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Background: Curcumin is a multi-functional polyphenol with anti-bacterial and anti-inflammatory effects and may have potential for treatment of periodontal diseases. The present study was conducted to examine the molecular basis of the anti-bacterial effect of curcumin against Porphyromonas gingivalis using metabolome analysis. Materials and Methods: P. gingivalis were incubated with 10 µg/mL curcumin, and then metabolites were analyzed with CE-TOF/MS. Expression levels of sigma factors were also evaluated using RT-PCR assays. The activities of dipeptidyl peptidases (DPPs) were assessed by examining the degradation reactions of MCA-labeled peptides. Results: The relative amounts of various glycogenic amino acids were significantly decreased when P. gingivalis was incubated with curcumin. Furthermore, the metabolites on the amino acid degradation pathway, including high-energy compounds such as ATP, various intermediate metabolites of RNA/DNA synthesis, nucleoside sugars and amino sugars were also decreased. Additionally, the expression levels of sigma-54 and sigma-70 were significantly decreased, and the same results as noted following nutrient starvation. Curcumin also significantly suppressed the activities of some DPPs, while the human DPP-4 inhibitors markedly inhibited the growth of P. gingivalis and activities of the DPPs. Conclusions: Curcumin suppresses the growth of P. gingivalis by inhibiting DPPs and also interferes with nucleic acid synthesis and central metabolic pathways, beginning with amino acid metabolism. [ABSTRACT FROM AUTHOR]

Background: Enhancing the prognosis and treatment outcomes of oral cancer relies heavily on its early detection. This study aims to establish a connection between serum and salivary dipeptidyl peptidase-4 (DPP-4) levels and oral squamous cell carcinoma (OSCC), comparing them with oral potentially malignant lesions (OPMLs) and control subjects and validating salivary DPP-4 as a diagnostic marker for the early detection of oral cancer. Methodology: Forty-five systemically healthy individuals were categorized into three groups: Group I consisted of 15 patients diagnosed with OSCC, Group II comprised 15 patients with OPMLs (including leukoplakia and oral lichen planus), and Group III included 15 participants without any oral mucosal lesions. Serum and whole unstimulated salivary samples were collected from all participants to assess DPP-4 levels using an enzyme-linked immunosorbent assay (ELISA) kit. Receiver operating characteristic (ROC) analysis was conducted to determine the area under the curve (AUC), sensitivity, specificity, and diagnostic accuracy of DPP-4. Results: Both serum and salivary DPP-4 levels were highest in the healthy group, followed by OPMLs, and lowest in the OSCC group, with statistically significant differences observed. ROC analysis demonstrated excellent diagnostic accuracy of salivary DPP-4 in distinguishing OSCC from healthy individuals, OPMLs from healthy individuals, and OSCC from OPMLs, with accuracies of 100%, 100%, and 96.67%, respectively. Salivary DPP-4 levels also exhibited a statistically significant correlation with OSCC grades. Conclusions: DPP-4 appears to play a protective, anti-oncogenic role in maintaining oral tissue health. The remarkable diagnostic accuracy of both serum and salivary DPP-4 in discriminating between OSCC, OPMLs, and healthy controls suggests its potential utility as a well-established marker for early oral cancer diagnosis. Salivary DPP-4, being non-invasive, could serve as a convenient chair-side diagnostic tool for the early detection of OSCC. Clinical trial registration: The study was retrospectively registered on clinicaltrial.gov with NCT06087042, date of registration (first posted date): 17/10/2023 [ABSTRACT FROM AUTHOR]

