Journal articles: 'KK/Ay Murine Model'

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Ishii, Hideto, Megumi Hiraoka, Akira Tanaka, Kentaro Shimokado, and Masayuki Yoshida. "Recombinant annexin-2 inhibits the progress of diabetic nephropathy in a diabetic mouse model via recovery of hypercoagulability." Thrombosis and Haemostasis 97, no. 01 (2007): 124–28. http://dx.doi.org/10.1160/th06-07-0381.

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SummaryDiabetic nephropathy, a major complication of diabetes mellitus that leads to mortality, has been shown to involve a dysregulation of the coagulation system. Annexin-2, a co-receptor for plasminogen and tissue plasminogen activator on endothelial cells, is one of the molecules required to maintain the antithrombogenic properties of endothelial cells. Previously, we showed that recombinant annexin-2 protein (rAN II) modulated impaired fibrinolytic activity in the carotid arteries of rats. In the present study, to investigate its protective effects against diabetic nephropathy, rAN II was administered to KK-Ay mice, a murine model of type 2 diabetes, for eight weeks, and albuminuria, kidney size, and histological glomerular lesions were investigated. The mean weight of kidneys from KK-Ay mice treated with rAN II was significantly less than that of those treated with PBS (control) (p<0.02). Furthermore, the level of albuminuria observed in rAN II-treated KK-Ay mice was significantly less than that of the control group (rAN II, 0.90+/-0.12 µg/day; PBS, 1.55+/-0.31 µg/day; p<0.01); also, the area of diffuse glomerular lesions was significantly smaller (rAN II, 41.51+/-4.54%; PBS, 81.81+/-8.10%; p<0.01). Bleeding time, prothrombin time (PT), and active partial thromboplastin time (APTT) did not significantly differ between the two groups. Our results suggest that rAN II may inhibit the progression of diabetic nephropathy in KK-Ay mice without influencing the coagulation system, indicating that annexin-2 may be considered as a possible new therapeutic tool for patients with diabetic nephropathy.

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Lee, So-Young, So-Lim Park, Jin-Taek Hwang, Sung-Hun Yi, Young-Do Nam, and Seong-Il Lim. "Antidiabetic Effect ofMorinda citrifolia(Noni) Fermented byCheonggukjangin KK-AyDiabetic Mice." Evidence-Based Complementary and Alternative Medicine 2012 (2012): 1–8. http://dx.doi.org/10.1155/2012/163280.

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Antidiabetic effects ofMorinda citrifolia(aka Noni) fermented byCheonggukjang(fast-fermented soybean paste) were evaluated using a T2DM (type 2 diabetes mellitus) murine model. Six-week-old KK-Ay/TaJcl mice were randomly divided into four groups: (1) the diabetic control (DC) group, provided with a normal mouse diet; (2) the positive control (PC) group, provided with a functional health food diet; (3) theM. citrifolia(MC) group, provided with an MC-based diet; (4) the fermentedM. citrifolia(FMC) group, provided with an FMC-based diet. Over a testing period of 90 days, food and water intake decreased significantly in the FMC and PC groups compared with the DC group. Blood glucose levels in the FMC group were 211.60–252.20 mg/dL after 90 days, while those in the control group were over 400 mg/dL after 20 days. In addition, FMC supplementation reduced glycosylated hemoglobin (HbA1c) levels, enhanced insulin sensitivity, and significantly decreased serum triglycerides and low-density lipoprotein (LDL) cholesterol. Furthermore, a fermentedM. citrifolia70% ethanolic extract (FMCE) activated peroxisome proliferator-activated receptor-(PPAR-)γand stimulated glucose uptake via stimulation of AMP-activated protein kinase (AMPK) in cultured C2C12 cells. These results suggest that FMC can be employed as a functional health food for T2DM management.

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Hunt, Heather B., Jared C. Pearl, David R. Diaz, Karen B. King, and Eve Donnelly. "Bone Tissue Collagen Maturity and Mineral Content Increase With Sustained Hyperglycemia in the KK-Ay Murine Model of Type 2 Diabetes." Journal of Bone and Mineral Research 33, no. 5 (February 8, 2018): 921–29. http://dx.doi.org/10.1002/jbmr.3365.

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Evans, Mark J., Paige E. Mahaney, Lisa Borges-Marcucci, KehDih Lai, Shuguang Wang, Julie A. Krueger, Stephen J. Gardell, et al. "A synthetic farnesoid X receptor (FXR) agonist promotes cholesterol lowering in models of dyslipidemia." American Journal of Physiology-Gastrointestinal and Liver Physiology 296, no. 3 (March 2009): G543—G552. http://dx.doi.org/10.1152/ajpgi.90585.2008.

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The nuclear hormone receptor farnesoid X receptor (FXR) plays a critical role in the regulation of bile acid, triglyceride (TG), and cholesterol homeostasis. WAY-362450 (FXR-450/XL335) is a potent synthetic FXR agonist as characterized in luciferase reporter assays and in mediating FXR target gene regulation in primary human and immortalized mouse hepatocytes. In vivo, WAY-362450 dose dependently decreased serum TG levels after 7 days of oral dosing in western diet-fed low-density lipoprotein receptor−/− mice and in the diabetic mouse strains KK-Ay and db/db comparable to that achieved with the peroxisome proliferator activated receptor-α agonist, fenofibrate. WAY-362450 treatment also reduced serum cholesterol levels via reductions in LDLc, VLDLc, and HDLc lipoprotein fractions that were not accompanied by hepatic cholesterol accumulation. This cholesterol lowering was dependent on FXR as demonstrated in a hypothyroid-induced hypercholesterolemia setting in FXR−/− mice. In fructose-fed models, WAY-362450 also decreased TG and VLDLc levels in rats and hamsters but significantly increased HDLc levels in rats while reducing HDLc levels in hamsters. The differential effect of WAY-362450 on HDLc is likely due to a murine-specific induction of endothelial lipase and scavenger receptor-BI that does not occur in rats. These studies demonstrate a consistent ability of WAY-362450 to lower both serum TG and cholesterol levels and suggest that synthetic FXR agonists may have clinical utility in the treatment of mixed dyslipidemia.

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Kon, Kazuyoshi, Kenichi Ikejima, Kyoko Okumura, Kumiko Arai, Tomonori Aoyama, and Sumio Watanabe. "Diabetic KK-Ay mice are highly susceptible to oxidative hepatocellular damage induced by acetaminophen." American Journal of Physiology-Gastrointestinal and Liver Physiology 299, no. 2 (August 2010): G329—G337. http://dx.doi.org/10.1152/ajpgi.00361.2009.

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Despite pathophysiological similarities to alcoholic liver disease, susceptibility to acetaminophen hepatotoxicity in metabolic syndrome-related nonalcoholic steatohepatitis (NASH) has not been well elucidated. In this study, therefore, we investigated acetaminophen-induced liver injury in KK-Ay mice, an animal model of metabolic syndrome. Twelve-week-old male KK-Ay and C57Bl/6 mice were injected intraperitoneally with 300 or 600 mg/kg acetaminophen, and euthanized 6 h later. Liver histology was assessed, and hepatic expression of 4-hydroxy-2-nonenal was detected by immunohistochemistry. Levels of reduced glutathione were determined spectrophotometrically. Phosphorylation of c-Jun NH2-terminal kinase (JNK) was analyzed by Western blotting. Hepatocytes were isolated from both strains by collagenase perfusion, and cell death and oxidative stress were measured fluorometrically by use of propidium iodide and 5-(and-6)-chloromethyl-2′7′-dichloro-dihydrofluorescein diacetate acetyl ester, respectively. Acetaminophen induced more severe necrosis and apoptosis of hepatocytes in KK-Ay mice than in C57Bl/6 mice and significantly increased serum alanine aminotransferase levels in KK-Ay mice. Acetaminophen-induction of 4-hydroxy-2-nonenal in the liver was potentiated, whereas the levels of reduced glutathione in liver were lower in KK-Ay mice. Acetaminophen-induced phosphorylation of JNK in the liver was also enhanced in KK-Ay mice. Exposure to 20 μM tert-butyl hydroperoxide did not kill hepatocytes isolated from C57Bl/6 mice but induced cell death and higher oxidative stress in hepatocytes from KK-Ay mice. These results demonstrated that acetaminophen toxicity is increased in diabetic KK-Ay mice mainly due to enhanced oxidative stress in hepatocytes, suggesting that metabolic syndrome-related steatohepatitis is an exacerbating factor for acetaminophen-induced liver injury.

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Shao, Xi, Yongqing Yang, Zhifen Tan, Yuanjun Ding, Erping Luo, Da Jing, and Jing Cai. "Amelioration of bone fragility by pulsed electromagnetic fields in type 2 diabetic KK-Ay mice involving Wnt/β-catenin signaling." American Journal of Physiology-Endocrinology and Metabolism 320, no. 5 (May 1, 2021): E951—E966. http://dx.doi.org/10.1152/ajpendo.00655.2020.

