DPP4 Levels Research Articles

Alanyl-Glutamine Inhibits the Epithelial-Mesenchymal Transition of Airway Epithelial Cells in Asthmatic Mice via DPP4-SIRT1 Pathway

Introduction: Alanyl-glutamine (Ala-Gln) is a compound known for its protective effects in various tissue injuries. However, its role in asthma-related lung injuries remains underexplored. This study investigates the mechanisms by which Ala-Gln modulates sDPP4-induced airway epithelial-mesenchymal transition and ovalbumin (OVA)-induced asthma in a mouse model. Methods: An asthma model was established in female C57BL/6 J mice by using OVA. CD4+ T cells and bronchial epithelial cells (BECs) were isolated from the spleen and bronchi of the mice, respectively. Interventions included recombinant sCD26/sDPP4 protein, Ala-Gln, and EX527 (a SIRT1 inhibitor). Flow cytometry was used to assess Th17 and Treg cell populations. Mice were treated with Ala-Gln, EX527, and budesonide (BUD). Histopathological changes in lung tissues were evaluated using hematoxylin-eosin and Masson staining. White blood cell counts were measured with a hematology analyzer. The expression levels of DPP4, IL-17, SIRT1, SMAD2/3, N-cadherin, E-cadherin, MMP9, and α-SMA proteins were analyzed. Results: Treatment with recombinant sCD26/sDPP4 resulted in decreased E-cadherin expression in BECs and increased levels of α-SMA, MMP9, and N-cadherin, effects that were mitigated by Ala-Gln. Ala-Gln also prevented the reduction in SIRT1 expression in BECs and the increase in Th17 cell differentiation induced by recombinant sCD26/sDPP4. EX527 administration alongside Ala-Gln reversed these changes and enhanced the phosphorylation of SMAD2/3 through SIRT1 signaling. BUD alone reduced inflammation and fibrosis in bronchial tissue and lowered the Th17/Treg ratio in peribronchial lymph nodes. The therapeutic effect of BUD was further improved with concurrent Ala-Gln treatment. Conclusion: Ala-Gln can inhibit BEC fibrosis and Th17 cell differentiation mediated by recombinant sCD26/sDPP4 through the SIRT1 pathway. Combined with BUD, Ala-Gln enhanced therapeutic efficacy in OVA-induced asthma in mice, which could offer improved outcomes for asthmatic patients with elevated DPP4 levels.

In Silico Analysis of novel Phytocompounds targetting Dipeptidyl peptidase 4 Enzyme: A New Link between Prediabetes and its cardio-metabolic complications

BackgroundDPP-4 inhibitors, are widely used clinically for treatment of Diabetes. Increase in circulating DPP4 levels have been well demonstrated in patients with Type 2 Diabetes mellitus. The present study assessed the contribution of DPP-4 axis to the pathophysiology of Prediabetes and its cardiometabolic complications. In addition, in silico analysis of phytocompounds that target DPP 4 enzyme was undertaken to identify novel Phytocompounds with therapeutic potential in Prediabetes. MethodologyA novel experimental model of Prediabetes coexisting with hypertension and dyslipidemia was developed in experimental rats to elucidate the pathophysiological role of DPP-4 in Prediabetes and its resultant cardio-metabolic sequale. In the Prediabetic rats, DPP-4 levels, lipid profile, blood pressure readings, fasting blood sugar values, insulin resistance, beta cell function were measured and compared to Normal Control group. In addition, the DPP-4 Inhibitory activity of Phytocompounds (Arjunetin, Guggulsterone) was studied by molecular docking studies including Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), DPP 4 binding affinity and Protein-ligand simulation between the DPP4 and the Phytocompounds was performed. Results were compared to Vildagliptin, the synthetic DPP-4 inhibitor and metformin (Glucophage), the standard antidiabetic drug used in clinical settings. ResultsA statistically significant increase (p < 0.001) in DPP-4 levels along with a decline in bea cell function with increase in Insulin resistance was observed in Prediabetic rats. A positive correlation (p < 0.001) between serum DPP-4 with HbA1c, lipids, and systolic blood pressure was found. The novel model of Prediabetes co-existing with hypertension and dyslipidemia was successfully developed and validated. The silico active site interaction data from simulation studies demonstrated that Arjunetin and Guggulsterone shows effective and stable binding with DPP-4. Arjunetin maintains its contact with Glu205, Glu206, and Asn710 and by interacting with Val207 and His740, it effectively occupies the flanking residues of the active site area. Based on their protein-ligand contact report, Vildagliptin maintains its connection through Tyr547 and during simulation, Guggulsterone interacts with Ser630. ConclusionThe current study offers experimental evidence of DPP-4′s causal role in the development of cardio-metabolic consequences (dyslipidemia and hypertension) of Prediabetes. Arjunetin and Guggulsterone are two Phytocompounds whose potential as promising DPP-4 inhibitors has been further documented using in silico molecular docking studies.

