Serum WFA(+)-M2BP values are useful for assessing the stage of liver fibrosis in patients with NAFLD.

BackgroundRheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the destruction of bone and cartilage. Although its etiology is unknown, the hydroxyl radical has been suggested to be involved in the pathogenesis of RA. Recently, molecular hydrogen (H2) was demonstrated to be a selective scavenger for the hydroxyl radical. Also, the method to prepare water containing extremely high concentration of H2 has been developed. We hypothesized that H2 in the water could complement conventional therapy by reducing the oxidative stress in RA.MethodsTwenty patients with rheumatoid arthritis (RA) drank 530 ml of water containing 4 to 5 ppm molecular hydrogen (high H2 water) every day for 4 weeks. After a 4-week wash-out period, the patients drank the high H2 water for another 4 weeks. Urinary 8-hydroxydeoxyguanine (8-OHdG) and disease activity (DAS28, using C-reactive protein [CRP] levels) was estimated at the end of each 4-week period.ResultsDrinking high H2 water seems to raise the concentration of H2 more than the H2 saturated (1.6 ppm) water in vivo. Urinary 8-OHdG was significantly reduced by 14.3% (p < 0.01) on average. DAS28 also decreased from 3.83 to 3.02 (p < 0.01) during the same period. After the wash-out period, both the urinary 8-OHdG and the mean DAS28 decreased, compared to the end of the drinking period. During the second drinking period, the mean DAS28 was reduced from 2.83 to 2.26 (p < 0.01). Urinary 8-OHdG was not further reduced but remained below the baseline value. All the 5 patients with early RA (duration < 12 months) who did not show antibodies against cyclic citrullinated peptides (ACPAs) achieved remission, and 4 of them became symptom-free at the end of the study.ConclusionsThe results suggest that the hydroxyl radical scavenger H2 effectively reduces oxidative stress in patients with this condition. The symptoms of RA were significantly improved with high H2 water.

Mitochondrial quality is controlled by the selective removal of damaged mitochondria through mitophagy. Mitophagy impairment is associated with aging and many pathological conditions. An iron loss induced by iron chelator triggers mitophagy by a yet unknown mechanism. This type of mitophagy may have therapeutic potential, since iron chelators are clinically used. Here, we aimed to clarify the mechanisms by which iron loss induces mitophagy. Deferiprone, an iron chelator, treatment resulted in the increased expression of mitochondrial ferritin (FTMT) and the localization of FTMT precursor on the mitochondrial outer membrane. Specific protein 1 and its regulator hypoxia‐inducible factor 1α were necessary for deferiprone‐induced increase in FTMT. FTMT specifically interacted with nuclear receptor coactivator 4, an autophagic cargo receptor. Deferiprone‐induced mitophagy occurred selectively for depolarized mitochondria. Additionally, deferiprone suppressed the development of hepatocellular carcinoma (HCC) in mice by inducing mitophagy. Silencing FTMT abrogated deferiprone‐induced mitophagy and suppression of HCC. These results demonstrate the mechanisms by which iron loss induces mitophagy and provide a rationale for targeting mitophagic activation as a therapeutic strategy.

Background & AimsCD26, a multifunctional transmembrane glycoprotein, is expressed in various cancers and functions as dipeptidyl peptidase 4 (DPP4). We investigated whether CD26 expression is associated with hepatocellular carcinoma (HCC) progression and whether DPP4 inhibitors exert antitumor effects against HCC.MethodsCD26 expression was examined in 41 surgically resected HCC specimens. The effects of DPP4 inhibitors on HCC were examined by using HCC cell lines (Huh-7 and Li-7), xenograft tumors in nude mice, and a nonalcoholic steatohepatitis–related HCC mouse model.ResultsCD26 expression in HCC specimens was associated with increased serum DPP4 activity, as well as a more advanced stage, less tumor immunity, and poorer prognosis in HCC patients. The HCC cell lines and xenograft tumors exhibited CD26 expression and DPP4 activity. The DPP4 inhibitors did not exhibit antitumor effects in vitro, but natural killer (NK) and/or T-cell tumor accumulation suppressed growth of xenograft tumor and HCC in vivo. The antitumor effects of DPP4 inhibitors were abolished by the depletion of NK cells or the neutralization of CXCR3, a chemokine receptor on NK cells. EZ-TAXIScan, an optical horizontal chemotaxis apparatus, identified enhanced NK and T-cell chemotaxis by DPP4 inhibitors ex vivo in the presence of Huh-7 cells and the chemokine CXCL10, which binds to CXCR3. The DPP4 inhibitors prevented the biologically active form of CXCL10 from being truncated by Huh-7 cell DPP4 activity. DPP4 inhibitors also suppressed tumor angiogenesis.ConclusionsThese results provide a rationale for verifying whether DPP4 inhibitors clinically inhibit the progression of HCC or augment the antitumor effects of molecular-targeting drugs or immunotherapies against HCC.

BackgroundPancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive desmoplastic stromal response. Fibroblast activation protein-α (FAP) is best known for its presence in stromal cancer-associated fibroblasts (CAFs). Our aim was to assess whether FAP expression was associated with the prognosis of patients with PDAC and to investigate how FAP expressing CAFs contribute to the progression of PDAC.MethodsFAP expression was immunohistochemically assessed in 48 PDAC specimens. We also generated a fibroblastic cell line stably expressing FAP, and examined the effect of FAP-expressing fibroblasts on invasiveness and the cell cycle in MiaPaCa-2 cells (a pancreatic cancer cell line).ResultsStromal FAP expression was detected in 98 % (47/48) of the specimens of PDAC, with the intensity being weak in 16, moderate in 19, and strong in 12 specimens, but was not detected in the 3 control noncancerous pancreatic specimens. Patients with moderate or strong FAP expression had significantly lower cumulative survival rates than those with negative or weak FAP expression (mean survival time; 352 vs. 497 days, P = 0.006). Multivariate analysis identified moderate to strong expression of FAP as one of the factors associated with the prognosis in patients with PDAC. The intensity of stromal FAP expression was also positively correlated to the histological differentiation of PDAC (P < 0.05). FAP-expressing fibroblasts promoted the invasiveness of MiaPaCa-2 cells more intensively than fibroblasts not expressing FAP. Coculture with FAP-expressing fibroblasts significantly activated cell cycle shift in MiaPaCa-2 cells compared to coculture with fibroblasts not expressing FAP. Furthermore, coculture with FAP expressing fibroblasts inactivated retinoblastoma (Rb) protein, an inhibitor of cell cycle progression, in MiaPaCa-2 cells by promoting phosphorylation of Rb.ConclusionsThe present in vitro results and the association of FAP expression with clinical outcomes provide us with a better understanding of the effect of FAP-expressing CAFs on the progression of PDAC.