المؤلفون: Yamato, Mayumi¹ (AUTHOR) m.yamato68@gmail.com, Kato, Nao¹ (AUTHOR), Yamada, Ken-ichi¹ (AUTHOR), Inoguchi, Toyoshi² (AUTHOR)

المصدر: Diabetes. Jul2024, Vol. 73 Issue 7, p1153-1166. 14p.

مصطلحات موضوعية: *DIABETIC retinopathy, *SODIUM-glucose cotransporter 2 inhibitors, *SODIUM-glucose cotransporters, *VASCULAR endothelial growth factors, *FLUORESCENCE angiography, *STREPTOZOTOCIN

مستخلص: The early pathogenetic mechanism of diabetic retinopathy (DR) and its treatment remain unclear. Therefore, we used streptozotocin-induced diabetic mice to investigate the early pathogenic alterations in DR and the protective effect of sodium–glucose cotransporter 2 (SGLT2) inhibitors against these alterations. Retinal vascular leakage was assessed by dextran fluorescence angiography. Retinal thickness and vascular leakage were increased 2 and 4 weeks after onset of diabetes, respectively. Immunostaining showed that morphological change of microglia (amoeboid form) was observed at 2 weeks. Subsequently, increased angiopoietin-2 expression, simultaneous loss of pericytes and endothelial cells, decreased vessel density, retinal hypoxia, and increased vascular endothelial growth factor (VEGF)-A/VEGF receptor system occurred at 4 weeks. SGLT2 inhibitors (luseogliflozin and ipragliflozin) had a significant protective effect on retinal vascular leakage and retinal thickness at a low dose that did not show glucose-lowering effects. Furthermore, both inhibitors at this dose attenuated microglia morphological changes and these early pathogenic alterations in DR. In vitro study showed both inhibitors attenuated the lipopolysaccharide-induced activation of primary microglia, along with morphological changes toward an inactive form, suggesting the direct inhibitory effect of SGLT2 inhibitors on microglia. In summary, SGLT2 inhibitors may directly prevent early pathogenic mechanisms, thereby potentially playing a role in preventing DR. Article Highlights: We used streptozotocin-induced diabetic mice to investigate the early pathogenic alterations in diabetic retinopathy (DR) and the protective effect of sodium–glucose cotransporter 2 inhibitors (SGLT2i) against these alterations. SGLT2i had a significant protective effect on retinal vascular leakage and retinal thickness at a low dose that did not show glucose-lowering effects. SGLT2i at this dose attenuated early pathogenic alterations, including microglia morphological changes, increased angiopoietin-2 expression, and decreased vessel density and hypoxia induced by diabetes. SGLT2i may break an early pathogenic vicious cycle and exert protective effects against DR. [ABSTRACT FROM AUTHOR]

المؤلفون: Yokota, Takashi, Kinugawa, Shintaro, Hirabayashi, Kagami, Yamato, Mayumi, Takada, Shingo, Suga, Tadashi, Nakano, Ippei, Fukushima, Arata, Matsushima, Shouji, Okita, Koichi, Tsutsui, Hiroyuki

المساهمون: Center of Innovation Program from the Japan Science and Technology Agency, KAKENHI Grants-in-Aid for Scientific Research

المصدر: Scientific Reports ; volume 11, issue 1 ; ISSN 2045-2322

مصطلحات موضوعية: Multidisciplinary

الوصف: Oxidative stress plays a role in the progression of chronic heart failure (CHF). We investigated whether systemic oxidative stress is linked to exercise intolerance and skeletal muscle abnormalities in patients with CHF. We recruited 30 males: 17 CHF patients, 13 healthy controls. All participants underwent blood testing, cardiopulmonary exercise testing, and magnetic resonance spectroscopy (MRS). The serum thiobarbituric acid reactive substances (TBARS; lipid peroxides) were significantly higher (5.1 ± 1.1 vs. 3.4 ± 0.7 μmol/L, p < 0.01) and the serum activities of superoxide dismutase (SOD), an antioxidant, were significantly lower (9.2 ± 7.1 vs. 29.4 ± 9.7 units/L, p < 0.01) in the CHF cohort versus the controls. The oxygen uptake (VO 2 ) at both peak exercise and anaerobic threshold was significantly depressed in the CHF patients; the parameters of aerobic capacity were inversely correlated with serum TBARS and positively correlated with serum SOD activity. The phosphocreatine loss during plantar-flexion exercise and intramyocellular lipid content in the participants' leg muscle measured by 31 phosphorus- and 1 proton-MRS, respectively, were significantly elevated in the CHF patients, indicating abnormal intramuscular energy metabolism. Notably, the skeletal muscle abnormalities were related to the enhanced systemic oxidative stress. Our analyses revealed that systemic oxidative stress is related to lowered whole-body aerobic capacity and skeletal muscle dysfunction in CHF patients.