Neutrophil extracellular traps activate Notch–γ-secretase signaling in hidradenitis suppurativa

BackgroundHidradenitis suppurativa (HS) is an inflammatory chronic skin disorder of unknown etiology characterized by inflamed abscess-like nodules and boils resulting in sinus tract formation, tissue scarring and massive infiltration of neutrophils. Multiple lines of evidence have highlighted the potential association between alterations in the Notch pathway and HS pathogenesis, but the mechanisms remain incompletely characterized. ObjectiveHerein, we aim to elucidate the role of neutrophil extracellular traps in Notch-γ-secretase, signaling. MethodsTwenty-six HS lesional tissues, primary HS macrophages and skin fibroblasts were interrogated by quantitative PCR, western blot, and Elisa analyses. γ-Secretase, and TACE activities were measured in HS skin lesions, macrophages and skin fibroblasts. Immunofluorescence and RNAscope analyzes were performed in HS and control skin. ResultsA prominent presence of Notch ligands, DLL4 and JAG2 were detected at the protein and mRNA levels in HS skin lesion when compared to control. Levels of DLL4, JAG1, cit-H3-DNA and γ-secretase activity correlated with HS disease severity. Additionally, significantly elevated levels of Notch ligands and γ-secretase activity were found in dissected sinus tracts when compared to the rest of HS tissue. Immunofluorescence microscopy in HS skin lesions showed activation of Notch 1 signaling in macrophages and skin fibroblasts. Neutrophil extracellular traps (NETs) purified from HS patients displayed elevated levels of DLL4. HS-NETs activated the Notch pathway in macrophages and dermal fibroblasts isolated from HS patients. HS skin fibroblasts displayed elevated levels of CD90 and DPP4 in association with increased migratory capacity and Notch activation. Inhibition of Notch decreased migratory capacity and pro-fibrotic markers in HS fibroblasts. ConclusionThese data support a pathogenic connection between NETs, Notch- γ-secretase activation and the release of pro-fibrotic molecules that promote dysregulation of macrophages and skin fibroblasts in HS. Unveiling the relevance of these molecular events not only expands our understanding of HS but also opens new venues for the development of targeted therapies to address the fibrotic complications of advanced stages of HS.

Excessive accumulation of epicardial adipose tissue promotes microvascular obstruction formation after myocardial ischemia/reperfusion through modulating macrophages polarization

BackgroundOwing to its unique location and multifaceted metabolic functions, epicardial adipose tissue (EAT) is gradually emerging as a new metabolic target for coronary artery disease risk stratification. Microvascular obstruction (MVO) has been recognized as an independent risk factor for unfavorable prognosis in acute myocardial infarction patients. However, the concrete role of EAT in the pathogenesis of MVO formation in individuals with ST-segment elevation myocardial infarction (STEMI) remains unclear. The objective of the study is to evaluate the correlation between EAT accumulation and MVO formation measured by cardiac magnetic resonance (CMR) in STEMI patients and clarify the underlying mechanisms involved in this relationship.MethodsFirstly, we utilized CMR technique to explore the association of EAT distribution and quantity with MVO formation in patients with STEMI. Then we utilized a mouse model with EAT depletion to explore how EAT affected MVO formation under the circumstances of myocardial ischemia/reperfusion (I/R) injury. We further investigated the immunomodulatory effect of EAT on macrophages through co-culture experiments. Finally, we searched for new therapeutic strategies targeting EAT to prevent MVO formation.ResultsThe increase of left atrioventricular EAT mass index was independently associated with MVO formation. We also found that increased circulating levels of DPP4 and high DPP4 activity seemed to be associated with EAT increase. EAT accumulation acted as a pro-inflammatory mediator boosting the transition of macrophages towards inflammatory phenotype in myocardial I/R injury through secreting inflammatory EVs. Furthermore, our study declared the potential therapeutic effects of GLP-1 receptor agonist and GLP-1/GLP-2 receptor dual agonist for MVO prevention were at least partially ascribed to its impact on EAT modulation.ConclusionsOur work for the first time demonstrated that excessive accumulation of EAT promoted MVO formation by promoting the polarization state of cardiac macrophages towards an inflammatory phenotype. Furthermore, this study identified a very promising therapeutic strategy, GLP-1/GLP-2 receptor dual agonist, targeting EAT for MVO prevention following myocardial I/R injury.

