Activation of AMPK/SIRT1/FOXO3a signaling by BMS-477118 (saxagliptin) mitigates chronic colitis in rats: uncovering new anti-inflammatory and antifibrotic roles.

Ulcerative colitis (UC) is a debilitating chronic disease marked by persistent inflammation and intestinal fibrosis. Despite the availability of various treatments, many patients fail to achieve long-term remission, underscoring a significant unmet therapeutic need. BMS-477118, a reversible inhibitor of dipeptidyl peptidase 4 (DPP4), has demonstrated anti-inflammatory properties in preclinical and clinical studies with minimal adverse effects compared to other antidiabetic agents. However, the potential benefits of BMS-477118 in chronic UC have not yet been explored. In this study, we aimed to investigate the effects of BMS-477118 in rats subjected to chronic dextran sodium sulfate (DSS) administration. Our findings indicate that BMS-477118 activates the interconnected positive feedback loop involving AMPK, SIRT1, and FOXO3a, improving histological appearance in injured rat colons. BMS-477118 also reduced fibrotic changes associated with the chronic nature of the animal model, alleviated macroscopic damage and disease severity, and improved the colon weight-to-length ratio. Additionally, BMS-477118 prevented DSS-induced weight loss and enhanced tight junction proteins. These effects, in conjunction with reduced oxidative stress and its potential anti-inflammatory, antiapoptotic, and autophagy-inducing properties, fostered prolonged survival in rats with chronic UC. To conclude, BMS-477118 has the potential to activate the AMPK/SIRT1/FOXO3a signaling pathway in inflamed colons. These results suggest that the AMPK/SIRT1/FOXO3a pathway could be a new therapeutic target for UC. Further research is mandatory to explore the therapeutic possibilities of this pathway. Additionally, continued studies on the therapeutic potential of BMS-477118 and other DPP4 inhibitors are promising for creating new treatments for various conditions, including UC in diabetic patients.

Vitamin D3 mitigates myopathy and metabolic dysfunction in rats with metabolic syndrome: the potential role of dipeptidyl peptidase-4.

Metabolic syndrome is associated with vitamin D3 deficiency. This work aims to examine the efficacy of vitamin D3 in inhibiting MetS-induced myopathy and to determine whether the beneficial effects of vitamin D3 are mediated by the inhibition of dipeptidyl peptidase-4 (DPP-4). An in silico study investigated the potential effectiveness of vitamin D3 on the inhibition of the DPP-4 enzyme. An in vitro assay of the DPP-4 inhibitory effect of vitamin D3 was performed. In vivo and over 12 weeks, both diet (with 3% salt) and drinking water (with 10% fructose) were utilized to induce MetS. In the seventh week, rats received either vitamin D3, vildagliptin, a combination of both, or vehicles. Serum lipids, adipokines, glycemic indices, and glucagon-like peptide-1 (GLP-1), muscular glucose transporter type-4 (GLUT-4) content, DPP-4, adenosine monophosphate kinase (AMPK) activities, and Sudan Black B-stained lipids were assessed. Muscular reactive oxygen species (ROS), caspase-3, and desmin immunostaining were used to determine myopathy. MetS-induced metabolic dysfunction was ameliorated by vitamin D3, which also reduced intramuscular glycogen and lipid accumulation. This is demonstrated by the attenuation of MetS-induced myopathy by vitamin D3, decreased oxidative stress, increased desmin immuno-expression, and caspase-3 activity. Our in silico data demonstrated that vitamin D3 is capable of inhibiting DPP-4, which is further supported by biochemical findings. Vitamin D3 increased serum GLP-1, muscular AMPK activity, and GLUT-4 content, whereas the levels of muscular ROS were decreased in MetS. Vildagliptin and its combination with vitamin D3 yielded comparable results. It is suggested that the DPP-4 inhibitory potential of vitamin D3 is responsible for the amelioration of MetS-induced metabolic changes and myopathy.

Commentary on "Structural characterization of SLYM - a 4th meningeal membrane".

