Dipeptidyl Peptidase-4 Expression Research Articles

Dipeptidyl peptidase 4: A predictor of ferroptosis in ulcerative colitis.

With its rapidly increasing incidence and prevalence, ulcerative colitis (UC) has become a major global health challenge. Recent evidence suggests that ferroptosis plays a significant role in the development of UC. However, the relationship between ferroptosis and the progression of UC needs to be extensively studied. The differentially expressed genes in UC patients were screened from the GEO database. The ferroptosis-related genes were obtained from FErrDB and GeneCards. The UC subtypes were identified with the R package "CancerSubtype" and evaluated with consensus clustering (CC) to identify gene expression patterns in patients with UC. The key genes were detected with qRT-PCR, Western blot, and immunohistochemistry in vitro and in vivo models. Ferroptosis was identified with western blotting on ferrotic-associated proteins and staining on Fe2+ with commercial FerroOrange kits. Dipeptidyl peptidase 4 (DPP4), also known as CD26, is a potential biomarker for ferroptosis in UC patients. Transcriptome sequencing data showed a positive correlation between decreased DPP4 expression and proinflammatory cytokines such as TNF-α, IL-6, and IL-β, as well as immune cell infiltration in the colon tissues of UC patients. Furthermore, DPP4 was strongly associated with ferroptosis biomarkers, particularly in Subtype 2 of UC. Interestingly, our study also found that DPP4 expression was significantly reduced in RSL3-treated ferroptotic intestinal epithelial cells, more so than in LPS-treated cell models. Inhibition of DPP4 had a significant impact on the expression of ferroptotic biomarkers. Additionally, DPP4 expression was decreased in the colon tissues of DSS-treated mice, and the ferroptosis inhibitor Ferritin-1 effectively counteracted the effects of DSS on immune cell infiltration, colon length, and DPP4 expression. DPP4 can serve as a biomarker for ferroptosis in the diagnosis and management of UC.

Dipeptidyl peptidase-4 marks distinct subtypes of human adipose stromal/stem cells with different hepatocyte differentiation and immunoregulatory properties

BackgroundHuman adipose-derived stromal/stem cells (hASCs) play important roles in regenerative medicine and numerous inflammatory diseases. However, their cellular heterogeneity limits the effectiveness of treatment. Understanding the distinct subtypes of hASCs and their phenotypic implications will enable the selection of appropriate subpopulations for targeted approaches in regenerative medicine or inflammatory diseases.MethodshASC subtypes expressing dipeptidyl peptidase-4 (DPP4) were identified via fluorescence-activated cell sorting (FACS) analysis. DPP4 expression was knocked down in DPP4+ hASCs via DPP4 siRNA. The capacity for proliferation, hepatocyte differentiation, inflammatory factor secretion and T-cell functionality regulation of hASCs from DPP4−, DPP4+, and control siRNA-treated DPP4+ hASCs and DPP4 siRNA-treated DPP4+ hASCs were assessed.ResultsDPP4+ hASCs and control siRNA-treated DPP4+ hASCs presented a lower proliferative capacity but greater hepatocyte differentiation capacity than DPP4− hASCs and DPP4 siRNA-treated DPP4+ hASCs. Both DPP4+ hASCs and DPP4− hASCs secreted high levels of vascular endothelial growth factor-A (VEGF-A), monocyte chemoattractant protein-1 (MCP-1), and interleukin 6 (IL-6), whereas the levels of other factors, including matrix metalloproteinase (MMP)-1, eotaxin-3, fractalkine (FKN, CX3CL1), growth-related oncogene-alpha (GRO-alpha, CXCL1), monokine induced by interferon-gamma (MIG), macrophage inflammatory protein (MIP)-1beta, and macrophage colony-stimulating factor (M-CSF), were significantly greater in the supernatants of DPP4+ hASCs than in those of DPP4− hASCs. Exposure to hASC subtypes and their conditioned media triggered changes in the secreted cytokine profiles of T cells from healthy donors. The percentage of functional T cells that secreted factors such as MIP-1beta and IL-8 increased when these cells were cocultured with DPP4+ hASCs. The percentage of polyfunctional CD8+ T cells that secreted multiple factors, such as IL-17A, tumour necrosis factor alpha (TNF-α) and TNF-β, decreased when these cells were cocultured with supernatants derived from DPP4+ hASCs.ConclusionsDPP4 may regulate proliferation, hepatocyte differentiation, inflammatory cytokine secretion and T-cell functionality of hASCs. These data provide a key foundation for understanding the important role of hASC subpopulations in the regulation of T cells, which may be helpful for future immune activation studies and allow them to be customized for clinical application.