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Type 2 diabetes mellitus (T2DM) results in compromised bone microstructure and quality, and subsequently increased risks of fractures. However, it still lacks safe and effective approaches resisting T2DM bone fragility. Pulsed electromagnetic fields (PEMFs) exposure has proven to be effective in accelerating fracture healing and attenuating osteopenia/osteoporosis induced by estrogen deficiency. Nevertheless, whether and how PEMFs resist T2DM-associated bone deterioration remain not fully identified. The KK-Ay mouse was used as the T2DM model. We found that PEMF stimulation with 2 h/day for 8 wk remarkably improved trabecular bone microarchitecture, decreased cortical bone porosity, and promoted trabecular and cortical bone material properties in KK-Ay mice. PEMF stimulated bone formation in KK-Ay mice, as evidenced by increased serum levels of bone formation (osteocalcin and P1NP), enhanced bone formation rate, and increased osteoblast number. PEMF significantly suppressed osteocytic apoptosis and sclerostin expression in KK-Ay mice. PEMF exerted beneficial effects on osteoblast- and osteocyte-related gene expression in the skeleton of KK-Ay mice. Nevertheless, PEMF exerted no effect on serum biomarkers of bone resorption (TRAcP5b and CTX-1), osteoclast number, or osteoclast-specific gene expression ( TRAP and cathepsin K). PEMF upregulated gene expression of canonical Wnt ligands (including Wnt1, Wnt3a, and Wnt10b), but not noncanonical Wnt5a. PEMF also upregulated skeletal protein expression of downstream p-GSK-3β and β-catenin in KK-Ay mice. Moreover, PEMF-induced improvement in bone microstructure, mechanical strength, and bone formation in KK-Ay mice was abolished after intragastric administration with the Wnt antagonist ETC-159. Together, our results suggest that PEMF can improve bone microarchitecture and quality by enhancing the biological activities of osteoblasts and osteocytes, which are associated with the activation of the Wnt/β-catenin signaling pathway. PEMF might become an effective countermeasure against T2DM-induced bone deterioration. NEW & NOTEWORTHY PEMF improved trabecular bone microarchitecture and suppressed cortical bone porosity in T2DM KK-Ay mice. It attenuated T2DM-induced detrimental consequence on trabecular and cortical bone material properties. PEMF resisted bone deterioration in KK-Ay mice by enhancing osteoblast-mediated bone formation. PEMF also significantly suppressed osteocytic apoptosis and sclerostin expression in KK-Ay mice. The therapeutic potential of PEMF on T2DM-induced bone deterioration was associated with the activation of Wnt/ß-catenin signaling.

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Mizuno, Yu, Takeshi Yamamotoya, Yusuke Nakatsu, Koji Ueda, Yasuka Matsunaga, Masa-Ki Inoue, Hideyuki Sakoda, et al. "Xanthine Oxidase Inhibitor Febuxostat Exerts an Anti-Inflammatory Action and Protects against Diabetic Nephropathy Development in KK-Ay Obese Diabetic Mice." International Journal of Molecular Sciences 20, no. 19 (September 21, 2019): 4680. http://dx.doi.org/10.3390/ijms20194680.

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Hyperuricemia has been recognized as a risk factor for insulin resistance as well as one of the factors leading to diabetic kidney disease (DKD). Since DKD is the most common cause of end-stage renal disease, we investigated whether febuxostat, a xanthine oxidase (XO) inhibitor, exerts a protective effect against the development of DKD. We used KK-Ay mice, an established obese diabetic rodent model. Eight-week-old KK-Ay mice were provided drinking water with or without febuxostat (15 μg/mL) for 12 weeks and then subjected to experimentation. Urine albumin secretion and degrees of glomerular injury judged by microscopic observations were markedly higher in KK-Ay than in control lean mice. These elevations were significantly normalized by febuxostat treatment. On the other hand, body weights and high serum glucose concentrations and glycated albumin levels of KK-Ay mice were not affected by febuxostat treatment, despite glucose tolerance and insulin tolerance tests having revealed febuxostat significantly improved insulin sensitivity and glucose tolerance. Interestingly, the IL-1β, IL-6, MCP-1, and ICAM-1 mRNA levels, which were increased in KK-Ay mouse kidneys as compared with normal controls, were suppressed by febuxostat administration. These data indicate a protective effect of XO inhibitors against the development of DKD, and the underlying mechanism likely involves inflammation suppression which is independent of hyperglycemia amelioration.

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Hiramoto, Keiichi, Kenji Goto, Shota Tanaka, Tsuneki Horikawa, and Kazuya Ooi. "Skin, Liver, and Kidney Interactions Contribute to Skin Dryness in Aging KK-Ay/Tajcl Mice." Biomedicines 10, no. 10 (October 20, 2022): 2648. http://dx.doi.org/10.3390/biomedicines10102648.

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Type 2 diabetes is a lifestyle-related disease that affects people worldwide and is especially prevalent in the elderly. Many elderly people with diabetes also complain of dry skin; however, the relationship between aging and dry skin in type 2 diabetes is unknown. The purpose of this study was to examine the interaction between aging and dry skin using the specific pathogen-free KK-Ay/TaJcl type 2 diabetes mouse model. Skin dryness in this model increases with age and was evaluated at 10, 27, 40, and 50 weeks. We observed increased mast cell expression, increased histamine and matrix metalloproteinase-1 levels, and decreased collagen expression in the skin of aging KK-Ay/TaJcl mice. In addition, the increased expression of angiopoietin 2, interleukin-6, tumor necrosis factor-α, and endostatin in the blood indicated kidney damage in this model. Aging KK-Ay/TaJcl mice also showed fatty liver pathology, which led to increased reactive oxygen species in the blood and liver, as well as the increased expression of M1 macrophages in the liver. These results showed that dry skin is associated with skin, kidney, and liver interactions in an aging type 2 diabetes mouse model.

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Kitagawa, Ryuta, Kazuyoshi Kon, Akira Uchiyama, Kumiko Arai, Shunhei Yamashina, Kyoko Kuwahara-Arai, Teruo Kirikae, Takashi Ueno, and Kenichi Ikejima. "Rifaximin prevents ethanol-induced liver injury in obese KK-Ay mice through modulation of small intestinal microbiota signature." American Journal of Physiology-Gastrointestinal and Liver Physiology 317, no. 5 (November 1, 2019): G707—G715. http://dx.doi.org/10.1152/ajpgi.00372.2018.

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Exacerbation of alcoholic hepatitis (AH) with comorbid metabolic syndrome is an emerging clinical problem, where microbiota plays a profound role in the pathogenesis. Here, we investigated the effect of rifaximin (RFX) on liver injury following chronic-binge ethanol (EtOH) administration in KK-Ay mice, a rodent model of metabolic syndrome. Female, 8-wk-old KK-Ay mice were fed Lieber–DeCarli diet (5% EtOH) for 10 days, following a single EtOH gavage (4 g/kg body wt). Some mice were given RFX (0.1 g/L, in liquid diet) orally. Small intestinal contents were collected from mice without binge. Intestinal microbiota was quantified using aerobic and anaerobic culturing techniques and further analyzed by 16S rRNA sequencing in detail. EtOH feeding/binge caused hepatic steatosis, oxidative stress, and induction of inflammatory cytokines in KK-Ay mice, which were markedly prevented by RFX treatment. Hepatic mRNA levels for cluster of differentiation 14, Toll-like receptor (TLR) 4, TLR2, and NADPH oxidase 2 were increased following EtOH feeding/binge, and administration of RFX completely suppressed their increase. The net amount of small intestinal bacteria was increased over threefold after chronic EtOH feeding as expected; however, RFX did not prevent this net increase. Intriguingly, the profile of small intestinal microbiota was dramatically changed following EtOH feeding in the order level, where the Erysipelotrichales predominated in the relative abundance. In sharp contrast, RFX drastically blunted the EtOH-induced increases in the Erysipelotrichales almost completely, with increased proportion of the Bacteroidales. In conclusion, RFX prevents AH through modulation of small intestinal microbiota/innate immune responses in obese KK-Ay mice. NEW & NOTEWORTHY Here we demonstrated that rifaximin (RFX) prevents chronic-binge ethanol (EtOH)-induced steatohepatitis in KK-Ay mice. Chronic EtOH feeding caused small intestinal bacterial overgrowth, with drastic alteration in the microbiota profile predominating the order Erysipelotrichales. RFX minimized this EtOH induction in Erysipelotrichales with substitutive increases in Bacteroidales. RFX also prevented EtOH-induced increases in portal lipopolysaccharide, and hepatic cluster of differentiation 14, toll-like receptor (TLR) 2, and TLR4 mRNA levels, suggesting the potential involvement of microbiota-related innate immune responses.

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Jia, Yanmei, and Lirong Chen. "Antidiabetic Activity of Picris japonica Thunb Aqueous Extract in Diabetic KK-Ay Mice." Evidence-Based Complementary and Alternative Medicine 2018 (November 12, 2018): 1–5. http://dx.doi.org/10.1155/2018/1298030.