For centuries, the meninges have been described as three membranes: the inner pia, middle arachnoid and outer dura. It was therefore sensational when in early 2023 Science magazine published a report of a previously unrecognized - 4th - meningeal membrane located between the pia and arachnoid. Multiple features were claimed for this new membrane: a single cell layer marked by the transcription factor Prox1 that formed a barrier to low molecular weight substances and separated the subarachnoid space (SAS) into two fluid-filled compartments, not one as previously described. These features were further claimed to facilitate unidirectional glymphatic cerebrospinal fluid transport. These claims were immediately questioned by several researchers as misinterpretations of the authors' own data. The critics argued that (i) the 4th meningeal membrane as claimed did not exist as a separate structure but was part of the arachnoid, (ii) the "outer SAS" compartment was likely an artifactual subdural space created by the experimental procedures, and (iii) the 4th membrane barrier property was confused with the arachnoid barrier. Subsequent publications in late 2023 indeed showed that Prox1 + cells are embedded within the arachnoid and located immediately inside of and firmly attached to the arachnoid barrier cells by adherens junctions and gap junctions. In a follow-up study, published in this journal, the lead authors of the Science paper Kjeld Møllgård and Maiken Nedergaard reported additional observations they claim support the existence of a 4th meningeal membrane and the compartmentalization of the SAS into two non-communicating spaces. Their minor modification to the original paper was the 4th meningeal membrane was better observable at the ventral side of the brain than at the dorsal side where it was originally reported. The authors also claimed support for the existence of a 4th meningeal membrane in classical literature. Here, we outline multiple concerns over the new data and interpretation and argue against the claim there is prior support in the literature for a 4th meningeal membrane.

Discovery of the selective and nanomolar inhibitor of DPP-4 more potent than sitagliptin by structure-guided rational design.

Various therapeutic targets and approaches are commonly employed in the management of Type 2 Diabetes. These encompass diverse groups of drugs that target different mechanisms involved in glucose regulation. Inhibition of the DPP-4 enzyme has been proven an excellent target for antidiabetic drug design. Our previous work on discovering multitarget antidiabetic drugs led to the identification of a gallic acid-thiazolidinedione hybrid as a potent DPP4 inhibitor (IC50 = 36 nM). In current research, our efforts resulted in a new dihydropyrimidine-based scaffold with enhanced DPP4 inhibition potential. After virtual evaluation, the designed molecules with excellent interaction patterns and binding energy values were synthesized in the wet laboratory. The inhibition potential of synthesized compounds was assessed against the DPP-4 enzyme. Compound 46 with single digit IC50 value 2 nM exhibited 4-fold and 18-fold higher activity than Sitagliptin and our previously reported hybrid respectively. Moreover, compounds 46, 47 and 50 have shown manyfold selectivity against DPP8 and DPP9. Further pretreatment with compounds 43, 45-47 and 50 (at doses of 10 and 20 mg/kg) in OGTT conducted on rats resulted in a significant decrease in the serum glucose levels compared to the control group. In the long-term STZ-induced diabetic rats, tested compound 50 performed similarly to the reference drug. Molecular dynamics simulations and in-silico molecular docking studies were employed to elucidate the time-dependent interactions of inhibitors within the active sites of DPP4. The compounds examined in this work might serve as a possible lead in the development of effective diabetic mellitus treatments.

Sex-specific Cardiovascular Risk Factors and Treatment in Females with T2DM and CVD: Developments and Knowledge Gaps.

