Phenethyl iosothiocyanate activates leptin signaling

Obesity, a principal risk factor for the development of diabetes mellitus, heart disease, and hypertension, is a growing and serious health problem all over the world. Leptin is a weight-reducing hormone produced by adipose tissue, which decreases food intake via hypothalamic leptin receptors (Ob-Rb) and the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway. Protein tyrosine phosphatase 1B (PTP1B) negatively regulates leptin signaling by dephosphorylating JAK2, and the increased activity of PTP1B is implicated in the pathogenesis of obesity. Hence, inhibition of PTP1B may help prevent and reduce obesity. In this study, we revealed that phenethyl isothiocyanate (PEITC), a naturally occurring isothiocyanate in certain cruciferous vegetables, potently inhibits recombinant PTP1B by binding to the reactive cysteinyl thiol. Moreover, we found that PEITC causes the ligand-independent phosphorylation of Ob-Rb, JAK2, and STAT3 by inhibiting cellular PTP1B in differentiated human SH-SY5Y neuronal cells. PEITC treatment also induced nuclear accumulation of phosphorylated STAT3, resulting in enhanced anorexigenic POMC expression and suppressed orexigenic NPY/AGRP expression. We demonstrated that oral administration of PEITC to mice significantly reduces food intake, and stimulates hypothalamic leptin signaling. Our results suggest that PEITC might help prevent and improve obesity

Partially functional outer arm dynein in a novel Chlamydomonas mutant expressing a truncated γ heavy chain

The outer dynein arm of Chlamydomonas flagella contains three heavy chains (α, β, and γ), each of which exhibits motor activity. How they assemble and cooperate is of considerable interest. Here we report the isolation of a novel mutant, oda2-t, whose γ heavy chain is truncated at about 30% of the sequence. While the previously isolated γ chain mutant oda2 lacks the entire outer arm, oda2-t retains outer arms that contain α and β heavy chains, suggesting that the N-terminal sequence (corresponding to the tail region) is necessary and sufficient for stable outer-arm assembly. Thin-section electron microscopy and image analysis localize the γ heavy chain to a basal region of the outer-arm image in the axonemal cross section. The motility of oda2-t is lower than that of the wild type and oda11 (lacking the α heavy chain) but higher than that of oda2 and oda4-s7 (lacking the motor domain of the β heavy chain). Thus, the outer-arm dynein lacking the γ heavy-chain motor domain is partially functional. The availability of mutants lacking individual heavy chains should greatly facilitate studies on the structure and function of the outer-arm dynein

Medical Treatment of Echinococcus multilocularis and New Horizons for Drug Discovery: Characterization of Mitochondrial Complex II as a Potential Drug Target

As an efficient drug for alveolar echinococcosis (AE) is still not available, new chemotherapy targets are necessary. The mitochondrial respiratory chain may be a good drug candidate because parasite respiratory chains are quite different from those of mammalian hosts. For example, Ascaris suum possesses an NADH‐fumarate reductase system (fumarate respiration) that is highly adapted to anaerobic environments such as the small intestine. It is composed of mitochondrial complex I (NADH‐ubiquinone reductase), complex II (succinate‐ubiquinone reductase), and rhodoquinone. We previously demonstrated that fumarate respiration is also essential in E. multilocularis. Quinazoline, a complex I inhibitor, inhibited growth of E. multilocularis larvae in vitro. These results indicate that fumarate respiration could be a target for E. multilocularis therapy. In the current chapter, we focused on complex II, which is another component of this system, because quinazoline exhibited strong toxicity to mammalian mitochondria. We evaluated the molecular and biochemical characterization of E. multilocularis complex II as a potential drug target. In addition, we found that ascofuranone, a trypanosome cyanide‐insensitive alternative oxidase inhibitor, inhibited E. multilocularis complex II at the nanomolar order. Our findings demonstrate the potential development of targeted therapy against Echinococcus complex II

Association between Vitamin D and Heart Failure Mortality in 10,974 Hospitalized Individuals

A broad range of chronic conditions, including heart failure (HF), have been associated with vitamin D deficiency. Existing clinical trials involving vitamin D supplementation in chronic HF patients have been inconclusive. We sought to evaluate the outcomes of patients with vitamin D supplementation, compared with a matched cohort using real-world big data of HF hospitalization. This study was based on the Diagnosis Procedure Combination database in the Japanese Registry of All Cardiac and Vascular Datasets (JROAD-DPC). After exclusion criteria, we identified 93,692 patients who were first hospitalized with HF between April 2012 and March 2017 (mean age was 79 ± 12 years, and 52.2% were male). Propensity score (PS) was estimated with logistic regression model, with vitamin D supplementation as the dependent variable and clinically relevant covariates. On PS-matched analysis with 10,974 patients, patients with vitamin D supplementation had lower total in-hospital mortality (6.5 vs. 9.4%, odds ratio: 0.67, p < 0.001) and in-hospital mortality within 7 days and 30 days (0.9 vs. 2.5%, OR, 0.34, and 3.8 vs. 6.5%, OR: 0.56, both p < 0.001). In the sub-group analysis, mortalities in patients with age < 75, diabetes, dyslipidemia, atrial arrhythmia, cancer, renin-angiotensin system blocker, and β-blocker were not affected by vitamin D supplementation. Patients with vitamin D supplementation had a lower in-hospital mortality for HF than patients without vitamin D supplementation in the propensity matched cohort. The identification of specific clinical characteristics in patients benefitting from vitamin D may be useful for determining targets of future randomized control trials