Fabrication of a Near-Infrared-Emissive Probe for Detecting Dipeptidyl Peptidase 4 in the Liver of Diabetic Mice and Clinical Serum.

Dipeptidyl peptidase 4 (DPP4) plays a key role in glucose metabolism, which has been a close target for diabetes pathology and treatment. It is significant for the evaluation of cellular DPP4 activity in various biological systems. Fluorescence imaging technology is currently a popular method for detecting enzymes in living cells due to its advantages of high selectivity, high sensitivity, high spatiotemporal resolution, and real-time visualization. Herein, a near-infrared (NIR)-emissive probe NEDP with a large Stokes shift (153 nm) was developed for the assay of DPP4 activity. Upon addition of DPP4, NEDP can emit a significant turn-on NIR fluorescence signal (673 nm) with high sensitivity and specificity. Moreover, NEDP can successfully be used for imaging of intracellular DPP4, confirming the regulation of DPP4 expression in hyperglucose and its treatment in living cells. Most importantly, NEDP can not only monitor the changes of DPP4 in vivo but also show that DPP4 in diabetes is mainly up-regulated in the liver, and the level of DPP4 is positively correlated with the pathological damage of the liver. In addition, NEDP can identify the serum of diabetic patients from healthy people through the fluorescence response to DPP4. These results demonstrated that the designed probe NEDP provides a prospective visual tool to explore the relationship between DPP4 and diabetes and would be applied for detecting serum of diabetes in the clinic.

Potential Role of Dipeptidyl Peptidase-4 in Regulating Mitochondria and Oxidative Stress in Cardiomyocytes.

Oxidative stress causes mitochondrial damage and bioenergetic dysfunction and inhibits adenosine triphosphate production, contributing to the pathogenesis of cardiac diseases. Dipeptidyl peptidase 4 (DPP4) is primarily a membrane-bound extracellular peptidase that cleaves Xaa-Pro or Xaa-Ala dipeptides from the N terminus of polypeptides. DPP4 inhibitors have been used in patients with diabetes and heart failure; however, they have led to inconsistent results. Although the enzymatic properties of DPP4 have been well studied, the substrate-independent functions of DPP4 have not. In the present study, we knocked down DPP4 in cultured cardiomyocytes to exclude the effects of differential alteration in the substrates and metabolites of DPP4 then compared the response between the knocked-down and wild-type cardiomyocytes during exposure to oxidative stress. H2O2 exposure induced DPP4 expression in both types of cardiomyocytes. However, knocking down DPP4 substantially reduced the loss of cell viability by preserving mitochondrial bioenergy, reducing intracellular reactive oxygen species production, and reducing apoptosis-associated protein expression. These findings demonstrate that inhibiting DPP4 improves the body's defense against oxidative stress by enhancing Nrf2 and PGC-1α signaling and increasing superoxide dismutase and catalase activity. Our results indicate that DPP4 mediates the body's response to oxidative stress in individuals with heart disease.

Dipeptidyl peptidase 4-positive cancer-associated fibroblasts enhance lung adenocarcinoma growth

Cancer-associated fibroblasts (CAFs) are a heterogeneous population of fibroblasts with various features in the cancer stroma and have been reported to influence cancer progression through cell–cell interactions in various types of malignancies, including lung adenocarcinoma (LUAD). Dipeptidyl peptidase 4 (DPP4) is a transmembrane protein with serine protease activity and is involved in the progression of tumors, metabolic diseases, and autoimmune diseases. In the present study, we focused on the role of DPP4-positive CAFs in LUAD. Immunohistochemistry revealed that 38 of 89 LUAD patients showed DPP4 expression in the fibrous stroma, and patients harboring DPP4-positive CAFs were more often male, had a higher Brinkman index, and had a higher Ki-67 labeling index of tumor cells than those with DPP4-negative CAFs. DPP4-positivity was associated with the expression of other CAF markers, α-SMA, periostin, and podoplanin, as well as a cellular senescence marker, p16. In the in vitro study, conditioned media collected from pulmonary fibroblast (OUS-11, HPF, and HPF-C)-induced overexpression of DPP4 significantly promoted the proliferation of LUAD cells (A549 and PC-9) and increased the expression levels of MCP-1, IL-8, IL-6, and GCSF in the media compared to those in controls. In addition, OUS-11 overexpression in DPP4 overexpression increased periostin expression. In conclusion, DPP4-positive CAFs could promote lung adenocarcinoma cell growth by producing soluble factors, and DPP4 inhibition may inhibit cancer progression.

