILND and contralateral DSNB without affecting positive node detection, IRRs and CSS.


Asunto(s)
Carcinoma de Células Escamosas , Neoplasias del Pene , Masculino , Humanos , Persona de Mediana Edad , Biopsia del Ganglio Linfático Centinela , Escisión del Ganglio Linfático , Ganglios Linfáticos/cirugía , Ganglios Linfáticos/patología , Pene/patología , Neoplasias del Pene/cirugía , Neoplasias del Pene/patología , Carcinoma de Células Escamosas/cirugía , Carcinoma de Células Escamosas/patología , Estadificación de Neoplasias
4.
Sci Rep ; 11(1): 17988, 2021 09 09.
Artículo en Inglés | MEDLINE | ID: mdl-34504135

RESUMEN

Type C hepatic encephalopathy (HE) is a neuropsychiatric disease caused by chronic liver disease. Management of type C HE remains an important challenge because treatment options are limited. Both the antibiotic rifaximin and probiotics have been reported to reduce the symptoms of HE, but longitudinal studies assessing their effects on brain metabolism are lacking and the molecular mechanisms underpinning their effects are not fully understood. Therefore, we evaluated in detail the effects of these different treatments on the neurometabolic changes associated with type C HE using a multimodal approach including ultra-high field in vivo 1H MRS. We analyzed longitudinally the effect of rifaximin alone or in combination with the probiotic Vivomixx on the brain metabolic profile in the hippocampus and cerebellum of bile duct ligated (BDL) rats, an established model of type C HE. Overall, while rifaximin alone appeared to induce no significant effect on the neurometabolic profile of BDL rats, its association with the probiotic resulted in more attenuated neurometabolic alterations in BDL rats followed longitudinally (i.e. a smaller increase in Gln and milder decrease in Glu and Cr levels). Given that both rifaximin and some probiotics are used in the treatment of HE, the implications of these findings may be clinically relevant.


Asunto(s)
Antibacterianos/uso terapéutico , Cerebelo/metabolismo , Encefalopatía Hepática/dietoterapia , Encefalopatía Hepática/tratamiento farmacológico , Hipocampo/metabolismo , Metaboloma/efectos de los fármacos , Probióticos/uso terapéutico , Rifaximina/uso terapéutico , Transducción de Señal/efectos de los fármacos , Animales , Bilirrubina/sangre , Modelos Animales de Enfermedad , Encefalopatía Hepática/sangre , Estudios Longitudinales , Masculino , Espectroscopía de Protones por Resonancia Magnética/métodos , Ratas , Ratas Wistar , Resultado del Tratamiento
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