PURPOSE: There are large disparities in the impact of diabetes on cardiovascular disease (CVD) risk and outcomes by sex and gender. Achieving health equity requires understanding risks and medication efficacy in female patients, especially now, as novel pharmacologic treatments are transforming the diabetes and CVD treatment landscape. This review examines two bodies of research that can inform sex differences in CVD in patients with diabetes: female-specific risk factors for CVD and sex-related limitations of clinical trial research in evaluating novel diabetes and CVD treatments. METHODS: Two literature searches were performed using Ovid Medline(R) All. The first retrieved manuscripts covering sex and gender differences related to CVD risk and therapies and diabetes. The second focused on randomized controlled trial data on sex/gender differences and GLP-1/SGLT-2/DPP-4 drugs. RESULTS: Female-specific risk factors for CVD include early menarche, premature or early menopause, irregular cycles and polycystic ovary syndrome (PCOS); pregnancy; adverse pregnancy outcomes; history of breast cancer; and autoimmune diseases. Clinical trials of novel pharmacological treatments for diabetes and CVD have undersampled female populations, and clinical characteristics of male and female participants have differed significantly. Thus, evidence to evaluate potential sex differences in treatment efficacy and side effects has been lacking. CONCLUSION: To improve health of female patients with diabetes, sex-specific cardiovascular risk factors should be taken into account in screening and treatment decisions. Further, studies of cardiovascular and diabetes medications must ensure adequate representation by sex and report participant characteristics and outcomes by sex.

Why Do People Choose to Enroll or Not Enroll in the National Diabetes Prevention Program Lifestyle Change Program? A Mixed-Methods Analysis From a Sample of Adults With a Prediabetes Diagnosis.

INTRODUCTION: The Diabetes Prevention Program (DPP) is effective; enrollment is low. Little research has examined factors driving individuals' enrollment decisions. METHODS: In our final survey of a randomized trial comparing methods to increase enrollment in the DPP, we asked participants about factors impacting enrollment. We conducted interviews with a subgroup. RESULTS: Participants who completed the survey (n = 299) were primarily female (96 male); middle-aged (mean 52.9, SD = 14.7); white (86%); non-Hispanic (85%). Only 19% reported awareness of the DPP prior to the study. Cost, online availability, and behavior-change motivation were the most highly rated factors influencing enrollment. The median amount participants were willing to pay for the program was $66.50. Phone interviews included 17 individuals who were/were not interested in receiving a referral to the DPP. Those interested described risk awareness, family history, social support, and healthcare-provider influence as facilitating enrollment. Cost, time, travel, unsupportive family, incomplete knowledge about the program's impact and low self-efficacy were barriers. Among those uninterested, some were already engaging in lifestyle change, and some didn't see a benefit. CONCLUSIONS: Results suggest that, even among high-risk individuals, efforts to increase awareness and benefits of the DPP are needed, as are efforts to address cost of enrollment and low motivation. TRIAL REGISTRATION: ClinicalTrials.gov protocol ID: 00132307. The Effect of 360 Video and MAPS on Enrollment in the DPP. URL: https://www.clinicaltrials.gov/study/NCT04746781?id=00132307&rank=1.

SOX9 promotes hypoxic pulmonary hypertension through stabilization of DPP4 in pulmonary artery smooth muscle cells.

Pulmonary hypertension (PH) is a progressive cardiopulmonary disorder characterized by pulmonary vascular remodeling (PVR), primarily due to the excessive proliferation of pulmonary artery smooth muscle cells (PASMCs). This study aimed to investigate the role and molecular mechanism of SOX9 in hypoxic PH in rats. The findings revealed that SOX9 was upregulated in the pulmonary arteries and PASMCs of hypoxia-exposed rats. SOX9 knockdown inhibited hypoxia-induced proliferation and migration of PASMCs, reduced PVR, and subsequently alleviated hypoxia-induced PH in rats, suggesting that SOX9 plays a critical role in PH. Further investigation demonstrated that SOX9 interacted with DPP4, preventing its ubiquitin degradation in hypoxia-exposed PASMCs. DPP4 knockdown inhibited hypoxia-induced PASMC proliferation and migration, and administration of the DPP4 inhibitor sitagliptin (5 mg/kg) significantly reduced PVR and alleviated hypoxia-induced PH in rats, indicating that SOX9 contributes to PH by stabilizing DPP4. The results also showed that hypoxia induced YAP1 expression and dephosphorylation, leading to YAP1 nuclear localization. YAP1 knockdown promoted the degradation of HIF-1α in hypoxia-exposed PASMCs and inhibited hypoxia-induced proliferation and migration of PASMCs. Additionally, HIF-1α, as a transcription factor, promoted SOX9 expression by binding to the SOX9 promoter in hypoxia-exposed PASMCs. In conclusion, hypoxia promotes the proliferation and migration of PASMCs through the regulation of the YAP1/HIF-1α/SOX9/DPP4 signaling pathway, leading to PH in rats. These findings suggest that SOX9 may serve as a potential prognostic marker and therapeutic target for PH.