Epigallocatechin gallate alleviates non-alcoholic fatty liver disease through the inhibition of the expression and activity of Dipeptide kinase 4

BackgroundNon-alcoholic fatty liver disease (NAFLD) has emerged as the most prevalent glocal cause of chronic hepatic disease, with incidence rates that continue to rise steadily. Treatment options for affected patients are currently limited to dietary changes and exercise interventions, with no drugs having been licensed for the treatment of this disease. There is thus a pressing need for the development of novel therapeutic strategies. Work from our group suggests that the primary bioactive ingredient in green tea, epigallocatechin gallate (EGCG), may help reduce liver fat content and protect against hepatic injury through the inhibition of dipeptidyl peptidase 4 (DPP4) expression and activity. The study investigated the potential pathways by which EGCG may improve NAFLD, identified the sites of interaction between EGCG and DPP4, and proposed novel clinical treatment strategies. MethodsA clinical randomized controlled trial was conducted to investigate the potential efficacy of EGCG in NAFLD patients. The study compared relevant indices before and after EGCG administration. Animal models of NAFLD were constructed using male C57BL/6J mice fed a high-fat diet to observe the ameliorative effects of EGCG on the livers of the model mice and to investigate the potential pathways by which EGCG alleviates NAFLD. The interaction mechanism between EGCG and DPP4 was investigated using oleic acid and palmitic acid-treated HepG2 cell lines. Plasmids in which different sites had been disrupted were used to identify the effective interaction sites. ResultsECGC was found to suppress the accumulation of lipids, inhibit inflammation, remediate dysregulated lipid metabolism, and improve the pathogenesis of NAFLD via the inhibition of the expression and activity of DPP4. ConclusionsThe study results indicate that EGCG has a positive impact on improving NAFLD. These results highlight promising new opportunities to safely and effectively treat NAFLD in the clinic. Study id numberChiCTR2300076741; https://www.chictr.org.cn/

Dipeptidyl peptidase 4 interacts with porcine coronavirus PHEV spikes and mediates host range expansion.

Porcine hemagglutinating encephalomyelitis virus (PHEV), a neurotropic betacoronavirus, is prevalent in natural reservoir pigs and infects mice. This raises concerns about host jumping or spillover, but little is known about the cause of occurrence. Here, we revealed that dipeptidyl peptidase 4 (DPP4) is a candidate binding target of PHEV spikes and works as a broad barrier to overcome. Investigations of the host breadth of PHEV confirmed that cells derived from pigs and mice are permissive to virus propagation. Both porcine DPP4 and murine DPP4 have high affinity for the viral spike receptor-binding domain (RBD), independent of their catalytic activity. Loss of DPP4 expression results in limited PHEV infection. Structurally, PHEV spike protein binds to the outer surface of blades IV and V of the DPP4 β-propeller domain, and the DPP4 residues N229 and N321 (relative to human DPP4 numbering) participate in RBD binding via its linked carbohydrate entities. Removal of these N-glycosylations profoundly enhanced the RBD-DPP4 interaction and viral invasion, suggesting they act as shielding in PHEV infection. Furthermore, we found that glycosylation, rather than structural differences or surface charges, is more responsible for DPP4 recognition and species barrier formation. Overall, our findings shed light on virus-receptor interactions and highlight that PHEV tolerance to DPP4 orthologs is a putative determinant of its cross-species transmission or host range expansion.IMPORTANCEPHEV is a neurotropic betacoronavirus that is circulating worldwide and has raised veterinary and economic concerns. In addition to being a reservoir species of pigs, PHEV can also infect wild-type mice, suggesting a "host jump" event. Understanding cross-species transmission is crucial for disease prevention and control but remains to be addressed. Herein, we show that the multifunctional receptor DPP4 plays a pivotal role in the host tropism of PHEV and identifies the conserved glycosylation sites in DPP4 responsible for this restriction. These findings highlight that the ability of PHEV to utilize DPP4 orthologs potentially affects its natural host expansion.

Stool Protein Mass Spectrometry Identifies Biomarkers for Early Detection of Diffuse-type Gastric Cancer.