Evaluating Serum Biomarkers (DPP-4, GLP-1, Ki-67 Protein) Levels for Early Detection of Diabetic Breast Cancer

Background: Breast tumours are the second most common cancer in women. A mammary cancer is a multi-step process that involves several cell types and is yet difficult to prevent globally. One of the best ways to prevent breast cancers is by early detection. In many affluent nations, the 5-year proportional perseverance ratio for people with mammary neoplasms is over 80% because to early detection. Over the past ten years, significant progress has been made in both the understanding of mammary tumours and the development of preventative interventions. Diabetes, often known as diabetes mellitus (DM), is a collection of illnesses characterized by elevated blood sugar levels brought on by flaws in the body's capacity to make and/or utilize insulin. Objectives: This study aimed to evaluate the levels of serum biomarkers (DPP-4, GLP-1, Ki-67 protein) in individuals with diabetes, breast cancer, diabetic breast cancer, and a control group. Methods: The samples were taken from individuals at Al-Najaf Teaching Hospital and the Najaf Cancer Centre between 30/10/2023 and 1/3/2024. The blood samples were 120 blood samples acquired from Iraqi subjects. The participants included four groups and each group consisted of 30 participants, (Diabetes type 2 patient group, Breast cancer patient group, Diabetic breast cancer patient group, and Control group). Results: The difference in serum DPP-4 levels, between diabetic, breast cancer individuals and healthy control groups, is statistically noteworthy. The results show a higher DPP-4 level in patient groups than in the control group. While there was no significance in the GLP-1 and Ki-67 proteins in the patient and control groups. Conclusion: These results suggest that high serum DPP-4 could serve as a useful screening marker for the early detection of diabetic breast cancer. ًWhile, The lack of differences in GLP-1 and Ki-67 proteins levels across the groups indicates these biomarkers may not be as informative for identifying diabetic breast cancer in this population.

Dipeptidyl-Peptidase-4 and Glucagon-like-Peptide-1, a Link in the Connection between Periodontitis and Diabetes Mellitus—What Do We Know So Far?—A Scoping Review

Periodontitis is a common condition affecting the tissues surrounding and supporting teeth. In addition to oral health concerns, periodontal disease increases the chance of developing systemic illnesses including type 2 diabetes mellitus. Porphyromonas gingivalis, a key-stone pathogen that has been linked to the pathophysiology of periodontal disease, can generate a series of dipeptide producing exopeptidases, dipeptidyl peptidases (DPP). DPP-4 levels in gingival crevicular fluid have been shown to increase during active periodontal disease, which may lead to their association with the disease’s progression. Following oral glucose administration, mice injected with DPP-4 had higher blood glucose than the control group. DPP-4 inhibitors are used to treat patients with type 2 diabetes mellitus in order to extend the half-life of incretins. Elevated glucagon-like peptide-1 (GLP-1) levels following periodontal therapy could be considered new and applicable real-world evidence confirming the experimental findings of a beneficial interaction between oral microbiota and incretin axis. GLP-1 receptor agonist exendin-4 enhanced the osteoblast proliferation and development of these stem cells and inhibited the effects of glucose on the cells. In addition to lowering blood sugar, liraglutide, a GLP-1 receptor agonist, also possesses anti-inflammatory and bone-protective properties. These findings support the use of GLP-1 in the management and prevention of diabetic periodontitis.

Co-Analysis of Serum and Urine Differentially Expressed Proteins in Mucopolysaccharidosis Type I.

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease caused by the deficiency of the enzyme α-l-iduronidase (IDUA), typically leading to devastating secondary pathophysiological cascades. Due to the irreversible nature of the disease's progression, early diagnosis and interventional treatment has become particularly crucial. Considering the fact that serum and urine are the most commonly used specimens in clinical practice for detection, we conducted an analysis to identify the differential protein profile in the serum and urine of MPS I patients using the tandem mass tag (TMT) technique. A total of 182 differentially expressed proteins (DEPs) were detected in serum, among which 9 showed significant differences as confirmed by parallel reaction monitoring (PRM) analysis. The proteins APOA1 and LGFBP3 were downregulated in serum, while the expression levels of ALDOB, CD163, CRTAC1, DPP4, LAMP2, SHBG, and SPP2 exhibited an increase. In further exploratory studies of urinary proteomics, 32 identified DEPs were consistent with the discovered findings in serum tests, specifically displaying a high diagnostic area under the curve (AUC) value. Thus, our study demonstrates the value of serum-urine integrated proteomic analysis in evaluating the clinical course of MPS I and other potential metabolic disorders, shedding light on the importance of early detection and intervention in these conditions.

