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1.
Mol Cell ; 81(18): 3749-3759, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34469752

RESUMO

The expression of the urea cycle (UC) proteins is dysregulated in multiple cancers, providing metabolic benefits to tumor survival, proliferation, and growth. Here, we review the main changes described in the expression of UC enzymes and metabolites in different cancers at various stages and suggest that these changes are dynamic and should hence be viewed in a context-specific manner. Understanding the evolvability in the activity of the UC pathway in cancer has implications for cancer-immune cell interactions and for cancer diagnosis and therapy.


Assuntos
Carcinogênese/metabolismo , Transformação Celular Neoplásica/metabolismo , Ureia/metabolismo , Amônia/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Expressão Gênica/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Distúrbios Congênitos do Ciclo da Ureia/metabolismo , Distúrbios Congênitos do Ciclo da Ureia/fisiopatologia
2.
Transplantation ; 103(9): 1903-1915, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30801523

RESUMO

BACKGROUND: Regenerative medicine using stem cell technology is an emerging field that is currently tested for inborn and acquired liver diseases. OBJECTIVE: This phase I/II prospective, open label, multicenter, randomized trial aimed primarily at evaluating the safety of Heterologous Human Adult Liver-derived Progenitor Cells (HepaStem) in pediatric patients with urea cycle disorders (UCDs) or Crigler-Najjar (CN) syndrome 6 months posttransplantation. The secondary objective included the assessment of safety up to 12 months postinfusion and of preliminary efficacy. METHODS: Fourteen patients with UCDs and 6 with CN syndrome were divided into 3 cohorts by body weight and intraportally infused with 3 doses of HepaStem. Clinical status, portal vein hemodynamics, morphology of the liver, de novo detection of circulating anti-human leukocyte antigen antibodies, and clinically significant adverse events (AEs) and serious adverse events to infusion were evaluated by using an intent-to-treat analysis. RESULTS: The overall safety of HepaStem was confirmed. For the entire study period, patient-month incidence rate was 1.76 for the AEs and 0.21 for the serious adverse events, of which 38% occurred within 1 month postinfusion. There was a trend of higher events in UCD as compared with CN patients. Segmental left portal vein thrombosis occurred in 1 patient and intraluminal local transient thrombus in a second patient. The other AEs were in line with expectations for catheter placement, cell infusion, concomitant medications, age, and underlying diseases. CONCLUSIONS: This study led to European clinical trial authorization for a phase II study in a homogeneous patient cohort, with repeated infusions and intermediate doses.


Assuntos
Síndrome de Crigler-Najjar/tratamento farmacológico , Transplante de Fígado , Fígado/metabolismo , Transplante de Células-Tronco , Distúrbios Congênitos do Ciclo da Ureia/cirurgia , Adolescente , Fatores Etários , Criança , Pré-Escolar , Síndrome de Crigler-Najjar/sangue , Síndrome de Crigler-Najjar/diagnóstico , Síndrome de Crigler-Najjar/fisiopatologia , Europa (Continente) , Feminino , Humanos , Lactente , Fígado/patologia , Fígado/fisiopatologia , Regeneração Hepática , Transplante de Fígado/efeitos adversos , Masculino , Estudos Prospectivos , Transplante de Células-Tronco/efeitos adversos , Fatores de Tempo , Transplante Heterólogo , Resultado do Tratamento , Distúrbios Congênitos do Ciclo da Ureia/sangue , Distúrbios Congênitos do Ciclo da Ureia/diagnóstico , Distúrbios Congênitos do Ciclo da Ureia/fisiopatologia
3.
Expert Opin Drug Metab Toxicol ; 13(4): 439-448, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27860485

