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IntroductionSodium glucose cotransporter-2 (SGLT2) inhibitors are widely used for diabetes treatment. Although SGLT2 inhibitors have been clinically observed to increase food intake, roles or even the presence of SGLT2 in the central nervous system (CNS) has not been established. We aimed to elucidate potential functions of SGLT2 in the CNS, and the effects of CNS-targeted SGLT2 inhibitors on food intake.Research design and methodsWe administered three kinds of SGLT2 inhibitors, tofogliflozin, dapagliflozin, and empagliflozin, into the lateral ventricle (LV) in rats and evaluated their effects on food intake. We also evaluated the effects of tofogliflozin administration in the third (3V) and fourth ventricle (4V). Intraperitoneal administration of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist known to suppress food intake, was combined with central tofogliflozin to elucidate whether GLP-1 signaling antagonizes the effect of central SGLT2 inhibitors on food intake. To elucidate potential molecular mechanisms mediating changes in feeding, hypothalamic areas associated with food intake regulation were harvested and analyzed after intracerebroventricular administration (ICV) of tofogliflozin.ResultsBolus ICV injection of tofogliflozin induced a robust increase in food intake starting at 1.5 hours postinjection, and lasting for 5 days. No effect was observed when the same dose of tofogliflozin was administered intraperitoneally. ICV dapagliflozin and empagliflozin significantly enhanced food intake, although the strength of these effects varied among drugs. Food intake was most markedly enhanced when tofogliflozin was infused into the LV. Fewer or no effects were observed with infusion into the 3V or 4V, respectively. Systemic administration of liraglutide suppressed the effect of ICV tofogliflozin on food intake. ICV tofogliflozin increased phosphorylation of AMPK and c-fos expression in the lateral hypothalamus.ConclusionsSGLT2 inhibitors in the CNS increase food intake. SGLT2 activity in the CNS may regulate food intake through AMPK phosphorylation in the lateral hypothalamic area.

Sodium glucose cotransporter-2 (SGLT2) inhibitors are widely used for diabetes treatment. Although SGLT2 inhibitors have been clinically observed to increase food intake, roles or even the presence of SGLT2 in the central nervous system (CNS) has not been established. We aimed to elucidate potential functions of SGLT2 in the CNS, and the effects of CNS-targeted SGLT2 inhibitors on food intake. We administered three kinds of SGLT2 inhibitors, tofogliflozin, dapagliflozin, and empagliflozin, into the lateral ventricle (LV) in rats and evaluated their effects on food intake. Bolus ICV SGLT2 inhibitor induced an increase in food intake. Tofogliflozin had the strongest effect among these drugs. No effect was observed when the same dose of tofogliflozin was administered intraperitoneally. We also evaluated the effects of tofogliflozin administration in the third (3V) and fourth ventricle (4V). Food intake was most markedly enhanced when tofogliflozin was infused into the LV. Fewer or no effects were observed with infusion into the 3V or 4V, respectively. Intraperitoneal administration of liraglutide, a GLP-1 receptor agonist known to suppress food intake, was combined with central tofogliflozin to elucidate whether GLP-1 signaling antagonizes the effect of central SGLT2 inhibitors on food intake. Systemic administration of liraglutide suppressed the effect of ICV tofogliflozin on food intake. To elucidate potential molecular mechanisms mediating changes in feeding, hypothalamic areas associated with food intake regulation were harvested and analyzed after intracerebroventricular administration (ICV) of tofogliflozin. ICV tofogliflozin increased phosphorylation of AMPK in the lateral hypothalamus. In conclusion, SGLT2 activity in the CNS may regulate food intake through AMPK phosphorylation in the lateral hypothalamic area. Disclosure K. Takeda: None. H. Ono: None. T. Ohno: None. K. Yokote: None. Funding Japan Society for the Promotion of Science (15K09398, 18K08502, 20H00524); Japan Agency for Medical Research and Development (17GM5010002H0001, 18GM5010002H0002, 19GM5010002H0003, 20GM5010002H0004)

Objective: Insulin promotes glucose uptake, lipogenesis, cell proliferation and cell growth mainly via Akt phosphorylation. FoxO1 is a substrate of Akt, which is inactivated when phosphorylated by Akt. Via this mechanism, FoxO1 antagonizes insulin. On the other hand, constitutive activation of FoxO1 reportedly enhances Akt phosphorylation. Thus, FoxO1 activation, via Akt phosphorylation, may mimic the functions of insulin. Methods: We overexpressed constitutively-active FoxO1 (CA-FoxO1) and FoxO1Δ256, a dominant-negative mutant, in 3T3-L1 adipocytes by adenoviruses and investigated the effects of these proteins on insulin’s functions. Results: CA-FoxO1 enhanced Akt phosphorylation, glucose uptake (275%, P Conclusion: Activation of FoxO1 selectively mimics the metabolic functions of insulin, without its proliferative effects. Contrary to previously reported results, FoxO1Δ256 does not always exert a dominant negative action. Disclosure T. Ohno: None. H. Ono: None. K. Takeda: None. K. Yokote: None.