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Objective. To evaluate the hypoglycemic effect of Picris japonica Thunb (Asteraceae) on KK-Ay mice. Methods. The hypoglycemic effect of Picris japonica aqueous extract (PJE) in a spontaneous type 2 diabetic model (KK-Ay mice) was studied in the present research. PJE was administrated at doses of 700 mg/kg and 350 mg/kg (calculated as crude herb) for 14 days and blood glucose, oral glucose tolerance test, plasma insulin level, and blood lipid were evaluated. Meanwhile, Rosiglitazone was used for the positive control. Results. It was found the PJE treatment significantly reduced blood glucose level and improved oral glucose tolerance ability (p < 0.01 or p < 0.05) in a dose-dependent manner compared to the control diabetic mice. The blood insulin levels were significantly reduced in PJE-treated mice (700 mg/kg) and Rosiglitazone compared with the diabetic control (p < 0.01). Compared with the control diabetic group, the serum total cholesterol, triglyceride, and low density lipoprotein cholesterol were reduced by PJE (700 mg/kg) and Rosiglitazone (p < 0.05), and the serum high density lipoprotein cholesterol was significantly increased only by Rosiglitazone (p < 0.01). Conclusions. The findings demonstrate that Picris japonica has remarkable antidiabetic effect in diabetic KK-Ay mice, which suggests that Picris japonica may be beneficial to the treatment of type 2 diabetes mellitus.

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Yang, Lixia, Jianjun Xue, Xiangyun Meng, Yongsheng Wang, Lili Wu, Cuiyan Lv, Tonghua Liu, and Yu Bai. "Effects of total flavonoids from Oxytropis falcata Bunge on the SOCS/JAK/STAT inflammatory signaling pathway in the kidneys of diabetic nephropathy model mice." European Journal of Inflammation 17 (January 2019): 205873921986187. http://dx.doi.org/10.1177/2058739219861877.

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To investigate the effects of total flavonoids from Oxytropis falcata Bunge on the inflammatory signaling pathway suppressor of cytokine signaling (SOCS)/Janus kinase (JAK)/signal transducer and activator of transcription (STAT) in diabetic nephropathy KK-Ay mice. KK-Ay mice were used to establish a diabetic nephropathy model. The general condition of the mice treated with different concentrations of total flavonoids from O. falcata was monitored, respectively. Body weight, blood glucose, 24-h urinary albumin (UAlb), serum creatinine (Cre), blood urea nitrogen (BUN), and uric acid (UA) levels were measured at different time points. Hematoxylin and eosin staining quantitative reverse transcription-polymerase chain reaction and western blotting were used to detect changes in renal tissues and glomerular mesangial cells. Four weeks after model establishment, body weight, blood glucose, and 24 h UAlb significantly increased in KK-Ay mice compared with that in control C57BL/6j mice ( P < 0.05). Compared with non-treated model mice, mice treated with total flavonoids from O. falcata for 4 weeks had significantly decreased serum Cre, BUN, and UA; monocyte chemoattractant protein-1(MCP-1), nuclear factor(NF)-κB, interleukin(IL)-6, and transforming growth factor(TGF)-β1, JAK 1, STAT 3 and STAT 4 mRNA levels; and p-JAK2 and p-STAT1 protein levels and significantly increased SOCS-1 and SOCS-3 protein levels in the kidneys. The treatment effects were dose-dependent and same to in vitro. Our results reflected that total flavonoids from O. falcata relieved renal tissue inflammation in diabetic mice by reducing blood glucose levels and inhibiting JAK/STAT signaling, thereby protecting against the development of diabetic nephropathy.

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Liu, Liping, Anmei Shu, Yihui Zhu, and Yuping Chen. "Cornuside Alleviates Diabetes Mellitus-Induced Testicular Damage by Modulating the Gut Microbiota." Evidence-Based Complementary and Alternative Medicine 2021 (August 30, 2021): 1–13. http://dx.doi.org/10.1155/2021/5301942.

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Background. Male reproductive damage, as a common complication of diabetes mellitus (DM), is getting more attention lately. We aimed to explore the protective effects and mechanism of cornuside (Cor) modulating gut microbiota to alleviate diabetes mellitus- (DM-) induced testicular damage. Methods. KK-Ay mice with reproductive damage were randomly divided into the model and Cor treatment groups, and the C57BL/6J mice were used as the normal group. These mice were orally administered Cor for 8 weeks. Results. Cor administration ameliorated the diabetes-related symptoms of polydipsia and polyphagia and lowered the fasting blood glucose (FBG) level. The results of pathological injury showed that Cor improved testicular lesions (the rupture of seminiferous tubules, degeneration of germ cells, and structural shrinkage and separation from each other) in DM model mice. Cor significantly increased the testis/body weight ratio, testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels in KK-Ay mice. Cor also protected from reproductive damage by inhibiting apoptosis in the testes of KK-Ay mice. Moreover, Cor significantly increased the sperm count and sperm motility. Additionally, 16S rDNA sequencing analysis showed that Cor could notably reverse the changes in the distribution of gut microbiota and decrease the abundance of Weissella confusa (Weissella), Clostridium sp. ND2 (Clostridium sensu stricto 1), uncultured bacterium (Roseburia), Anaerotruncus colihominis DSM 17241 (Anaerotruncus), [Clostridium] leptum (Anaerotruncus), unidentified (Ruminococcus 1), and uncultured bacterium (Bilophila), which may be a potential biomarker for diagnosing the testicular injury caused by DM. Meanwhile, the heat map of phylum level suggested that the testicular injury caused by DM is closely related to gut microbiota. Conclusions. Cor could alleviate DM-induced testicular damage, probably by modulating the gut microbiota.

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Omote, Keisuke, Tomohito Gohda, Maki Murakoshi, Yu Sasaki, Saiko Kazuno, Tsutomu Fujimura, Masanori Ishizaka, Yuji Sonoda, and Yasuhiko Tomino. "Role of the TNF pathway in the progression of diabetic nephropathy in KK-Ay mice." American Journal of Physiology-Renal Physiology 306, no. 11 (June 1, 2014): F1335—F1347. http://dx.doi.org/10.1152/ajprenal.00509.2013.

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Chronic inflammation promotes the progression of diabetic nephropathy (DN). However, the role of TNF-α remains unclear. The objectives of the present study were to examine whether TNF-α inhibition with a soluble TNF receptor (TNFR)2 fusion protein, i.e., etanercept (ETN), improves the early stage of DN in the type 2 diabetic model of the KK-Ay mouse and to also investigate which TNF pathway, TNFR1 or TNFR2, is predominantly involved in the progression of this disease. ETN was injected intraperitoneally into mice for 8 wk. Renal damage was evaluated by immunohistochemistry, Western blot analysis, and/or real-time PCR. In vitro, mouse tubular proximal cells were stimulated by TNF-α and/or high glucose (HG) and treated with ETN. ETN dramatically improved not only albuminuria but also glycemic control. Renal mRNA and/or protein levels of TNFR2, but not TNF-α and TNFR1, in ETN-treated KK-Ay mice were significantly decreased compared with untreated KK-Ay mice. mRNA levels of ICAM-1, VCAM-1, and monocyte chemoattractant protein-1 and the number of F4/80-positive cells were all decreased after treatment. Numbers of cleaved caspase-3- and TUNEL-positive cells in untreated mice were very few and were not different from ETN-treated mice. In vitro, stimulation with TNF-α or HG markedly increased both mRNA levels of TNFRs, unlike in the in vivo case. Furthermore, ETN partly recovered TNF-α-induced but not HG-induced TNFR mRNA levels. In conclusion, it appears that ETN may improve the progression of the early stage of DN predominantly through inhibition of the anti-inflammatory action of the TNF-α-TNFR2 pathway.

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Shi, Si, Hua‐Jing Yin, Jiang Li, Ling Wang, Wei‐Ping Wang, and Xiao‐Liang Wang. "Studies of pathology and pharmacology of diabetic encephalopathy with KK‐Ay mouse model." CNS Neuroscience & Therapeutics 26, no. 3 (August 11, 2019): 332–42. http://dx.doi.org/10.1111/cns.13201.

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Arai, Kiyoshi, Yuka Morikawa, Naoko Ubukata, and Kotaro Sugimoto. "Synergistic reduction in albuminuria in type 2 diabetic mice by esaxerenone (CS-3150), a novel nonsteroidal selective mineralocorticoid receptor blocker, combined with an angiotensin II receptor blocker." Hypertension Research 43, no. 11 (July 2, 2020): 1204–13. http://dx.doi.org/10.1038/s41440-020-0495-0.

