Search Results (161)

Background/Objectives: Uncontrolled diabetes and associated comorbidities disproportionately affect African American (AA) adults. Medication adherence is key to diabetes control yet is often suboptimal, particularly among AA adults. This study examined associations between patient characteristics and adherence among AA adults with uncontrolled diabetes and compared two medication adherence instruments for predicting diabetes control. Methods: This cross-sectional analysis used baseline data from the Management of Diabetes in Everyday Life (MODEL) study, a clinical trial to improve diabetes self-care among AA adults with uncontrolled diabetes. Internal consistency of the 12-item Adherence to Medication Refills and Medications Scale for diabetes medications (ARMS-D) was evaluated by comparing its Cronbach α to the standardized Cronbach α calculated from MODEL data. Associations with variables were examined using correlations, t-tests, or ANOVA, as appropriate. Stepwise multiple regression identified predictors of diabetes control assessed by hemoglobin A1c (HbA1c). Results: Among 665 participants (mean age = 54 years, HbA1c = 10.24%; 67% female; 73% high health literacy), 75% reported perfect adherence on the Summary of Diabetes Self-Care Activities Medications Subscale (SDSCA-MS) versus 7.3% on ARMS-D. ARMS-D showed strong internal consistency (α = 0.81). Lower adherence by ARMS-D was associated with younger age, higher social complexity, and depression (all p ≤ 0.001). ARMS-D score, age, depression, and insulin, dipeptidyl peptidase 4 inhibitor, and sodium-glucose co-transporter 2 inhibitor use predicted baseline HbA1c. Conclusions: This study demonstrates that younger age, depression, and high social complexity are associated with lower medication adherence measured using the ARMS-D. Adherence gaps identified by ARMS-D may validly predict diabetes control and help guide interventions to improve diabetes care in AA adults with uncontrolled diabetes. Full article

Background/Objectives: Elastin-derived peptides (EPs) from food sources may be multifunctional dietary components that support metabolic and vascular health. However, their in vivo physiological actions remain incompletely understood. This study investigated the effects of bonito bulbus arteriosus-derived EPs on glucose metabolism, GLP-1 elevation associated with enhanced early-phase insulin secretion, and renal vascular integrity in stroke-prone spontaneously hypertensive rats (SHRSP) with glucose intolerance. Methods: Male SHRSP were administered EPs orally as a single dose (1000 mg/kg) or 4-week regimen (600 mg/kg/day). Glucose tolerance, plasma GLP-1 and insulin levels, and blood glucose levels were measured following glucose loading. Renal morphology was assessed histologically. Dpp4, Icam-1, and Agtr1 expression was quantified in glomerular and leukocyte fractions. Leukocyte oxidative signaling was evaluated by quantifying reactive oxygen species production associated with inducible nitric oxide synthase (iNOS). Age-matched Wistar–Kyoto rats were included as normotensive controls. Results: A single dose increased plasma GLP-1 and insulin levels and improved glucose tolerance compared with controls. The 4-week regimen resulted in sustained improvements in glucose tolerance, without changes in blood pressure, a lower nephrosclerosis incidence, and reduced renal and leukocytic inflammatory marker expression. Dpp4, Icam-1, and Agtr1 expression was downregulated, and leukocyte iNOS-driven oxidative signaling was reduced. These effects occurred despite the modest DPP4 inhibitory activity of EPs. Conclusions: Food-derived EPs may exert multi-target physiological actions, including GLP-1 elevation with enhanced early-phase insulin secretion and leukocyte oxidative and inflammatory response suppression, which potentially improve metabolic and renal vascular outcomes. EPs warrant further exploratory investigation as candidate functional food ingredients for metabolic and vascular health. Full article