Abstract Background Enhancing the prognosis and treatment outcomes of oral cancer relies heavily on its early detection. This study aims to establish a connection between serum and salivary dipeptidyl peptidase-4 (DPP-4) levels and oral squamous cell carcinoma (OSCC), comparing them with oral potentially malignant lesions (OPMLs) and control subjects and validating salivary DPP-4 as a diagnostic marker for the early detection of oral cancer. Methodology Forty-five systemically healthy individuals were categorized into three groups: Group I consisted of 15 patients diagnosed with OSCC, Group II comprised 15 patients with OPMLs (including leukoplakia and oral lichen planus), and Group III included 15 participants without any oral mucosal lesions. Serum and whole unstimulated salivary samples were collected from all participants to assess DPP-4 levels using an enzyme-linked immunosorbent assay (ELISA) kit. Receiver operating characteristic (ROC) analysis was conducted to determine the area under the curve (AUC), sensitivity, specificity, and diagnostic accuracy of DPP-4. Results Both serum and salivary DPP-4 levels were highest in the healthy group, followed by OPMLs, and lowest in the OSCC group, with statistically significant differences observed. ROC analysis demonstrated excellent diagnostic accuracy of salivary DPP-4 in distinguishing OSCC from healthy individuals, OPMLs from healthy individuals, and OSCC from OPMLs, with accuracies of 100%, 100%, and 96.67%, respectively. Salivary DPP-4 levels also exhibited a statistically significant correlation with OSCC grades. Conclusions DPP-4 appears to play a protective, anti-oncogenic role in maintaining oral tissue health. The remarkable diagnostic accuracy of both serum and salivary DPP-4 in discriminating between OSCC, OPMLs, and healthy controls suggests its potential utility as a well-established marker for early oral cancer diagnosis. Salivary DPP-4, being non-invasive, could serve as a convenient chair-side diagnostic tool for the early detection of OSCC. Clinical trial registration The study was retrospectively registered on clinicaltrial.gov with NCT06087042, date of registration (first posted date): 17/10/2023

Bioactive peptides derived from foods provide physiological health benefits beyond nutrition. This study focused on profiling small peptide inhibitors against two key serine proteases, dipeptidyl peptidase‐IV (DPP‐IV) and prolyl oligopeptidase (POP). DPP‐IV is a well‐known protein involved in diverse pathways regulating inflammation, renal, cardiovascular physiology, and glucose homeostasis. POP is yet another key target protein for neurodegenerative disorders. The study evaluated peptide libraries of buffalo colostrum whey and fat globule membrane proteins derived from pepsin and pepsin–pancreatin digestion through in silico web tools and structure‐based analysis by molecular docking and binding free‐energy estimation, followed by in vitro assay for DPP‐IV inhibition for the lead peptides. The bioinformatic study indicated 49 peptides presented motifs with DPP‐IV inhibition while 5 peptides with sequences for POP inhibition. In the molecular docking interactions study, 22 peptides interacted with active site residues of DPP‐IV and 3 peptides with that of POP. The synthesized peptides, SFVSEVPEL and LTFQHNF inhibited DPP‐IV in vitro with an IC50 of 193.5 μM and 1.782 mM, respectively. The study revealed the key residues for inhibition of DPP‐IV and POP thus affirming the DPP‐IV inhibitory potential of milk‐derived peptides. [ABSTRACT FROM AUTHOR]

Background Curcumin is a multi-functional polyphenol with anti-bacterial and anti-inflammatory effects and may have potential for treatment of periodontal diseases. The present study was conducted to examine the molecular basis of the anti-bacterial effect of curcumin against Porphyromonas gingivalis using metabolome analysis.Materials and Methods P. gingivalis were incubated with 10 µg/mL curcumin, and then metabolites were analyzed with CE-TOF/MS. Expression levels of sigma factors were also evaluated using RT-PCR assays. The activities of dipeptidyl peptidases (DPPs) were assessed by examining the degradation reactions of MCA-labeled peptides.Results The relative amounts of various glycogenic amino acids were significantly decreased when P. gingivalis was incubated with curcumin. Furthermore, the metabolites on the amino acid degradation pathway, including high-energy compounds such as ATP, various intermediate metabolites of RNA/DNA synthesis, nucleoside sugars and amino sugars were also decreased. Additionally, the expression levels of sigma-54 and sigma-70 were significantly decreased, and the same results as noted following nutrient starvation. Curcumin also significantly suppressed the activities of some DPPs, while the human DPP-4 inhibitors markedly inhibited the growth of P. gingivalis and activities of the DPPs.Conclusions Curcumin suppresses the growth of P. gingivalis by inhibiting DPPs and also interferes with nucleic acid synthesis and central metabolic pathways, beginning with amino acid metabolism.

