The role of DPYD and the effects of DPYD suppressor luteolin combined with 5-FU in pancreatic cancer.

BACKGROUND: Despite advances in the treatment of cancer, pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to the lack of effective therapies. Our previous study showed that Luteolin (Lut), a flavonoid, suppressed pancreatocarcinogenesis and reduced the expression of dihydropyrimidine dehydrogenase (DPYD), an enzyme that degrades pyrimidines such as 5-fluorouracil (5-FU), in PDACs. In this study, we investigated the role of DPYD and evaluated the therapeutic potential of combining 5-FU with Lut in PDACs. METHODS AND RESULTS: PDAC cells overexpressing DPYD showed increased proliferation, and invasiveness, adding to the resistance to 5-FU. The xenograft tumors of DPYD-overexpressing PDAC cells also exhibit enhanced growth and invasion compared to the control xenograft tumors. RNA-seq analysis of the DPYD-overexpressing PDAC xenograft tumors revealed an upregulation of genes associated with metallopeptidase activity-MMP9 and MEP1A. Furthermore, the overexpression of MEP1A in PDAC was associated with invasion. Next, we investigated the combined effects of Lut, a DPYD suppressor, and 5-FU on DPYD-overexpressing xenograft tumors and PDAC of Pdx1-Cre; LSL-KrasG12D/+; Trp53flox/flox(KPPC) mice. Neither single administration of 5-FU nor Lut showed significant inhibitory effects; however, the combined administration of 5-FU and Lut exhibited a significant tumor-suppressive effect in both the xenograft tumors and KPPC models. CONCLUSION: We have elucidated that DPYD expression contributes to proliferation, invasiveness, and 5-FU resistance, in PDACs. The combination therapy of Lut and 5-FU holds the potential for enhanced efficacy against PDACs.

Hexane insoluble fraction from purple rice extract improves steatohepatitis and fibrosis via inhibition of NF-κB and JNK signaling.

Nonalcoholic fatty liver disease (NAFLD) is fatty liver mainly related to metabolic syndrome. NAFLD with inflammation and hepatocellular damage is defined as nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis and hepatocellular carcinoma. We have previously reported that a hexane insoluble fraction from an anthocyanin-rich purple rice ethanolic extract (PRE-HIF) can suppress prostate carcinogenesis. However, the extract's effect on NASH has not yet been established. In the present study, we investigated the chemopreventive effect of a PRE-HIF on NASH and liver fibrosis using a connexin 32 (Cx32) dominant negative transgenic (Cx32ΔTg) rat NASH model. Seven-week-old male Cx32ΔTg rats were fed a control diet, a high-fat diet (HFD), or an HFD with 1% PRE-HIF and intraperitoneal administration of dimethylnitrosamine for 17 weeks. Histological findings of NASH such as fat deposition, lobular inflammation, hepatocyte ballooning injury, and bridging fibrosis were observed in the HFD group but not in the control group, and all histological parameters were significantly improved by PRE-HIF treatment. Corresponding to the histological changes, increased expression of inflammatory cytokine mRNAs (TNF-α, IL-6, IL-18, IFN-γ, IL-1ß, TGF-ß1, TIMP1, TIMP2, COL1A1), along with and activation of nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) signaling were observed in the HFD group, which was significantly decreased by PRE-HIF. The number and area of hepatic precancerous glutathione S-transferase placental form-positive foci tended to be decreased by PRE-HIF. These results indicate that intake of purple rice as a dietary supplement may reduce steatohepatitis, liver injury, and fibrosis in NASH by inactivation of NF-κB or JNK.

Testicular seminoma arising from infertile testes 6 years after microdissection testicular sperm extraction.

INTRODUCTION: In Western countries, the risk of a testicular germ cell tumor in men with male factor infertility is greater than in the general population. However, Japanese data on this risk are lacking. Additionally, the clinical course for the pathogenesis involved has not been clearly characterized. CASE PRESENTATION: A 35-year-old Japanese male underwent a right orchiectomy because of a mass in his right scrotum. He had a previous history of microdissection testicular sperm extraction undertaken 6 years ago. The final diagnosis of the right scrotal mass was a stage I seminoma. However, a relapse occurred in the left inguinal lymph node 2 years after surgery and the patient was consequently treated with systemic chemotherapy. Pathological analysis of a microdissection testicular sperm extraction sample yielded a germ cell neoplasia in situ in the right testis. CONCLUSION: In Japan, men who seek an evaluation for infertility might be more likely to develop testicular germ cell tumor.

Lactoferrin Prevents Hepatic Injury and Fibrosis via the Inhibition of NF-κB Signaling in a Rat Non-Alcoholic Steatohepatitis Model.

Non-alcoholic steatohepatitis (NASH) can cause liver cirrhosis and hepatocellular carcinoma (HCC), with cases increasing worldwide. To reduce the incidence of liver cirrhosis and HCC, NASH is targeted for the development of treatments, along with viral hepatitis and alcoholic hepatitis. Lactoferrin (LF) has antioxidant, anti-cancer, and anti-inflammatory activities. However, whether LF affects NASH and fibrosis remains unelucidated. We aimed to clarify the chemopreventive effect of LF on NASH progression. We used a NASH model with metabolic syndrome established using connexin 32 (Cx32) dominant negative transgenic (Cx32ΔTg) rats. Cx32ΔTg rats (7 weeks old) were fed a high-fat diet and intraperitoneally injected with dimethylnitrosamine (DMN). Rats were divided into three groups for LF treatment at 0, 100, or 500 mg/kg/day for 17 weeks. Lactoferrin significantly protected steatosis and lobular inflammation in Cx32ΔTg rat livers and attenuated bridging fibrosis or liver cirrhosis induced by DMN. By quantitative RT-PCR, LF significantly down-regulated inflammatory (Tnf-α, Il-6, Il-18, and Il-1ß) and fibrosis-related (Tgf-ß1, Timp2, and Col1a1) cytokine mRNAs. Phosphorylated nuclear factor (NF)-κB protein decreased in response to LF, while phosphorylated JNK protein was unaffected. These results indicate that LF might act as a chemopreventive agent to prevent hepatic injury, inflammation, and fibrosis in NASH via NF-κB inactivation.