Defatted Wheat Germ Protein-Derived Peptides Showed Multiple Biological Activities from the Stomach to Small Intestine: In Silico and In Vitro Approaches.

This study aimed to test the hypothesis that bioactive peptides can exert multiple bioactivities at different sites in the gastrointestinal tract. Our previous research identified 33 gastric-resistant peptides derived from wheat germ with potential antiadhesive activity against Helicobacter pylori in the stomach. In this work, in silico digestion of these peptides with trypsin, thermolysin, and chymotrypsin produced 67 peptide fragments. Molecular docking was conducted to predict their ACE and DPP-IV inhibitory activities in the small intestine. Three peptides (VPIPNPSGDR, VPY, and AR) were selected and synthesized for in vitro validation. Their generation in the gastrointestinal tract was verified via in vitro digestion, followed by mass spectrometry analysis. The IC50 values for ACE inhibition were 199.5 µM (VPIPNPSGDR), 316.3 µM (VPY), and 446.7 µM (AR). For DPP-IV inhibition, their IC50 values were 0.5, 1.6, and 4.0 mM, respectively. This research pioneers new directions in the emerging field of multifunctional peptides, providing scientific evidence to support the utilization of wheat germ as value-added food ingredients.

The effects of dipeptidyl peptidase-4 inhibitors on cardiac structure and function using cardiac magnetic resonance: a meta-analysis of clinical studies.

Objective: The aim of the study was to evaluate the effect of dipeptidyl peptidase-4 inhibitors (DPP4i) on cardiac structure and function by cardiac magnetic resonance (CMR). Research Methods & Procedures: Database including PubMed, Cochrane library, Embase and SinoMed for clinical studies of DPP4i on cardiac structure and function by CMR were searched. Two authors extracted the data and evaluated study quality independently. Mean difference (MD) or standardized MD and 95% confidence intervals (CI) were used for continuous variables. Review Manager 5.3 was used to performed the analysis. Results: Ten references (nine studies) were included in this meta-analysis. Most of the studies were assessed as well quality by the assessment of methodological quality. For clinical control studies, the merged MD values of △LVEF by fixed-effect model and the pooled effect size in favor of DPP4i was 1.55 (95% CI 0.35 to 2.74, P=0.01). Compared with positive control drugs, DPP4i can significantly improve the LVEF (MD=4.69, 95%CI=2.70 to 6.69), but no such change compared to placebo (MD=-0.20, 95%CI=-1.69 to 1.29). For single-arm studies and partial clinical control studies that reported LVEF values before and after DPP4i treatment, random-effect model was used to combine effect size due to a large heterogeneity (Chi2 = 11.26, P=0.02, I2 = 64%), and the pooled effect size in favor of DPP4i was 2.31 (95% CI 0.01 to 4.62, P=0.05). DPP4i significantly increased the Peak filling rate (PFR) without heterogeneity when the effect sizes of two single-arm studies were combined (MD=31.98, 95% CI 13.69 to 50.27, P=0.0006; heterogeneity test: Chi2 = 0.56, P=0.46, I2 = 0%). Conclusions: In summary, a possible benefit of DPP4i in cardiac function (as measured by CMR) was found, both including ventricular systolic function and diastolic function.

Exploring CD26-/lo subpopulations of lymphocytes in asthma phenotype and severity: A novel CD4+ T cell subset expressing archetypical granulocyte proteins.