There is a high unmet need for early detection approaches for diffuse gastric cancer (DGC). We examined whether the stool proteome of mouse models of gastric cancer (GC) and individuals with hereditary diffuse gastric cancer (HDGC) have utility as biomarkers for early detection. Proteomic mass spectrometry of the stool of a genetically engineered mouse model driven by oncogenic KrasG12D and loss of p53 and Cdh1 in gastric parietal cells [known as Triple Conditional (TCON) mice] identified differentially abundant proteins compared with littermate controls. Immunoblot assays validated a panel of proteins, including actinin alpha 4 (ACTN4), N-acylsphingosine amidohydrolase 2 (ASAH2), dipeptidyl peptidase 4 (DPP4), and valosin-containing protein (VCP), as enriched in TCON stool compared with littermate control stool. Immunofluorescence analysis of these proteins in TCON stomach sections revealed increased protein expression compared with littermate controls. Proteomic mass spectrometry of stool obtained from patients with HDGC with CDH1 mutations identified increased expression of ASAH2, DPP4, VCP, lactotransferrin (LTF), and tropomyosin-2 relative to stool from healthy sex- and age-matched donors. Chemical inhibition of ASAH2 using C6 urea ceramide was toxic to GC cell lines and GC patient-derived organoids. This toxicity was reversed by adding downstream products of the S1P synthesis pathway, which suggested a dependency on ASAH2 activity in GC. An exploratory analysis of the HDGC stool microbiome identified features that correlated with patient tumors. Herein, we provide evidence supporting the potential of analyzing stool biomarkers for the early detection of DGC. Prevention Relevance: This study highlights a novel panel of stool protein biomarkers that correlate with the presence of DGC and has potential use as early detection to improve clinical outcomes.

MiR-548ag promotes DPP4 expression in hepatocytes through activation of TLR(7/8)/NF-κB pathway

ObjectiveIn our previous study, we identified a notable increase in miR-548ag content after obesity, which contributes to the progression of Type 2 diabetes Mellitus(T2DM) through the up-regulation of Dipeptidyl Peptidase-4(DPP4) expression within the liver. However, the precise molecular mechanisms underlying the upregulation of DPP4 by miR-548ag remain elusive. Mature miRNAs rich in GU sequences can activate the TLR(7/8)/NF-κB signalling pathway, which transcriptionally activates DPP4 expression. Notably, the proportion of GU sequences in hsa-miR-548ag was found to be 47.6%. The study proposes a hypothesis suggesting that miR-548ag could potentially increase DPP4 expression in hepatocytes by activating the TLR(7/8)/NF-κB signalling pathway.MethodsMale C57BL/6J mice were fed normal chow diet (NCD, n = 16) or high-fat diet (HFD, n = 16) for 12 weeks. For a duration of 6 weeks, NCD mice received intraperitoneal injections of a miR-548ag mimic, while HFD mice and db/db mice (n = 16) were administered intraperitoneal injections of a miR-548ag inhibitor. qRT-PCR and Western Blot were used to detect the expression level of miR-548ag, DPP4 and the activation of TLR(7/8)/NF-κB signalling pathway. HepG2 and L02 cells were transfected with miR-548ag mimic, miR-548ag inhibitor, TLR7/8 interfering fragment, and overexpression of miR-548ag while inhibiting TLR7/8, respectively.Results(1) We observed elevated levels of miR-548ag in the serum, adipose tissue, and liver of obese mice, accompanied by an upregulation of TLR7/8, pivotal protein in the NF-κB pathway, and DPP4 expression in the liver. (2) miR-548ag promotes DPP4 expression in hepatocytes via the TLR(7/8)/NF-κB signalling pathway, resulting in a reduction in the glucose consumption capacity of hepatocytes. (3) The administration of a miR-548ag inhibitor enhanced glucose tolerance and insulin sensitivity in db/db mice.ConclusionsMiR-548ag promotes the expression of DPP4 in hepatocytes by activating the TLR(7/8)/NF-κB signalling pathway. MiR-548ag may be a potential target for the treatment of T2DM.