Pulmonary arterial hypertension (PAH) is a chronic and progressive cardiopulmonary vascular disorder associated with poor clinical prognosis. Its hallmark pathological feature is sustained elevation of pulmonary vascular resistance resulting from extensive vascular remodeling. Endothelial-to-mesenchymal transition (EndMT), a critical event driving vascular remodeling, is increasingly recognized as central to PAH development and progression. This review systematically outlines the convergence of multiple pathophysiological insults on endothelial dysfunction and intimal remodeling in PAH, highlighting their roles in initiating EndMT. Principal factors include: (1) genetic and molecular alterations, such as BMPR2 mutations and epigenetic dysregulation; (2) environmental and toxic exposures, including chronic hypoxia and anorexigens; (3) inflammatory and immune dysregulation, exemplified by chronic inflammatory infiltrates and autoimmune conditions; and (4) hemodynamic and metabolic disturbances, notably aberrant shear stress and lipid metabolic imbalance. Given the critical contribution of EndMT to PAH pathogenesis, therapeutic strategies aimed at reversing EndMT represent promising anti-remodeling interventions. Preclinical studies have begun exploring EndMT-targeted therapies, including mesenchymal stem cell (MSC) transplantation and dipeptidyl peptidase-4 (DPP-4) inhibitors. Herein, we summarize recent advances regarding EndMT in PAH, dissect the molecular drivers and modulators initiating and sustaining EndMT, and critically evaluate emerging therapeutic strategies harnessing this pathway for clinical benefit. Full article

Background: Acute graft-versus-host disease (aGVHD) is a leading cause of morbidity and mortality following pediatric hematopoietic stem cell transplantation (HSCT). Approximately half of children achieve complete response (CR) to corticosteroids, whereas steroid-refractory (SR) disease carries a 1–2-year mortality of 41–44%. Mortality risk is 2.6-fold higher in children > 13.9 years, and respiratory failure accounts for 26% of deaths. Existing second-line agents—ruxolitinib, tocilizumab, or extracorporeal photopheresis—have delayed onset or high toxicity. Begelomab (BEGESAND^®), a monoclonal antibody targeting CD26/dipeptidyl peptidase-4 (DPP4), inhibits CD26-mediated T-cell activation and has demonstrated 75% response in adults with minimal toxicity. However, pediatric data are lacking. Methods: We retrospectively reviewed five consecutive pediatric patients (ages 3–20 years) treated with Begelomab (BEGESAND^®) for SR (n = 4) or steroid-dependent (SD; n = 1) aGVHD between 2017–2021 under emergency IND authorization. Begelomab (BEGESAND^®) was administered intravenously at 2.7 mg/m²/day on days 1–5, 10, 14, 17, 21, 24, and 28. GVHD was graded by MAGIC criteria; flow cytometry and immunohistochemistry (IHC) assessed CD26 expression and immune effects. Results: All patients had grade IV disease after ≥2 prior agents. Two with pre-existing sepsis died early, before treatment response could be assessed. Of three evaluable patients, two (67%) achieved CR within 21 days and one achieved durable control by 6 months. All three remain alive; no Begelomab (BEGESAND^®)-related toxicity, cytopenia, or new infections occurred. Flow cytometry showed preserved T-cell subsets, and IHC demonstrated CD26 localization at sites of epithelial injury. Conclusions: Begelomab (BEGESAND^®) showed promising timely and durable responses with excellent safety in pediatric SR/SD-aGVHD, supporting further evaluation in multicenter pediatric trials. Full article

Background/Objectives: Type 1 diabetes mellitus (T1DM) is a chronic autoimmune condition often managed exclusively with insulin. However, the search for adjuvant therapies has gained attention, including dipeptidyl peptidase-4 inhibitors (DPP4i) and sodium-glucose cotransporter 2 inhibitors (SGLT2i), despite limited evidence in pediatric populations. To evaluate the impact of DPP4i, alone or combined with SGLT2i, on glycemic control (HbA1c), lipid profile (ApoB and ApoA-I), and renal function (eGFR and albuminuria) in children, adolescents, and young adults with T1DM, this study was conducted. Methods: This cohort study analyzed data from 76 patients with T1DM aged under 25, followed for 4 to 20 months. Patients were grouped based on exposure to DPP4i alone, DPP4i + SGLT2i, or no additional therapy. Glycemic, lipid, and renal parameters were assessed at baseline and follow-up. Results: A significant reduction in HbA1c was observed in the overall sample (p < 0.001), regardless of treatment group, suggesting a positive effect of interdisciplinary care. There were no statistically significant differences in HbA1c variation among the groups. ApoB decreased significantly over time (p < 0.001), and ApoA-I levels were initially higher in the DPP4i + SGLT2i group. A significant reduction in albuminuria was identified in the DPP4i-only group compared to controls (p = 0.029), indicating a potential renoprotective effect. No significant changes in eGFR were observed. The use of DPP4i, with or without SGLT2i, was not associated with significant improvements in glycemic or lipid outcomes compared to standard therapy. However, DPP4i monotherapy was associated with a reduction in albuminuria, suggesting a possible benefit for renal protection. Conclusions: These findings highlight the need for larger, randomized studies to confirm the therapeutic role of these agents in young individuals with T1DM. Full article