الإتاحة: https://doi.org/10.1038/s41598-021-81736-0Test
https://www.nature.com/articles/s41598-021-81736-0.pdfTest
https://www.nature.com/articles/s41598-021-81736-0Test

المؤلفون: Ide, Makoto, Sonoda, Noriyuki, Inoue, Tomoaki, Kimura, Shinichiro, Minami, Yohei, Makimura, Hiroaki, Hayashida, Eiichi, Hyodo, Fuminori, Yamato, Mayumi, Takayanagi, Ryoichi, Inoguchi, Toyoshi

المساهمون: Bader, Michael, the Special Coordination Funds for Promoting Science and Technology

المصدر: PLOS ONE ; volume 15, issue 2, page e0228750 ; ISSN 1932-6203

الإتاحة: https://doi.org/10.1371/journal.pone.0228750Test

المؤلفون: Yamato, Mayumi, Kato, Nao, Kakino, Ai, Yamada, Ken-ichi, Inoguchi, Toyoshi

المساهمون: Ministry of Education, Culture, Sports, Science, Japan Agency for Medical Research and Development

المصدر: Metabolism Open ; volume 7, page 100049 ; ISSN 2589-9368

مصطلحات موضوعية: General Medicine

الإتاحة: https://doi.org/10.1016/j.metop.2020.100049Test
https://api.elsevier.com/content/article/PII:S2589936820300293?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S2589936820300293?httpAccept=text/plainTest

المؤلفون: Inoguchi, Toyoshi, Fukuhara, Saki, Yamato, Mayumi, Nakai, Michikazu, Etoh, Tomoaki, Masakado, Mitsunori, Suehiro, Satoshi, Umeda, Fumio, Yamauchi, Teruaki

المصدر: Scientific Reports ; volume 9, issue 1 ; ISSN 2045-2322

مصطلحات موضوعية: Multidisciplinary

الوصف: Elderly patients with diabetes are at increased risk of frailty and disability in activities of daily living (ADL). Recent evidence has shown that oxidative stress is associated with these conditions. In this cross-sectional study, we aimed to assess whether serum level of bilirubin, a strong endogenous antioxidant, can predict ADL disability in elderly patients with diabetes. Forty elderly patients aged 70 years and older with diabetes and ADL disability and 158 elderly patients with diabetes and without ADL disability were continuously recruited. Multivariate logistic regression models showed that serum bilirubin level was a significant predictor for ADL disability. Receiver operating characteristic analysis showed that the area under the curve (AUC) of serum bilirubin level alone for ADL disability was 0.887 (95% CI 0.837–0.936, P < 0.001) and the cut-off value was 0.4 mg/dL (sensitivity = 88.0% and specificity = 65.0%). The predictive ability was further increased by the addition of age (AUC = 0.921) or addition of age, body mass index, red blood cell count, cerebrovascular disease and chronic renal failure (AUC = 0.953). In conclusion, low serum bilirubin level is a strong predictive biomarker for ADL disability in elderly patients with diabetes, and its clinical utility is suggested.

الإتاحة: https://doi.org/10.1038/s41598-019-43543-6Test
https://www.nature.com/articles/s41598-019-43543-6.pdfTest
https://www.nature.com/articles/s41598-019-43543-6Test

المؤلفون: Maki, Toshinobu, Maeno, Sayaka, Maeda, Yasutaka, Yamato, Mayumi, Sonoda, Noriyuki, Ogawa, Yoshihiro, Wakisaka, Masanori, Inoguchi, Toyoshi

المساهمون: Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan

المصدر: Scientific Reports ; volume 9, issue 1 ; ISSN 2045-2322

مصطلحات موضوعية: Multidisciplinary

الوصف: Several clinical studies have shown the beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on diabetic nephropathy. The underlying mechanisms are not fully understood. We found that administration of canagliflozin at a low dose (0.01 mg/kg/day) did not affect either blood glucose levels or glycosuria, but it improved albuminuria and mesangial expansion in db/db mice to a similar extent as at a high dose (3.0 mg/kg/day) that lowered blood glucose levels. This indicated the existence of a tubular SGLT2-independent reno-protective mechanism. Here we focused on the potential role of SGLT2 in mesangial cells (MCs). Western blot analysis revealed the expression of SGLT2 in cultured mouse MCs. Exposure of MCs to high glucose levels for 72 h significantly increased the expression of SGLT2. Canagliflozin or ipragliflozin (both 100 nM) treatment inhibited glucose consumption in the medium under high-glucose conditions but not under normal-glucose conditions. Furthermore, canagliflozin inhibited high-glucose-induced activation of the protein kinase C (PKC)-NAD(P)H oxidase pathway and increases in reactive oxygen species (ROS) production. Thus, the inhibition of mesangial SGLT2 may cause an inhibition of PKC activation and ROS overproduction in diabetic nephropathy, and this may at least in part account for the reno-protective effect of SGLT2 inhibitors.

