Preventive effects of black soybean polyphenols on non-alcoholic fatty liver disease in three different mouse models.

Non-alcoholic fatty liver disease (NAFLD) and its advanced stage, non-alcoholic steatohepatitis (NASH), are a major health issue throughout the world. Certain food components such as polyphenols are expected to possess preventive effects on NAFLD and NASH. In this study, the preventive effects of black soybean polyphenols were examined by using three NAFLD/NASH animal models. In a choline-deficient and L-amino acid-defined high-fat diet-induced NASH model, the intake of black soybean polyphenols decreased oxidative stress, but failed in attenuating liver injury and decreasing the expression of alpha-smooth muscle actin (α-SMA). In a Western diet with sucrose and fructose containing sweetened water-induced NAFLD model, black soybean polyphenols suppressed hepatic lipid accumulation, oxidative stress, aminotransferase activities in the plasma, inflammatory cytokine expression, and α-SMA expression accompanied by modulation of lipid metabolism. In a combination of Western diet and carbon tetrachloride model, black soybean polyphenols also suppressed hepatic lipid accumulation, oxidative stress, aminotransferase activities in the plasma, and α-SMA expression. In conclusion, black soybean is an attractive food for the prevention of NAFLD and NASH due to its strong antioxidant activity.

[Autoimmune Hepatitis in Small Cell Lung Cancer-A Case Report].

A 64-year-old female presented to our hospital with a chronic cough. She was diagnosed with cStage ⅢA small cell lung cancer(cT2aN2M0, limited disease). On admission for chemoradiation therapy, laboratory data incidentally revealed liver dysfunction. Further examination resulted in the patient being diagnosed with autoimmune hepatitis. Oral prednisolone therapy was started, and after the improvement of liver function tests, consecutive chemoradiation therapy with cisplatin and etoposide was administered. To the best of our knowledge, this is the first report of a patient with autoimmune hepatitis and small cell lung cancer. Autoimmune hepatitis might arise as a paraneoplastic syndrome.

Effects of synbiotics containing Bifidobacterium animalis subsp. lactis GCL2505 and inulin on intestinal bifidobacteria: A randomized, placebo-controlled, crossover study.

A number of studies have shown the bifidogenic effects of either probiotic bifidobacteria or inulin, and this bifidogenic shift in the composition of the colonic microbiota is likely the basis for their positive impact on human health. This study aimed to evaluate the effects of synbiotics containing the probiotic bacterium Bifidobacterium animalis subsp. lactis (B. lactis) GCL2505 and inulin on the levels of intestinal bifidobacteria compared with B. lactis GCL2505 alone. A randomized, double-blind, placebo-controlled, crossover trial was carried out involving 60 healthy subjects with a tendency for constipation using fermented milk containing B. lactis GCL2505 and inulin (synbiotic), only B. lactis GCL2505 (probiotic), and placebo. Fecal samples were collected at the end of each 2-week intervention period, and the bifidobacterial count was analyzed by quantitative real-time PCR. The numbers of total bifidobacteria and B. lactis in feces were significantly increased during the probiotic and synbiotic intake periods compared with the placebo intake period. Furthermore, the numbers of total bifidobacteria and endogenous bifidobacteria were significantly higher in the synbiotic intake period compared with the probiotic intake period, while there was no difference in the number of B. lactis. These results suggested that the synbiotics containing B. lactis GCL2505 and inulin had a greater effect on the number of bifidobacteria than a drink containing probiotics alone and could be useful for the improvement of the intestinal environment.

Relationships between Lifestyle, Living Environments, and Incidence of Hypertension in Japan (in Men): Based on Participant's Data from the Nationwide Medical Check-Up.

This study aims to investigate factors that contribute to the differences in incidence of hypertension between different regions in Japan, by accounting for not only individual lifestyles, but also their living environments. The target participants of this survey were individuals who received medical treatment for hypertension, as well as hypertension patients who have not received any treatment. The objective variable for analysis was the incidence of hypertension as data aggregated per prefecture. We used data (in men) including obesity, salt intake, vegetable intake, habitual alcohol consumption, habitual smoking, and number of steps walked per day. The variables within living environment included number of rail stations, standard/light vehicle usage, and slope of habitable land. In addition, we analyzed data for the variables related to medical environment including, participation rate in medical check-ups and number of hospitals. We performed multiple stepwise regression analyses to elucidate the correlation of these variables by using hypertension incidence as the objective variable. Hypertension incidence showed a significant negative correlation with walking and medical check-ups, and a significant positive correlation with light-vehicle usage and slope. Between the number of steps and variables related to the living environment, number of rail stations showed a significant positive correlation, while, standard- and light-vehicle usage showed significant negative correlation. Moreover, with stepwise multiple regression analysis, walking showed the strongest effect. The differences in daily walking based on living environment were associated with the disparities in the hypertension incidence in Japan.