RESUMO

INTRODUCTION: Ammonia-scavenging drugs, benzoate and phenylacetate (PA)/phenylbutyrate (PB), modulate hepatic nitrogen metabolism mainly by providing alternative pathways for nitrogen disposal. Areas covered: We review the major findings and potential novel applications of ammonia-scavenging drugs, focusing on urea cycle disorders and liver disease. Expert opinion: For over 40 years, ammonia-scavenging drugs have been used in the treatment of urea cycle disorders. Recently, the use of these compounds has been advocated in acute liver failure and cirrhosis for reducing hyperammonemic-induced hepatic encephalopathy. The efficacy and mechanisms underlying the antitumor effects of these ammonia-scavenging drugs in liver cancer are more controversial and are discussed in the review. Overall, as ammonia-scavenging drugs are usually safe and well tolerated among cancer patients, further studies should be instigated to explore the role of these drugs in liver cancer. Considering the relevance of glutamine metabolism to the progression and resolution of liver disease, we propose that ammonia-scavenging drugs might also be used to non-invasively probe liver glutamine metabolism in vivo. Finally, novel derivatives of classical ammonia-scavenging drugs with fewer and less severe adverse effects are currently being developed and used in clinical trials for the treatment of acute liver failure and cirrhosis.


Assuntos
Amônia/metabolismo , Hepatopatias/tratamento farmacológico , Distúrbios Congênitos do Ciclo da Ureia/tratamento farmacológico , Animais , Benzoatos/metabolismo , Desenho de Fármacos , Glutamina/metabolismo , Humanos , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/fisiopatologia , Hepatopatias/fisiopatologia , Falência Hepática Aguda/tratamento farmacológico , Falência Hepática Aguda/fisiopatologia , Nitrogênio/metabolismo , Fenilacetatos/metabolismo , Fenilbutiratos/metabolismo , Distúrbios Congênitos do Ciclo da Ureia/fisiopatologia
4.
Cell Transplant ; 19(1): 21-8, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-19796502

RESUMO

The first indication of hepatocyte transplantation is inborn liver-based metabolic disorders. Among these, urea cycle disorders leading to the impairment to detoxify ammonia and Crigler-Najjar Syndrome type I, a deficiency in the hepatic UDP-glucuronosyltransferase 1A1 present the highest incidence. Metabolically qualified human hepatocytes are required for clinical infusion. We proposed fast and sensitive procedures to determine their suitability for transplantation. For this purpose, viability, attachment efficiency, and metabolic functionality (ureogenic capability, cytochrome P450, and phase II activities) are assayed prior to clinical cell infusion to determine the quality of hepatocytes. Moreover, the evaluation of urea synthesis from ammonia and UDP-glucuronosyltransferase 1A1 activity, a newly developed assay using beta-estradiol as substrate, allows the possibility of customizing cell preparation for receptors with urea cycle disorders or Crigler-Najjar Syndrome type I. Sources of human liver and factors derived from the procurement of the liver sample (warm and cold ischemia) have also been investigated. The results show that grafts with a cold ischemia time exceeding 15 h and steatosis should not be accepted for hepatocyte transplantation. Finally, livers from non-heart-beating donors are apparently a potential suitable source of hepatocytes, which could enlarge the liver donor pool.


Assuntos
Bioensaio/métodos , Transplante de Células/métodos , Sobrevivência de Enxerto/fisiologia , Hepatócitos/metabolismo , Hepatócitos/transplante , Hepatopatias/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Separação Celular/métodos , Sobrevivência Celular/fisiologia , Células Cultivadas , Criança , Pré-Escolar , Isquemia Fria/métodos , Síndrome de Crigler-Najjar/metabolismo , Síndrome de Crigler-Najjar/fisiopatologia , Síndrome de Crigler-Najjar/cirurgia , Seleção do Doador/métodos , Seleção do Doador/normas , Feminino , Glucuronosiltransferase/análise , Glucuronosiltransferase/metabolismo , Hepatócitos/citologia , Humanos , Lactente , Recém-Nascido , Hepatopatias/metabolismo , Hepatopatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Receptores de Superfície Celular/análise , Receptores de Superfície Celular/metabolismo , Ureia/metabolismo , Distúrbios Congênitos do Ciclo da Ureia/metabolismo , Distúrbios Congênitos do Ciclo da Ureia/fisiopatologia , Distúrbios Congênitos do Ciclo da Ureia/cirurgia , Adulto Jovem
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