DPP4 Inhibitor Sitagliptin Reduces Inflammatory Responses and Mast Cell Activation in Allergic Rhinitis.

INTRODUCTION: DPP4 is thought to be involved in certain immune processes and plays an important role in allergic reactions in the lungs. The effect of the DPP4 inhibitor sitagliptin on the effector phase of allergic rhinitis (AR) in ovalbumin (OVA)-sensitized mice and on mast cell degranulation in vitro was assessed. METHODS: The AR mouse model was established by intraperitoneal injection combined with OVA intranasal method. OVA was injected intraperitoneally 3 times for the first 2 weeks, and the mice were subsequently given DPP4 inhibitors by oral gavage, accompanied by an OVA intranasal challenge. The impacts of DPP4 inhibitors on DPP4 levels in mouse model were determined. Nasal mucosa tissue was collected for H&E staining and toluidine blue staining. Immunoglobulin E (IgE) levels and histamine levels were analyzed, and IL-4, IL-5, and IL-12 as well as IFN-γ levels were assessed. Following the treatment of dinitrophenol (DNP)-IgE or DNP-IgE plus sitagliptin in RBL-2H3 cells, ß-hexosaminidase activity was analyzed and toluidine blue staining was performed. RESULTS: DPP4 level was reduced in AR patients, as well as in AR mouse models. Nasal allergic symptoms such as sneezing and nose-scratching showed high frequency in OVA-induced mice. Sitagliptin treatment during the intranasal challenge of OVA decreased DPP4 levels, suppressed allergic symptoms, eosinophil infiltration, IgE levels, mast cell infiltration, as well as the levels of inflammatory cytokines. We further found that sitagliptin inhibited mast cell activation and histamine levels in vitro. CONCLUSION: Sitagliptin suppresses the effector phase of AR, and this mechanism is partly attributed to the suppression of inflammatory response and mast cell degranulation.

Metformin Mitigates DPP-4 Inhibitor-Induced Breast Cancer Metastasis via Suppression of mTOR Signaling.

The biological influence of antidiabetic drugs on cancer cells and diabetic cancer patients has not yet been completely elucidated. We reported that a dipeptidyl peptidase (DPP)-4 inhibitor accelerates mammary cancer metastasis by inducing epithelial-mesenchymal transition (EMT) through the CXCL12/CXCR4/mTOR axis. Metformin has been shown to inhibit the mTOR signaling pathway. In this study, we investigated whether metformin mitigates breast cancer metastasis induced by a DPP-4 inhibitor via suppression of mTOR signaling. In cultured mouse mammary and human breast cancer cells, metformin suppressed DPP-4 inhibitor KR62436 (KR)-induced EMT and cell migration via suppression of the mTOR pathway associated with AMPK activation. For the in vivo study, metformin intervention was performed in an allograft 4T1 breast cancer model mouse with or without KR. We also analyzed mice transplanted with shRNA-mediated DPP-4 knockdown 4T1 cells. Treatment with metformin inhibited the lung metastasis of DPP-4-deficient 4T1 mammary tumor cells generated by either KR administration or DPP-4 knockdown. Immunostaining of primary tumors indicated that DPP-4 suppression promoted the expression of EMT-inducing transcription factor Snail through activation of the CXCR4-mediated mTOR/p70S6K pathway in an allograft breast cancer model; metformin abolished this alteration. Metformin treatment did not alter DPP-4-deficiency-induced expression of CXCL12 in either plasma or primary tumors. Our findings suggest that metformin may serve as an antimetastatic agent by mitigating the undesirable effects of DPP-4 inhibitors in patients with certain cancers. IMPLICATIONS: Metformin could combat the detrimental effects of DPP-4 inhibitor on breast cancer metastasis via mTOR suppression, suggesting the potential clinical relevance. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/19/1/61/F1.large.jpg.

Linagliptina y penfigoide ampolloso: la historia continúa / Linagliptin and bullous pemphigoid: the story continues

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Soluble dipeptidyl peptidase-4 induces microvascular endothelial dysfunction through proteinase-activated receptor-2 and thromboxane A2 release.