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AbstractEsaxerenone is a novel selective mineralocorticoid receptor (MR) blocker that was recently approved in Japan to treat hypertension. In phase II and III studies, esaxerenone plus a renin–angiotensin system inhibitor markedly reduced the urinary albumin-to-creatinine ratio (UACR) in hypertensive patients with diabetic nephropathy. To evaluate a direct renoprotective effect by MR blockade independent of an antihypertensive effect in the context of diabetic nephropathy, esaxerenone (3 mg/kg), olmesartan (an angiotensin II receptor blocker; 1 mg/kg), or both were orally administered to KK-Ay mice, a type 2 diabetes model, once daily for 56 days. Urinary albumin (Ualb), UACR, and markers, such as podocalyxin, monocyte chemoattractant protein-1 (MCP-1), and 8-hydroxy-2′-deoxyguanosine (8-OHdG), were measured, along with systolic blood pressure (SBP), fasting blood glucose, and serum K+ levels. Prior to the initiation of drug administration, KK-Ay mice showed higher blood glucose, insulin, Ualb excretion, and UACR levels than C57BL/6 J mice, a nondiabetic control, indicating the development of diabetic renal injury. Combined treatment with esaxerenone and olmesartan significantly reduced the change in UACR from baseline compared with the change associated with vehicle at week 8 (−1.750 vs. 0.339 g/gCre; P < 0.002) and significantly inhibited the change in Ualb from baseline compared with the change associated with vehicle at week 8 (P < 0.002). The combination treatment also reduced urinary excretion of podocalyxin and MCP-1, but did not influence 8-OHdG excretion, SBP, blood glucose, or serum K+ levels. Overall, esaxerenone plus olmesartan treatment ameliorated diabetic nephropathy in KK-Ay mice without affecting SBP, suggesting that the renoprotective effects of esaxerenone could be exerted independently of its antihypertensive effect.

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Kondo, Shinji, Shin-ichi Adachi, Fumiaki Yoshizawa, and Kazumi Yagasaki. "Antidiabetic Effect of Taxifolin in Cultured L6 Myotubes and Type 2 Diabetic Model KK-Ay/Ta Mice with Hyperglycemia and Hyperuricemia." Current Issues in Molecular Biology 43, no. 3 (September 26, 2021): 1293–306. http://dx.doi.org/10.3390/cimb43030092.

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Muscle is the largest tissue in our body and plays an important role in glucose homeostasis and hence diabetes. In the present study, we examined the effects of taxifolin (TXF) on glucose metabolism in cultured L6 muscle cells (myotubes) and in type 2 diabetic (T2D) model KK-Ay/Ta mice. TXF dose-dependently increased glucose uptake (GU) in L6 myotubes under the condition of insulin absence. This increase in GU was partially, but significantly canceled by TXF treatment in combination with either LY294002, an inhibitor of phosphatidylinositol 3-kinase (PI3K), which phosphorylates protein kinase B (Akt) or Compound C, an inhibitor of 5’-adenosine monophosphate-activated protein kinase (AMPK). Furthermore, TXF was demonstrated to activate (=phosphorylate) both Akt and AMPK, and promote glucose transporter 4 (GLUT4) translocation to the plasma membrane from cytosol of L6 myotubes via both PI3K/Akt and AMPK signaling pathways. Based on these in vitro findings, we conducted an in vivo experiment in KK-Ay/Ta mice with hyperglycemia and hyperuricemia. Fasting plasma glucose, insulin, uric acid levels and an index of insulin resistance (HOMA-IR) increased significantly in the T2D model mice compared with normal ones. Such rises in the T2D state were significantly suppressed by oral administration of TXF for four weeks. These results suggest that TXF is a potent antihyperglycemic and antihyperuricemic phytochemical in the T2D state.

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Sørensen, Lasse E., Per B. Jeppesen, Christine B. Christiansen, Kjeld Hermansen, and Søren Gregersen. "Nordic Seaweed and Diabetes Prevention: Exploratory Studies in KK-Ay Mice." Nutrients 11, no. 6 (June 25, 2019): 1435. http://dx.doi.org/10.3390/nu11061435.

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Background: The global epidemic of type 2 diabetes (T2D) is a challenging health problem. Lifestyle changes, including nutrition therapy, areimportant for the prevention and management of T2D. Seaweeds contain several bioactive substances with potential health properties and may be a low-cost alternative functional food in the prevention of T2D. Objective: The aim of this study was to explore the preventive effects of dried Nordic seaweed species on diabetes in an animal model of T2D. Method: Fiftymale KK-Ay mice were randomly assigned to one of four diets: control diet (chow) or diets supplemented with Alaria esculenta (AE), Saccharina latissima (SL), or Palmaria palmata (PP). The effect of the interventions on the progression of T2D was monitored over 10 weeks and evaluated by circulating glucose, glycated hemoglobin (HbA1c), insulin, glucagon, and lipid levels. Results: The SL group had significantly lower bodyweight, lower HbA1c and insulin levels, as well as higher high density lipoprotein (HDL) cholesterol levels after the 10-week intervention than the control group. At the end of the study, the control group had significantly higher HbA1c (p < 0.001) than all of the seaweed groups. Conclusion: All seaweed groups improved HbA1C compared to control and Saccharinalatissima seaweed had concomitantly beneficial effects on glycemic control and lipid levels in KK-Ay diabetic mice.

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Horie, Kayo, Hayato Maeda, Naoki Nanashima, and Indrawati Oey. "Potential Vasculoprotective Effects of Blackcurrant (Ribes nigrum) Extract in Diabetic KK-Ay Mice." Molecules 26, no. 21 (October 26, 2021): 6459. http://dx.doi.org/10.3390/molecules26216459.

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Polyphenols are bioactive compounds found naturally in fruits and vegetables; they are widely used in disease prevention and health maintenance. Polyphenol-rich blackcurrant extract (BCE) exerts beneficial effects on vascular health in menopausal model animals. However, the vasculoprotective effects in diabetes mellitus (DM) and atherosclerotic vascular disease secondary to DM are unknown. Therefore, we investigated whether BCE is effective in preventing atherosclerosis using KK-Ay mice as a diabetes model. The mice were divided into three groups and fed a high-fat diet supplemented with 1% BCE (BCE1), 3% BCE (BCE2), or Control for 9 weeks. The mice in the BCE2 group showed a considerable reduction in the disturbance of elastic lamina, foam cell formation, and vascular remodeling compared to those in the BCE1 and Control groups. Immunohistochemical staining indicated that the score of endothelial nitric oxide synthase staining intensity was significantly higher in both BCE2 (2.9) and BCE1 (1.9) compared to that in the Control (1.1). Furthermore, the score for the percentage of alpha-smooth muscle actin was significantly lower in the BCE2 (2.9%) than in the Control (2.1%). Our results suggest that the intake of anthocyanin-rich BCE could have beneficial effects on the blood vessels of diabetic patients.

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Ravi Kumar, Sangeetha, Ippei Yamauchi, Bhaskar Narayan, Ami Katsuki, Masashi Hosokawa, and Kazuo Miyashita. "Squalene modulates fatty acid metabolism: Enhanced EPA/DHA in obese/diabetic mice (KK-Ay) model." European Journal of Lipid Science and Technology 118, no. 12 (May 17, 2016): 1935–41. http://dx.doi.org/10.1002/ejlt.201600006.

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YABUKI, Akira, Kazuyuki TANIGUCHI, and Osamu YAMATO. "Immunohistochemical Examination of Cyclooxygenase-2 and Renin in a KK-Ay Mouse Model of Diabetic Nephropathy." Experimental Animals 59, no. 4 (2010): 479–86. http://dx.doi.org/10.1538/expanim.59.479.

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Otabe, S., N. Wada, T. Hashinaga, X. Yuan, I. Shimokawa, T. Fukutani, K. Tanaka, et al. "Hyperadiponectinemia protects against premature death in metabolic syndrome model mice by inhibiting AKT signaling and chronic inflammation." Journal of Endocrinology 213, no. 1 (January 26, 2012): 67–76. http://dx.doi.org/10.1530/joe-11-0329.

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We previously reported that transgenic (Tg) expression of adiponectin significantly prolonged the lifespan of normal mice. The aim of this study was to elucidate the mechanism involved in the longevity effects of adiponectin using KK/Ta mice, a murine model of metabolic syndrome. We established a Tg line of KK/Ta (Tg-KK/Ta) mice expressing human adiponectin in the liver, and assessed their lifespan. The cause of death was determined by macroscopic and microscopic examinations immediately after death. The expressions of SIRT1, C-reactive protein (CRP), inflammatory cytokines, AMPK, and AKT were measured by quantitative real-time PCR, ELISAs, and/or western blotting. KK/Ta mice had lower serum adiponectin levels and shorter lifespan (57.6±13.9 vs 106.5±18.3 weeks, P<0.0001) than C57BL/6N mice. Tg adiponectin expression significantly extended the lifespan of KK/Ta mice (73.6±16.6 weeks, P<0.001) without affecting body weight, daily food consumption, or plasma glucose levels. Neoplasms were observed in only three of 22 KK/Ta mice that died spontaneously because of tumors. Atherosclerotic lesions were not detected in any mice. SIRT1 levels were not significantly different between KK/Ta and Tg-KK/Ta mice. Gene expressions of Crp, Tnfα, Il6, and Nfκb were increased in KK/Ta mice, but they were significantly attenuated in Tg-KK/Ta mice. Phosphorylated AMPK levels were increased and phosphorylated AKT levels were decreased in Tg-KK/Ta mice. The anti-inflammatory effects of adiponectin, achieved by inhibiting the AKT signaling pathway, may explain how adiponectin slows the accelerated aging process associated with the metabolic syndrome.

