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1.
Nihon Yakurigaku Zasshi ; 156(5): 275-281, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34470931

RESUMO

Nonalcoholic steatohepatitis (NASH) is one of the most common causes of chronic liver disease, with the increased prevalence of obesity, type 2 diabetes, and metabolic disorders in recent years. As the disease progresses, it leads to hepatic fibrosis, which may progress to hepatocellular carcinoma, but there is still no cure for severe hepatic fibrosis. Currently, in order to develop drugs for the treatment of NASH, the effects of candidate drugs are evaluated by a long-term administration to mice and rats that are fed a high-fat or methionine-deficient diet to reproduce the pathology of fatty liver and liver fibrosis. Since drug development using these experimental animals is time-consuming and costly, in vitro models that reproduce the pathology of NASH have recently been developing. In this review, we will outline the current issues in the diagnosis and treatment of NASH, and introduce our research for the discovery of early diagnostic markers and the development of new therapeutic agents using liver organoid cultures derived from mouse models of NASH.


Assuntos
Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Animais , Dieta Hiperlipídica , Modelos Animais de Doenças , Descoberta de Drogas , Fígado , Cirrose Hepática , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/patologia , Organoides , Ratos
2.
Int J Mol Sci ; 22(16)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34445428

RESUMO

While many antitumor drugs have yielded unsatisfactory therapeutic results, drugs are one of the most prevalent therapeutic measures for the treatment of cancer. The development of cancer largely results from mutations in nuclear DNA, as well as from those in mitochondrial DNA (mtDNA). Molecular hydrogen (H2), an inert molecule, can scavenge hydroxyl radicals (·OH), which are known to be the strongest oxidizing reactive oxygen species (ROS) in the body that causes these DNA mutations. It has been reported that H2 has no side effects, unlike conventional antitumor drugs, and that it is effective against many diseases caused by oxidative stress and chronic inflammation. Recently, there has been an increasing number of papers on the efficacy of H2 against cancer and its effects in mitigating the side effects of cancer treatment. In this review, we demonstrate the efficacy and safety of H2 as a novel antitumor agent and show that its mechanisms may not only involve the direct scavenging of ·OH, but also other indirect biological defense mechanisms via the regulation of gene expression.


Assuntos
Antineoplásicos/farmacologia , Hidrogênio/farmacologia , Neoplasias/genética , Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Hidrogênio/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
3.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281264

RESUMO

Mibyou, or pre-symptomatic diseases, refers to state of health in which a disease is slowly developing within the body yet the symptoms are not apparent. Common examples of mibyou in modern medicine include inflammatory diseases that are caused by chronic inflammation. It is known that chronic inflammation is triggered by the uncontrolled release of proinflammatory cytokines by neutrophils and macrophages in the innate immune system. In a recent study, it was shown that molecular hydrogen (H2) has the ability to treat chronic inflammation by eliminating hydroxyl radicals (·OH), a mitochondrial reactive oxygen species (ROS). In doing so, H2 suppresses oxidative stress, which is implicated in several mechanisms at the root of chronic inflammation, including the activation of NLRP3 inflammasomes. This review explains these mechanisms by which H2 can suppress chronic inflammation and studies its applications as a protective agent against different inflammatory diseases in their pre-symptomatic state. While mibyou cannot be detected nor treated by modern medicine, H2 is able to suppress the pathogenesis of pre-symptomatic diseases, and thus exhibits prospects as a novel protective agent.


