Search Results (438)

Flavones are natural substances widely distributed in fruits and vegetable. Their compounds are characterized by a broad spectrum of activities, including antioxidant activity. Their most interesting biological effect, however, is antihyperglycemic activity, mediated by the inhibition of α-glucosidase. A series of 7-hydroxyflavone derivatives was synthesized and comprehensively characterized using nuclear resonance magnetic spectroscopy. The biological potential of the synthesized derivatives was assessed through antioxidant (DPPH) and α-glucosidase inhibitory assays. The physicochemical and pharmacokinetic properties were analyzed using in silico methods. Finally, molecular docking studies were performed to elucidate the binding mode of compounds within the catalytic site of α-glucosidase. Full article

(1) Background: Impaired diabetic wound healing stems from systemic dysregulation of the wound-healing cascade under hyperglycemic conditions, producing a disordered microenvironment marked by sustained inflammation, defective angiogenesis, and aberrant extracellular matrix remodeling, multifactorial, multistage pathological interactions demanding multi-target intervention. (2) Methods: We constructed a multifunctional nanocomposite hydrogel dressing (PGAs@CDV) based on a “drug-carrier integration” strategy, targeting the dysregulated hemostasis, inflammation, and proliferation phases of diabetic wound healing. An amphiphilic micelle carrier (PNO-GA) was synthesized by covalently conjugating Panax notoginseng oligosaccharide with gallic acid, loaded with Anemoside B4 to yield drug-loaded nanomicelles (PGAs), embedded into a carboxymethyl chitosan-dopamine-vanillin hydrogel (CDV) matrix to form PGAs@CDV. We then examined how PGAs@CDV affected diabetic wound healing. (3) Results: In vitro, PGAs@CDV enhanced cell migration and angiogenic capacity, exhibited potent antioxidant activity, and promoted M1-to-M2 macrophage polarization. We tested PGAs@CDV in a streptozotocin-induced diabetic mouse wound model. Wounds treated with PGAs@CDV closed faster than those treated with the control, CDV, PNO@CDV, and AB4@CDV. Four readouts tracked this difference: hemostasis was quicker, inflammation was lower, more blood vessels formed, and collagen deposition was higher. At the pathway level, PGAs@CDV suppressed NF-κB signaling and activated PI3K/AKT/HIF-1α. These two arms map onto the anti-inflammatory and pro-angiogenic effects observed above. (4) Conclusions: This nanocomposite hydrogel integrates a bioactive carrier with a therapeutic payload to enable coordinated intervention across multiple phases of diabetic wound repair. By combining structural support with sustained pharmacological activity, it offers a promising strategy for the treatment of chronic diabetic wounds. Full article

Background/Objectives: Chronic hyperglycemia drives gingival fibroblast dysfunction, disrupting extracellular matrix homeostasis and the migratory capacity required for wound healing, which contributes to increased periodontal susceptibility in diabetes. Ferulic acid (FA), a dietary phenolic compound with antioxidant and anti-inflammatory properties, has demonstrated wound-healing activity in various tissues; however, its effects on human gingival fibroblasts (HGFs) under hyperglycemic conditions remain unclear. This study investigated the effects of FA on HGF viability, wound closure, and the secreted concentrations of matrix metalloproteinase-1 (MMP-1), tissue inhibitor of metalloproteinase-1 (TIMP-1), and interleukin-6 (IL-6) under normoglycemic and hyperglycemic conditions. Methods: Cultured HGFs (HGF-1 cell line) were pre-conditioned for 72 h under normal glucose (5.5 mM) or high glucose (25 mM), with an iso-osmolar mannitol control to distinguish glucose-specific effects from osmotic changes. Viability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and wound closure by scratch assay following FA treatment, while MMP-1, TIMP-1, and IL-6 concentrations in conditioned medium were quantified by enzyme-linked immunosorbent assay (ELISA). Results: FA was non-cytotoxic at all tested concentrations, whereas 50 µM transiently increased viability. FA significantly enhanced wound closure under both conditions, independent of osmotic effects. High glucose increased IL-6 concentration in the conditioned medium (significant at 48 h) and MMP-1 levels. FA partially attenuated MMP-1 levels at specific time points, modestly reduced IL-6 levels, and markedly increased TIMP-1 concentration under both glucose conditions. Conclusions: FA enhanced wound closure in scratch assay and shifted the secreted MMP-1/TIMP-1 concentration ratio toward a more favorable, matrix-protective profile at the protein level, without cytotoxicity, supporting further investigation of its potential role in periodontal tissue repair under high glucose conditions. Full article

