Browsing by Author "Ma, Kaiwen"

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    12-Lipoxygenase Inhibitor Improves Functions of Cytokine-Treated Human Islets and Type 2 Diabetic Islets
    (Oxford University Press, 2017-08-01) Ma, Kaiwen; Xiao, An; Park, So Hyun; Glenn, Lindsey; Jackson, Laura; Barot, Tatvam; Weaver, Jessica R.; Taylor-Fishwick, David A.; Luci, Diane K.; Maloney, David J.; Mirmira, Raghavendra G.; Imai, Yumi; Nadler, Jerry L.; Pediatrics, School of Medicine
    Context: The 12-lipoxygenase (12-LO) pathway produces proinflammatory metabolites, and its activation is implicated in islet inflammation associated with type 1 and type 2 diabetes (T2D). Objectives: We aimed to test the efficacy of ML355, a highly selective, small molecule inhibitor of 12-LO, for the preservation of islet function. Design: Human islets from nondiabetic donors were incubated with a mixture of tumor necrosis factor α , interluekin-1β, and interferon-γ to model islet inflammation. Cytokine-treated islets and human islets from T2D donors were incubated in the presence and absence of ML355. Setting: In vitro study. Participants: Human islets from organ donors aged >20 years of both sexes and any race were used. T2D status was defined from either medical history or most recent hemoglobin A1c value >6.5%. Intervention: Glucose stimulation. Main Outcome Measures: Static and dynamic insulin secretion and oxygen consumption rate (OCR). Results: ML355 prevented the reduction of insulin secretion and OCR in cytokine-treated human islets and improved both parameters in human islets from T2D donors. Conclusions: ML355 was efficacious in improving human islet function after cytokine treatment and in T2D islets in vitro. The study suggests that the blockade of the 12-LO pathway may serve as a target for both form of diabetes and provides the basis for further study of this small molecule inhibitor in vivo.
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    Deletion of 12/15-Lipoxygenase Alters Macrophage and Islet Function in NOD-Alox15null Mice, Leading to Protection against Type 1 Diabetes Development
    (Public Library of Science, 2013) Green-Mitchell, Shamina M.; Tersey, Sarah A.; Cole, Banumathi K.; Ma, Kaiwen; Kuhn, Norine S.; Duong Cunningham, Tina; Maybee, Nelly A.; Chakrabarti, Swarup K.; McDuffie, Marcia; Taylor-Fishwick, David A.; Mirmira, Raghavendra G.; Nadler, Jerry L.; Morris, Margaret A.; Pediatrics, School of Medicine
    Aims: Type 1 diabetes (T1D) is characterized by autoimmune depletion of insulin-producing pancreatic beta cells. We showed previously that deletion of the 12/15-lipoxygenase enzyme (12/15-LO, Alox15 gene) in NOD mice leads to nearly 100 percent protection from T1D. In this study, we test the hypothesis that cytokines involved in the IL-12/12/15-LO axis affect both macrophage and islet function, which contributes to the development of T1D. Methods: 12/15-LO expression was clarified in immune cells by qRT-PCR, and timing of expression was tested in islets using qRT-PCR and Western blotting. Expression of key proinflammatory cytokines and pancreatic transcription factors was studied in NOD and NOD-Alox15(null) macrophages and islets using qRT-PCR. The two mouse strains were also assessed for the ability of splenocytes to transfer diabetes in an adoptive transfer model, and beta cell mass. Results: 12/15-LO is expressed in macrophages, but not B and T cells of NOD mice. In macrophages, 12/15-LO deletion leads to decreased proinflammatory cytokine mRNA and protein levels. Furthermore, splenocytes from NOD-Alox15(null) mice are unable to transfer diabetes in an adoptive transfer model. In islets, expression of 12/15-LO in NOD mice peaks at a crucial time during insulitis development. The absence of 12/15-LO results in maintenance of islet health with respect to measurements of islet-specific transcription factors, markers of islet health, proinflammatory cytokines, and beta cell mass. Conclusions: These results suggest that 12/15-LO affects islet and macrophage function, causing inflammation, and leading to autoimmunity and reduced beta cell mass.
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    Key Role of STAT4 Deficiency in the Hematopoietic Compartment in Insulin Resistance and Adipose Tissue Inflammation
    (Hindawi Publishing Corporation, 2017) Dobrian, Anca D.; Ma, Kaiwen; Glenn, Lindsey M.; Hatcher, Margaret A.; Haynes, Bronson A.; Lehrer, Eric J.; Kaplan, Mark H.; Nadler, Jerry L.; Pediatrics, School of Medicine
    Dobrian, A. D., Ma, K., Glenn, L. M., Hatcher, M. A., Haynes, B. A., Lehrer, E. J., … Nadler, J. L. (2017). Key Role of STAT4 Deficiency in the Hematopoietic Compartment in Insulin Resistance and Adipose Tissue Inflammation. Mediators of Inflammation, 2017, 5420718. http://doi.org/10.1155/2017/5420718
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    STAT4 deficiency reduces obesity-induced insulin resistance and adipose tissue inflammation
    (American Diabetes Association, 2013-12) Dobrian, Anca D.; Galkina, Elena V.; Ma, Qian; Hatcher, Margaret; Aye, Sabai Myo; Butcher, Mathew J.; Ma, Kaiwen; Haynes, Bronson A.; Kaplan, Mark H.; Nadler, Jerry L.; Department of Pediatrics, IU School of Medicine
    Signal transducer and activator of transcription (STAT) 4 is one of the seven members of the STAT family. STAT4 has a prominent role in mediating interleukin-12-induced T-helper cell type 1 lineage differentiation. T cells are key players in the maintenance of adipose tissue (AT) inflammation. The role of STAT4 in obesity and AT inflammation is unknown. We sought to determine the role of STAT4 in AT inflammation in obesity-induced insulin resistance. We studied STAT4-null mice on the C57Bl6/J background. We have found that STAT4(-/-)C57Bl6/J mice develop high-fat diet-induced obesity (DIO) similar to wild-type controls, but that they have significantly improved insulin sensitivity and better glucose tolerance. Using flow cytometry and real-time PCR, we show that STAT4(-/-) mice with DIO produce significantly reduced numbers of inflammatory cytokines and chemokines in adipocytes, have reduced numbers of CD8(+) cells, and display increased alternative (M2) macrophage polarization. CD8(+) cells, but not CD4(+) cells, from STAT4(-/-) mice displayed reduced in vitro migration. Also, we found that adipocyte inflammation is reduced and insulin signaling is improved in STAT4(-/-) mice with DIO. We have identified STAT4 as a key contributor to insulin resistance and AT inflammation in DIO. Targeting STAT4 activation could be a novel approach to reducing AT inflammation and insulin resistance in obesity.