Vildagliptin inhibits high fat and fetuin-A mediated DPP-4 expression, intracellular lipid accumulation and improves insulin secretory defects in pancreatic beta cells

Dipeptidyl peptidase-4 (DPP-4), a ubiquitous proteolytic enzyme, inhibits insulin secretion from pancreatic beta cells by inactivating circulating incretin hormones GLP-1 and GIP. High circulating levels of DPP-4 is presumed to compromise insulin secretion in people with type 2 diabetes (T2D). Our group recently reported lipid induced DPP-4 expression in pancreatic beta cells, mediated by the TLR4-NFkB pathway. In the present study, we looked at the role of Vildagliptin on pancreatic DPP-4 inhibition, preservation of islet mass and restoration of insulin secretion. MIN6 mouse insulinoma cells incubated with palmitate and fetuin-A, a proinflammatory organokine associated with insulin resistance, showed activation of TLR4-NFkB pathway, which was rescued on Vildagliptin treatment. In addition, Vildagliptin, by suppressing palmitate-fetuin-A mediated DPP-4 expression in MIN6, prevented the secretion of IL-1beta and fetuin-A in the culture media. DPP-4 siRNA abrogated TLR4-NFkB pathway mediated islet cell inflammation. Vildagliptin also reduced palmitate-fetuin-A mediated intracellular lipid accumulation in MIN6 and isolated islets from high fat fed (HFD) mice as observed by Oil O Red staining with downregulation of CD36 and PPARgamma. Vildagliptin also preserved islet mass and rescued insulin secretory defect in HFD mice. Our results suggest that inhibition of DPP-4 by Vildagliptin protects pancreatic beta cells from the deleterious effects of lipid and fetuin-A, preserves insulin secretory functions and improves hyperglycemia.

A Systems Biology Approach Unveils a Critical Role of DPP4 in Upper Gastrointestinal Cancer Patient Outcomes.

Gastrointestinal (GI) cancers comprise of cancers that affect the digestive system and its accessory organs. The late detection and poor prognosis of GI cancer emphasizes the importance of identifying reliable and precise biomarkers for early diagnosis and prediction of prognosis. The membrane-bound glycoprotein dipeptidyl-peptidase 4 (DPP4), also known as CD26, is ubiquitously expressed and has a wide spectrum of biological roles. The role of DPP4/CD26 in tumor progression in different types of cancers remains elusive. However, the link between DPP4 and tumor-infiltrating cells, as well as its prognostic significance in malignancies, still require further investigation. This study was intended to elucidate the correlation of DPP4 expression and survival along with prognosis, followed by its associated enriched molecular pathways and immune cell marker levels in upper GI cancers. Results demonstrated a strong correlation between increased DPP4 expression and a worse prognosis in esophageal and gastric cancer and the co-expressed common genes with DPP4 were associated with crucial molecular pathways involved in tumorigenesis. Additionally, DPP4 was shown to be significantly linked to several immune infiltrating cell marker genes, including Macrophages (M1, M2 and Tumor Associated Macrophages), neutrophils, Treg, T-cell exhaustion, Th1 and Th2. Overall, our findings suggest that DPP4 may serve as a substantial prognostic biomarker, a possible therapeutic target, as well as it can play a critical role in the regulation of immune cell invasion in patients with gastroesophageal (esophageal, gastroesophageal junction and gastric) cancer. KEY WORDS: DPP4, integrated analysis, GI cancer, gastroesophageal cancer, gastroesophageal junction, prognosis.

MiR-23b-3p Ameliorates LPS-Induced Pulmonary Fibrosis by Inhibiting EndMT via DPP4 Inhibition.

Acute respiratory distress syndrome is a disease triggered by severe pulmonary and systemic inflammation that may lead to fibrosis and the decline of lung function. Lung capillary endothelial-to-mesenchymal transition (EndMT) is one of the primary sources of fibroblasts in pulmonary fibrosis. The role of miRNAs as molecular markers of pulmonary fibrosis, and miRNAs as nucleic acid drugs has attracted increasing attention. To mock EndMT process, Human pulmonary microvascular endothelial cells (HPMECs) were induced with lipopolysaccharide (LPS). Similarly, LPS treatment was used to generate a mouse model of LPS-induced EndMT and pulmonary fibrosis. LPS-induced EndMT in HPMECs resulted in a significant reduction of miR-23b-3p. miR-23b-3p inhibited the interstitial transition of HPMECs, and miR-23b-3p could mediate this process via inhibiting dipeptidyl peptidase-4 (DPP4). Dual-luciferase assays confirmed the regulatory mechanism of miR-23b-3p. In our mouse model of LPS-induced pulmonary fibrosis, miR-23b-3p and a DPP4 inhibitor (sitagliptin) individually alleviated LPS-induced EndMT progression and pulmonary fibrosis, and their combined use achieved the strongest remission effect. To sum up, miR-23b-3p alleviates EndMT in pulmonary fibrosis by inhibiting the expression of DPP4.

Increased Thyroid DPP4 Expression Is Associated With Inflammatory Process in Patients With Hashimoto Thyroiditis.