The present study utilized Analytical Quality by Design (AQbD) approach to develop a stability‐indicating high‐performance liquid chromatography (HPLC) method for estimating evogliptin tartrate using design expert software. The key parameters were methodically optimized, contours were plotted, and stability was evaluated using various forced degradation conditions. Using an Agilent HPLC system with a photo diode array (PDA) detector along with Fortis C18 column (250 × 4.6 mm, 5 μm) effectively separated the drug from its degradants. The mobile phase used was methanol: water (pH adjusted to 3.0, 76:24; v/v) at 0.8 mL/min flow rate. Evogliptin was eluted at 2.98 min, at a detection wavelength of 267 nm. The proposed method was found to be specific, precise, linear and robust. The drug was sensitive to acidic, basic, oxidative, thermal, and photodegradation resolving six degradation products. Thus, the developed AQbD‐based stability‐indicating HPLC method is applicable in analyzing evogliptin in bulk, tablet dosage form and stability samples. [ABSTRACT FROM AUTHOR]

Yan Zhang,1,2 Yang Liu,1,2 Xiangyu Zhang,1,2 V Wee Yong,3 Mengzhou Xue1,2 1Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 2Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 3Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, CanadaCorrespondence: V Wee Yong, Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada, Email vyong@ucalgary.ca Mengzhou Xue, Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450001, People’s Republic of China, Email xuemengzhou@zzu.edu.cnPurpose: Intracerebral hemorrhage (ICH) is a fatal disease without effective treatment. The damage of the blood–brain barrier (BBB) is a key cause of brain edema and herniation after ICH. Omarigliptin (also known as MK3102) is a potent antidiabetic that inhibits dipeptidyl peptidase (DPP4); the latter has the ability to bind and degrade matrix metalloproteinases (MMPs). The present study aims to investigate the protective effects of omarigliptin against the destruction of BBB following ICH in mice.Methods and Materials: Collagenase VII was used to induce ICH in C57BL/6 mice. MK3102 (7 mg/kg/day) was administered after ICH. The modified neurological severity scores (mNSS) were carried out to assess neurological functions. Nissl staining was applied to evaluate neuronal loss. Brain water content, Evans blue extravasation, Western blots, immunohistochemistry and immunofluorescence were used to study the protective effects of BBB with MK3102 at 3 days after ICH.Results: MK3102 reduced DPP4 expression and decreased hematoma formation and neurobehavioral deficits of ICH mice. This was correspondent with lowered activation of microglia/macrophages and infiltration of neutrophils after ICH. Importantly, MK3102 protected the integrity of the BBB after ICH, associated with decreased expression of MMP-9, and preservation of the tight junction proteins ZO-1 and Occludin on endothelial cells through putative degradation of MMP-9, and inhibition of the expression of CX43 on astrocytes.Conclusion: Omarigliptin protects the integrity of the BBB in mice after ICH injury.Keywords: intracerebral hemorrhage, dipeptidyl peptidase, blood–brain barrier, omarigliptin

