trelagliptin and Inflammation

Cognitive impairment frequently coexists with diabetes. Trelagliptin is a once-weekly taking selective dipeptidyl peptidase-4 (DPP-4) inhibitor and a long-term effective hypoglycemic medicine; nonetheless, its effects for the treatment of diabetes-related cognitive impairment have only sometimes been explored. In this study, a DM model was built using streptozotocin (STZ) and a high-fat diet (HFD). The morris water maze test on DM rats revealed a considerably reduced capacity for spatial learning and memory, but trelagliptin was able to restore function. Trelagliptin could lower the mRNA expression of inflammatory factors such IL-1β, TNF-α, and IL-6 in DM rats. It could also reduce the ratio of p-IKKα/IKKα, and the immunofluorescence result of NF-κB also demonstrated a drop. Trelagliptin partially restored dendritic spines and prevented the loss or shrinkage of neurons, respectively, according to the results of Nissl's staining and golgi staining. Furthermore, PI3K/Akt/GSK-3β has been activated, and synaptic plasticity has been modified during this process. In conclusion, trelagliptin improved the cognitive lesion in DM rats by suppressing the activation of the inflammatory route and by activating the PI3K/Akt/GSK-3β pathway at the same time, as well as interacting with the pathways that protect neurons, which still need further research.

Topics: Animals; Cognitive Dysfunction; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Glycogen Synthase Kinase 3 beta; Hypoglycemic Agents; I-kappa B Kinase; Inflammation; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats

This study investigated the effects of trelagliptin and remogliflozin, alone and in combination with alpha lipoic acid (ALA), on cardiac biomarkers in diabetic cardiomyopathy (DCM). We aimed to assess the management of glucotoxicity consequences in streptozotocin-induced diabetic rats by measuring serum levels of pharmacologically active endogenous ligands. Forty-eight male rats were divided into different treatment groups, including negative control, positive control, and four experimental groups. After inducing diabetes, the rats were treated for 28 days, and serum levels of biomarkers associated with oxidative stress (malondialdehyde and thioredoxin-interacting protein), inflammation (nuclear factor NF-kappa-B p105 and lipoprotein-associated phospholipase A2), and myopathy (neprilysin and high selective cardiac troponin T) were measured. Immunohistochemical analysis of heart cells was also performed. The results showed that inducing hyperglycemia increased serum glucose levels and biomarkers associated with DCM. However, all treatment groups exhibited a significant decrease in these biomarkers and an increase in insulin levels compared to the diabetic control group. The groups receiving combination therapy with ALA showed greater improvements in cardiac biomarkers compared to the individual treatments. The immunohistochemical analysis supported these findings by demonstrating a reduction in the percentage area of cathepsin B, a protein involved in DCM pathophysiology. In conclusion, supplementing the base treatments with ALA showed promise in enhancing cardiac biomarkers associated with DCM. The combination of trelagliptin, remogliflozin, and ALA may have additional clinical value in managing DCM by targeting oxidative stress, inflammation, and glucotoxicity. However, further research is needed to validate these findings and explore their potential clinical applications.

Topics: Animals; Biomarkers; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Inflammation; Male; Oxidative Stress; Rats; Rats, Wistar; Streptozocin; Thioctic Acid

Acute lung injury (ALI) is an urgent disease lacking effective therapies, resulting in relatively high morbidity and mortality. The pathological mechanism of ALI is reported to be related to excessive inflammation and activated oxidative stress. The present study aims to investigate the protective effects of the DPP-4 inhibitor Trelagliptin against lipopolysaccharide (LPS)-induced ALI and the underlying mechanism. LPS was used to induce ALI mice models. The pathological condition of ALI mice was evaluated using MPO activity assay, lung wet to dry weight ratio detection, and HE staining on the lung tissues. Lung function was assessed using a spirometer. The oxidative stress level in the lung tissues was checked by MDA measurement and GPx detection using commercial kits. The leukocyte and neutrophil numbers were determined using a hemocytometer and the total concentration of protein in the BALF was detected using a bicinchoninic acid method. The expression levels of TNF-α, IL-6, and CXCL2 in the lung tissues were evaluated using qRT-PCR and ELISA. Western blot analysis was used to determine the expression levels of TLR4 and p-NF-κB p65. LPS-induced elevated MPO activity, pulmonary wet to dry weight ratio, airway resistance (RAW), the total number of leukocytes and neutrophils, production of inflammatory factors, decreased pulmonary dynamic compliance (Cdyn), and peak expiratory flow (PEF), and an aggravated histopathological state (such as disordered alveolar structure, significant pulmonary interstitial edema, and large numbers of red blood cells and inflammatory cells in the alveolar cavity) were significantly reversed by the administration of Trelagliptin. The TLR4/NF-κB signaling pathway was activated and oxidative stress was induced by stimulation with LPS; however, both effects were suppressed by the administration of Trelagliptin. Trelagliptin might alleviate LPS-induced inflammation and oxidative stress in acute lung injury mice.

Topics: Acute Lung Injury; Animals; Inflammation; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Oxidative Stress; Uracil

Cardiovascular diseases remain the major cause of death worldwide. Atherosclerosis is recognized as the common ground of cardiovascular diseases. Inflammatory cytokines-induced attachment of monocytes to endothelial cells is a significant event in the progression of atherosclerosis. As a highly selective dipeptidyl peptidase (DPP)-4 inhibitor, trelagliptin is used for the treatment of type 2 diabetes mellitus (T2DM). However, whether trelagliptin possesses an inhibitory effect on endothelial dysfunction and monocyte adhesion is unknown. In the current study, we tested the effect of trelagliptin in endothelial cells. We used human aortic endothelial cells (HAECs) exposed to interleukin (IL)-1β to mimic the microenvironment of atherosclerosis. Our results showed that trelagliptin inhibited the expression of pro-inflammatory chemokines including monocyte chemoattractant protein 1 (MCP-1), CXCL-1, and IL-6. Furthermore, trelagliptin suppressed the expression of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). Mechanistically, trelagliptin suppressed the activation of activator protein-1 (AP-1) and NF-κB signaling pathways, which modulate the inflammatory process and monocyte adhesion. Collectively, our results showed that trelagliptin had a powerful inhibitory effect on the attachment of monocytes to endothelial cells, indicating that trelagliptin might have a protective effect on cardiovascular diseases such as atherosclerosis.

Topics: Anti-Inflammatory Agents; Cell Adhesion; Cell Adhesion Molecules; Coculture Techniques; Cytokines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Endothelial Cells; Humans; Inflammation; Inflammation Mediators; Interleukin-1beta; Monocytes; NF-kappa B; Signal Transduction; THP-1 Cells; Transcription Factor AP-1; Uracil