Background: Metabolic syndrome is characterized by dysregulated glucose metabolism and is a major risk factor for type 2 diabetes mellitus and cardiovascular disease. Although glucose-lowering therapies such as glucagon-like peptide-1 receptor (GLP-1R) agonists are effective, their use may be limited by cost, administration route, side effects and tolerability. Bergamot (Citrus bergamia Risso et Poiteau) extract, rich in flavanones, has shown favorable metabolic effects in clinical studies, although its mechanisms of action remain insufficiently defined. This study aimed to investigate the potential glucose-modulating mechanisms of a standardized phospholipid-formulated bergamot extract (BP) (Vazguard™) in vitro. Methods: GLP-1R activation was assessed in a U2OS cell line expressing cyclic adenosine monophosphate (cAMP)-sensitive Nomad Biosensors™. Dipeptidyl peptidase-4 (DPP4) activity was evaluated using a cell-free enzymatic assay, while Glucose transporter type 4 (GLUT4)-mediated glucose uptake was assessed in CHO-K1 cells stably expressing human GLUT4 using an adenosine triphosphate (ATP)-based readout. Cytotoxicity was also using lactate dehydrogenase (LDH), MTT, and nuclei count assays. Results: BP exhibited a dose-dependent (0.31–5 mg/mL) increase in cAMP biosensor fluorescence, consistent with GLP-1R-associated signaling and a maximal response of approximately 60% relative to the positive control (GLP-1R agonist II). No cytotoxic effects were observed. In contrast, BP showed no inhibitory effect on DPP4 activity and did not alter GLUT4-mediated glucose uptake under the experimental conditions tested. Conclusions: These findings provide novel mechanistic evidence that phospholipid-formulated bergamot extract suggests a possible involvement in GLP-1R-associated signaling in vitro, without detectable effects on DPP4 or GLUT4 pathways under the conditions tested. This suggests a mechanism consistent with weak agonist or allosteric modulation of GLP-1R and supports further investigation of bergamot formulated with phospholipids as potential natural adjuncts in metabolic health management. Full article

Female malignancies, including breast, cervical, ovarian, and endometrial cancers, remain a significant health challenge. Meanwhile, treatment options for advanced-stage remain limited. Drug repurposing has emerged as a promising approach to accelerate the development of effective cancer therapies using existing medications. Growing evidence indicates that metabolic disorders such as type 2 diabetes mellitus are linked with an elevated risk of tumors, highlighting antidiabetic drugs as potential anticancer agents. Among these, inhibitors of dipeptidyl peptidase 4 (DPP4) have attracted attention as potential therapeutic candidates, due to their diverse biological functions in glucose metabolism, inflammation, immune regulation, and tumor biology. This review summarizes current epidemiological, preclinical, and clinical evidence regarding the role of DPP4 in female cancers and the therapeutic potential of DPP4 inhibitors. Studies demonstrate that DPP4 influences key oncogenic processes, including proliferation, invasion, metastasis, immune modulation, and metabolic reprogramming. However, available data on DPP4 inhibition and its influence in cancer therapy are controversial and scarce. Further mechanistic studies and well-designed clinical investigations are required to clarify their safety and clinical applicability in the management of female malignancies. Full article

