JNK suppression of chemotherapeutic agents-induced ROS confers chemoresistance on pancreatic cancer stem cells

Chemoresistance associated with cancer stem cells (CSCs), which is now being held responsible for the pervasive therapy resistance of pancreatic cancer, poses a major challenge to the successful management of this devastating malignancy. However, the molecular mechanism underlying the marked chemoresistance of pancreatic CSCs remains largely unknown. Here we show that JNK, which is upregulated in pancreatic CSCs and contributes to their maintenance, is critically involved in the resistance of pancreatic CSCs to 5-fluorouracil (5-FU) and gemcitabine (GEM). We found that JNK inhibition effectively sensitizes otherwise chemoresistant pancreatic CSCs to 5-FU and GEM. Significantly, JNK inhibition promoted 5-FU- and GEM-induced increase in intracellular reactive oxygen species (ROS), and scavenging intracellular ROS by use of N-acetylcysteine impaired JNK inhibition-mediated promotion of the cytotoxicity of 5-FU and GEM. Our findings thus suggest that JNK may contribute to the chemoresistance of pancreatic CSCs through prevention of chemotherapeutic agents-induced increase in intracellular ROS. Our findings also suggest that JNK inhibition combined with 5-FU- and/or GEM-based regimens may be a rational therapeutic approach to effectively eliminate pancreatic CSCs.     

High hemoglobin A1c levels within the non‐diabetic range are associated with the risk of all cancers

Previous studies have reported associations between diabetes and cancer risk. However, specific association of hemoglobin A1c (HbA1c) levels with cancer risk remains inconclusive. We followed 29,629 individuals (11,336 men; 18,293 women) aged 46–80 years who participated in the Japan Public Health Center‐based prospective study who had HbA1c measurements available and were cancer‐free at baseline. Cancer incidence was assessed by systemic surveys. We estimated hazard ratios (HRs) for cancer risk with adjustment for age sex, geographic area, body mass index, smoking status, physical activity, alcohol, coffee, vegetable and total energy consumption, and history of cardiovascular disease. After a median follow‐up of 8.5 years, 1,955 individuals had developed cancer. Higher HbA1c levels within both the non‐diabetic and diabetic ranges in individuals without known diabetes were associated with overall cancer risk. Compared with individuals without known diabetes and HbA1c levels of 5.0–5.4%, the HRs for all cancers were 1.27 (95% confidence interval, 1.07–1.52); 1.01 (0.90–1.14); 1.28 (1.09–1.49); and 1.43 (1.14–1.80) for individuals without known diabetes and HbA1c levels <5.0%, 5.5–5.9%, 6.0–6.4%, and ≥6.5%, respectively, and 1.23 (1.02–1.47) for individuals with known diabetes. The lowest HbA1c group had the highest risk of liver cancer, and HbA1c levels were linearly associated with the risk of all cancers after excluding liver cancer (P for linear trend, 0.004). In conclusion, our findings corroborate the notion that glycemic control in individuals with high HbA1c levels may be important not only to prevent diabetes but also to prevent cancer.     

CYP1A1, GSTM1 and GSTT1 genetic polymorphisms and gastric cancer risk among Japanese: A nested case–control study within a large‐scale population‐based prospective study

Cytochrome P450 (CYP) 1A1 and glutathione S‐transferases (GST) M1 and T1 are major enzymes in the carcinogen metabolizing pathway. We examined the association between single nucleotide polymorphisms (SNPs) of CYP1A1 (rs4646421, rs4646422 and rs1048943), GSTM1 and GSTT1 and gastric cancer risk in Japan. This is a nested case–control study (457 cases and 457 matched controls) of our population‐based cohort involving 36,745 subjects who answered a baseline questionnaire and supplied blood samples. The odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were calculated using conditional logistic regression models. We found that CYP1A1 (rs4646422) variant allele was associated with a statistically significant increased risk of gastric cancer compared with the homozygous wild‐type genotype (OR = 1.65; 95% CI = 1.17–2.32). GSTM1 null, GSTT1 null and GSTM1/T1 both or either null genotypes were associated with increased risk, but not statistically significantly. Combination of the CYP1A1 (rs4646422) variant allele and GSTM1/T1 both or either null genotypes was associated with a statistically significant increased risk compared with the combination of the CYP1A1 homozygous wild‐type genotype and the GSTM1/T1 both active genotypes. In addition, compared with CYP1A1 (rs4646422) homozygous wild‐type genotypes in those who were never‐smokers, CYP1A1 variant alleles in those who smoked ≥30 pack‐years were associated with an increased risk; neither gene–gene nor gene–environment interactions were significant. The CYP1A1 (rs4646422) polymorphism might be involved in gastric carcinogenesis among the Japanese population.     