Adolescents with obesity treated with exenatide maintain endogenous GLP-1, reduce DPP-4, and improve glycemic control.

GLP-1 receptor agonists (GLP-1RA) are increasingly used to treat adolescent obesity. However, the effect on endogenous GLP-1 secretory patterns following treatment in adolescents is unknown. The GLP-1RA exenatide was shown to significantly lower BMI and 2-hour glucose in adolescents with obesity, in the placebo-controlled, randomized controlled trial Combat-JUDO. The aim of this study was to evaluate effects of weekly injections of 2 mg exenatide extended release on secretory patterns of endogenous hormones during OGTT. This study was a pre-planned sub-study of the Combat-JUDO trial, set at the Pediatric clinic at Uppsala University Hospital, Sweden and Paracelsus Medical University, Austria. 44 adolescents with obesity were included and randomized 1:1 to treatment:placebo. 19 patients in the treatment group and 18 in the placebo group completed the trial. Before and after treatment, GLP-1, glucose, insulin, glucagon and glicentin levels were measured during OGTT; DPP-4 and proinsulin were measured at fasting. A per-protocol approach was used in the analyses. Exenatide treatment did not affect GLP-1 levels during OGTT. Treatment significantly lowered DPP-4, proinsulin and the proinsulin-to-insulin ratio at fasting, increased glicentin levels but did not affect insulin, C-peptide or glucagon levels during OGTT. Weekly s.c. injections with 2 mg of exenatide maintains endogenous total GLP-1 levels and lowers circulating DPP-4 levels. This adds an argument in favor of using exenatide in the treatment of pediatric obesity. clinicaltrials.gov, identifier NCT02794402.

Down-regulation of DPP4 by TGFβ1/miR29a-3p inhibited proliferation and promoted migration of ovarian cancer cells

ObjectiveTo explore the DPP4 expression changes and functions in ovarian cancer (OV), as well as the regulation mechanism for DDP4.MethodsGEPIA2, GSE18520, GSE26712 and UALCAN were used to analyze differences in DPP4 expression between OV tumors and control tissues. Serum DPP4 levels were measured by ELISA. The prognostic values of DPP4 were evaluated using a Kaplan–Meier (KM) plotter. Small interfering RNA was used for DPP4 knockdown in OVCAR-3 and SKOV-3 cells. CCK-8 and scratch healing assays were used to determine the cells’ proliferation and migration abilities. Flow cytometry (FCM) was used to detect the cell cycle and apoptosis. A dual-luciferase assay was designed to confirm the regulatory effect of miR-29a-3p on DPP4.ResultsThe expressions of DPP4 mRNA and protein were decreased in OV tumor tissues. Serum DPP4 levels decreased in OV patients. KM plotter analysis showed correlation between high DPP4 expression and a poor prognosis in OV patients. By targeting knockdown of DPP4, we found that OVCAR-3 and SKOV-3 cells’ proliferation was inhibited, while cell’s migration ability was significantly promoted. FCM analysis showed that DPP4 knockdown induced a decrease in the S phase. Furthermore, DPP4 was shown to be downregulated by miR-29a-3p and TGFβ1 in OVCAR-3 cells, and miR-29a-3p expression was upregulated by TGFβ1. The effects of miR-29a-3p and TGFβ1 on OVCAR-3 cells’ biological behaviors were consistent with DPP4 knockdown.ConclusionDPP4 was downregulated in OV patients. DPP4 knockdown significantly inhibited OVCAR-3 and SKOV-3 cell proliferation and promoted cell migration. DDP4 can be downregulated by TGFβ1 through the upregulation of miR-29a-3p in OV cells.

Denosumab Improves Glycaemic Parameters in Postmenopausal Osteoporosis Patients with Combined Type 2 Diabetes Mellitus.