Dipeptidyl peptidase 4 (DPP4) plays a pivotal role in the treatment of type 2 diabetes as an important glucose-regulating enzyme. We evaluated the molecular interactions between 13 major aromatic compounds from Cinnamomi ramulus and DPP4 enzyme through molecular docking simulation and molecular dynamics. The results showed that the studied compounds exhibited a wide range of docking energies with DPP4, in which benzyl benzoate was the most promising compound with a docking energy of −7.4 kcal/mol, which was comparable with that of saxagliptin and alogliptin. Detailed analysis revealed that hydrophobic interactions (three–eight interactions/complex) and hydrogen bonds (three–five bonds in some complexes) played major roles in stabilizing the complexes. Molecular dynamics simulation results demonstrated ligand selectivity for the DPP4 receptor, with only four out of 13 tested compounds stabilizing at the interaction site. Evaluation results of the method using Lipinski’s rule showed that all compounds met four–five criteria for drug-likeness, indicating potential for drug development. These results provide the first scientific evidence of the potential molecular mechanism of cinnamon bark in the treatment of type 2 diabetes through DPP4 inhibition. Full article

Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder requiring safe, multitarget therapeutic strategies. Marine macroalgae represent an underexplored source of bioactives with pleiotropic metabolic effects. This study investigated the antidiabetic potential of an ultrasound-assisted ethanolic extract of Caulerpa racemosa (UAECr) and its key phytosterol, campesterol, through an integrative framework combining metabolomics, network pharmacology, molecular docking, molecular dynamics simulation, and in vitro validation. Untargeted ultra-high-performance liquid chromatography–high-resolution mass spectrometry (UHPLC–HRMS) metabolomics characterized UAECr constituents, followed by in silico bioactivity prediction, target-network analysis, molecular docking, and 100 ns molecular dynamics simulation of the peroxisome proliferator-activated receptor gamma (PPARγ)–campesterol complex. Functional validation was performed in differentiated 3T3-L1 adipocytes assessing glucose uptake, PPARγ expression, dipeptidyl peptidase 4 (DPP-4) inhibition, and cytotoxicity. Metabolomics identified campesterol as a prominent bioactive. Network pharmacology highlighted PPARγ as a central hub, supported by strong docking affinity of campesterol toward PPARγ (−11.4 kcal/mol) and DPP-4 (−8.3 kcal/mol). Molecular dynamics simulations demonstrated stable PPARγ–campesterol interactions, with preserved protein compactness and low residue fluctuation. In vitro, UAECr and campesterol significantly enhanced glucose uptake (up to 134% vs. control, p < 0.001), upregulated PPARγ expression (4-fold, p < 0.0001), and moderately inhibited DPP-4 activity (p < 0.01) without cytotoxicity. C. racemosa-derived extracts and campesterol exert antidiabetic effects primarily via stable PPARγ-mediated insulin sensitization with complementary DPP-4 modulation, supporting its potential as a marine-derived functional food candidate. Full article

Glaucoma is a neurodegenerative disease characterized by progressive degeneration of optic nerve axons and loss of retinal ganglion cells (RGCs). Although elevated intraocular pressure (IOP) is a major risk factor, many patients develop glaucoma with normal IOP, highlighting the need for neuroprotective therapies. Sitagliptin, a dipeptidyl peptidase-4 inhibitor, has shown beneficial effects in diabetes-induced retinal neurodegeneration. This study aimed to evaluate whether sitagliptin eye drops, previously effective in diabetes-induced retinal neurodegeneration, could prevent corticosteroid-induced glaucoma. Glaucoma was induced in mice by periocular injection of dexamethasone (DEX) once weekly for five weeks. Sitagliptin or vehicle eye drops were administered from day 14 to 35. Untreated mice served as controls. DEX treatment caused significant loss of RGC bodies and optic nerve axons compared to controls, which was prevented by sitagliptin eye drops (p < 0.001), without affecting IOP. Sitagliptin also inhibited DEX-induced activation of macroglia and microglia and prevented oligodendrocyte loss. Furthermore, it suppressed overexpression of galectin-3 and gamma-synuclein in the optic nerve head (ONH) (p < 0.001), key mediators of inflammation and apoptosis. Sitagliptin eye drops exert a potent neuroprotective effect against corticosteroid-induced glaucoma, supporting their potential as a novel therapeutic strategy for glaucoma. Full article