BACKGROUND: Asthma pathology may induce changes in naïve/memory lymphocyte proportions assessable through the evaluation of surface CD26 (dipeptidyl peptidase 4/DPP4) levels. Our aim was to investigate the association of asthma phenotype/severity with the relative frequency of CD26-/lo, CD26int and CD26hi subsets within different lymphocyte populations. METHODS: The proportion of CD26-/lo, CD26int and CD26hi subsets within CD4+ effector T cells (Teff), total CD4- lymphocytes, γδ-T cells, NK cells and NKT cells was measured in peripheral blood samples from healthy (N = 30) and asthma (N = 119) donors with different phenotypes/severities by flow cytometry. We performed K-means clustering analysis and further characterised the CD4+CD26-/lo Teff cell subset by LC-MS/MS and immunofluorescence. RESULTS: Cluster analysis including clinical and flow cytometry data resulted in four groups, two of them with opposite inflammatory profiles (neutrophilic vs. eosinophilic). Neutrophilic asthma presented reduced CD4-CD26hi cells, which negatively correlated with systemic inflammation. Eosinophilic asthma displayed a general expansion of CD26-/lo subsets. Specifically, CD4+CD26-/lo Teff expansion was confirmed in asthma, especially in atopic patients. Proteomic characterisation of this subset with a TEM/TEMRA phenotype revealed upregulated levels of innate (e.g. MPO and RNASE2) and cytoskeleton/extracellular matrix (e.g. MMP9 and ACTN1) proteins. Immunofluorescence assays confirmed the presence of atypical proteins for CD4+ T cells, and an enrichment in 'flower-like' nuclei and MMP9/RNASE2 levels in CD4+CD26-/lo Teff compared to CD4+ T lymphocytes. CONCLUSION: There is an association between CD26 levels in different lymphocyte subsets and asthma phenotype/severity. CD4+CD26-/loTEMRA cells expressing innate proteins specific to eosinophils/neutrophils could be determinant in sustaining long-term inflammation in adult allergic asthma.

Liraglutide prevents body and fat mass gain in ovariectomized Wistar rats.

Estrogens exert beneficial metabolic effects by reducing food intake and enhancing energy expenditure through both central and peripheral mechanisms. The decrease of estrogen, as occurs in ovariectomy (OVX), leads to metabolic disturbances, such as increased body weight, adipose tissue mass, basal blood glucose, and impaired glucose tolerance. These effects can be reversed by reintroducing estrogen. GLP-1 and its receptor agonists, known for their antihyperglycemic properties, also exhibit anorexigenic effects. Besides that, research indicates that GLP-1 analogs can induce metabolic changes peripherally, such as increased fatty acid oxidation and inhibited lipogenesis. Given the shared metabolic actions of GLP-1 and estrogens, we explored whether liraglutide, a GLP-1 agonist, could mitigate the metabolic effects of estrogen deficiency. We tested this hypothesis using ovariectomized rats, a model that simulates menopausal estrogen deficiency, and treated them with either liraglutide or 17ß-Estradiol benzoate for 21 days. Ovariectomy resulted in elevated DPP-IV activity in both plasma and inguinal white adipose tissue (iWAT). While estrogen replacement effectively countered the DPP-IV increase in both plasma and iWAT, liraglutide only prevented the rise in iWAT DPP-IV activity. Liraglutide prevented body weight and fat mass gain after ovariectomy to the same extent as estradiol treatment. This can be explained by the lower food intake and food efficiency caused by estradiol and liraglutide. However, liraglutide was associated with increased pro-inflammatory cytokines and inflammatory cells in white adipose tissue. Further research is crucial to fully understand the potential benefits and risks of using GLP-1 receptor agonists in the context of menopause.

Purification and Identification of Novel Dipeptidyl Peptidase IV Inhibitory Peptides Derived from Bighead Carp (Hypophthalmichthys nobilis).