Visual dysfunction in workers exposed to a mixture of organic solvents

The aim of this study was to investigate the relationship between the workers occupationally exposed to a mixture of organic solvents and their visual functions. Here the visual functions included color vision (CV), visual contrast sensitivity (CS) and visual evoked potentials (VEP). Test subjects were 182 workers at 53 furniture factories in the same industrial area of Japan. As control, a group consisted of 96 workers without exposure to any organic solvent was also tested. Exposure assessments were made both by the environmental concentration and biological monitoring. CV and CS tests were carried out for all the subjects. VEP was measured for 21 exposed subjects who were considered to have impaired CV and CS. In the results, the color confusion index (CCI) values of the exposed subjects were significantly higher than that of the age-matched controls (P<0.01). Their CS values were significantly lower than those in the controls at spatial frequencies of 6 and 12 cycles per degree (cpd) (P<0.01 and <0.05, respectively). A significant correlation between the concentration of urinary methylhippuric acid and contrast sensitivity was found by a multiple regression analysis (P<0.05). CCI showed a negative correlation at all spatial frequencies of CS in a simple regression analysis, no abnormal data were found by the VEP test in the exposed subjects who were found to have impaired CV and CS. The results suppose that a low concentration of the mixed organic solvents might affect the retina and optic nerve. However, it needs to be further researched if such an impact affects the Brodmann's areas of visual cortex in the brain.     

Role of hypertension, dyslipidemia and diabetes mellitus in the development of coronary atherosclerosis in Japan

The present study evaluated the effect of hypertension (HT), dyslipidemia and diabetes mellitus (DM) on the development of coronary atherosclerosis in the Japanese population, using a cross-sectional study of 433 patients (254 men and 179 women) aged 30 years or older who underwent coronary angiography for suspected or known coronary heart disease angina at 5 cardiology departments in the Fukuoka area between September 1996 and August 1997. Patients with a disease duration of 6 months or more were excluded. The main outcome measure was angiographically defined coronary artery stenosis and was found to a significant degree in 146 patients (33.7%). HT, DM, low levels of high-density lipoprotein cholesterol (HDL-C) and hypertriglyceridemia remained as significant coronary artery disease (CAD) risk factors even after controlling for age, sex, hospital, smoking, alcohol use, body mass index and leisure time physical activity. However, hypercholesterolemia was not a significant risk factor after adjusting for these variables. After controlling for these variables, DM, low HDL-C and hypertriglyceridemia were significant CAD risk factors for men, but only DM was a significant CAD risk factor in women. These results indicate that in Japan DM, low HDL-C and hypertriglyceridemia may be more important CAD risk factors than hypercholesterolemia.     

Pruni cortex ameliorates skin inflammation possibly through HMGB1-NFκB pathway in house dust mite induced atopic dermatitis NC/Nga transgenic mice

Pruni cortex, the bark of Prunus jamasakura Siebold ex Koidzumi, has been used in the Japanese systems of medicine for many years for its anti-inflammatory, antioxidant and antitussive properties. In this study, we investigated the effect of pruni cortex on atopic dermatitis NC/Nga mouse model. Atopic dermatitis-like lesion was induced by the application of house dust mite extract to the dorsal skin. After induction of atopic dermatitis, pruni cortex aqueous extract (1 g/kg, p.o.) was administered daily for 2 weeks. We evaluated dermatitis severity, histopathological changes and cellular protein expression by Western blotting for nuclear and cytoplasmic high mobility group box 1, receptor for advanced glycation end products, nuclear factor κB, apoptosis and inflammatory markers in the skin of atopic dermatitis mice. The clinical observation confirmed that the dermatitis score was significantly lower when treated with pruni cortex than in the atopic dermatitis group. Similarly pruni cortex inhibited hypertrophy and infiltration of inflammatory cells as identified by histopathology. In addition, pruni cortex significantly inhibited the protein expression of cytoplasmic high mobility group box 1, receptor for advanced glycation end products, nuclear p-nuclear factor kappa B, apoptosis and inflammatory markers. These results indicate that pruni cortex may have therapeutic potential in the treatment of atopic dermatitis by attenuating high mobility group box 1 and inflammation possibly through the nuclear factor κB pathway.     

Infantile hypophosphatasia combined with vitamin B6-responsive seizures and reticular formation lesions on magnetic resonance imaging: A case report

Background

Hypophosphatasia (HPP) is a rare genetic disorder characterized by rachitic bone manifestations and a low serum alkaline phosphatase (ALP) level. It is caused by mutations in the tissue non-specific alkaline phosphatase (TNSALP) gene, which encodes the tissue non-specific isozyme of ALP. HPP patients exhibit various presentations depending on their age at onset, such as infantile HPP combined with vitamin B6-responsive seizures.