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Zhao, Shao-Yang, Huan-Huan Zhao, Ting-Ting Hao, Wei-Wei Li, and Hao Guo. "Effect of Bushen Huoxue Prescription on Cognitive Dysfunction of KK-Ay Type 2 Diabetic Mice." Evidence-Based Complementary and Alternative Medicine 2021 (March 12, 2021): 1–14. http://dx.doi.org/10.1155/2021/6656362.

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Diabetic cognitive impairment is one of the common complications of type 2 diabetes, which can cause neurological and microvascular damage in the brain. Bushen Huoxue prescription (BSHX), a compound Chinese medicine, has been used clinically to treat diabetes-induced cognitive impairment. However, its underlying mechanisms remain unclear. In this study, KK-Ay diabetic model mouse was administered BSHX daily for 12 weeks. Bodyweight, random blood glucose (RBG), and fasting blood glucose (FBG) were measured every 4 weeks. Triglycerides (TG), cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), fasting serum insulin (FINS), and Morris water maze were tested after 12 weeks of administration. On the day of sacrifice, the hippocampus was collected for pathological staining and advanced glycation end products (AGEs) analysis to evaluate the neuroprotective effect of BSHX. Our results showed that BSHX treatment significantly ameliorated the T2DM related insults, including the increased bodyweight, blood glucose, TG, insulin levels, AGEs, the reduced HDL-C, the impaired spatial memory, and the neurological impairment. Moreover, Western blot analysis showed that increased expression of receptors of AGEs (RAGEs), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and activation of nuclear factor-κB (NF-κB) in the hippocampus were significantly inhibited by BSHX treatment. These results indicate that BSHX can significantly ameliorate glucose and lipid metabolism dysfunction, reduce the morphological changes in hippocampus tissues, and improve the cognitive function of KK-Ay mice. These protective effects of BSHX may involve regulation of the AGEs/RAGE/NF-κB signaling pathway.

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Viswanadham, K. K. DurgaRao, Roland Böttger, Lukas Hohenwarter, Anne Nguyen, Elham Rouhollahi, Alexander Smith, Yi-Hsuan Tsai, et al. "An Effective and Safe Enkephalin Analog for Antinociception." Pharmaceutics 13, no. 7 (June 22, 2021): 927. http://dx.doi.org/10.3390/pharmaceutics13070927.

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Opioids account for 69,000 overdose deaths per annum worldwide and cause serious side effects. Safer analgesics are urgently needed. The endogenous opioid peptide Leu-Enkephalin (Leu-ENK) is ineffective when introduced peripherally due to poor stability and limited membrane permeability. We developed a focused library of Leu-ENK analogs containing small hydrophobic modifications. N-pivaloyl analog KK-103 showed the highest binding affinity to the delta opioid receptor (68% relative to Leu-ENK) and an extended plasma half-life of 37 h. In the murine hot-plate model, subcutaneous KK-103 showed 10-fold improved anticonception (142%MPE·h) compared to Leu-ENK (14%MPE·h). In the formalin model, KK-103 reduced the licking and biting time to ~50% relative to the vehicle group. KK-103 was shown to act through the opioid receptors in the central nervous system. In contrast to morphine, KK-103 was longer-lasting and did not induce breathing depression, physical dependence, and tolerance, showing potential as a safe and effective analgesic.

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Sekijima, Hidehisa, Kenji Goto, Keiichi Hiramoto, Rio Komori, and Kazuya Ooi. "Characterization of dry skin associating with type 2 diabetes mellitus using a KK-Ay/TaJcl mouse model." Cutaneous and Ocular Toxicology 37, no. 4 (July 31, 2018): 391–95. http://dx.doi.org/10.1080/15569527.2018.1490746.

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ITO, TAKAMICHI, MITSUO TANIMOTO, KAORI YAMADA, SHIGERU KANEKO, MASAKAZU MATSUMOTO, KEIKO OBAYASHI, SHINJI HAGIWARA, et al. "Glomerular changes in the KK-Ay/Ta mouse: A possible model for human type 2 diabetic nephropathy." Nephrology 11, no. 1 (February 2006): 29–35. http://dx.doi.org/10.1111/j.1440-1797.2006.00543.x.

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Ishikawa, Yuji, Takamichi Ito, Mitsuo Tanimoto, Shinji Hagiwara, Masako Furukawa, Saori Yamaguchi, Keisuke Omote, et al. "Podocyte loss and albuminuria of KK-Ay mouse: A spontaneous animal model for human type 2 diabetic nephropathy." Journal of Diabetes Mellitus 02, no. 03 (2012): 346–52. http://dx.doi.org/10.4236/jdm.2012.23054.

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Chakraborty, Goutam, Sherin Thumpayil, David-Erick Lafontant, Wolde Woubneh, and Jeffrey H. Toney. "Age dependence of glucose tolerance in adult KK-Ay mice, a model of non–insulin dependent diabetes mellitus." Lab Animal 38, no. 11 (November 2009): 364–68. http://dx.doi.org/10.1038/laban1109-364.

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Zha, Jun, Xiao-wei Chi, Xiao-lin Yu, Xiang-meng Liu, Dong-qun Liu, Jie Zhu, Hui Ji, and Rui-tian Liu. "Interleukin-1β-Targeted Vaccine Improves Glucose Control and β-Cell Function in a Diabetic KK-Ay Mouse Model." PLOS ONE 11, no. 5 (May 6, 2016): e0154298. http://dx.doi.org/10.1371/journal.pone.0154298.

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Tomino, Yasuhiko. "Lessons From the KK-Ay Mouse, a Spontaneous Animal Model for the Treatment of human Type 2 Diabetic Nephropathy." Nephro-Urology Monthly 4, no. 3 (June 20, 2012): 524–29. http://dx.doi.org/10.5812/numonthly.1954.

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Kamakura, Remi, Myoung Jin Son, Dalene de Beer, Elizabeth Joubert, Yutaka Miura, and Kazumi Yagasaki. "Antidiabetic effect of green rooibos (Aspalathus linearis) extract in cultured cells and type 2 diabetic model KK-Ay mice." Cytotechnology 67, no. 4 (November 20, 2014): 699–710. http://dx.doi.org/10.1007/s10616-014-9816-y.

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Chen, Zhong-Hua, Jie Li, Jie Liu, Yuan Zhao, Pu Zhang, Meng-Xue Zhang, and Liu Zhang. "Saponins Isolated from the Root of Panax notoginseng Showed Significant Anti-Diabetic Effects in KK-Ay Mice." American Journal of Chinese Medicine 36, no. 05 (January 2008): 939–51. http://dx.doi.org/10.1142/s0192415x08006363.

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Panax notoginseng, a well-known and commonly used traditional Chinese herb, has been used in China for six hundred years. Panax notoginseng Saponins (PNS) were extracted from the root of the plant. This is the first study on anti-hyperglycemic and anti-obese effects of PNS in genetic model mice. Additionally, the preventive effect on diabetic nephropathy was investigated. Animals received intraperitoneal injections of PNS 50 or 200 mg/kg daily. On day 12, 22 and 30, PNS-treated groups had significantly lower fasting blood glucose levels and smaller body weight incremental percentage. After a 12-day treatment, glucose tolerance of PNS groups were significantly improved; these indices in PNS-treated mice exhibited a dose-dependent improvement. Furthermore, on day 30, the serum insulin resistance index and triglyceride levels of PNS-treated groups decreased significantly, and the development of the mice glomerular lesions was prevented significantly. The results in this present paper indicate that PNS possesses anti-diabetes and anti-obese activities and may prove to be of clinical importance in improving the management of type 2 diabetes.

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MIURA, Toshihiro, Yasushi ITOH, and Torao ISHIDA. "Impairment of Insulin-induced GLUT4 Translocation in Skeletal Muscle of KK-Ay Mouse, a Genetic Animal Model of Type 2 Diabetes." Biomedical Research 23, no. 5 (2002): 209–12. http://dx.doi.org/10.2220/biomedres.23.209.

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Kang, Inhae, Seojin Choi, Tae Joung Ha, Munji Choi, Hae-Ri Wi, Byong Won Lee, and Myoungsook Lee. "Effects of Mung Bean (Vigna radiata L.) Ethanol Extracts Decrease Proinflammatory Cytokine-Induced Lipogenesis in the KK-Ay Diabese Mouse Model." Journal of Medicinal Food 18, no. 8 (August 2015): 841–49. http://dx.doi.org/10.1089/jmf.2014.3364.

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Kato, H., M. Ohue, K. Kato, A. Nomura, K. Toyosawa, Y. Furutani, S. Kimura, and T. Kadowaki. "Mechanism of Amelioration of Insulin Resistance by 3-Adrenoceptor Agonist AJ-9677 in the KK-Ay/Ta Diabetic Obese Mouse Model." Diabetes 50, no. 1 (January 1, 2001): 113–22. http://dx.doi.org/10.2337/diabetes.50.1.113.