The effect of isoflavone-daidzein oral medication on cutaneous wound healing in female ovariectomized mice

This study investigated the influence of oral administration of isoflavone-daidzein on the cutaneous wound healing process in female ovariectomized mice. Eight-week-old female mice were divided into groups of ovariectomized mice and mice administered daidzein after an ovariectomy. Two full-thickness wounds on the dorsum were made in mice in both groups. There was no significant difference between wound areas of the two groups from wounding to healing during 15 days. The area in the group administered daidzein tended to be smaller than that in the ovariectomized group during the inflammatory phase 4 and 5 days after wounding . The rate of re-epithelialization in the group administered daidzein tended to be higher than that in the ovariectomized group in the inflammatory phase on day 3 (40.7 ± 17.6% and 21.0 ± 16.8%, respectively). Therefore, the administration of daidzein under lack of estrogen is expected to reduce the inflammation period and promote re-epithelialization. この研究は、卵巣摘出した雌マウスに皮膚創傷を作製し、経口投与したイソフラボン の一種であるダイゼインが、創傷治癒にどのような影響を与えるかを観察したもので ある。8 週令の雌マウスを卵巣摘出群と卵巣摘出し創作製した後にダイゼインを与え た2 群に分けた。両群共、卵巣摘出後、ダイゼインを含まない精製飼料で２週間飼育 後に、左右の背部に直径4mm の皮膚全層欠損層を作製した。創作製後、ダイゼインを 含まない飼料とダイゼインを含む飼料で2 週間飼育した。ダイゼインは、飼料1g に 0.01mg 含むように作製した。両群の創面積は、2 週間の間の毎日において、有意差は 見られなかった。しかし、炎症期である創作製後4 と5 日では、ダイゼイン食で飼育 した群が無ダイゼイン食で飼育した群が、やや創面積が小さい傾向がみられた（それ ぞれ、p 値が0.061、0.083 であった）。創作製後の3 日での、再上皮化の割合は、ダイゼイン群で40.7 ± 17.6%、無ダイゼイン群で21.0 ± 16.8%となり、ダイゼイ ン群はより上皮化が進んでいる傾向が見られた (p = 0.07)。これらの結果は、エス トロゲン欠乏状態で、ダイゼインの経口投与が、創傷治癒において、炎症を抑制し上 皮化を促進することを示唆している

Induction of hepatocyte growth factor production in human dermal fibroblasts and their proliferation by the extract of bitter melon pulp

Hepatocyte growth factor (HGF) is useful as a potential therapeutic agent for hepatic and renal fibrosis and cardiovascular diseases through inducing proliferation of epithelial and endothelial cells. HGF inducers may also be useful as therapeutic agents for these diseases. However, there have been no reports on induction of HGF production by plant extracts or juices. An extract of bitter melon (Momordica charantia L.) pulp markedly induced HGF production. There was a time lag of 72 h before induction of HGF production after the extract addition. Its stimulatory effect was accompanied by upregulation of HGF gene expression. Increases in mitogen-activated protein kinases (MAPKs) were observed from 72 h after the extract addition. Inhibitors of MAPKs suppressed the extract-induced HGF production. The extract also stimulated cell proliferation. Both activities for induction of HGF production and cell proliferation were eluted together in a single peak with 14,000 Da on gel filtration. The results indicate that bitter melon pulp extract induced HGF production and cell proliferation of human dermal fibroblasts and suggest that activation of MAPKs is involved in the HGF induction. Our findings suggest potential usefulness of the extract for tissue regeneration and provide an insight into the molecular mechanism underlying the wound-healing property of bitter melon

Identification of mTEC precursor cells

Medullary thymic epithelial cells (mTECs) expressing autoimmune regulator (Aire) are critical for preventing the onset of autoimmunity. However, the differentiation program of Aire-expressing mTECs (Aire+ mTECs) is unclear. Here, we describe novel embryonic precursors of Aire+ mTECs. We found the candidate precursors of Aire+ mTECs (pMECs) by monitoring the expression of receptor activator of nuclear factor-κB (RANK), which is required for Aire+ mTEC differentiation. pMECs unexpectedly expressed cortical TEC molecules in addition to the mTEC markers UEA-1 ligand and RANK and differentiated into mTECs in reaggregation thymic organ culture. Introduction of pMECs in the embryonic thymus permitted long-term maintenance of Aire+ mTECs and efficiently suppressed the onset of autoimmunity induced by Aire+ mTEC deficiency. Mechanistically, pMECs differentiated into Aire+ mTECs by tumor necrosis factor receptor-associated factor 6-dependent RANK signaling. Moreover, nonclassical nuclear factor-κB activation triggered by RANK and lymphotoxin-β receptor signaling promoted pMEC induction from progenitors exhibiting lower RANK expression and higher CD24 expression. Thus, our findings identified two novel stages in the differentiation program of Aire+ mTECs

〔伝統的な言語文化〕の学習指導改善 －落語教材の検討を通して－

Review of the book Leimon: Studies Presented to Lennart Rydén on his Sixty-Fifth Birthday (edited by Jan Olof Rosenqvist)