Dipeptidyl peptidase-4 (DPP4) is originally described as a surface protein in lymphocytes. Lymphocyte infiltration and subsequent destruction of thyroid tissue have been considered as the central pathological mechanism in Hashimoto thyroiditis (HT). The present study aimed to investigate DPP4 expression in peripheral blood and thyroid tissue in HT patients, and explore the role of DPP4 in the pathophysiological process of HT. This case-control study recruited 40 drug-naive HT patients and 81 control individuals. Peripheral blood and thyroid specimens were collected for assessing the expression and activity of DPP4. Moreover, single-cell RNA sequencing (scRNA-seq) analysis of 6 "para-tumor tissues" samples from scRNA-seq data set GSE184362 and in vitro cell experiments were also conducted. The HT patients had similar DPP4 serum concentration and activity as the controls. However, the expression and activity of DPP4 was significantly increased in the thyroid of the HT group than in the control group. The scRNA-seq analysis showed that DPP4 expression was significantly increased in the HT group, and mainly expressed in T cells. Further in vitro studies showed that inhibition of lymphocyte DPP4 activity with sitagliptin downregulated the production of inflammatory factors in co-cultured thyroid cells. DPP4 expression was significantly increased in the thyroid of the HT group compared with the control group, and was mainly localized in the lymphocytes. Inhibition of lymphocyte DPP4 activity reduced the production of inflammatory factors in co-cultured thyroid cells. Therefore, inhibition of DPP4 may have a beneficial effect by alleviating inflammatory reactions in HT patients.

Dipeptidyl Peptidase 4 Stimulation Induces Adipogenesis-Related Gene Expression of Adipose Stromal Cells.

Adipogenesis has emerged as a new therapeutic target for regulating metabolism and achieving anti-inflammatory and anti-atherosclerotic effects via the release of adiponectin. However, at present, the effects and mechanism of action of dipeptidyl peptidase 4 (DPP4) stimulation on adiponectin production and adipogenesis have not been clarified. Here, we investigated the effects of DPP4 stimulation with monocyte chemoattractant protein-1 (MCP-1) on platelet-derived growth factor receptor alpha (PDGFRα) expression in adipose tissue and blood adiponectin levels. Stromal vascular fractions (SVFs) purified from human subcutaneous adipose tissue and inguinal adipose tissue of obese and diabetic (Leprdb/db) mice were treated with 50 ng of MCP-1 and plasma from control (Lepr+/+) mice supplemented with 10 ng or 50 ng of MCP-1. Treatment of SVFs from human subcutaneous adipose tissues with 50 ng of MCP-1 significantly increased AdipoQ, DPP4, peroxisome proliferator-activated receptor gamma (PPARγ), fatty-acid-binding protein (FABP4), and SERBF1 mRNA expression. MCP-1-supplemented plasma increased adiponectin, CCAAT-Enhancer-binding protein alpha (C/EBPα), DPP4, IL-33, and PDGFRα mRNA expression and adiponectin and DPP4 protein expression, while decreasing the expression of IL-10 mRNA in SVFs compared with the levels in the plasma treatment group. MCP-1-supplemented plasma was shown to increase PPARγ, PPARγ2, adiponectin, DPP4, and FABP4 and decrease IL-10 mRNA expression in PDGFRα cells from adipose tissue. Meanwhile, MCP-1-supplemented plasma increased MCP-1, PDGFRα, TNFα, adiponectin, and IL-1β and decreased IL-10 and FOXP3 mRNA expression in DPP4 cells. Moreover, the injection of MCP-1-supplemented plasma into adipose tissue increased the proportion of DPP4+ cells among PDGFRα+ cells from adipose tissue and plasma adiponectin levels of Leprdb/db mice compared with the levels in the plasma injection group. Our results demonstrate that DPP4+ cells are important adipose progenitor cells. Stimulation of DPP4 with MCP-1 increases adipogenesis-related gene expression and the population of DPP4+ cells among PDGFRα+ cells in SVFs and blood adiponectin levels. DPP4 stimulation could be a novel therapy to increase local adipogenesis and systemic adiponectin levels.