Background/Objectives: Bullous pemphigoid (BP) is an autoimmune blistering skin disease. The association between dipeptidyl peptidase 4 inhibitors (DPP-4 inhibitors) and bullous pemphigoid (BP) has been studied in many countries; however, controversy has arisen from analyzing the related risk factors. The objectives of this study are to assess whether the association between DPP-4 inhibitors and bullous pemphigoid in EudraVigilance is statistically significant and to identify the presence of risk factors found in previous studies in a case/exposure group. Our results will be compared with those obtained from the Food and Drug Administration Adverse Event Reporting System database (FAERS). Methods: A case/control retrospective observational study was performed using data from the European database EudraVigilance. All reports from 2007 to 2024 (a total of 11,451,738 reports) were gathered and filtered by exposure to DPP-4 inhibitors and development of BP or lack thereof. Association was measured using reporting odds ratios with a 95% confidence interval, and Fisher’s exact test was used to obtain p-values, assuming an alpha error of 0.05. Results: The results indicate an association between the consumption of DPP-4 inhibitors and the development of BP (with an odds ratio of 153.5; 95% confidence interval 144.1–163.5; ROR = (a/c)/(b/d); a: 1345 reports of BP associated with DPP-4i; c: 3870 reports of BP associated with other different drugs; b: 25,857 reports of other ADRs and DPP-4i; and d: 11,420,666 reports of ADRs associated with other drugs). The predominant factors in the case/exposure group were male gender (58.6%), age between 65 and 85 years (43.3%), medical history of type 2 diabetes mellitus (30.4%) and consumption of vildagliptin (44.2%). Similar results were found in a prior analysis of the FAERS database (2006–2020). Conclusions: This study provides evidence of the association between the consumption of gliptins and the development of BP. Disproportionality measures were estimated to be higher in the exposure group than in the positive controls. As such, BP could appear after several months of exposure, and dermatological monitoring is crucial. Full article

SARS-CoV and MERS-CoV are two coronaviruses that have received significant attention due to their high pathogenicity and mortality rates in human populations. In this study, we compared their evolutionary dynamics to provide a One Health perspective on their differences in terms of the results of disease control. The phylogenetic network of SARS-CoVs showed that human isolates gathered into a “super-spreader” cluster and were distinct from civet isolates. In contrast, dromedary camel- and human-isolated MERS-CoVs were clustered together. Thus, most clades of MERS-CoV can infect humans, and MERS-CoVs seem to more easily spill over the animal-to-human interface. Additionally, the civet can be easily controlled, while the intermediate host (dromedary camels) of MERS-CoV is an important livestock species, so it is impossible to eliminate all animals. This further leads to difficulties in disease control in MERS. Although MERS-CoVs are endemic to dromedary camels in both the Middle East and Africa, human infections are mainly linked to the Middle East. The nucleotide sequences of the MERS-CoV receptor gen (dipeptidyl peptidase 4 (DPP4)) from 30 Egyptians, 36 Sudanese, and 34 Saudi Arabians showed little difference. These findings suggest that the observed disparities in MERS prevalence between populations in the Middle East and Africa may be more strongly attributed to inadequate disease surveillance and the limited camel-to-human transmission of clade C MERS-CoV in Africa, rather than variations in DPP4 gene. Full article

Background: There is growing evidence suggesting that SARS-CoV-2 may contribute to metabolic dysfunction. SARS-CoV-2 infection is associated with systemic inflammation, oxidative stress, and metabolic dysregulation, all of which may impair liver function and promote glucose intolerance. This study investigated the role of SARS-CoV-2, specifically its Main Protease (M^pro), in accelerating insulin resistance and metabolic dysfunction in HepG2 cells in vitro. Methods: HepG2 cells were treated with varying concentrations of M^pro (2.5, 5, 10, 20, 40, 80, and 160 nmol/mL) for 24 h to assess cytotoxicity and glucose uptake. Based on initial findings, subsequent assays focused on higher concentrations (40, 80, and 160 nmol/mL). The effects of M^pro on cell viability, protein kinase B (AKT) expression, matrix metallopeptidase-1 (MMP1), dipeptidyl peptidase 4 (DPP4), interleukin-6 (IL-6) expression, and lipid peroxidation were investigated. Results: Our findings reveal that the SARS-CoV-2 M^pro treatment led to a concentration-dependent reduction in glucose uptake in HepG2 cells. Additionally, the M^pro treatment was associated with reduced insulin-stimulated AKT activation, particularly at higher concentrations. Inflammatory markers such as IL-6 were elevated in the extracellular medium, while DPP4 expression was decreased. However, extracellular soluble DPP4 (sDPP4) levels did not show a significant change. Despite these changes, cell viability remained relatively unaffected, suggesting that the HepG2 cells were able to maintain overall metabolic functions under M^pro exposure. Conclusions: This study demonstrated the concentration-dependent impairment of hepatic glucose metabolism, insulin signaling, and inflammatory pathways in HepG2 cells acutely exposed to the SARS-CoV-2 M^pro. These findings warrant further investigation to explore the long-term metabolic effects of SARS-CoV-2 and its proteases in the liver and to develop potential therapeutic approaches for post-viral metabolic complications. Full article