Dipeptidyl peptidase IV (DPP-IV) inhibitors are widely used in treating type 2 diabetes due to their ability to lower blood glucose levels. However, synthetic versions often lead to gastrointestinal side effects. This study explores DPP-IV inhibitory properties in peptides from bighead carp skin. Collagen was prepared, hydrolyzed into collagen peptides, and then fractionated for DPP-IV inhibitory activity examination. The most effective fractions were identified, and their peptide sequences were determined. Molecular docking analysis identified nine peptides with potential inhibitory activity, four of which (VYP, FVA, PPGF, PGLVG) were synthesized and tested in vitro. PPGF exhibited the highest potency with an IC50 of 4.63 nM, competitively binding to key DPP-IV sites, including ARG125, VAL711, TYR666, and TYR662. Other peptides showed varying effectiveness, with IC50 values of 398.87 nM (VYP), 402.02 nM (FVA), and 110.20 nM (PGLVG). These findings highlight bighead carp skin peptides as potent DPP-IV inhibitors with hypoglycemic potential, suggesting a novel avenue for diabetes management using natural peptides. Moreover, this research underscores the utilization of bighead carp by-products, contributing to environmental sustainability.

Influence of InVitro Digestion on Dipeptidyl Peptidase-IV (DPP-IV) Inhibitory Activity of Plant-Protein Hydrolysates Obtained from Agro-Industrial By-Products.

This study investigates the production of protein hydrolysates with dipeptidyl peptidase-IV (DPP-IV) inhibitory activity from agro-industrial by-products, namely olive seed, sunflower seed, rapeseed, and lupin meals, as well as from two plant protein isolates such as pea and potato. Furthermore, the effect of simulated gastrointestinal digestion on the DPP-IV inhibitory activity of all the hydrolysates was evaluated. Overall, the lowest values of IC50 (1.02 ± 0.09 - 1.24 ± 0.19 mg protein/mL) were observed for the hydrolysates with a high proportion of short-chain [< 1 kDa] peptides (i.e., olive seed, sunflower seed, and lupin) or high content of proline (i.e., rapeseed). Contrarily, the IC50 of the pea and potato hydrolysates was significantly higher (1.50 ± 0.13 - 1.93 ± 0.13 mg protein/mL). In vitro digestion led to an increase in peptides <1 kDa for almost all hydrolysates (except olive and sunflower seed meals), which was noticeable for rapeseed, pea, and potato hydrolysates. Digestion did not significantly modify the DPP-IV inhibitory activity of olive, sunflower, rapeseed, and potato hydrolysates, whereas a significant decrease in IC50 value was obtained for pea hydrolysate and a significant increase in IC50 was obtained for lupin hydrolysate. Thus, this work shows the potential of agro-industrial by-products for the production of protein hydrolysates exhibiting DPP-IV inhibition.

DPP-IV Inhibitory Peptide against In Vitro Gastrointestinal Digestion Derived from Goat's Milk Protein and Its Activity Enhancement via Amino Acid Substitution.

Goat milk protein can release a variety of bioactive peptides after digestion, while most of them are digested into free amino acids or dipeptides via the GI tract. We investigated the peptide profiles of goat milk protein following in vitro gastrointestinal digestion using LC-MS/MS and identified 683 bioactive peptides, including 105 DPP-IV inhibitory peptides. Among these peptides, ILDKVGINY (IL), derived from ß-lactoglobulin, was found to be high in content and resistance to digestion. Herein, we explore the effect of amino acid residue substitution at the second N-terminus on its DPP-IV inhibitory activity. Three 9 polypeptide fragments (peptide IL, IP, and II) were synthesized and subjected to molecular docking and activity analysis. The peptide IL demonstrated the highest affinity for DPP-IV with a binding energy of -8.4 kcal/mol and a moderate IC50 value of 1.431 mg/mL determined based on the Caco-2 cell model. The replacement of specific amino acid residues by Pro and Leu led to an increase in the hydrophobic force interaction between the inhibitor peptide and DPP-IV. The inhibition rates of the three peptides were significantly different (p < 0.05). Peptide II containing an Ile residue instead of Leu resulted in a significant enhancement of DPP-IV inhibitory activity, with an IC50 value of 0.577 mg/mL. The GRAVY changes in the three peptides were consistent with the trend of the inhibitory rates. Therefore, the GRAVY of peptides and branch-chain amino acids should be considered in its activity improvement. The present study revealed the presence and activity of DPP-IV inhibitory peptides in goat milk, providing important insights for further investigation of their potential food functionality and health benefits.