Objective: FoxO1 is a substrate of serine/threonine-kinase Akt. Although FoxO1 is phosphorylated by Akt and inactivated by insulin stimulation, constitutive activation of FoxO1 is reported to enhance Akt phosphorylation. Therefore, constitutive activation of FoxO1 may mimic insulin’s functions via Akt phosphorylation. Methods: Constitutively-active FoxO1 (CA-FoxO1) in 3T3-L1 adipocytes is overexpressed by adenovirus and Changes in insulin signaling and downstream actions was studied. Results: CA-FoxO1 induced Akt phosphorylation in differentiated 3T3-L1 adipocytes. Regarding downstream actions, CA-FoxO1 significantly enhanced glucose uptake (148.6% compared to controls, P =0.030), GLUT4 translocation (297.6%, P Conclusion: Constitutive activation of FoxO1 induced Akt phosphorylation even in differentiated 3T3-L1 adipocytes, but FoxO1 activation mimicked only metabolic functions of glucose but not proliferative or oncogenic functions of insulin. This selective mimicking of insulin by FoxO1 activation in adipocytes may improve glucose metabolism with a low risk of tumorigenesis. The mechanisms of FoxO1-Akt feedback is suggested not to be the increase in IR-β or p110α subunit of PI 3-kinase as previously reported, but to be mainly downstream of PI 3-kinase. Disclosure T. Ohno: None. H. Ono: None. K. Yokote: Research Support; Self; Astellas Pharma Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi K.K., Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker’s Bureau; Self; Abbott, Astellas Amgen, AstraZeneca K.K., Bayer Inc., FUJIFILM Pharmaceuticals U.S.A., Inc., Kaken Pharmaceutical Co., Ltd., Sanwa Kagaku Kenkyusho.

The Japanese government has promoted dissemination of Japanese legal information to the world, and it has released English translations of Japanese statutes as well as a Japanese-English bilingual dictionary for statutory terms. However, the number of these translations is insufficient. The bilingual dictionary, the Japanese-English Standard Legal Terms Dictionary, contains only 3782 entries. To expand this key reference work, we focused on the Japanese Official Gazette, English Edition, which was published from 1946 to 1952 under order of the Supreme Commander for the Allied Powers. We conducted an experiment on targeted phrase extraction to acquire legal translations and confirm the usefulness of the Japanese Official Gazette, English Edition.

Hypertension is a lifestyle-related disease which often leads to serious conditions such as heart disease and cerebral hemorrhage. Angiotensin II (Ang II) plays an important role in regulating cardiovascular homeostasis. Consequently, antagonists that block the interaction of Ang II with its receptors are thought to be effective in the suppression of hypertension. In this study, we searched for plant compounds that had antagonist-like activity toward Ang II receptors. From among 435 plant samples, we found that EtOH extract from the resin of sweet gum Liquidambar styraciflua strongly inhibited Ang II signaling. We isolated benzyl benzoate and benzyl cinnamate from this extract and found that those compounds inhibited the function of Ang II in a dose-dependent manner without cytotoxicity. An in vivo study showed that benzyl benzoate significantly suppressed Ang II-induced hypertension in mice. In addition, we synthesized more than 40 derivatives of benzyl benzoate and found that the meta-methyl and 3-methylbenzyl 2'-nitrobenzoate derivatives showed about 10-fold higher activity than benzyl benzoate itself. Thus, benzyl benzoate, its derivatives, and benzyl cinnamate may be useful for reducing hypertension.

Objective: Low back pain is one of the most common subjective symptoms presenting in Japan, but has no established curative therapy. Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed for low back pain, and are generally effective in alleviating pain; however, such drugs are frequently associated with adverse effects such as gastrointestinal symptoms. The present study thus investigated the effectiveness of a compound supplement containing piperines, theanine, creatine, α -lipoic acid, and proteoglycan for managing the subjective symptoms of low back pain. Methods: We conducted a double-blind, placebo-controlled, parallel-comparison study in 79 adult men and women with chronic low back pain. Subjects took either placebo or the investigational compound supplement containing long pepper extract powder at a dose of 150 mg (45 μ g as piperines), theanine at 50 mg, creatine at 250 mg, α -lipoic acid at 3 mg, and salmon nasal cartilage extract powder at 50 mg (10 mg as proteoglycan) or placebo for 8 weeks. Subjective symptoms were assessed immediately before starting to take the supplement or placebo (baseline), 4 weeks after the start (Week 4), and 8 weeks after the start (Week 8). Results: Japan Low Back Pain Evaluation Questionnaire (JLEQ) scores were significantly lowered at Week 4 and Week 8 in the supplement group compared to those measured at baseline, and they were significantly lower at Week 8 compared to those of the placebo group (P=0.022). Approximately 30% of the JLEQ score of low back pain in the supplement group showed significantly improved compared to the placebo group. No clinically significant adverse events were reported during the study period. Conclusions: The compound supplement tested herein, provided some relief for subjects with low back pain, and therefore could be useful in managing low back pain, and safe alternative or complement to NSAID therapy.

The senescence accelerated mouse prone 8 substrain (SAM-P8), widely accepted as an animal model for studying aging and antiaging drugs, was used to examine the effects of dietary supplementation with extracts ofCistanche deserticola(ECD) which has been used extensively in traditional Chinese medicine because of its perceived ability to promote immune function in the elderly. Eight-month-old male SAM-P8 mice were treated with ECD by daily oral administrations for 4 weeks. The results showed that dietary supplementation of 150 mg/kg and 450 mg/kg of ECD could extend the life span measured by Kaplan-Meier survival analysis in dose-dependent manner. Dietary supplementation of SAM-P8 mice for 4 weeks with 100, 500, and 2500 mg/kg of ECD was shown to result in significant increases in both naive T and natural killer cells in blood and spleen cell populations. In contrast, peripheral memory T cells and proinflammatory cytokine, IL-6 in serum, were substantially decreased in the mice that ingested 100 and 500 mg/kg of ECD daily. Additionally, Sca-1 positive cells, the recognized progenitors of peripheral naive T cells, were restored in parallel. Our results provide clear experimental support for long standing clinical observational studies showing thatCistanche deserticolapossesses significant effects in extending life span and suggest this is achieved by antagonizing immunosenescence.