Background/Objectives: Women-specific short-term body mass index and metabolic changes after Roux-en-Y gastric bypass remain incompletely characterized. This retrospective cohort study evaluated 12-month changes in body mass index, glycemic markers, and lipid profile after Roux-en-Y gastric bypass in women with severe obesity treated at a public bariatric reference center in Brazil. Methods: Women who underwent Roux-en-Y gastric bypass between September 2017 and January 2020 were assessed preoperatively and at 30 days, 3 months, 6 months, and 12 months postoperatively. Longitudinal changes were analyzed using linear mixed-effects models. Results: Of 168 women who underwent bariatric surgery, 150 had complete 12-month follow-up data. Mean age was 43.6 ± 9.8 years and mean preoperative body mass index was 45.4 ± 5.4 kg/m². Body mass index decreased progressively from 45.5 kg/m² at baseline to 31.5 kg/m² at 12 months. Fasting plasma glucose and HbA1c declined significantly within the first postoperative month and remained improved. Total cholesterol decreased at 30 days, whereas low-density lipoprotein (LDL) cholesterol and triglycerides decreased by 6 months. Among baseline users, 86% discontinued antihyperglycemic therapy, 87% lipid-lowering therapy, and 72% antihypertensive therapy; these exploratory medication-discontinuation outcomes should not be interpreted as validated remission of diabetes, dyslipidemia, or hypertension. Conclusions: Roux-en-Y gastric bypass was associated with substantial short-term body mass index reduction and improved cardiometabolic markers among women. Full article

Colorectal cancer (CRC) remains a leading cause of cancer morbidity worldwide, highlighting the need for improved therapies. Metformin, a widely used antihyperglycemic agent, has gained attention for its potential antitumor properties. In this study, we evaluated the effects of the tumor suppressor genes TP53 and CDKN1A on metformin responsiveness in a KRAS-mutant CRC in vitro model using HCT116 cells harboring a G13D mutation in KRAS. Using parental (p53^+/+, p21^+/+) and isogenic knockout cell lines, we assessed cell-cycle distribution and transcriptomic responses following metformin treatment. In parental wild-type cells, metformin exposure was associated with a dose- and time-dependent reduction in cell viability and an increased proportion of cells in the G0/G1 phase, with significance levels across treatment conditions ranging from p = 0.03 to p < 0.0001. Loss of p53 or p21 was associated with attenuated cellular responses to metformin, with p21-deficient cells responding primarily at higher doses and prolonged exposure (72 h). Transcriptomic profiling revealed extensive differential gene expression in parental cells (1399 DEGs), compared with more limited responses in p53^−/− (270 DEGs) and p21^−/− cells (32 DEGs). Differentially expressed genes associated with MAPK signaling (DUSP5) and inflammatory regulation (TNFAIP3) were observed across genotypes, whereas pathway enrichment of DNA replication and chromatin organization was specific to p53-deficient cells. These findings provide a transcriptomic and phenotypic characterization of genotype-dependent cellular responses to metformin and establish a basis for future mechanistic and functional validation studies. Full article

Background: Glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide-1 receptor (GLP-1R) activation exert anti-diabetic and anti-obesity effects. Tirzepatide, a dual GIPR/GLP-1R agonist, has demonstrated cardiovascular benefits in clinical studies. However, the direct vascular actions of tirzepatide and their potential advantages over selective GLP-1 receptor agonists (GLP-1RAs) remain unclear. We investigated the vasoprotective effects of tirzepatide and compared them with those of GLP-1 receptor agonists in vivo and in vitro. Methods: Non-diabetic C57BL/6 and diabetic KK-Ay mice received tirzepatide, semaglutide, or vehicle. Arterial remodeling was induced by femoral artery wire injury. A subset of mice was co-treated with the nitric oxide synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME). After 4 weeks, biochemical, morphometric, and immunofluorescence analyses were performed. In vitro, human umbilical vein endothelial cells (HUVECs) were stimulated with tirzepatide or liraglutide to assess nitric oxide (NO) production. Results: In non-diabetic mice, tirzepatide suppressed intimal hyperplasia, including at a low dose that did not affect metabolic parameters, whereas semaglutide had no significant effect on intimal hyperplasia at the same molar dose. The protective effects of tirzepatide were abolished by L-NAME. In diabetic mice, tirzepatide and semaglutide similarly improved metabolic parameters and attenuated intimal hyperplasia. In HUVECs, tirzepatide increased NO production in a dose-dependent manner, and this effect was preserved under hyperglycemic conditions. Tirzepatide and liraglutide induced comparable NO production at equivalent molar concentrations. Conclusions: Tirzepatide, but not semaglutide, exerted vasoprotective effects under non-diabetic conditions in a NO-dependent manner, whereas both agents exhibited comparable vasoprotective effects under diabetic conditions. Full article