This study aimed to determine whether RANKL inhibitors in postmenopausal osteoporosis patients with combined type 2 diabetes mellitus (T2DM) could improve their glucose metabolism index. First of all, 84 patients affected with postmenopausal osteoporosis with combined T2DM attending the Department of Endocrinology at the Third Hospital of Hebei Medical University were selected and randomized into two groups of 42 patients each. One group was given Denosumab 60 mg once every six months (denosumab group, D.G.), and the other group was given 2 mg ibandronate once every three months (ibandronate group, I.G.). Blood glucose parameters were compared before and after treatment in both groups and serum active GLP-1 levels and DPP-4 levels were also assessed. After treatment, there was no significant difference in fasting glucose between the two groups, but there was a significant decrease in fasting glucose in the Denosumab Group (D.G.) compared to before treatment. There was a significant difference in 2-hour postprandial glucose (2hPG) between the two groups after treatment, with the D.G. being lower than the ibandronate group (I.G.). Glycosylated haemoglobin (HbA1c) was lower in the D.G. than in the I.G. after treatment, but the difference between them was insignificant. In the D.G., serum active GLP-1 levels increased after treatment, and serum DPP-4 levels decreased. Serum GLP-1 and DPP-4 levels in the I.G. did not change compared with those before treatment. In conclusion, In the clinical management of postmenopausal osteoporosis patients with combined T2DM, the choice of RANKL inhibitors as anti-osteoporosis therapy may benefit their glycaemic parameters by elevating serum active GLP-1 levels and decreasing serum DPP-4 levels.

Resveratrol Mitigates Bisphenol A-Induced Metabolic Disruptions: Insights from Experimental Studies.

The aim of this study was to investigate the disruptions of metabolic pathways induced by bisphenol A (BPA) and explore the potential therapeutic intervention provided by resveratrol (RSV) in mitigating these disruptions through the modulation of biochemical pathways. Wistar albino rats were divided into three groups: group 1 served as the control, group 2 received 70 mg/Kg of BPA, and group 3 received 70 mg/kg of BPA along with 100 mg/Kg of RSV. After the treatment period, various biomarkers and gene expressions were measured to assess the effects of BPA and the potential protective effects of RSV. The results revealed that BPA exposure significantly increased the serum levels of α-amylase, α-glucosidase, G6PC, insulin, HbA1c, HMG-CoA reductase, FFAs, TGs, DPP-4, MDA, and proinflammatory cytokines such as TNF-α and IL-6. Concurrently, BPA exposure led to a reduction in the levels of antioxidant enzymes such as catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD), as well as GLUT4 and HDL cholesterol. However, the administration of RSV along with BPA significantly ameliorated these alterations in the biomarker levels induced through BPA exposure. RSV treatment effectively reduced the elevated levels of α-amylase, α-glucosidase, G6PC, insulin, HbA1c, HMG-CoA reductase, FFAs, TGs, DPP-4, MDA, and proinflammatory cytokines, while increasing the levels of antioxidant enzymes, GLUT4, and HDL cholesterol. Furthermore, BPA exposure suppressed the mRNA expression of glucokinase (GCK), insulin-like growth factor 1 (IGF-1), and glucose transporter 2 (GLUT2) and up-regulated the mRNA expression of uncoupling protein 2 (UCP2), which are all critical biomarkers involved in glucose metabolism and insulin regulation. In contrast, RSV treatment effectively restored the altered mRNA expressions of these biomarkers, indicating its potential to modulate transcriptional pathways and restore normal metabolic function. In conclusion, the findings of this study strongly suggest that RSV holds promise as a therapeutic intervention for BPA-induced metabolic disorders. By mitigating the disruptions in various metabolic pathways and modulating gene expressions related to glucose metabolism and insulin regulation, RSV shows potential in restoring normal metabolic function and counteracting the adverse effects induced by BPA exposure. However, further research is necessary to fully understand the underlying mechanisms and optimize the dosage and duration of RSV treatment for maximum therapeutic benefits.

Genetic variants of dipeptidyl peptidase IV are linked to the clinicopathologic development of prostate cancer.