The cellular prion protein (PrPC) converts to alternatively folded pathogenic conformations (PrPSc) in prion infections and binds neurotoxic oligomers formed by amyloid-ß a-synuclein, and tau. ß-Endoproteolysis, which splits PrPC into N- and C-terminal fragments (N2 and C2, respectively), is of interest because a protease-resistant, C2-sized fragment (C2Sc) accumulates in the brain during prion infections, seemingly comprising the majority of PrPSc at disease endpoint in mice. However, candidates for the underlying proteolytic mechanism(s) remain unconfirmed in vivo. Here, a cell-based screen of protease inhibitors unexpectedly linked type II membrane proteins of the S9B serine peptidase subfamily to PrPC ß-cleavage. Overexpression experiments in cells and assays with recombinant proteins confirmed that fibroblast activation protein (FAP) and its paralog, dipeptidyl peptidase-4 (DPP4), cleave directly at multiple sites within PrPC's N-terminal domain. For wild-type mouse and human PrPC substrates expressed in cells, the rank orders of activity were human FAP ~ mouse FAP > mouse DPP4 > human DPP4 and human FAP > mouse FAP > mouse DPP4 >> human DPP4, respectively. C2 levels relative to total PrPC were reduced in several tissues from FAP-null mice, and, while knockout of DPP4 lacked an analogous effect, the combined DPP4/FAP inhibitor linagliptin, but not the FAP-specific inhibitor SP-13786, reduced C2Sc and total PrPSc levels in two murine cell-based models of prion infections. Thus, the net activity of the S9B peptidases FAP and DPP4 and their cognate inhibitors/modulators affect the physiology and pathogenic potential of PrPC. [ABSTRACT FROM AUTHOR]

Enzyme histochemistry via mass spectrometry imaging (MSI) has garnered attention as a straightforward approach for visualizing enzymatic reactions. While several studies in the medical and physiological fields have shown its promising application potential, its applicability to agricultural or food studies has not yet been demonstrated. Rice koji , known as an enzyme source for various fermented products, is a suitable model for demonstrating the applicability of this method to food-related materials. In this study, the enzymatic reaction of dipeptidyl peptidase B (DppB) in rice koji was visualized using MSI for the first time. The method was optimized and applied to investigate the effects of rice variety, polishing ratio, and cultivation time on the location of the DppB reaction. The DppB enzymatic reaction was found to occur in different locations in each of the two rice varieties, Yamadanishiki and Hakutsurunishiki. The polishing ratio also affected the distribution of the DppB enzymatic reactions. Furthermore, a time-course investigation of rice koji cultivation revealed that while the location of the reaction was largely associated with mycelial penetration, the structure and features of the rice grain may also affect the location of the enzymatic reaction. In summary, these results demonstrate the applicability of enzyme histochemistry by MSI to food-related materials. • Applicability of mass spectrometry imaging (MSI) to food analysis was studied. • The enzymatic activity of dipeptidyl peptidase B in rice koji was analyzed via MSI. • The method was optimized. • The effects of rice variety, polishing ratio, and cultivation time were studied. • MSI was demonstrated to be applicable for food-material analysis. [ABSTRACT FROM AUTHOR]

Dipeptidyl-peptidase IV (DPP4), originally identified as an aminopeptidase in 1960s, is an ubiquitously expressed protease presented as either a membrane-bound or soluble form. DPP4 cleaves dipeptide off from the N-terminal of its substrates, altering the bioactivity of its substrates. Subsequent studies reveal that DPP4 is also involved in various cellular processes by directly binding to a number of ligands, including adenosine deaminase, CD45, fibronectin, plasminogen, and caveolin-1. In recent years, many novel functions of DPP4, such as promoting fibrosis and mediating virus entry, have been discovered. Due to its implication in fibrotic response and immunoregulation, increasing studies are focusing on the potential role of DPP4 in inflammatory disorders. As a moonlighting protein, DPP4 possesses multiple functions in different types of cells, including both enzymatic and non-enzymatic functions. However, most of the review articles on the role of DPP4 in autoimmune disease were focused on the association between DPP4 enzymatic inhibitors and the risk of autoimmune disease. An updated comprehensive summary of DPP4's immunoregulatory actions including both enzymatic dependent and independent functions is needed. In this article, we will review the recent advances of DPP4 in immune regulation and autoimmune rheumatic disease. [ABSTRACT FROM AUTHOR]

