alogliptin and Inflammation

Cyclophosphamide (CP) is widely used as a chemotherapy against various types of cancers. However, CP is accompanied with multiple organ toxicity due to production of reactive oxygen species (ROS), induction of inflammation and consequently apoptosis. Alogliptin (Alo) is a dipeptidyl peptidase 4 (DPP-IV) inhibitor, which is booming as an antidiabetic agent. Interestingly, gliptins are currently studied for their counter-regulatory effects against oxidative stress and inflammation via multiple pathways, among which is the mitogen-activated protein kinase (MAPK)/c-Jun N-terminal kinase (JNK) pathway. This cascade can reduce inflammation via mitigating the activity of mothers against decapentaplegic homolog 3 (SMAD3) and c-Jun. However, Alo effect against CP-induced kidney injury has not been previously elucidated. This tempted us to investigate the possible beneficial effect of Alo against CP-induced kidney injury via modulating the MAP3K/JNK/SMAD3 signaling cascade. Thirty-two male Wistar rats were randomly allocated into four groups. CP-treated group received a single dose of CP (200 mg/kg; i.p.). Alo-treated group received Alo (20 mg/kg/day; p.o.) for 7 days with single CP injection on day 2. Marked decrease in renal injury was observed upon Alo treatment, as evidenced through declined serum kidney function markers, oxidative stress and apoptosis markers, MAP3K expression, phospho (p)-SMAD3, p-JNK, and p-c-Jun levels. These cellular effects were reflected in reduced transforming growth factor beta (TGF-β) and tumor necrosis factor alpha (TNF-α) fibrotic and inflammatory mediators, coinciding with improved histopathological portrait. In conclusion, the current study provides novel application of Alo as a therapeutic modality against CP-induced nephrotoxicity.

Topics: Animals; Cyclophosphamide; Inflammation; Male; Oxidative Stress; Piperidines; Rats; Rats, Wistar; Signal Transduction; Uracil

Stress evokes lipolytic release of free fatty acid (FFA) and low-grade inflammation in visceral adipose tissue, mediated by increased adipokine secretion, and contributes to glucose metabolism disorder and prothrombotic state. We tested the hypothesis that alogliptin, a dipeptidyl peptidase-4 inhibitor, can ameliorate the biological effects of chronic stress in mice.. C57BL/6J mice were subjected to 2-week intermittent restraint stress and orally treated with vehicle or alogliptin (dose: 15 or 45mg/kg/day). Plasma levels of lipids, proinflammatory cytokines (monocyte chemoattractant protein-1, tumor necrosis factor-α, and interleukin-6), and 8-hydroxydeoxyguanosine were measured with enzyme-linked immunosorbent assay. Monocyte/macrophage accumulation in inguinal white adipose tissue (WAT) was examined by CD11b-positive cell count and mRNA expression of CD68 and F4/80 was examined by immunohistochemistry and RT-PCR, respectively. The mRNA levels of the above-mentioned proinflammatory cytokines, NADPH oxidase 4, adiponectin, and coagulation factors (plasminogen activation inhibitor-1 and tissue factor) in WAT were also assessed with RT-PCR. Glucose metabolism was assessed by glucose and insulin tolerance tests, plasma levels of DPP-4 activity, glucagon-like peptide-1, expression of DPP-4, insulin receptor substrate-1 and glucose transporter 4 in WAT and skeletal muscle. Alogliptin administration suppressed stress-induced FFA release, oxidative stress, adipose tissue inflammation, DPP-4 activation, and prothrombotic state in a dose-dependent manner, and improved insulin sensitivity in stressed mice.. The results indicate that alogliptin improves stress-induced prothrombotic state and insulin resistance; suggesting that alogliptin could have beneficial therapeutic effects against cardiovascular complications in diabetic patients under stress.

Topics: Adipose Tissue; Animals; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Inflammation; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Piperidines; Stress, Psychological; Thrombophilia; Uracil

Dipeptidyl-peptidase 4 (DPP-4) inhibitors are increasingly used to accomplish glycemic targets in patients with type II diabetes mellitus. Because DPP-4 is expressed in inflammatory cells, we hypothesized that its inhibition will exert favorable effects in atherosclerosis.. Male LDLR(-/-) mice (6 weeks) were fed a high-fat diet or normal chow diet for 4 weeks and then randomized to vehicle or alogliptin, a high-affinity DPP-4 inhibitor (40 mg · kg(-1) · d(-1)), for 12 weeks. Metabolic parameters, blood pressure, vascular function, atherosclerosis burden, and indexes of inflammation were obtained in target tissues, including the vasculature, adipose, and bone marrow, with assessment of global and cell-specific inflammatory pathways. In vitro and in vivo assays of DPP-4 inhibition (DPP-4i) on monocyte activation/migration were conducted in both human and murine cells and in a short-term ApoE(-/-) mouse model. DPP-4i improved markers of insulin resistance and reduced blood pressure. DPP-4i reduced visceral adipose tissue macrophage content (adipose tissue macrophages; CD11b(+), CD11c(+), Ly6C(hi)) concomitant with upregulation of CD163. DPP-4 was highly expressed in bone marrow-derived CD11b(+) cells, with DPP-4i downregulating proinflammatory genes in these cells. DPP-4i decreased aortic plaque with a striking reduction in plaque macrophages. DPP-4i prevented monocyte migration and actin polymerization in in vitro assays via Rac-dependent mechanisms and prevented in vivo migration of labeled monocytes to the aorta in response to exogenous tumor necrosis factor-α and DPP-4.. DPP-4i exerts antiatherosclerotic effects and reduces inflammation via inhibition of monocyte activation/chemotaxis. These findings have important implications for the use of this class of drugs in atherosclerosis.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Blood Pressure; Cell Movement; Chemotaxis; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Glucose; Inflammation; Insulin Resistance; Male; Metabolism; Mice; Mice, Knockout; Monocytes; Piperidines; Receptors, LDL; Time Factors; Uracil