Dipeptidyl peptidase 4 inhibition sensitizes radiotherapy by promoting T cell infiltration

ABSTRACT Radiotherapy could regulate systemic antitumor immunity, while the immune state in the tumor microenvironment (TME) also affects the efficacy of radiotherapy. We have found that higher CD8+ T cell infiltration is associated with longer overall survival of lung adenocarcinoma and melanoma patients receiving radiotherapy. 8-Gray radiation increased the transcriptional levels of chemokines in tumor cells in vitro. However, it was not sufficient to induce significant lymphocyte infiltration in vivo. Dipeptidyl peptidase 4 (DPP4) has been reported to inactivate chemokines via post-translational truncation. Single-cell sequencing revealed that dendritic cells (DCs) had a higher DPP4 expression among other cells in the TME and upregulated DPP4 expression after radiation. Combining a DPP4 inhibitor with radiotherapy could promote chemokines expression and T cell infiltration in the TME, enhancing the antitumor effect of radiotherapy. Moreover, this therapy further enhanced the therapeutic efficacy of anti-PD-1. In this study, we demonstrated the underlying mechanism of why radiotherapy failed to induce sufficient T cell infiltration and proposed an effective strategy to promote T cell infiltration and sensitize radiotherapy. These findings demonstrate the translational value of DPP4 inhibition as a complementary approach to enhance the efficacy of radiotherapy and the combination of radiotherapy with immunotherapy.

Fructus Lycii and Salvia miltiorrhiza Bunge extract attenuate oxidative stress-induced photoreceptor ferroptosis in retinitis pigmentosa

Aim of the studyTo assess the impact of Fructus Lycii and Salvia miltiorrhiza Bunge extract (FSE) on retinitis pigmentosa (RP) and to explore the mechanisms by which FSE can prevent oxidative stress-induced photoreceptor ferroptosis in RP. MethodsHydrogen peroxide(H2O2) was used to induce oxidative stress in 661 W cells, which were then examined using flow cytometry and enzyme linked immunosorbent assay (ELISA). Changes in mitochondria were observed by using an electron microscope to characterize the ferroptosis of the cells. The protective effect of FSE on the retina function and structure of rd10 mice was evaluated using histopathological examination, fundus photographs, and electroretinography (ERG). Protein expression levels of Tumor Protein p53 (P53), Solute Carrier Family 7 Member 11 (SLC7A11), Glutathione peroxidase 4 (GPX4), Arachidonate-12-Lipoxygenase (ALOX12), and Dipeptidyl peptidase 4 (DPP4) were evaluated by Western blot assays in Vivo and in Vitro. ResultsH2O2-induced 661 W cells increased oxidative stress products and P53 and ALOX12, decreasing the expression of SLC7A11, GPX4, and DPP4. GPX4 activator does not reduce reactive oxygen species (ROS) generation and has little effect on ferroptosis. Fer-1 and FSE attenuate ROS generation and inhibit ferroptosis of photoreceptors in RP via inhibited P53 expression and increased SLC7A11 and GPX4 expression. ConclusionFSE may be available in clinical therapeutics to alleviating RP and the mechanism by which inhibits ferroptosis of photoreceptors following oxidative stress via the P53/ SLC7A11 pathway.

Ugonin P inhibits lung cancer motility by suppressing DPP-4 expression via promoting the synthesis of miR-130b-5p

Lung cancer is the leading cause of cancer-related death worldwide, and the survival rate of metastatic lung cancer is exceedingly low. Helminthostatchys Zeylanica (H. Zeylanica) is a Chinese herbal medicine renowned for its anti-inflammatory, immunomodulatory, and anti-cancer activities in various cellular and animal studies. The current study evaluated the effects of H. Zeylanica derivatives on lung cancer cells. We determined that dipeptidyl peptidase-4 (DPP-4) expression levels were higher in lung cancer tissues than in normal tissues. We also determined that DPP-4 expression levels were higher in the metastatic stage and strongly correlated with lung cancer survival rates. An H. Zeylanica derivative (ugonin P) was shown to inhibit DPP-4 mRNA and protein expression in two lung cancer cell lines in a dose-dependent manner. Ugonin P was shown to decrease migration and invasion activities in lung cancer cells while promoting the synthesis of miR-130b-5p, which was found to negatively regulate DPP-4 protein expression and cell motility in lung cancer. We determined that ugonin P suppresses the DPP-4-dependent migration and invasion of lung cancer cells by downregulating the RAF/MEK/ERK signalling pathway and enhancing the expression of miR-130b-5p. This study provides compelling evidence that ugonin P could be used to develop novel therapeutic agents for the treatment of lung cancer.