Dipeptidyl-peptidase IV (DPP4), originally identified as an aminopeptidase in 1960s, is an ubiquitously expressed protease presented as either a membrane-bound or soluble form. DPP4 cleaves dipeptide off from the N-terminal of its substrates, altering the bioactivity of its substrates. Subsequent studies reveal that DPP4 is also involved in various cellular processes by directly binding to a number of ligands, including adenosine deaminase, CD45, fibronectin, plasminogen, and caveolin-1. In recent years, many novel functions of DPP4, such as promoting fibrosis and mediating virus entry, have been discovered. Due to its implication in fibrotic response and immunoregulation, increasing studies are focusing on the potential role of DPP4 in inflammatory disorders. As a moonlighting protein, DPP4 possesses multiple functions in different types of cells, including both enzymatic and non-enzymatic functions. However, most of the review articles on the role of DPP4 in autoimmune disease were focused on the association between DPP4 enzymatic inhibitors and the risk of autoimmune disease. An updated comprehensive summary of DPP4’s immunoregulatory actions including both enzymatic dependent and independent functions is needed. In this article, we will review the recent advances of DPP4 in immune regulation and autoimmune rheumatic disease.

Aim: To study the functions and signaling pathways controlled by dipeptidyl peptidase IV (DPPIV) in endometrial carcinoma (EC). Methods: DPPIV expression in EC cells was detected by flow cytometry, reverse transcription‐polymerase chain reaction analysis and Western blot. Interleukin‐6 (IL‐6) expression in the supernatant was measured by enzyme‐linked immunosorbent assay. The protein levels of signal transducers and activators of transcription‐3 (STAT3), phosphorylate STAT3, cellular Myc, and vascular endothelial growth factor in EC cells were measured by Western blot. Colony formation assays were used to assess the clonogenicity of EC cells. Ki67 immunostaining and cell counting were used to test the proliferative ability of EC cells. Nude mouse tumorigenicity assay was used to confirm DPPIV promotes the tumorigenicity of EC cells. A cell counting kit‐8 assay was used to determine the half‐maximal inhibitory concentration of sitagliptin. Results: Overexpression of DPPIV in EC cells with low DPPIV expression promoted cell proliferation in vitro (p < 0.01) and enhanced tumorigenicity in vivo (p < 0.05). Conversely, knocking down DPPIV expression in EC cells with high DPPIV expression inhibited cell proliferation (p < 0.01) and in vivo tumorigenicity (p < 0.01). DPPIV promoted EC cell proliferation via activation of IL‐6/STAT3 signaling pathway, and that IL‐6 could trigger a positive feedback loop that increased DPPIV expression (p < 0.01). Furthermore, the DPPIV inhibitor reduced STAT3 expression (p < 0.01) and inhibited growth of EC cells (p < 0.001). Conclusion: DPPIV enhances the properties that allow tumorigenesis in EC via IL‐6 and STAT3 signaling. [ABSTRACT FROM AUTHOR]

The precise targeting of cytotoxic agents to specific cell types or cellular compartments is of significant interest in medicine, with particular relevance for infectious diseases and cancer. Here, we describe a method to exploit aberrant levels of mobile ferrous iron (Fe(II)) for selective drug delivery in vivo. This approach makes use of a 1,2,4-trioxolane moiety, which serves as an Fe(II)-sensitive "trigger," making drug release contingent on Fe(II)-promoted trioxolane fragmentation. We demonstrate in vivo validation of this approach with the Plasmodium berghei model of murine malaria. Malaria parasites produce high concentrations of mobile ferrous iron as a consequence of their catabolism of host hemoglobin in the infected erythrocyte. Using activity-based probes, we successfully demonstrate the Fe(II)-dependent and parasite-selective delivery of a potent dipeptidyl aminopeptidase inhibitor. We find that delivery of the compound in its Fe(II)-targeted form leads to more sustained target inhibition with greatly reduced off-target inhibition of mammalian cathepsins. This selective drug delivery translates into improved efficacy and tolerability. These findings demonstrate the utility of a purely chemical means to achieve selective drug targeting in vivo. This approach may find useful application in parasitic infections and more broadly in any disease state characterized by aberrant production of reactive ferrous iron.