Assuntos
Doenças Assintomáticas , Hidrogênio/farmacologia , Substâncias Protetoras/farmacologia , Doença de Alzheimer/prevenção & controle , Animais , Doença Crônica , Diabetes Mellitus Tipo 2/prevenção & controle , Sequestradores de Radicais Livres/farmacologia , Hepatite/prevenção & controle , Humanos , Hipertensão/prevenção & controle , Inflamação/prevenção & controle , Modelos Biológicos , Neoplasias/prevenção & controle , Estresse Oxidativo , Doença de Parkinson/prevenção & controle , Insuficiência Renal Crônica/prevenção & controle
4.
Int J Mol Sci ; 22(9)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33925430

RESUMO

Although ionizing radiation (radiation) is commonly used for medical diagnosis and cancer treatment, radiation-induced damages cannot be avoided. Such damages can be classified into direct and indirect damages, caused by the direct absorption of radiation energy into DNA and by free radicals, such as hydroxyl radicals (•OH), generated in the process of water radiolysis. More specifically, radiation damage concerns not only direct damages to DNA, but also secondary damages to non-DNA targets, because low-dose radiation damage is mainly caused by these indirect effects. Molecular hydrogen (H2) has the potential to be a radioprotective agent because it can selectively scavenge •OH, a reactive oxygen species with strong oxidizing power. Animal experiments and clinical trials have reported that H2 exhibits a highly safe radioprotective effect. This paper reviews previously reported radioprotective effects of H2 and discusses the mechanisms of H2, not only as an antioxidant, but also in intracellular responses including anti-inflammation, anti-apoptosis, and the regulation of gene expression. In doing so, we demonstrate the prospects of H2 as a novel and clinically applicable radioprotective agent.


Assuntos
Hidrogênio/farmacologia , Neoplasias/terapia , Lesões por Radiação/prevenção & controle , Protetores contra Radiação/farmacologia , Animais , Antioxidantes/farmacologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/prevenção & controle , Gastroenteropatias/etiologia , Gastroenteropatias/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos da radiação , Humanos , Hidrogênio/uso terapêutico , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/efeitos da radiação , Masculino , Qualidade de Vida , Protetores contra Radiação/uso terapêutico , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Espermatozoides/efeitos dos fármacos , Espermatozoides/efeitos da radiação
5.
Int J Mol Sci ; 22(5)2021 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-33806292

RESUMO

Mitochondria are the largest source of reactive oxygen species (ROS) and are intracellular organelles that produce large amounts of the most potent hydroxyl radical (·OH). Molecular hydrogen (H2) can selectively eliminate ·OH generated inside of the mitochondria. Inflammation is induced by the release of proinflammatory cytokines produced by macrophages and neutrophils. However, an uncontrolled or exaggerated response often occurs, resulting in severe inflammation that can lead to acute or chronic inflammatory diseases. Recent studies have reported that ROS activate NLRP3 inflammasomes, and that this stimulation triggers the production of proinflammatory cytokines. It has been shown in literature that H2 can be based on the mechanisms that inhibit mitochondrial ROS. However, the ability for H2 to inhibit NLRP3 inflammasome activation via mitochondrial oxidation is poorly understood. In this review, we hypothesize a possible mechanism by which H2 inhibits mitochondrial oxidation. Medical applications of H2 may solve the problem of many chronic inflammation-based diseases, including coronavirus disease 2019 (COVID-19).


Assuntos
COVID-19/terapia , Hidrogênio/farmacologia , Hidrogênio/uso terapêutico , Inflamação/terapia , Mitocôndrias/fisiologia , Animais , Doença Crônica , Humanos , Inflamação/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo
6.
Clin Genitourin Cancer ; 15(3): 403-410.e2, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28254206