CD26/dipeptidyl peptidase IV (DPP4) is a multifunctional cell-surface glycoprotein widely found in many cell types, and a soluble form is present in body fluids. There is longstanding evidence indicating a tumour-promoting or -suppressive role of DPP4 in different cancer types. However, studies focusing on the impacts of genetic variants of DPP4 on cancers are very rare. Herein, we conducted a case-control study to evaluate whether single-nucleotide polymorphisms (SNPs) of DPP4 were associated with the risk or clinicopathologic development of prostate cancer (PCa). We genotyped four loci of DPP4 SNPs, including rs7608798 (A/G), rs3788979 (C/T), rs2268889 (T/C) and rs6741949 (G/C), using a TaqMan allelic discrimination assay in 704 PCa patients and 704 healthy controls. Our results showed that PCa patients with the DPP4 rs7608798 AG+GG genotype or rs2268889 TC+CC genotype had a higher risk of developing an advanced clinical primary tumour (cT) stage (adjusted odds ratio (AOR): 1.680, 95% confidence interval (CI): 1.062-2.659, p = 0.025; AOR: 1.693, 95% CI: 1.092-2.624, p = 0.018). Additionally, in The Cancer Genome Atlas (TCGA) database, we observed that lower DPP4 expression levels were correlated with higher Gleason scores, advanced cT and pathological stages, tumour metastasis, and shorter progression-free survival rates in PCa patients. Furthermore, overexpression of DPP4 suppressed migration/invasion of metastatic PC3 PCa cells. Our findings suggest that DPP4 levels may affect the progression of PCa, and the DPP4 rs7608798 and rs2268889 SNPs are associated with the clinicopathologic development of PCa in a Taiwanese population.

DPP4 Inhibitors: Could they be One of the Solutions for COVID-19 Patients with Prediabetes?

Recent reports suggest that prediabetes is a risk factor for developing severe COVID-19 complications through underlying mechanisms involving undiagnosed sub-clinical inflammation. However, we remain without a clinical approach for managing COVID-19 in prediabetic cases. The subclinical inflammation in prediabetes is associated with elevated DPP4 levels and activity. DPP4 has pleiotropic actions, including glycaemia regulation and immuno-modulation. Recently, DPP4 has been recognised as a co-receptor for COVID-19 for entering host cells. In addition to improving glycaemia, DPP4 inhibition is associated with reduced inflammation. In this submission, we explore the potential use of DPP4 inhibitors as therapeutic agents for prediabetic patients in managing the deleterious effects of COVID-19. DPP4 inhibitors (gliptins), such as linagliptin and sitagliptin, have therapeutic effects, which have been shown to extend beyond glycaemic control with no risk of hypoglycaemia. By the nature of their mechanism of action, gliptins are not associated with hypoglycaemia, unlike their anti-glycaemic counterparts, as they mainly target postprandial glycaemia. Moreover, DPP4 inhibitors may represent a safer option for prediabetic individuals in managing prediabetes either as a prophylactic or curative treatment for COVID-19. We envisage that beyond improved glycaemic control, the use of DPP4 inhibitors would also alleviate the cytokine storm, resulting in a reduction in the severity of COVID-19 symptoms and consequently reducing the morbidity and mortality in prediabetic COVID- 19 patients.

Single-cell transcriptome dynamics of the autotaxin-lysophosphatidic acid axis during muscle regeneration reveal proliferative effects in mesenchymal fibro-adipogenic progenitors.

Lysophosphatidic acid is a growth factor-like bioactive phospholipid recognising LPA receptors and mediating signalling pathways that regulate embryonic development, wound healing, carcinogenesis, and fibrosis, via effects on cell migration, proliferation and differentiation. Extracellular LPA is generated from lysophospholipids by the secreted hydrolase-ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2; also, AUTOTAXIN/ATX) and metabolised by different membrane-bound phospholipid phosphatases (PLPPs). Here, we use public bulk and single-cell RNA sequencing datasets to explore the expression of Lpar 1-6, Enpp2, and Plpp genes under skeletal muscle homeostasis and regeneration conditions. We show that the skeletal muscle system dynamically expresses the Enpp2-Lpar-Plpp gene axis, with Lpar1 being the highest expressed member among LPARs. Lpar1 was expressed by mesenchymal fibro-adipogenic progenitors and tenocytes, whereas FAPs mainly expressed Enpp2. Clustering of FAPs identified populations representing distinct cell states with robust Lpar1 and Enpp2 transcriptome signatures in homeostatic cells expressing higher levels of markers Dpp4 and Hsd11b1. However, tissue injury induced transient repression of Lpar genes and Enpp2. The role of LPA in modulating the fate and differentiation of tissue-resident FAPs has not yet been explored. Ex vivo, LPAR1/3 and ENPP2 inhibition significantly decreased the cell-cycle activity of FAPs and impaired fibro-adipogenic differentiation, implicating LPA signalling in the modulation of the proliferative and differentiative fate of FAPs. Together, our results demonstrate the importance of the ENPP2-LPAR-PLPP axis in different muscle cell types and FAP lineage populations in homeostasis and injury, paving the way for further research on the role of this signalling pathway in skeletal muscle homeostasis and regeneration, and that of other organs and tissues, in vivo.