Metformin as a promising target for DPP4 expression: computational modeling and experimental validation

Metformin is a regularly prescribed and low-cost generic medication. Metformin has been proposed as a target for Dipeptidyl-peptidase 4 (DPP4) expression in various clinical disorders. We provide insilco investigations on molecular docking and dynamic modeling of metformin and DPP4 potential interactions. Moreover, we conducted bioinformatic studies to highlight the clinical significance of DPP4 expression and mutation in various types of malignancies, as well as the invasion of different immune cells into the tumor microenvironment. We believe the present proposal’s findings have crucial implications for understanding how metformin may confer health advantages by targeting DPP4 expression in malignancies.Graphical abstract

Potential interaction between the oral microbiota and COVID-19: a meta-analysis and bioinformatics prediction.

The purpose of this study was to evaluate available evidence on the association between the human oral microbiota and coronavirus disease 2019 (COVID-19) and summarize relevant data obtained during the pandemic. We searched EMBASE, PubMed, and the Cochrane Library for human studies published up to October 2022. The main outcomes of the study were the differences in the diversity (α and β) and composition of the oral microbiota at the phylum and genus levels between patients with laboratory-confirmed SARS-CoV-2 infection (CPs) and healthy controls (HCs). We used the Human Protein Atlas (HPA), Gene Expression Profiling Interactive Analysis (GEPIA) database, Protein-protein interaction (PPI) network (STRING) and Gene enrichment analysis (Metascape) to evaluate the expression of dipeptidyl peptidase 4 (DPP4) (which is the cell receptor of SARS CoV-2) in oral tissues and evaluate its correlation with viral genes or changes in the oral microbiota. Out of 706 studies, a meta-analysis of 9 studies revealed a significantly lower alpha diversity (Shannon index) in CPs than in HCs (standardized mean difference (SMD): -0.53, 95% confidence intervals (95% CI): -0.97 to -0.09). Subgroup meta-analysis revealed a significantly lower alpha diversity (Shannon index) in older than younger individuals (SMD: -0.54, 95% CI: -0.86 to -0.23/SMD: -0.52, 95% CI: -1.18 to 0.14). At the genus level, the most significant changes were in Streptococcus and Neisseria, which had abundances that were significantly higher and lower in CPs than in HCs based on data obtained from six out of eleven and five out of eleven studies, respectively. DPP4 mRNA expression in the oral salivary gland was significantly lower in elderly individuals than in young individuals. Spearman correlation analysis showed that DPP4 expression was negatively correlated with the expression of viral genes. Gene enrichment analysis showed that DPP4-associated proteins were mainly enriched in biological processes, such as regulation of receptor-mediated endocytosis of viruses by host cells and bacterial invasion of epithelial cells. The oral microbial composition in COVID-19 patients was significantly different from that in healthy individuals, especially among elderly individuals. DPP4 may be related to viral infection and dysbiosis of the oral microbiome in elderly individuals.

Screening compounds for treating the diabetes and COVID-19 from Miao medicine by molecular docking and bioinformatics

Both diabetes and Corona Virus Disease 2019 (COVID-19) are seriously harmful to human health, and they are closely related. It is of great significance to find drugs that can simultaneously treat diabetes and COVID-19. Based on the theory of traditional Chinese medicine for treating COVID-19, this study first sorted out the compounds of Guizhou Miao medicine with “return to the lung channel” and “clear heat and detoxify” effects in China. The active components against COVID-19 were screened by molecular docking with SARS-CoV-2 PLpro and angiotensin-converting enzyme II as targets. Furthermore, the common target dipeptidyl peptidase 4 (DPP4) of diabetes and COVID-19 was used as a screening protein, and molecular docking was used to obtain potential components for the treatment of diabetes and COVID-19. Finally, the mechanism of potential ingredients in the treatment of diabetes and COVID-19 was explored with bioinformatics. More than 80 kinds of Miao medicine were obtained, and 584 compounds were obtained. Further, 110 compounds against COVID-19 were screened, and top 6 potential ingredients for the treatment of diabetes and COVID-19 were screened, including 3-O-β-D-Xylopyranosyl-(1-6)-β-D-glucopyranosyl-(1-6)-β-D-glucopyranosyl oleanolic acid 28-O-β-D-glucopyranosyl ester, Glycyrrhizic acid, Sequoiaflavone, 2-O-Caffeoyl maslinic acid, Pholidotin, and Ambewelamide A. Bioinformatics analysis found that their mechanism of action in treating diabetes and COVID-19 may be related to regulating the expression of DPP4, angiotensin II type 1 receptor, vitamin D receptor, plasminogen, chemokine C–C-motif receptor 6, and interleukin 2. We believe that Guizhou Miao medicine is rich in potential ingredients for the treatment of diabetes and COVID-19.