Papillary thyroid cancer (PTC) exhibits Warburg-type metabolic reprogramming with enhanced glycolysis and dependence on glucose-driven pathways. This study evaluated the effects of antihyperglycemic interventions on cytokine secretion, angiogenic signaling, metabolic activity, and proliferation in thyroid-derived cell models. Two PTC cell lines (MDA-T32 and SCC147) and a normal thyroid line (Nthy-ori) were analyzed for intracellular and extracellular cytokines, secretion efficiency (index), relative metabolic index (RMI), and marker of proliferation (Ki-67) expression following exposure to vandetanib (VDT), sodium–glucose cotransporter 2 (SGLT2), or dipeptidyl peptidase (DPP) inhibitors. Baseline analysis revealed distinct cell line-specific profiles. Compared with Nthy-ori cells, MDA-T32 cells exhibited increased vascular endothelial growth factor (VEGF) concentrations in lysates and conditioned medium (p < 0.001, q < 0.001) with enhanced VEGF secretion efficiency (p = 0.002, q = 0.008), elevated intracellular fibroblast growth factor (FGF) (p < 0.001, q < 0.001) with reduced FGF secretion index (p = 0.004, q = 0.01), and lower interleukin 8 (IL-8) concentrations accompanied by increased IL-8 secretion efficiency (p = 0.006, q = 0.02). In contrast, SCC147 cells demonstrated reduced VEGF secretion (p < 0.001, q < 0.001), decreased intracellular IL-8 (p = 0.008, q = 0.02), reduced chemokines of the growth-regulated oncogene GROβ family (GROβ) secretion (p = 0.01, q = 0.04), increased IL-8 secretion efficiency (p = 0.01, q = 0.03), and decreased GROβ secretion efficiency (p = 0.008, q = 0.02). Nthy-ori cells displayed a balanced profile. Among the investigated interventions, VDT produced the most pronounced effects. In MDA-T32 cells, VDT significantly reduced VEGF levels (p < 0.001, q < 0.001) and increased IL-8 and GROβ concentrations in conditioned medium (q < 0.05), whereas no significant effects after FDR correction were observed in SCC147 or Nthy-ori cells. SGLT2 and DPP inhibitors produced only nominal effects (p < 0.05), which did not remain significant after correction for multiple testing. VDT reduced RMI by approximately 50% in MDA-T32 cells while Ki-67 expression increased, whereas SCC147 cells remained largely unchanged. In Nthy-ori cells, SGLT2 inhibition increased RMI and decreased Ki-67 expression. These findings demonstrate marked heterogeneity among PTC cell lines and suggest that alterations in metabolic activity were not consistently accompanied by proportional changes in proliferative status under the experimental conditions used. VDT predominantly affected angiogenic and inflammatory signaling in MDA-T32 cells, whereas SGLT2 and DPP inhibition exerted limited measurable effects at clinically achievable concentrations. Full article

Objective: Diabetes mellitus (DM) is a major metabolic disorder associated with hyper-glycemia and oxidative stress. Traditional medicinal plants remain important sources of bioactive compounds with potential antidiabetic activity. Salacia reticulata and Caralluma tuberculata are two important medicinal plants that have been reported to have antidiabetic effects. The growing burden of type 2 diabetes and the need for therapies that address both hyperglycemia and oxidative stress underscore the necessity to investigate these two medicinal plants. Therefore, the current study evaluated the antihyperglycemic, antioxidant, and protective effects of Salacia reticulata and Caralluma tuberculata in an alloxan-induced diabetic female rat model. Methods: Ethanolic extracts of S. reticulata and C. tuberculata were characterized by total phenolic content (TPC), total flavonoid content (TFC), DPPH radical-scavenging assay, and UPLC–MS/MS metabolite profiling. Female Wistar rats (n = 42) were randomly assigned to seven groups (n = 6/group), including normal control, diabetic control, extract-treated non-diabetic groups, diabetic extract-treated groups, and a metformin-treated diabetic group. Diabetes was induced by alloxan (130 mg/kg), followed by oral treatment for 8 days with extracts or metformin (500 mg/kg/day). Fasting blood glucose, oral glucose tolerance, serum malondialdehyde (MDA), antioxidant markers (SOD1, GSH, and CAT), and liver and kidney histopathology were assessed. Results: Both plant extracts significantly reduced fasting blood glucose compared with baseline, with S. reticulata showing a greater reduction (22.8%) than C. tuberculata (12.3%), and a response comparable to metformin (27.4%). Diabetic rats exhibited increased MDA and reduced antioxidant enzyme activities. C. tuberculata significantly lowered MDA levels and increased SOD1 activity, suggesting moderate antioxidant effects, whereas S. reticulata showed higher phenolic and flavonoid contents and the highest DPPH scavenging activity. UPLC–MS/MS identified 33 compounds in S. reticulata and 24 in C. tuberculata. Histopathological findings supported improvement of diabetes-associated renal and hepatic damage. Conclusions: Within the eight-day experimental period, both extracts demonstrated significant acute antidiabetic and antioxidant effects with distinct redox–metabolic profiles. However, further long-term studies are recommended to evaluate their sustained efficacy, safety, and potential as complementary therapeutic agents for diabetes management. Full article