Antidiabetic effect of Withania Somnifera Root in STZ induced diabetic rats

Objective: To study the antidiabetic effect of Withania Somnifera root powder (WSR) in Streptozotocin induced diabetic rats. Methods: Diabetes in rats were induced by injecting Streptozotocin intraperitoneally (45 mg/kg of body weight) to overnight fasting rats. Withania Somnifera root was given to group C (100 mg/ kg of body weight) and Pioglitazone to group D (20 mg/kg of body weight) orally for 4 weeks respectively. Blood glucose level, glycated Hb, insulin, protein tyrosine kinase activity and serum DPP-4 levels were measured. Results: Significant Improvement in body weight, glycemic profile, dyslipidemia and tyrosine kinase activity were observed in WSR treated rats at week 4 of the study compared to diabetic control rats. Blood glucose level, glycated Hb and Serum DPP4 levels, were also found to be decreased in WSR treated rats compared to diabetic control rats at the end of study. This is possibly due to augmented serum insulin levels and increased insulin sensitivity after treatment with WSR. Conclusion: The results from above study it was concluded that Withania Somnifera root powder has antidiabetic activity. Further study required to confirm the exact mechanism of action.

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, β-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.

Hepatocyte-derived DPP4 regulates portal GLP-1 bioactivity, glucose production, and its absence alters liver disease progression.

Elevated circulating dipeptidyl-peptidase 4 is a biomarker for liver disease, but its involvement in gluconeogenesis and in metabolic-associated fatty liver disease (MAFLD) progression remains unclear. Here we identified that DPP4 in hepatocytes but not Tie2+ endothelial cells regulates the local bioactivity of incretin hormones and gluconeogenesis. However, the complete absence of DPP4 (Dpp4-/-) in aged mice with metabolic syndrome accelerates liver fibrosis without altering dyslipidemia and steatosis. Analysis of transcripts from the livers of whole body Dpp4-/- displayed enrichment for inflammasome, p53, and senescence programs compared to littermate controls. High-fat high-cholesterol (HFHC)-feeding decreased Dpp4 expression in F4/80+ cells, with only minor changes in immune signaling. Moreover, in a lean mouse model of severe non-alcoholic fatty liver disease (NAFLD), phosphatidylethanolamine N-methyltransferase (Pemt -/-) mice fed with HFHC diet, we observed a 4-fold increase in circulating DPP4, disassociating its release from obesity. Lastly, we evaluated DPP4 levels in patients with hepatitis C infection with dysglycemia (HOMA-IR > 2) who underwent direct antiviral treatment (with or without ribavirin). DPP4 protein levels decreased with viral clearance, and DPP4 activity levels were reduced at longer-term follow-up in ribavirin-treated patients, although metabolic factors did not improve. These data suggest elevations in DPP4 during HCV infection are not primarily regulated by metabolic disturbances.

The role of fine suspended particles of atmospheric air in the formation of eosinophilic inflammation in T2-endotype of asthma

BACKGROUND: Allergens induce eosinophilic inflammation in the T2 endotype of asthma. However, much less is known about the role of non-specific factors (suspended particles in the atmospheric air-PM).&#x0D; AIMS: To define eosinophilic inflammation on the basis of several biomarkers in the T2 endotype of asthma exposed to PM.&#x0D; MATERIALS AND METHODS: We studied 150 patients with asthma, and 61 patients with T2 endotype of asthma (ages 1865 years) were enrolled. Group 1 included 34 patients with allergic asthma, and group 2 included 27 patients with non-allergic asthma. Moreover, 30 healthy matched controls without asthma and other allergic diseases were enrolled in the study. Clinical examination and allergy testing were performed. Additionally, serum levels of IL-33, IL-25, IL-4, IL-5, IL-13, DPP4 (multiplex assay), and periostin (ELISA) were evaluated. The analyses of the average annual concentrations (Avr) and the maximal annual concentrations (MaxAvr) of PM2.5 and PM10 in Kazan were conducted using the database of the Center for Hygiene and Epidemiology in the Republic of Tatarstan, being averaged over the period from 2014 to 2020 years in monitoring points at residential areas. Statistical analyses were performed using R version 4.0.5. The study was funded by RFBR (Project no. 19-05-50094).&#x0D; RESULTS: We detected increased blood eosinophil count and IL-5 levels in patients with asthma. High levels of total IgE (p=0.0001) that correlated with IL-4 levels were observed only in patients with allergic asthma (rS=0.38; p=0.045). Moreover, elevated IL-25 levels were found in patients with allergic asthma (p=0.009). No significant differences in IL-13 levels in patient with asthma were found. The regression analysis revealed that the PM2.5Avr increase by 1 mcg/m3 increases IL-33 and IL-25 levels, but the PM10Avr increase raises the IL-25 levels only in patients with non-allergic asthma. No significant increase in IL-25 and IL-33 levels under exposure to PM2.5Avr and PM 10Avr was detected in patients with allergic asthma.&#x0D; CONCLUSIONS: The results of this study indicate the pivotal role of fine suspended particles in the development and maintenance of eosinophilic inflammation in patients with non-allergic asthma.