RESUMO

BACKGROUND: A significant subgroup of metastatic renal cell carcinoma (mRCC) patients discontinue vascular endothelial growth factor-targeted therapies (VEGF-TT) because of toxicity. Whether clinical outcomes differ in patients who receive second-line (2L) targeted therapy on the basis of reason for discontinuation of first-line (1L) therapy is unknown. PATIENTS AND METHODS: Patients from 15 International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) centers who started 2L targeted therapy were included and the reason for discontinuation of 1L therapy retrospectively collected. Treatment outcomes of 2L, including response, time to treatment failure, and overall survival (OS) were assessed. RESULTS: In total, 1124 patients were identified: 866 patients (77%) discontinued 1L VEGF-TT because of disease progression, and 208 patients (19%) because of toxicity. The reason for discontinuation of 1L therapy did not differ according to IMDC risk group. Compared with patients who stopped 1L VEGF-TT because of disease progression, patients who stopped because of toxicity had greater clinical benefit (nonprogressive disease as best response) in 2L treatment (68% vs. 56%; adjusted odds ratio, 1.58; 95% confidence interval [CI], 1.07-2.35; P = .023) and longer OS (17.4 vs. 11.2 months; adjusted hazard ratio, 0.69; 95% CI, 0.56-0.84; P = .0002) adjusted for type of therapy, time to initiation of 2L treatment, IMDC risk group, and number of metastases at initiation of 2L treatment. CONCLUSION: mRCC patients who discontinue 1L VEGF-TT because of toxicity have better outcomes with 2L therapy than patients who stop therapy because of disease progression. These findings should be taken into consideration when designing clinical trials for 2L therapies in mRCC.


Assuntos
Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Progressão da Doença , Feminino , Humanos , Masculino , Terapia de Alvo Molecular , Metástase Neoplásica , Estudos Retrospectivos , Resultado do Tratamento
8.
Eur Urol ; 71(2): 204-209, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27318422

RESUMO

BACKGROUND: The use of third-line targeted therapy (TTT) in metastatic renal cell carcinoma (mRCC) is not well characterized and varies due to the lack of robust data to guide treatment decisions. This study examined the use of third-line therapy in a large international population. OBJECTIVE: To evaluate the use and efficacy of targeted therapy in a third-line setting. DESIGN, SETTING, AND PARTICIPANTS: Twenty-five international cancer centers provided consecutive data on 4824 mRCC patients who were treated with an approved targeted therapy. One thousand and twelve patients (21%) received TTT and were included in the analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patients were analyzed for overall survival (OS) and progression-free survival using Kaplan-Meier curves, and were evaluated for overall response. Cox regression analyses were used to determine the statistical association between OS and the six factors included in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic model. Subgroup analysis was performed on patients stratified by their IMDC prognostic risk status. RESULTS AND LIMITATIONS: Everolimus was the most prevalent third-line therapy (27.5%), but sunitinib, sorafenib, pazopanib, temsirolimus, and axitinib were all utilized in over ≥9% of patients. Patients receiving any TTT had an OS of 12.4 mo, a progression-free survival of 3.9 mo, and 61.1% of patients experienced an overall response of stable disease or better. Patients not receiving TTT had an OS of 2.1 mo. Patients with favorable- (7.2%) or intermediate-risk (65.3%) disease had the highest OS with TTT, 29.9 mo and 15.5 mo, respectively, while poor-risk (27.5%) patients survived 5.5 mo. Results are limited by the retrospective nature of the study. CONCLUSIONS: TTT remains highly heterogeneous. The IMDC prognostic criteria can be used to stratify third-line patients. TTT use in favorable- and intermediate-risk patients was associated with the greatest OS. PATIENT SUMMARY: Patients with favorable- and intermediate-prognostic criteria disease treated with third-line targeted therapy have an associated longer overall survival compared with those with poor risk disease.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/secundário , Bases de Dados Factuais , Feminino , Humanos , Internacionalidade , Neoplasias Renais/mortalidade , Neoplasias Renais/secundário , Masculino , Estudos Retrospectivos , Medição de Risco , Análise de Sobrevida
9.
Acad Med ; 91(9): 1205-10, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27415444

