Oxidative stress is a critical mediator in liver injury of steatohepatitis. The transcription factor Nrf2 serves as a cellular stress sensor and is a key regulator for induction of hepatic detoxification and antioxidative stress systems. The involvement of Nrf2 in defense against the development of steatohepatitis remains unknown. We aimed to investigate the protective roles of Nrf2 in nutritional steatohepatitis using wild-type (WT) and Nrf2 gene-null (Nrf2-null) mice. WT and Nrf2-null mice were fed a methionine- and choline-deficient (MCD) diet for 3 and 6 wk, and the liver tissues were analyzed for pathology and for expression levels of detoxifying enzymes and antioxidative stress genes via the Nrf2 transcriptional pathway. In WT mice fed an MCD diet, Nrf2 was potently activated in the livers, and steatohepatitis did not develop over the observation periods. However, in Nrf2-null mice fed an MCD diet, the pathological state of the steatohepatitis was aggravated in terms of fatty changes, inflammation, fibrosis, and iron accumulation. In the livers of the Nrf2-null mice, oxidative stress was significantly increased compared with that of WT mice based on the increased levels of 4-hydroxy-2-nonenal and malondialdehyde. This change was associated with the decreased levels of glutathione, detoxifying enzymes, catalase, and superoxide dismutase activity. Correlating well with the liver pathology, the mRNA levels of factors involved in fatty acid metabolism, inflammatory cytokines, and fibrogenesis-related genes were significantly increased in the livers of the Nrf2-null mice. These findings demonstrate that Nrf2 deletion in mice leads to rapid onset and progression of nutritional steatohepatitis induced by an MCD diet. Activation of Nrf2 could be a promising target toward developing new options for prevention and treatment of steatohepatitis.

Decreased muscle mass coupled with increased visceral fat mass is closely associated with an increased risk for exacerbating NAFLD pathophysiology.

Sulforaphane (SFN) plays an important role in preventing oxidative stress by activating the nuclear factor (erythroid derived 2)-like 2 (Nrf2) signalling pathway. SFN may improve exercise endurance capacity by counteracting oxidative stress-induced damage during exercise. We assessed running ability based on an exhaustive treadmill test (progressive-continuous all-out) and examined the expression of markers for oxidative stress and muscle damage. Twelve- to 13-week-old Male wild-type mice (Nrf2 +/+) and Nrf2-null mice (Nrf2 −/−) on C57BL/6J background were intraperitoneally injected with SFN or vehicle prior to the test. The running distance of SFN-injected Nrf2 +/+ mice was significantly greater compared with that of uninjected mice. Enhanced running capacity was accompanied by upregulation of Nrf2 signalling and downstream genes. Marker of oxidative stress in SFN-injected Nrf2 +/+ mice were lower than those in uninjected mice following the test. SFN produced greater protection against muscle damage during exhaustive exercise conditions in Nrf2 +/+ mice than in Nrf2 −/− mice. SFN-induced Nrf2 upregulation, and its antioxidative effects, might play critical roles in attenuating muscle fatigue via reduction of oxidative stress caused by exhaustive exercise. This in turn leads to enhanced exercise endurance capacity. These results provide new insights into SFN-induced upregulation of Nrf2 and its role in improving exercise performance.

Long‐term efficacy of proton beam therapy (PBT) remains unclear for patients with previously untreated hepatocellular carcinoma (HCC). We aimed to study the long‐term outcomes of PBT according to Barcelona Clinic Liver Cancer (BCLC) staging classifications in patients with previously untreated HCC. The major eligibility criteria of this observational study were an Eastern Cooperative Oncology Group performance status (PS) 0–2, Child–Pugh grade A or B, previously untreated HCC covered within an irradiation field, and no massive ascites. A total of 66.0–77.0 GyE was administered in 10–35 fractions. Local tumor control (LTC), defined as no progression in the irradiated field, progression‐free survival (PFS), and overall survival (OS) were assessed according to BCLC staging. From 2002 to 2009 at our institution, 129 patients were eligible. The 5‐year LTC, PFS, and OS rates were 94%, 28%, and 69% for patients with 0/A stage disease (n = 9/21), 87%, 23%, and 66% for patients with B stage disease (n = 34), and 75%, 9%, and 25% for patients with C stage disease (n = 65), respectively. The 5‐year LTC and OS rates of 15 patients with tumor thrombi in major vessels were 90% and 34%, respectively. Multivariate analyses revealed that PS (0 versus 1–2) was a significant prognostic factor for OS. No grade 3 or higher adverse effects were observed. PBT showed favorable long‐term efficacies with mild adverse effects in BCLC stage 0 to C, and can be an alternative treatment for localized HCC especially when accompanied with tumor thrombi. This study was registered with UMIN Clinical Trials Registry (UMIN000025342).

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