Role of the Senescence-Associated Factor Dipeptidyl Peptidase 4 in the Pathogenesis of SARS-CoV-2 Infection.

During cellular senescence, persistent growth arrest and changes in protein expression programs are accompanied by a senescence-associated secretory phenotype (SASP). In this study, we detected the upregulation of the SASP-related protein dipeptidyl peptidase 4 (DDP4) in human primary lung cells rendered senescent by exposure to ionizing radiation. DPP4 is an exopeptidase that plays a crucial role in the cleavage of various proteins, resulting in the loss of N-terminal dipeptides and proinflammatory effects. Interestingly, our data revealed an association between severe coronavirus disease 2019 (COVID-19) and DDP4, namely that DPP4 levels increased in the plasma of patients with COVID-19 and were correlated with age and disease progression. Although we could not determine the direct effect of DDP4 on viral replication, mechanistic studies in cell culture revealed a negative impact on the expression of the tight junction protein zonula occludens-1 (ZO-1), which contributes to epithelial barrier function. Mass spectrometry analysis indicated that DPP4 overexpressing cells exhibited a decrease in ZO-1 and increased expression of pro-inflammatory cytokines and chemokines. By investigating the effect of DPP4 on the barrier function of human primary cells, we detected an increase in ZO-1 using DPP4 inhibitors. These results provide an important contribution to our understanding of DPP4 in the context of senescence, suggesting that DPP4 plays a major role as part of the SASP. Our results provide evidence that cellular senescence, a hallmark of aging, has an important impact on respiratory infections.

Vitamin D ameliorates diethylnitrosamine-induced liver preneoplasia: A pivotal role of CYP3A4/CYP2E1 via DPP-4 enzyme inhibition

Growing evidence has indicated that vitamin D (Vit D) regulates cell proliferation and differentiation in cancer cells. Accordingly, the present study was conducted to investigate the possible beneficial effects of Vit D on diethylnitrosamine (DEN)-induced liver preneoplasia. The effect of Vit D on HepG2 cells was investigated using MTT assay. Additionally, liver preneoplasia was induced in Swiss male albino mice by giving overnight fasted animals 5 consecutive doses of DEN (75 mg/kg/week). Oral treatment with Vit D (200 IU/kg/day) was initiated either 2 weeks before DEN (first protocol) or 1 week after the first dose of DEN injection (second protocol). At the end of the experiment, tissue levels of GGT, DPP-4, TNF-α, IL-6, CYP2E1, and CYP3A4 were also estimated. Moreover, the histopathological study of liver tissue and immunohistochemical detection of GST-P, PCNA, and NF-κB were performed. Vit D exerted a significant cytotoxic effect on HepG2 cells via significantly increasing BAX, p53, and BAX/Bcl2 ratio, and significantly decreasing Bcl2 mRNA expression. In both in vivo protocols, Vit D was capable of normalizing relative liver weight, PCNA, altered hepatocellular foci, and ductular proliferation. Moreover, Vit D significantly reduced the DEN-induced elevation of AST, ALT, ALP, GGT, DDP-4, TNF-α, IL-6, CYP2E1, liver DNA damage, GST-P, NF-κB, nuclear hyperchromasia/pleomorphism, cholestasis, and inflammatory cell aggregates, but significantly increased CYP3A4 content. In conculsion, current results reflect the potential impact of Vit D in the management of early stages of liver cancer.