[Contamination and Cleaning of Touch Panels Used in Everyday Life and the Awareness of Persons in Charge and Users of Devices about Contamination].

OBJECTIVES: The purpose of this study was to clarify the contamination and cleaning of touch panels used in everyday life and the awareness of persons in charge and users of devices about contamination. METHODS: Samples from touch panels were cultured to detect viable bacteria (n=132), Staphylococcus aureus (n=66) and Escherichia coli (n=64). A questionnaire survey was conducted on persons in charge and users of the devices on the day of sampling. RESULTS: Viable bacterial cells were detected in more than 90% of the automatic teller machines (ATMs) at banks, the ticket machines at stations, and the copy machines at convenience stores. S. aureus and E. coli were detected in more than one-half of such devices examined. The detection rate of viable bacterial cells in smartphones was 57.5% and was lower than those in other devices. More than 65% of the ATMs, ticket machines, and copy machines were cleaned once or twice a day. More than one-half of the users of smartphones or button-type mobile phones did not clean their devices. Those who did not aware about the contamination of touch panels were 46.6% of the persons in charge and 38.2% of the users. CONCLUSION: It is necessary to examine the suitable number of times and methods of cleaning of touch panels and to raise the awareness of persons in charge or users of such devices about contamination.

Orthostatic Blood Pressure Changes and Subclinical Markers of Atherosclerosis.

BACKGROUND: Using a simple standing-up test in normotensive subjects, we evaluated orthostatic upright postural blood pressure (BP) changes and autonomic nervous function, as well as the relationship between orthostatic BP changes and subclinical markers of atherosclerosis. METHODS: A total of 515 normotensive subjects aged 35-75 years (58.4±10.0 years) were enrolled. We measured body mass index (BMI), systolic BP (SBP) and diastolic BP (DBP), serum lipids, hemoglobin A1c (HbA1c), high-sensitivity C-reactive protein (hs-CRP), and urinary albumin-to-creatinine ratio. Brachial to ankle pulse wave velocity (baPWV) and carotid mean intima-media thickness (IMT) were measured. Participants underwent a simple standing-up test involving sitting then standing for 2 minutes each, followed again by sitting. To evaluate autonomic fluctuations, we calculated the coefficient of variation of the R-R interval, the ratio of low to high frequency heart rate variability (LF/HF), and the coefficient of component variance of high frequency. RESULTS: SBP and DBP decreased when standing, with a reduction of SBP when changing position of -8.0±10.2mm Hg. Orthostatic hypotension (OH) produced a significantly higher SBP than without OH. The baPWV was significantly higher in OH than in without OH. Stepwise regression analysis adjusted for age, sex, BMI, baseline SBP, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, fasting glucose, HbA1c, hs-CRP, IMT, late systolic peak of the pressure wave form (SBP2), and baPWV confirmed that baPWV, SBP2, and triglycerides were independently related to orthostatic BP changes. Multiple regression analyses showed that a decrease in SBP as well as baseline SBP, age, BMI, and fasting glucose were independent determinants of PWV. CONCLUSIONS: We have shown that increased arterial stiffness was associated with OH during a standing-up test. Arterial stiffness may contribute to greater BP responses to postural changes from standing.

Importance of polypeptide chain length for the correct local folding of a ß-sheet protein.

Equine ß-lactoglobulin is a 162-residue ß-sheet protein. A partially folded form of equine ß-lactoglobulin contains a ß-hairpin and an α-helix. The ß-hairpin converts into non-native α-helices at temperatures <0°C. CHIBL, a truncated equine ß-lactoglobulin (residues 88-142), contains the low-temperature α-helical structure even at room temperature, indicating that the interactions responsible for the stability of the ß-hairpin reside in non-CHIBL residues. For the study reported herein, we characterized two truncated mutants and their leucine103 → proline103 variants to identify residues that stabilize the ß-hairpin. The dependence of their circular dichroism spectra on chloride ion concentration and temperature revealed that the ability to transition from the non-native α-helices to the ß-hairpin depends on the polypeptide chain length and improves as the chain length increases despite the apparent absence of any ordered structure in the extended sequences.