Diabetic foot ulcers (DFUs), which affect approximately 15% of individuals with diabetes mellitus (DM), result from complex molecular disturbances involving chronic hyperglycemia, immune dysfunction, and infection. At the molecular level, chronic hyperglycemia promotes the formation of advanced glycation end products (AGEs), activates the AGE-RAGE-NF-κB axis, increases oxidative stress, and impairs macrophage polarization from the pro-inflammatory M1 to the reparative M2 phenotype, collectively disrupting normal wound healing processes. The local wound environment is further worsened by antibiotic-resistant polymicrobial infections, which sustain inflammatory signaling and promote extracellular matrix degradation. The rising threat of antimicrobial resistance complicates infection management even further. Recent studies emphasize that optimal glycemic control using antihyperglycemic agents such as metformin, Glucagon-like Peptide 1 receptor agonists (GLP-1 receptor agonists), and Dipeptidyl Peptidase 4 enzyme inhibitors (DPP-4 inhibitors) improves overall metabolic balance. These agents also influence angiogenesis, inflammation, and tissue regeneration through pathways including AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), and vascular endothelial growth factor (VEGF) signaling. Evidence indicates that maintaining glycemic stability through continuous glucose monitoring (CGM) and adherence to antihyperglycemic treatment enhances antibiotic effectiveness by improving immune cell function and reducing bacterial virulence. This review consolidates current molecular evidence on the combined effects of glycemic and antibiotic therapies in DFUs. It advocates for an integrated approach that addresses both metabolic and microbial factors to restore wound homeostasis and minimize the risk of severe outcomes such as amputation. Full article

Background: The New Zealand pine bark has been demonstrated in vitro to inhibit digestive enzymes involved in carbohydrate digestion (alpha-amylase, alpha-glucosidase, and dipeptidyl-peptidase 4 (DPP-4)). Objective: This study aims to investigate the inhibitory effects of the New Zealand pine bark on sucrose uptake and glycaemic responses in humans. Methods: A single-blind, randomised, placebo-controlled, crossover trial was carried out involving healthy adults (n = 40 (M: 12, F: 28), 30.1 ± 1.3 years, BMI 23.4 ± 0.5 kg/m², HbA1c 32.5 ± 0.6 mmol/mol, FBG 4.7 ± 0.1 mmol/L). A control (75 g of sucrose powder only), and two doses of the pine bark extract (50 and 400 mg) were provided on separate occasions, with 75 g of sucrose mixed in 250 mL of water. Blood samples were collected at −10, 0, 15, 30, 45, 60, 90, and 120 min via a finger prick test. A linear mixed model for repeated measures (SPSS v30, IBM) was applied, and data presented as model-adjusted mean ± SEM. Results: Compared to control (247.5 ± 14.0 mmol/L⋅min), the iAUCglucose was significantly reduced with the 400 mg dose (211.8 ± 13.9 mmol/L⋅min, 14.4% reduction, and p = 0.037), but not with 50 mg dose (220.8 ± 14.2 mmol/L⋅min, 10.8% reduction, and p = 0.184). Compared to control (9.1 ± 0.2 mmol/L), glucose peak value was significantly reduced with the 50 mg dose (8.6 ± 0.2 mmol/L, 5.5% reduction, and p = 0.016) but not with the 400 mg dose (8.7 ± 0.2 mmol/L, 4.4% reduction, and p = 0.093). There were no statistically significant changes in postprandial insulin levels with the pine bark extract compared to control. Conclusions: The New Zealand pine bark extract attenuated sucrose uptake with improved glycaemic responses, and may therefore be useful as a hypoglycaemic adjunct to the diet. Full article