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Muto, Y., J. Satoh, G. Muto, T. Masuda, M. Sagara, M. Fukuzawa, S. Miyaguchi, et al. "Effect of Long-Term Treatment with Complete Freund's Adjuvant on KK-Ay Mouse, a Model of Non-Insulin-Dependent Diabetes Mellitus." Clinical Immunology and Immunopathology 83, no. 1 (April 1997): 53–59. http://dx.doi.org/10.1006/clin.1997.4328.

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Ueda-Wakagi, Manabu, Hironobu Nagayasu, Yoko Yamashita, and Hitoshi Ashida. "Green Tea Ameliorates Hyperglycemia by Promoting the Translocation of Glucose Transporter 4 in the Skeletal Muscle of Diabetic Rodents." International Journal of Molecular Sciences 20, no. 10 (May 16, 2019): 2436. http://dx.doi.org/10.3390/ijms20102436.

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It is known that green tea helps prevent obesity and diabetes mellitus. In this study, we aimed to determine whether green tea ameliorates hyperglycemia and the mechanism involved in diabetic rodents. Green tea consumption reduced blood glucose and ameliorated glucose intolerance, which was assessed using an oral glucose tolerance test in both streptozotocin-induced type 1 diabetic rats and type 2 diabetic KK-Ay mice. Green tea also reduced the plasma fructosamine and glycated hemoglobin concentrations in both models. Furthermore, it increased glucose uptake into the skeletal muscle of both model animals, which was accompanied by greater translocation of glucose transporter 4 (GLUT4). Moreover, epigallocatechin gallate (EGCG), the principal catechin in green tea, also ameliorated glucose intolerance in high-fat diet-induced obese and diabetic mice. These results suggest that green tea can ameliorate hyperglycemia in diabetic rodents by stimulating GLUT4-mediated glucose uptake in skeletal muscle, and that EGCG is one of the effective compounds that mediate this effect.

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MATSUZAKI, TAKESHI, RYUTA YAMAZAKI, SHUSUKE HASHIMOTO, and TERUO YOKOKURA. "Antidiabetic Effects of an Oral Administration of Lactobacillus casei in a Non-Insulin-Dependent Diabetes Mellitus (NIDDM) Model using KK-Ay Mice." Endocrine Journal 44, no. 3 (1997): 357–65. http://dx.doi.org/10.1507/endocrj.44.357.

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Matsuzaki, Takeshi, Ryuta Yamazaki, Shusuke Hashimoto, and Teruo Yokokura. "Antidiabetic effects of an oral administration of Lactobacillus casei in a non-insulin-dependent diabetes mellitus (NIDDM) model using KK-Ay mice." Japanese Journal of Pharmacology 73 (1997): 145. http://dx.doi.org/10.1016/s0021-5198(19)45083-x.

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SUDO, Takako, Aiko ISHII, Jun ASAMI, Yoshikatsu UEMATSU, Masako SAITOH, Atsushi NAKAMURA, Norihiro TADA, Tatsuya OHNUKI, Toshi KOMURASAKI, and Junichi NAKAGAWA. "Transgenic Mice Over-expressing Dicarbonyl/L-xylulose Reductase Gene Crossed with KK-Ay Diabetic Model Mice: An Animal Model for the Metabolism of Renal Carbonyl Compounds." Experimental Animals 54, no. 5 (2005): 385–94. http://dx.doi.org/10.1538/expanim.54.385.

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Guo, Beining, Kamilia Abdelraouf, Kimberly R. Ledesma, Kai-Tai Chang, Michael Nikolaou, and Vincent H. Tam. "Quantitative Impact of Neutrophils on Bacterial Clearance in a Murine Pneumonia Model." Antimicrobial Agents and Chemotherapy 55, no. 10 (August 1, 2011): 4601–5. http://dx.doi.org/10.1128/aac.00508-11.

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ABSTRACTThe rapid increase in the prevalence of antibiotic-resistant pathogens is a global problem that has challenged our ability to treat serious infections. Currently, clinical decisions on treatment are often based onin vitrosusceptibility data. The role of the immune system in combating bacterial infections is unequivocal, but it is not well captured quantitatively. In this study, the impact of neutrophils on bacterial clearance was quantitatively assessed in a murine pneumonia model.In vitrotime-growth studies were performed to determine the growth rate constants ofAcinetobacter baumanniiATCC BAA 747 andPseudomonas aeruginosaPAO1. The absolute neutrophil count in mice resulting from different cyclophosphamide preparatory regimens was determined. The dynamic change of bacterial (A. baumanniiBAA 747) burden in mice with graded immunosuppression over 24 h was captured by a mathematical model. The fit to the data was satisfactory (r2= 0.945). The best-fit maximal kill rate (Kk) of the bacterial population by neutrophils was 1.743 h−1, the number of neutrophils necessary for 50% maximal killing was 190.8/μl, and the maximal population size was 1.8 × 109CFU/g, respectively. Using these model parameter estimates, the model predictions were subsequently validated by the bacterial burden change ofP. aeruginosaPAO1 at 24 h. A simple mathematical model was proposed to quantify the contribution of neutrophils to bacterial clearance and predict the bacterial growth/suppression in animals. Our results provide a novel framework to linkin vitroandin vivoinformation and may be used to improve clinical treatment of bacterial infections.

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Takahashi, Eri, Akinori Okumura, Hiroyuki Unoki-Kubota, Hisashi Hirano, Masato Kasuga, and Yasushi Kaburagi. "Differential proteome analysis of serum proteins associated with the development of type 2 diabetes mellitus in the KK-Ay mouse model using the iTRAQ technique." Journal of Proteomics 84 (June 2013): 40–51. http://dx.doi.org/10.1016/j.jprot.2013.03.014.

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Green, W. R., and J. D. Phillips. "Differential induction of H-2K vs H-2D class I major histocompatibility complex antigen expression by murine recombinant interferon-gamma." Journal of Immunology 137, no. 3 (August 1, 1986): 814–18. http://dx.doi.org/10.4049/jimmunol.137.3.814.

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Abstract The results presented here indicate that recombinant murine interferon-gamma can cause a dramatic differential induction of two distinct class I MHC molecules. Thus, IFN-gamma treatment of the murine leukemia virus (MuLV)-induced AKR SL3 tumor, a cell line that normally expresses moderate levels of class I MHC antigens, resulted in a large increase in H-2Dk expression, but no change or a slight decrease in H-2Kk expression as measured by cytofluorography. Explanations of the selective enhancement of Dk expression based on increased Fc receptor display or differential kinetics of induction were ruled out. The phenomenon was observed over a wide range of doses of IFN-gamma and with two different monoclonal antibodies to Kk, the latter finding making it unlikely that an altered form of the Kk molecule was induced. The same differential induction of the Dk antigen was observed for the LBRM.5A4 tumor cell line. Because LBRM.5A4 is also MuLV+ but of congenic B10.BR (H-2k) origin, these results were consistent with the possibility that such differential induction was associated with the H-2k haplotype and/or MuLV. The implications of these results, as a possible mechanism of tumor cell escape from an immune surveillance system monitored by class I MHC-restricted T cells and as a useful model system to dissect the mechanism of IFN-gamma induction of class I MHC antigens, are discussed.

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Takagi, Satoshi, Takenori Yamashita, and Toshihiro Miura. "Does a Treadmill Running Exercise Contribute to Preventing Deterioration of Bone Mineral Density and Bone Quality of the Femur in KK-Ay Mice, a Type 2 Diabetic Animal Model?" Calcified Tissue International 101, no. 6 (August 4, 2017): 631–40. http://dx.doi.org/10.1007/s00223-017-0310-3.

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Sugizaki, Taichi, Mitsuhiro Watanabe, Yasushi Horai, Nao Kaneko-Iwasaki, Eri Arita, Teruo Miyazaki, Kohkichi Morimoto, Akira Honda, Junichiro Irie, and Hiroshi Itoh. "The Niemann-Pick C1 Like 1 (NPC1L1) Inhibitor Ezetimibe Improves Metabolic Disease Via Decreased Liver X Receptor (LXR) Activity in Liver of Obese Male Mice." Endocrinology 155, no. 8 (August 1, 2014): 2810–19. http://dx.doi.org/10.1210/en.2013-2143.

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Dyslipidemic patients with diabetes mellitus, including metabolic syndrome, are at increased risk of coronary heart disease. It has been reported that ezetimibe, a cholesterol absorption inhibitor, improves metabolic diseases in mice and humans. However, the underlying mechanism has been unclear. Here we explored the effects of ezetimibe on lipid and glucose homeostasis. Male KK-Ay mice were fed a high-fat diet, which is the mouse model of metabolic syndrome, with or without ezetimibe for 14 weeks. Ezetimibe improved dyslipidemia, steatosis, and insulin resistance. Ezetimibe decreased hepatic oxysterols, which are endogenous agonists of liver X receptor (LXR), to decrease hepatic lipogenic gene expressions, especially in stearoyl-CoA desaturase-1 (SCD1), leading to a remarkable reduction of hepatic oleate content that would contribute to the improvement of steatosis by reducing triglycerides and cholesterol esters. Simultaneously, hepatic β-oxidation, NADPH oxidase and cytochrome P450 2E1 (CYP2E1) were reduced, and thus reactive oxygen species (ROS) and inflammatory cytokines were also decreased. Consistent with these changes, ezetimibe diminished c-Jun N-terminal kinase (JNK) phosphorylation and improved insulin signaling in the liver. In vitro study using primary hepatocytes obtained from male SD rats, treated with oleate and LXR agonist, showed excess lipid accumulation, increased oxidative stress and impaired insulin signaling. Therefore, in obese subjects, ezetimibe reduces hepatic LXR activity by reducing hepatic oxysterols to lower hepatic oleate content. This improves steatosis and reduces oxidative stress, and this reduction improves insulin signaling in the liver. These results provide insight into pathogenesis and strategies for treatment of the metabolic syndrome.