A native disulfide stabilizes non-native helical structures in partially folded states of equine ß-lactoglobulin.

Equine ß-lactoglobulin (ELG) assumes non-native helices during refolding and in partially folded states. Previously, circular dichroism (CD) combined with site-directed mutagenesis identified helical regions in the acid- and cold-denatured states of ELG. It is also known that a fragment of ELG, CHIBL (residues 88-142), has a structure similar to that of the cold-denatured state. For the study reported herein, the structure of a shorter fragment, CHIBLΔF (residues 97-142), was investigated by CD and nuclear magnetic resonance spectroscopy. The secondary chemical shifts clearly showed that non-native α-helices are present in two different regions, residues 98-107 and 114-135, and are connected by a native disulfide bond. The CD spectra of two peptides that correspond to the helical regions are characterized by weak helical signatures, and the sum of their CD spectra is nearly the same as the spectrum of disulfide-reduced CHIBLΔF. Therefore, the non-native helices are stabilized by the disulfide, and non-native helix formation may occur only during the refolding of the disulfide-intact protein. Supporting this conclusion is the observation that tear lipocalin, a homologue of ELG that lacks the disulfide, does not form non-native helices during folding.

Intravascular B-cell lymphoma with hypercalcemia as the initial presentation.

Intravascular B-cell lymphoma (IVLBCL) is a rare subtype of extranodal diffuse large B-cell lymphoma, which is characterized by the growth of lymphoma cells within blood vessel lumina without nodular lesions, and which predominantly affects elderly patients. IVLBCL is characterized by B-symptoms and a variety of systemic symptoms due to focal obstruction of blood flow, but may be difficult to diagnose due to its peculiar intravascular localization and the lack of nodular lesions. While hypercalcemia is one of the complications of various types of cancerous diseases, it has rarely been reported as the first presentation of IVLBCL. In this report, we present the case of a 71-year-old male with IVLBCL who showed hypercalcemia accompanied by elevation of serum parathyroid hormone-related protein (PTH-rP) as the initial presentation. Interestingly, immunohistochemical staining revealed that the intravascular lymphoma cells expressed high levels of PTHrP. Six courses of immunochemotherapy, consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP), and two courses of high-dose methotrexate induced complete remission (CR) and retained CR for 4 months. We also reviewed other IVBCL cases in which hypercalcemia was the initial presentation. We suggest that IVLBCL, although rare, should be considered as a possible causative in hypercalcemia of unknown underlying disease.

Bcl-2 is a better therapeutic target than c-Myc, but attacking both could be a more effective treatment strategy for B-cell lymphoma with concurrent Bcl-2 and c-Myc overexpression.

OBJECTIVE: The prognosis for diffuse large B-cell lymphomas with concomitant overexpression of c-Myc and Bcl-2 remains dismal; there is an urgent need to clarify the significance of these two oncogenes as therapeutic targets for a more effective treatment strategy. MATERIALS AND METHODS: We established two novel cell lines, KPUM-MS3 and KPUM-UH1, from two chemoresistant patients with diffuse large B-cell lymphomas with concomitant overexpression of c-Myc and Bcl-2, and investigated the significance of c-Myc and Bcl-2 as therapeutic targets. RESULTS: KPUM-MS3 possesses t(14;18)(q32;q21) chromosomal translocation and KPUM-UH1 bcl-2 gene amplification, both of which account for Bcl-2 overexpression. Chromosomal translocation t(8;14)(q24;q34) was found to coexist only in KPUM-UH1, overexpression of pvt-1 messenger RNA was detected only in KPUM-MS3, and reduced expression of miR-143 and miR-145 was identified in both. Working together, these abnormalities can contribute to c-Myc overexpression. Using ABT-263, an inhibitor for Bcl-2, and 10058-F4, an inhibitor for c-Myc, we found that both cell lines were more highly sensitive to cell death as a result of Bcl-2 inhibition than of c-Myc inhibition. When combined with genotoxic agents, ABT-263 exerted additive and/or synergistic cell-killing effects, while 10058-F4 showed, at most, a modest combinatory effect. Importantly, the combination of ABT-263 and 10058-F4 had a synergistic cell-killing effect on both cell lines. CONCLUSIONS: Our data suggest that Bcl-2 is a better therapeutic target than c-Myc, but attacking both Bcl-2 and c-Myc would be an even more effective treatment strategy for diffuse large B-cell lymphomas with concurrent Bcl-2 and c-Myc overexpression.