الإتاحة: https://doi.org/10.1038/s41598-019-41253-7Test
https://www.nature.com/articles/s41598-019-41253-7.pdfTest
https://www.nature.com/articles/s41598-019-41253-7Test

المؤلفون: Kodama, Yoshimi, Hyodo, Fuminori, Yamato, Mayumi, Yasukawa, Keiji, Minami, Yohei, Sonoda, Noriyuki, Ogawa, Yoshihiro, Ichikawa, Kazuhiro, Inoguchi, Toyoshi

المساهمون: Ministry of Education, Culture, Sports, Science and Technology

المصدر: Kidney International ; volume 96, issue 3, page 787-792 ; ISSN 0085-2538

مصطلحات موضوعية: Nephrology

الإتاحة: https://doi.org/10.1016/j.kint.2019.04.034Test
https://api.elsevier.com/content/article/PII:S0085253819305150?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S0085253819305150?httpAccept=text/plainTest

المؤلفون: Yokota, Takashi, Kinugawa, Shintaro, Hirabayashi, Kagami, Suga, Tadashi, Takada, Shingo, Omokawa, Masashi, Kadoguchi, Tomoyasu, Takahashi, Masashige, Fukushima, Arata, Matsushima, Shouji, Yamato, Mayumi, Okita, Koichi, Tsutsui, Hiroyuki

المساهمون: Ministry of Education, Culture, Sports, Science and Technology, Uehara Memorial Foundation, Mochida Memorial Foundation for Medical and Pharmaceutical Research, Japan Science and Technology Agency

المصدر: Journal of Diabetes Investigation ; volume 8, issue 4, page 535-541 ; ISSN 2040-1116 2040-1124

الوصف: Aims/Introduction Low aerobic capacity is a strong and independent predictor of all‐cause mortality in patients with metabolic syndrome (MetS). Here, we investigated the effects of pioglitazone treatment on whole‐body aerobic capacity and skeletal muscle energy metabolism in MetS patients. Materials and Methods A total of 14 male patients with MetS received oral pioglitazone 15 mg/day for 4 months. To assess whole‐body aerobic capacity, exercise testing with a bicycle ergometer was carried out before and after pioglitazone treatment. To assess skeletal muscle energy metabolism, intramyocellular lipid in the resting leg and high‐energy phosphates in the calf muscle during plantar‐flexion exercise were measured using 1 proton‐ and 31 phosphorus magnetic resonance spectroscopy, respectively. Results Pioglitazone significantly increased peak oxygen uptake (25.1 ± 4.9 mL/kg/min pretreatment vs 27.2 ± 3.9 mL/kg/min post‐ treatment, P < 0.05) and anaerobic threshold (12.7 ± 1.9 mL/kg/min pretreatment vs 13.6 ± 1.6 mL/kg/min post‐treatment, P < 0.05), although daily physical activity was comparable before and after the treatment. Intramyocellular lipid content was significantly reduced after pioglitazone treatment by 26%, indicating improved skeletal muscle fatty acid metabolism. Pioglitazone also significantly decreased the muscle phosphocreatine loss during exercise by 13%, indicating improved skeletal muscle high‐energy phosphate metabolism. Notably, the increase in anaerobic threshold; that is, submaximal aerobic capacity, closely correlated with the decrease in intramyocellular lipid content after pioglitazone treatment. Conclusions Pioglitazone significantly improved the MetS patients’ whole‐body aerobic capacity and skeletal muscle energy metabolism. The beneficial effect of pioglitazone on whole‐body aerobic capacity might be at least in part through improved fatty acid metabolism in the skeletal muscle.

الإتاحة: https://doi.org/10.1111/jdi.12606Test

المؤلفون: Ishida, Yuma, Okamoto, Yuka, Matsuoka, Yuta, Tada, Arisa, Janprasit, Jindaporn, Yamato, Mayumi, Morales, Noppawan Phumala, Yamada, Ken-Ichi

المساهمون: JST PRESTO, JSPS KAKENHI, AMED, Naito Foundation, ONO Medical Research Foundation, Japan, Office of the Higher Education Commission, Mahidol University, National Research Universities Initiative, Kyushu University, Development and Promotion of Science and Technology Talents Projects (DPST), Thailand

المصدر: Free Radical Biology and Medicine ; volume 113, page 487-493 ; ISSN 0891-5849

الإتاحة: https://doi.org/10.1016/j.freeradbiomed.2017.10.388Test
https://api.elsevier.com/content/article/PII:S0891584917311711?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S0891584917311711?httpAccept=text/plainTest

المؤلفون: Yamato, Mayumi, Kawano, Kimika, Yamanaka, Yuki, Saiga, Misako, Yamada, Ken-ichi

المساهمون: Japan Society for the Promotion of Science KAKENHI, Japan Science and Technology PRESTO, Life Science Research from Japan Agency for Medical Research and development (AMED), Japan

المصدر: Redox Biology ; volume 8, page 316-322 ; ISSN 2213-2317

الإتاحة: https://doi.org/10.1016/j.redox.2016.02.007Test
https://api.elsevier.com/content/article/PII:S2213231716300180?httpAccept=text/plainTest
https://api.elsevier.com/content/article/PII:S2213231716300180?httpAccept=text/xmlTest