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Kubota, Sho, Kenji Tokunaga, Tomohiro Umezu, Takako Yokomizo, Motohiko Oshima, Eisaku Iwanaga, Norio Asou, et al. "Lineage-Specific RUNX2 Super-Enhancer Activates MYC Via Translocation (6;8) to Promote the Development of Blastic Plasmacytoid Dendritic Cell Neoplasm." Blood 132, Supplement 1 (November 29, 2018): 761. http://dx.doi.org/10.1182/blood-2018-99-110333.

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Abstract Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematological malignancy, characteristic of skin lesions followed by hematopoietic organ dissemination. The cell of origin of which is considered to be precursors of plasmacytoid dendritic cells (pDCs). BPDCN cells show high frequencies of mutations in TET2 and p53; however, the molecular mechanisms underlying the pathogenesis of BPDCN have not yet been elucidated. RUNX2 transcription factor, located on chromosome 6p21, is critical for the differentiation of pDCs and the enhancer of RUNX2 is activated in pDCs. Since translocation (6;8)(p21;q24), which is a rare, but specific anomaly for BPDCN, involves regions adjacent to RUNX2 and MYC, we demonstrate that the pDC-specific RUNX2 super-enhancer activates the expression of RUNX2, which functions as a lineage-survival transcription factor, but also is hijacked to activate expression of MYC via t(6;8) in BPDCN cells, and that RUNX2 and MYC promote the initiation and propagation of BPDCN by generating a novel mouse model. In order to identify the breakpoint of t(6;8)(p21;q24), we first performed fluorescent in situ hybridization and whole genome sequencing of CAL-1 cells, a BPDCN cell line, and identified a fusion point of chromosome translocation between chromosome 8 in 69 kilobases (kb) downstream of MYC and chromosome 6, which was 58 kb centromeric to a long and clustered super-enhancer of RUNX2 (791 kb upstream of RUNX2) defined by chromatin immunoprecipitation sequencing using anti-H3K27ac or anti-BRD4 antibodies. As we observed the enhanced levels of MYC and RUNX2 expression in BPDCN cells in patients and CAL-1 cells, we knocked down expression of MYC or RUNX2 using distinct shRNA vectors in CAL-1 cells. We found that the knockdown of MYC and/or RUNX2 significantly impaired colony formation capacities. By performing microarray analysis, we found that RUNX2 knockdown significantly reduced expression of pDCs-signature genes in CAL-1 cells, accompanied with the enhanced apoptosis in CAL-1 cells, implying that RUNX2 is critical for the survival of BPDCN cells due to expressing pDCs-signature genes. To evaluate the function of RUNX2 super-enhancer, we examined how BRD4 inhibition affected the proliferative capacities of CAL-1 cells in vitro. Indeed, we found that JQ1-treated CAL-1 cells showed significantly lower H3K27ac modification levels at the RUNX2 super-enhancer and significantly decreased levels of MYC and RUNX2 expression, resulting in the impaired colony formation capacities, which were rescued by the ectopic expression of both RUNX2 and MYC. We also genetically deleted the mutant-allele super-enhancer of RUNX2 on der(8) (seRUNX2der8), but not that on chromosome 6, using CRISPR-Cas9 vectors. After establishing single cell clones, all seRUNX2der8-deleted clones showed markedly impaired colony formation capacities accompanied with the reduced expression of MYC. Taken together, the seRUNX2der8 directly activates the expression of MYC to promote the development of BPDCN, which is reversed by the inhibition of BRD4. We finally examined whether the transduction of MYC and RUNX2 was sufficient for the initiation of BPDCN in vivo in the absence of Tet2 and p53. We purified Lineage-Sca-1+c-Kit+ stem/progenitor cells from wild-type and Tet2/p53 double knockout (DKO) mice and infected them with MYC- and RUNX2-retrovirus vectors. After a 9-day culture promoting the differentiation of pDCs, we transplanted transduced cells into recipient mice together with wild-type competitor cells. MYC+RUNX2-DKO mice showed robust leukocytosis, anemia, and thrombocytopenia and died by two months post-transplantation following the expansion of immature leukemic blasts. A FACS analysis showed that these leukemic blasts were CD11b-CD11cmid/+B220+Bst2+, which was consistent with the murine pDCs immunophenotype, and massively infiltrated the spleen and liver tissues. MYC+RUNX2-DKO leukemic cells were transplantable in secondary recipient mice with the same immunophenotype. Thus, the transduction of MYC and RUNX2 is sufficient to initiate the transformation of lethal BPDCN-like disease in mice lacking Tet2 and p53. We are now exploring the molecular mechanism of how MYC and RUNX2 collaborate to initiate the formation of BPDCN by performing RNA-sequencing analysis and transplantation assay of BPDCN-initiating cells. Disclosures Asou: Asahi Kasei Pharma Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; SRL Inc.: Consultancy; Yakult Honsha Co., Ltd.: Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Speakers Bureau; Astellas Pharma Inc.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding. Ohyashiki:Pfizer KK,: Honoraria, Research Funding; MSD,: Honoraria, Research Funding; Kyowakko Kirin KK,: Research Funding; Jansen Pharma KK,: Research Funding; Novartis KK,: Honoraria, Research Funding; Celegene KK,: Honoraria, Research Funding; Takeda Pharmaceutical KK,: Honoraria, Research Funding; Taiho Pharmaceutical KK: Honoraria, Research Funding; Asahikase: Research Funding; Asteras KK,: Research Funding; Nihon-Seiyaku,: Research Funding; Eizai,: Research Funding; Dainippon Sumitomo KK,: Honoraria, Research Funding; Nippon-shinyaku,: Honoraria, Research Funding; Bristol Meyer Squibb KK,: Honoraria, Research Funding; Ono Pharmaceutical KK,: Honoraria, Research Funding; Chugai KK,: Honoraria, Research Funding.

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Trevaskis, James, Ken Walder, Victoria Foletta, Lyndal Kerr-Bayles, Janine McMillan, Adrian Cooper, Scott Lee, et al. "Src Homology 3-Domain Growth Factor Receptor-Bound 2-Like (Endophilin) Interacting Protein 1, a Novel Neuronal Protein that Regulates Energy Balance." Endocrinology 146, no. 9 (September 1, 2005): 3757–64. http://dx.doi.org/10.1210/en.2005-0282.

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Abstract To identify genes involved in the central regulation of energy balance, we compared hypothalamic mRNA from lean and obese Psammomys obesus, a polygenic model of obesity, using differential display PCR. One mRNA transcript was observed to be elevated in obese, and obese diabetic, P. obesus compared with lean animals and was subsequently found to be increased 4-fold in the hypothalamus of lethal yellow agouti (Ay/a) mice, a murine model of obesity and diabetes. Intracerebroventricular infusion of antisense oligonucleotide targeted to this transcript selectively suppressed its hypothalamic mRNA levels and resulted in loss of body weight in both P. obesus and Sprague Dawley rats. Reductions in body weight were mediated by profoundly reduced food intake without a concomitant reduction in metabolic rate. Yeast two-hybrid screening, and confirmation in mammalian cells by bioluminescence resonance energy transfer analysis, demonstrated that the protein it encodes interacts with endophilins, mediators of synaptic vesicle recycling and receptor endocytosis in the brain. We therefore named this transcript Src homology 3-domain growth factor receptor-bound 2-like (endophilin) interacting protein 1 (SGIP1). SGIP1 encodes a large proline-rich protein that is expressed predominantly in the brain and is highly conserved between species. Together these data suggest that SGIP1 is an important and novel member of the group of neuronal molecules required for the regulation of energy homeostasis.

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Xu, Chunyang, Biyu Hou, Ping He, Peng Ma, Xinyu Yang, Xiuying Yang, Li Zhang, Guifen Qiang, Wenlan Li, and Guanhua Du. "Neuroprotective Effect of Salvianolic Acid A against Diabetic Peripheral Neuropathy through Modulation of Nrf2." Oxidative Medicine and Cellular Longevity 2020 (February 27, 2020): 1–22. http://dx.doi.org/10.1155/2020/6431459.