RESUMO

Attention to the health and wellness of postgraduate medical trainees has increased considerably in recent years, yet the scholarly literature consistently indicates that, in many instances, the medical and mental health care needs of this population remain unmet or only partially met. As a result, trainee health care often falls short of the current standards of the medical profession. Combined with the prevalence of burnout and other mental health conditions among trainees, inadequate health care for this patient population may result in significant negative consequences for trainees' health, safety, and performance.Here, the authors review the scholarly literature explicating the health care needs of postgraduate trainees. They explore the patient-centered medical home model as a potentially effective solution to address the unmet and partially met health care needs of trainees. The authors describe several practical interventions to improve access to care. These include care coordination and referral support, confidential care without perceived conflicts of interest in the training environment, co-location of medical and mental health care, and accommodations for schedule constraints. Finally, the authors explore the role of the medical home in developing and supporting broader institutional efforts to promote wellness.


Assuntos
Acesso aos Serviços de Saúde/organização & administração , Internato e Residência/métodos , Determinação de Necessidades de Cuidados de Saúde/organização & administração , Assistência Centrada no Paciente/métodos , Pacientes/psicologia , Médicos/psicologia , Estresse Psicológico/prevenção & controle , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Relações Médico-Paciente
10.
Allergy Asthma Proc ; 37(3): 259-62, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27178895

RESUMO

A 45-year-old man who presented with dyspnea and chest tightness was found to have obstructive lung disease and eosinophilia of 10,300 eosinophils/µL. The differential diagnosis encompassed causes of primary eosinophilia and secondary eosinophilia associated with pulmonary disease, including asthma, environmental allergic reaction, eosinophilic granulomatosis with polyangiitis, allergic bronchopulmonary aspergillosis, acute eosinophilic pneumonia, chronic eosinophilic pneumonia, parasitic infections, tuberculosis, fungal infection, sarcoidosis, mastocytosis, drug reaction with eosinophilia and systemic symptoms, lymphoproliferative hypereosinophilic syndrome, and myeloproliferative hypereosinophilic syndrome. Infectious workup, fiberoptic bronchoscopy with biopsy, and tests for myeloproliferative mutations help differentiate among these causes. Identifying the underlying cause of eosinophilia is imperative in guiding treatment.


Assuntos
Dor no Peito/etiologia , Dispneia/etiologia , Pneumopatias Obstrutivas/diagnóstico , Eosinofilia Pulmonar/diagnóstico , Diagnóstico Diferencial , Endoscopia , Humanos , Pneumopatias Obstrutivas/complicações , Pneumopatias Obstrutivas/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Transtornos Mieloproliferativos/complicações , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética
11.
J Child Adolesc Psychopharmacol ; 20(6): 517-20, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21186971

RESUMO

Following the completion of a 20-week, open-label study of the safety and efficacy of liquid rivastigmine for adolescents with Down syndrome, 5 of the 10 adolescents in the clinical trial continued long-term rivastigmine therapy and 5 did not. After an average period of 38 months, all 10 subjects returned for a follow-up assessment to determine the safety and efficacy of long-term rivastigmine use. Rivastigmine was well tolerated and overall health appeared to be unaffected by long-term rivastigmine use. Performance change on cognitive and language measures administered at the termination of the open-label clinical trial was compared between the two groups. No between-group difference in median performance change across the long-term period was found, suggesting that the long-term use of rivastigmine does not improve cognitive and language performance. However, two subjects demonstrated remarkable improvement in adaptive function over the long-term period. Both subjects had received long-term rivastigmine therapy. The discussion addresses the challenge of assessing cognitive change in clinical trials using adolescents with Down syndrome as subjects and the use of group versus individual data to evaluate the relevance of medication effects.


Assuntos
Cognição/efeitos dos fármacos , Síndrome de Down/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Fenilcarbamatos/uso terapêutico , Adolescente , Seguimentos , Humanos , Transtornos da Linguagem/tratamento farmacológico , Transtornos da Linguagem/etiologia , Testes de Linguagem , Masculino , Fármacos Neuroprotetores/efeitos adversos , Fenilcarbamatos/efeitos adversos , Rivastigmina , Fatores de Tempo
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