Cyclosporine A for chemotherapy-resistant subcutaneous panniculitis-like T cell lymphoma with hemophagocytic syndrome.

Subcutaneous panniculitis-like T cell lymphoma (SPTL) is a rare subtype of non-Hodgkin lymphoma for which a definitive therapeutic strategy has not been established yet. We report a case of chemotherapy-resistant SPTL with hemophagocytic syndrome (HPS) which was successfully treated with cyclosporine A (CsA) plus methylprednisolone (mPSL), and also reviewed 11 SPTL cases treated with CsA, previously reported in the literature. Our patient was a 38-year-old female with SPTL. The disease progressed despite conventional chemotherapy using cytotoxic agents including alkylators, anthracyclins or purine analogues, and, after 2 months of chemotherapy, was eventually complicated by HPS and disseminated intravascular coagulation (DIC). CsA (4 mg/kg/day) plus mPSL treatment dramatically improved HPS with DIC, reduced subcutaneous tumors within 2 weeks, and finally induced complete remission (CR) after 3 months. Currently, the patient has maintained CR while being treated with CsA for 12 months. In addition to our case, 9 of 11 SPTL cases were successfully treated with CsA, and 8 were induced to CR. Time to first response to CsA was within 2 weeks in most cases, regardless of prior treatment or the co-occurrence of HPS. Our case and this first comprehensive review on CsA for SPTL suggest that CsA may constitute a candidate treatment strategy for SPTL.

Targeting activating transcription factor 3 by Galectin-9 induces apoptosis and overcomes various types of treatment resistance in chronic myelogenous leukemia.

Tyrosine kinase inhibitors (TKI) against Bcr-Abl are the first-line therapeutics for chronic myelogenous leukemia (CML). However, the resistance to Bcr-Abl TKIs is induced in leukemic cells not only by loss of sensitivity to TKIs through Bcr-Abl-related molecular mechanisms but also by loss of addiction to Bcr-Abl TK activity by acquiring Bcr-Abl-unrelated additional oncogenic mutations. Therefore, the identification of an additional therapeutic target has been anticipated for achievement of a complete cure and to overcome resistance to treatment. We here showed that modified human Galectin-9 (hGal9), a lectin that show specific affinity for beta-galactosides, inhibits the proliferation of five CML-derived cell lines by inducing apoptosis at their IC(50)s from 17.5 to 164.9 nmol/L. Our study revealed that activating transcription factor 3 (ATF3), a member of the ATF/cAMP-responsive element binding protein family transcription factors, is the critical mediator for cell killing by hGal9, and that Noxa is one of the downstream effector molecules of ATF3. Bim, on the other hand, the BH3-only protein essential for apoptosis by Bcr-Abl TKIs, was not associated with hGal9-induced cell death. ATF3-mediated cell death by hGal9 was not hampered by the absence of p53, the presence of mutant Abl(T315I), or by P-glycoprotein overexpression. In addition, hGal9 showed the additive growth-inhibitory effect with imatinib on CML cell lines. Collectively, hGal9 is a candidate agent that may overcome various kinds of resistance to treatment for CML and may suggest that ATF3 may be a new target molecule for the development of new treatment modalities that can overcome resistance to currently available chemotherapeutics.

Expression of master regulators of helper T-cell differentiation in peripheral T-cell lymphoma, not otherwise specified, by immunohistochemical analysis.

The normal counterparts of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) have not been accurately identified. We immunohistochemically analyzed 10 PTCL-NOS cases to examine the expression of the master regulators of T-cell differentiation and of surface antigens, including chemokine receptors. All cases were positive for the master regulator of helper T cells (Th-POK) and the marker of effector T cells (CD45RO). Three cases each were positive for T-Bet and GATA3, which are master regulators of helper T cells (T(H) ) type 1 (T(H)1) and 2 (T(H)2), respectively. Two cases were positive for the surface antigens of central memory (Tcm) (CCR7 and CD62L), and 1 case was positive for follicular helper T-cell (TFH) phenotype (BCL6, CXCL13, and PD-1). The remaining case was negative for all markers of effector T(H) subtypes. These results suggest the postulated normal counterparts of PTCL-NOS identified in 9 of the 10 cases consist of T(H)1, T(H)2, TCM, and TFH.