DPP7 as a Potential Therapeutic Marker for Colorectal Cancer.

Background: Dipeptidyl peptidase 7 (DPP7) is overexpressed in various tumors, but its role in colorectal cancer (CRC) remains unclear. Study the Impact of DPP7 on malignant progression and tumor immunity in CRC. Methods: We utilized Tumor Immune Estimation Resource 2.0 (TIMER2.0) and The Cancer Genome Atlas (TCGA) analyses to assess the expression of DPP7 in tumors and validated it through immunohistochemistry and immunoblotting. Additionally, we investigated the relationship between DPP7 and immune cell infiltration using single-sample Gene Set Enrichment Analysis (ssGSEA) analysis. Finally, the impact of DPP7 on cell proliferation, invasion, migration, and immune cell function in the tumor microenvironment was confirmed through cell experiments and animal studies. Results: DPP7 is highly expressed in CRC, and high expression of DPP7 is associated with poor prognosis. Cell experiments demonstrate that overexpression of DPP7 enhances the proliferation, migration, and invasion capabilities of colorectal cancer cells both in vitro and in vivo. Immune infiltration analysis and co-culture results indicate that overexpression of DPP7 suppresses the immune cell's cytotoxic function against tumors in the tumor microenvironment. Conclusions: DPP7 promotes the malignant potential of colorectal cancer cells and inhibits tumor immune function, thereby promoting the progression of colorectal cancer.

"Emerging clinical approaches in diabetic cardiomyopathy: insights from clinical trials and future directions".

AIM: We aim to explore the potential of diverse treatments, including perhexiline, calcium channel blockers, anti-hypertensives, PDE5 inhibitors, anti-anginal drugs, aldose reductase inhibitors, and SGLT-2 inhibitors, supported by clinical evidence. Additionally, this review seeks to identify novel therapeutic targets and future avenues for improving cardiovascular outcomes in diabetic populations. METHOD: We performed a comprehensive literature review of English-language studies across multiple electronic databases, such as PubMed, ScienceDirect, Scopus, and Google Scholar, focusing on clinical trials. The search utilized keywords including 'Anti-hyperglycaemic drug,' 'Diabetic cardiomyopathy,' 'DPP-4 inhibitors,' 'GLP-1 receptor agonists,' 'Heart failure,' and 'SGLT-2 inhibitors.' RESULT: We assessed clinical investigations in the treatment of cardiomyopathy and diabetes mellitus (DM) that are enhancing our understanding through trials evaluating the Polypill, Perhexiline, Eplerenone, IMB-1018972, AT-001, tadalafil, and dapagliflozin inhibitors. The development of new targeted interventions is of paramount importance due to the overlooked early symptoms, the complexity of the cellular and molecular pathways involved, and the absence of effective drug therapies. CONCLUSION: Pharmacological treatments like GLP-1 agonists, SGLT-2 inhibitors, NHE-1, NHE-3, and PPAR-γ agonists show promise for treating DCM. These treatments improve myocardial glucose absorption, address dysregulated glucose and lipid metabolism, and lower heart failure and cardiovascular events. Further research is needed to confirm effectiveness and safety.

Hypoglycemic peptide preparation from Bacillus subtilis fermented with Pyropia: Identification, molecular docking, and in vivo confirmation.

Hypoglycemic foods have attracted increasing research interest. This study prepared a hypoglycemic product from Bacillus subtilis fermented with Pyropia (PBP), which has promising industrial potential, and elucidated its hypoglycemic mechanism. The aqueous PBP solution was orange, with protein as the main functional component. In vivo experiments demonstrated that PBP could increase insulin secretion and inhibit α-glucosidase activity, resulting in a hypoglycemic effect superior to that of acarbose at the same dose. Molecular docking revealed that the peptides APPVDID, GPPDSPY, PPSSPRP, and SPPPPPA from PBP could inhibit both α-glucosidase and dipeptidyl peptidase-IV (DPP-IV) activities. Pro residues promoted PBP peptide binding to the hydrophobic pocket S1 of DPP-IV. Additionally, PBP reduced inflammation and promoted the growth of beneficial gut bacteria (Prevotellaceae_UCG_003, Lachnospiraceae_UCG_001). This study presents a novel approach for the high-value utilization of Pyropia and a new option for the production of hypoglycemic functional foods and medicines.