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Oxidative stress has been recognized as the contributor to diabetic peripheral neuropathy (DPN). Antioxidant strategies have been most widely explored; nevertheless, whether antioxidants alone prevent DPN still remains inconclusive. In the present study, we established an in vitro DPN cell model for drug screening using Schwann RSC96 cells under high glucose (HG) stimulation, and we found that salvianolic acid A (SalA) mitigated HG-induced injury evidenced by cell viability and myelination. Mechanistically, SalA exhibited strong antioxidative effects by inhibiting 1,1-diphenyl-2-picrylhydrazyl (DPPH) and reducing reactive oxygen species (ROS), malondialdehyde (MDA), and oxidized glutathione (GSSG) content, as well as upregulating antioxidative enzyme mRNA expression. In addition, SalA significantly extenuated neuroinflammation with downregulated inflammatory factor mRNA expression. Furthermore, SalA improved the mitochondrial function of HG-injured Schwann cells by scavenging mitochondrial ROS, decreasing mitochondrial membrane potential (MMP), and enhancing ATP production, as well as upregulating oxidative phosphorylation gene expression. More importantly, we identified nuclear factor-E2-related factor 2 (Nrf2) as the upstream regulator which mediated protective effects of SalA on DPN. SalA directly bound to the Kelch domain of Kelch-like ECH-associated protein 1 (Keap1) and thus disrupted the interaction of Nrf2 and Keap1 predicted by LibDock of Discovery Studio. Additionally, SalA significantly inhibited Nrf2 promoter activity and downregulated Nrf2 mRNA expression but without affecting Nrf2 protein expression. Interestingly, SalA upregulated the nuclear Nrf2 expression and promoted Nrf2 nuclear translocation by high content screening assay, which was confirmed to be involved in its antiglucotoxicity effect by the knockdown of Nrf2 in RSC96 cells. In KK-Ay mice, we demonstrated that SalA could effectively improve the abnormal glucose and lipid metabolism and significantly protect against DPN by increasing the mechanical withdrawal threshold and sciatic nerve conduction velocity and restoring the ultrastructural impairment of the injured sciatic nerve induced by diabetes. Hence, SalA protected against DPN by antioxidative stress, attenuating neuroinflammation, and improving mitochondrial function via Nrf2. SalA may be prospective therapeutics for treating DPN.

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Liu, Liping, Yuping Chen, Qin Wu, Anmei Shu, and Jihu Sun. "Sodium Butyrate Attenuated Diabetes-Induced Intestinal Inflammation by Modulating Gut Microbiota." Evidence-Based Complementary and Alternative Medicine 2022 (August 22, 2022): 1–12. http://dx.doi.org/10.1155/2022/4646245.

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Background. Diabetes mellitus (DM) continues to be one of the world’s most costly and complex metabolic disorders. Accumulating evidence has shown that intestinal dysbiosis and associated inflammation can facilitate the onset and progression of DM. In this work, our goal was to investigate how sodium butyrate (SB) controls the gut microbiota to reduce the intestinal inflammation brought on by diabetes. Methods. Male KK-Ay mice were randomized into two groups: the DM model group (intragastric administration of 0.9% normal saline) and the SB treatment group (intragastric administration of 1,000 mg/kg/d SB). The C57BL/6J mice were used as the control group (intragastric administration of 0.9% normal saline). These mice were administered via gavage for 8 weeks. Results. The results revealed that SB-treated mice significantly reduced fasting blood glucose (FBG), body weight, 24 h food and water intake, and improved islet histopathology in DM model mice. SB reduced TNF-α, IL-1β, and iNOS, whereas it enhanced the expression of the anti-inflammatory Arg-1 marker on intestinal macrophages and the secretion of anti-inflammatory IL-10. Specifically, SB was linked to a marked drop in the expression of the Th17 marker RORγt and a substantial increase in the expression of the Treg marker Foxp3. SB treatment was associated with significant reductions in the levels of Th17-derived cytokines such as IL-17 and IL-6, whereas anti-inflammatory Treg-derived cytokines such as TGF-β were increased. Additionally, the analysis results from 16S rDNA sequencing suggested that SB significantly reversed the variations in intestinal flora distribution and decreased the relative abundance of Weissella confusa and Anaerotruncus colihominis DSM 17241 at the species level as well as Leuconostocaceae, Streptococcaceae, and Christensenellaceae at the family, genus, and species levels. These distinct florae may serve as a diagnostic biomarker for DM-induced intestinal inflammation. In addition, the heat map of phylum and OTU level revealed a close relationship between DM-induced intestinal inflammation and intestinal microbiota. Conclusions. The present study suggested that SB may reduce DM-induced intestinal inflammation by regulating the gut microbiota.

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Garland, John M., and Claudius Rudin. "Cytochrome c Induces Caspase-Dependent Apoptosis in Intact Hematopoietic Cells and Overrides Apoptosis Suppression Mediated by bcl-2, Growth Factor Signaling, MAP-Kinase-Kinase, and Malignant Change." Blood 92, no. 4 (August 15, 1998): 1235–46. http://dx.doi.org/10.1182/blood.v92.4.1235.

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Abstract It has been shown that cytochrome c is released from mitochondria during apoptosis, activates pro-caspase CPP32 (caspase III), and induces DNA fragmentation in mixtures of cytosolic extracts and isolated nuclei. To establish whether cytochrome c can primarily induce apoptosis in intact cells, we used direct electroporation of cytochrome c into murine interleukin-3 (IL-3)–dependent cells. Electroporation of micromolar external concentrations of cytochrome c rapidly induced apoptosis (2 to 4 hours) that was concentration-dependent, did not affect mitochondrial transmembrane potential, and was independent of cell growth. Only certain isoforms of cytochrome c were apoptogenic; yeast cytochrome c and other redox proteins were inactive. Cytochrome c-induced apoptosis was dependent on heme attachment to the apo-enzyme and was completely abolished by caspase inhibitors. Nonapoptogenic isoforms of cytochrome c did not compete for apoptogenic cytochrome c. Although apoptosis induced by IL-3 withdrawal was inhibited by bcl-2 overexpression and expression of an activated MAP-kinase-kinase (MAP-KK), cytochrome c induced apoptosis in the presence of IL-3 signaling, bcl-2 over-expression, expression of activated MAP-KK, and the combined antiapoptotic action of all three. Cytochrome c also induced apoptosis in the leukemic cell line WEHI 3b. However, human HL60 and CEM cells were resistant to cytochrome c-induced apoptosis. HL60 cells did not electroporate, but CEM cells were efficiently electroporated. Our studies with IL-3–dependent cells confirm that the apoptogenic attributes of cytochrome c are identical in intact cells to those in cell extracts. We conclude that cytochrome c can be a prime initiator of apoptosis in intact growing cells and acts downstream of bcl-2 and mitochondria, but that other cells are resistant to its apoptogenic activity. The system described offers a novel, simple approach for investigating regulation of apoptosis by cytochrome c and provides a model linking growth factor signaling to metabolism, survival, and apoptosis control. © 1998 by The American Society of Hematology.

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Garland, John M., and Claudius Rudin. "Cytochrome c Induces Caspase-Dependent Apoptosis in Intact Hematopoietic Cells and Overrides Apoptosis Suppression Mediated by bcl-2, Growth Factor Signaling, MAP-Kinase-Kinase, and Malignant Change." Blood 92, no. 4 (August 15, 1998): 1235–46. http://dx.doi.org/10.1182/blood.v92.4.1235.416k18_1235_1246.

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Abstract:

It has been shown that cytochrome c is released from mitochondria during apoptosis, activates pro-caspase CPP32 (caspase III), and induces DNA fragmentation in mixtures of cytosolic extracts and isolated nuclei. To establish whether cytochrome c can primarily induce apoptosis in intact cells, we used direct electroporation of cytochrome c into murine interleukin-3 (IL-3)–dependent cells. Electroporation of micromolar external concentrations of cytochrome c rapidly induced apoptosis (2 to 4 hours) that was concentration-dependent, did not affect mitochondrial transmembrane potential, and was independent of cell growth. Only certain isoforms of cytochrome c were apoptogenic; yeast cytochrome c and other redox proteins were inactive. Cytochrome c-induced apoptosis was dependent on heme attachment to the apo-enzyme and was completely abolished by caspase inhibitors. Nonapoptogenic isoforms of cytochrome c did not compete for apoptogenic cytochrome c. Although apoptosis induced by IL-3 withdrawal was inhibited by bcl-2 overexpression and expression of an activated MAP-kinase-kinase (MAP-KK), cytochrome c induced apoptosis in the presence of IL-3 signaling, bcl-2 over-expression, expression of activated MAP-KK, and the combined antiapoptotic action of all three. Cytochrome c also induced apoptosis in the leukemic cell line WEHI 3b. However, human HL60 and CEM cells were resistant to cytochrome c-induced apoptosis. HL60 cells did not electroporate, but CEM cells were efficiently electroporated. Our studies with IL-3–dependent cells confirm that the apoptogenic attributes of cytochrome c are identical in intact cells to those in cell extracts. We conclude that cytochrome c can be a prime initiator of apoptosis in intact growing cells and acts downstream of bcl-2 and mitochondria, but that other cells are resistant to its apoptogenic activity. The system described offers a novel, simple approach for investigating regulation of apoptosis by cytochrome c and provides a model linking growth factor signaling to metabolism, survival, and apoptosis control. © 1998 by The American Society of Hematology.

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Journal articles on the topic 'KK/Ay Murine Model'

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