BACKGROUND: Dipeptidyl peptidase-4 (DPP4) is a key protein in glucose homeostasis and a pharmacological target in type 2 diabetes mellitus. This study explored whether the novel adipokine soluble DPP4 (sDPP4) can cause endothelial dysfunction, an early marker of impaired vascular reactivity. METHOD: Reactivity was studied in mesenteric arteries from 3-month-old female mice, using a small vessel myograph. Thromboxane A2 (TXA2) release was explored in cultured human coronary artery endothelial cells by enzyme immunoassay. RESULTS: Neither the contractility to noradrenaline nor the endothelium-independent relaxations induced by sodium nitroprusside were modified by sDPP4. However, sDPP4 impaired in a concentration-dependent manner the endothelium-dependent relaxation elicited by acetylcholine. The DPP4 inhibitors K579 and linagliptin prevented the defective relaxation induced by sDPP4, as did the protease-activated receptor 2 (PAR2) inhibitor GB83. Downstream of PAR2, the cyclooxygenase (COX) inhibitor indomethacin, the COX2 inhibitor celecoxib or the thromboxane receptors blocker SQ29548 prevented the deleterious effects of sDPP4. Accordingly, sDPP4 triggered the release of TXA2 by endothelial cells, whereas TXA2 release was prevented by inhibiting DPP4, PAR2 or COX. CONCLUSION: In summary, these findings reveal sDPP4 as a direct mediator of endothelial dysfunction, acting through PAR2 activation and the release of vasoconstrictor prostanoids. By interfering with these actions, DPP4 inhibitors might help preserving endothelial function in the context of cardiometabolic diseases.

Therapeutic potential of propagated hepatocyte transplantation in liver failure.

BACKGROUND: This study aimed to evaluate the therapeutic potential of intrasplenic transplantation of culture-propagated homologous hepatocytes in rats suffering from acute liver failure (ALF). METHODS: ALF was induced in dipeptidyl peptidase IV-negative (DPPIV(-)) Fischer 344 rats by totally removing the two anterior liver lobes (68% of the liver) and ligating the pedicle of the right lobe (24% of the liver). Hepatocytes isolated from DPPIV(+) Fischer 344 rats were cultured for 11 d to propagate 3-fold, and the resulting hepatocytes were dubbed "culture-propagated hepatocytes (CPHEPs)". A total of 1.5 × 10(7) cells of CPHEPs were transplanted intrasplenically before ALF induction (CPHEP group). Similarly, freshly isolated hepatocytes (FIHEPs) were transplanted as a positive control (FIHEP group), and culture medium (CM) was injected into rats as a negative control (CM group). RESULTS: The survival of the CPHEP group was comparable to that of the FIHEP group and longer than that of the CM group (P < 0.01). Both CPHEP and FIHEP transplantation improved blood parameters such as ammonia, total bilirubin, glutamic pyruvic transaminase, and glutamic oxaloacetic transaminase; transplantation also affected liver tissue parameters such as apoptosis rate and bromodeoxyuridine-labeling index. CONCLUSIONS: Transplantation of culture-propagated homologous hepatocytes has a remarkable therapeutic potential for ALF in rats.

Emerging drug candidates of dipeptidyl peptidase IV (DPP IV) inhibitor class for the treatment of Type 2 Diabetes.

Dipeptidyl peptidase IV (DPP IV) is a key regulator of insulin-stimulating hormones, glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), thus it is a promising target for the treatment of Type 2 Diabetes mellitus (T2DM). Inhibition of plasma DPP IV enzyme leads to enhanced endogenous GLP-1 and GIP activity, which ultimately results in the potentiation of insulin secretion by pancreatic beta-cells and subsequent lowering of blood glucose levels, HbA[1(c)], glucagon secretion and liver glucose production. Various classes of structurally different DPP IV inhibitors are currently being explored and few of them such as Sitagliptin and Vildagliptin were successfully launched. These drugs have been approved as a once-daily oral monotherapy or as a combination therapy with current anti-diabetic agents like pioglitazone, glibenclamide, metformin etc. for the treatment of T2DM. Several other novel DPP IV inhibitors are in pipeline. The present review summarizes the latest preclinical and clinical trial data of different DPP IV inhibitors with a special emphasis on their DPP8/9 fold selectivity and therapeutic advantages over GLP-1 based approach.