Association of sodium-glucose cotransporter 2 inhibitors with risk of incident dementia and all-cause mortality in older patients with type 2 diabetes: A retrospective cohort study using the TriNetX US collaborative networks.

BACKGROUND: Limited evidence exists to support any specific medication over others to prevent dementia in older patients with type 2 diabetes (T2D). We investigated whether treatment with sodium-glucose cotransporter 2 (SGLT-2) inhibitors is associated with a lower risk of incident dementia and all-cause mortality, relative to dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RA). METHODS: In this retrospective, active-comparator cohort study, we used data from the TriNetX electronic health records network. Our primary cohort comprised patients with T2D aged ≥50 years, registered between January 2012 and December 2022. Patients with a history of dementia were excluded. We used Kaplan-Meier survival analysis to estimate the incidence of dementia and all-cause mortality in our cohort after they had used glucose-lowering drugs for at least 12 months. Propensity score matching was performed to balance the SGLT-2 inhibitor, DPP-4 inhibitor and GLP-1 RA cohorts. Subgroup analyses for sex and age were also conducted. RESULTS: Our first cohort comprised 193 948 patients treated with metformin and SGLT-2 inhibitors and an equal number of patients treated with metformin and DPP-4 inhibitors. In this cohort, the risk of dementia and all-cause mortality was lower in patients treated with SGLT-2 inhibitors than in those treated with DPP-4 inhibitors (hazard ratio [HR]: 0.62, 95% confidence interval [CI]: 0.59-0.65, for dementia; HR: 0.54, 95% CI: 0.52-0.56, for all-cause mortality). Our second cohort comprised 165 566 patients treated with metformin and SGLT-2 inhibitors and an equal number of patients treated with metformin and GLP-1 RAs. In this cohort, the risk of dementia and all-cause mortality was lower in those treated with SGLT-2 inhibitors than in those treated with GLP-1 RAs (HR: 0.92, 95% CI: 0.87-0.98, for dementia; HR: 0.88, 95% CI: 0.85-0.91, for all-cause mortality). CONCLUSIONS: The use of SGLT-2 inhibitor was associated with a lower risk of incident dementia and all-cause mortality in older adults with T2D compared to DPP-4 inhibitor and GLP-1 RA.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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-ß, 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. CONCLUSIONS: DPP4 can serve as a biomarker for ferroptosis in the diagnosis and management of UC.

DPP9 regulates NQO1 and ROS to promote resistance to chemotherapy in liver cancer cells.

Chemotherapy has been the standard treatment for liver cancer. However, intrinsic or acquired drug resistance remains a major barrier to successful treatment. At present, the underlying molecular mechanisms of chemoresistance in liver cancer have not been elucidated. Dipeptidyl peptidase 9 (DPP9) is a member of the dipeptidyl peptidase IV family that has been found to be highly expressed in a variety of tumors, including liver cancer. It is unclear whether DPP9 affects chemoresistance in liver cancer. In this study, we find that DPP9 weakens the responses of liver cancer cells to chemotherapy drugs by up-regulating NQO1 and inhibiting intracellular ROS levels. In terms of mechanism, DPP9 inhibits ubiquitin-mediated degradation of NRF2 protein by binding to KEAP1, up-regulates NRF2 protein levels, promotes mRNA transcription of NQO1, and inhibits intracellular ROS levels. In addition, the NQO1 inhibitor dicoumarol can enhance the efficacy of chemotherapy drugs in liver cancer cells. Collectively, our findings suggest that inhibiting DPP9/NQO1 signaling can serve as a potential therapeutic strategy for liver cancer.