Mango (Mangifera indica L.) pulp contains bioactive compounds with potential therapeutic effects against metabolic and immune-related disorders. However, the integrated effects of mango pulp extract on metabolic, cardiovascular, and immunomodulatory functions remain insufficiently characterized. Therefore, this study aimed to characterize the phytochemical composition and evaluate the activity of M. indica (Mahajanaka) pulp ethanolic extract (MPEE) in rat models. Streptozotocin (STZ)-induced diabetic rats and N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced hypertensive rats were used to assess metabolic and cardiovascular effects, while immune function was examined through neutrophil phagocytosis, splenocyte proliferation, lymphocyte subpopulation analysis, and cytokine secretion. MPEE exhibited a rich phytochemical profile, particularly phenolic compounds, along with strong antioxidant activity (339 ± 8.9 mg gallic acid equivalent/g extract). In STZ-induced diabetic rats, MPEE at 300 mg/kg significantly reduced plasma triglyceride (36.7%) and total cholesterol (45.3%) levels compared with untreated diabetic controls, although its antihyperglycemic effect was modest (6.8%). In L-NAME-induced hypertensive rats, MPEE at 400 mg/kg produced the greatest reduction in blood pressure (42.7%) and heart rate (53.5%). Furthermore, MPEE enhanced neutrophil phagocytic activity (43%), with significant increases observed at doses of 100–400 mg/kg. These findings indicate that MPEE exerts antioxidant, hypolipidemic, antihypertensive, and innate immunostimulatory activities. Full article

Type 2 diabetes mellitus (T2DM) is a highly prevalent and devastating chronic metabolic disease worldwide, with pathogenesis centrally characterized by insulin resistance and pancreatic β-cell dysfunction. Accumulating evidence has demonstrated that glucose metabolic reprogramming represents an adaptive metabolic shift from oxidative phosphorylation to aerobic glycolysis in cells in response to a hyperglycemic microenvironment. This shift acts as an upstream important event driving the initiation and progression of T2DM. This review summarizes the characteristics of glucose metabolic reprogramming in insulin-sensitive target organs under T2DM conditions, including the liver, skeletal muscle, adipose tissue and pancreatic β-cells. It also discusses four major downstream effector mechanisms: mitochondrial energy metabolism disturbance, augmented oxidative stress, disruption of mitochondria-associated endoplasmic reticulum membranes (MAMs) coupled with calcium homeostasis imbalance, and systemic inflammatory response. On this basis, we summarize the intervention strategies targeting the above signaling pathways, including antioxidant therapy, restoration of MAMs integrity and calcium homeostasis, systemic anti-inflammatory intervention, and multi-target regulatory effects of traditional Chinese medicine. Current studies indicate that early intervention in downstream stress events is induced by glucose metabolic reprogramming. This is particularly true for the preservation of MAMs’ integrity; restoration of calcium homeostasis; and inhibition of NLRP3 inflammasome activation, the latter of which is expected to block or delay the progression from prediabetes to clinical T2DM. Nevertheless, substantial gaps still remain in the understanding of the dynamic regulatory mechanisms of MAMs, tissue-specific therapeutic targets, and relevant clinical translational research. Future integration of multi-omics technologies will provide novel therapeutic strategies and theoretical foundations for the early prevention and treatment of T2DM. Full article

Ficus carica L. is traditionally used for diabetes management. This study evaluated the antihyperglycemic activity, safety, possible mechanisms, and phytochemical composition of its aqueous leaf extract (EAcFc). EAcFC activity was evaluated in streptozotocin–nicotinamide-induced type 2 diabetic (ST2D) mice under acute and subchronic conditions. EAcFc showed low acute toxicity (LD₅₀ > 3000 mg/kg). Acute and subchronic oral administration of EAcFc (300 mg/kg) significantly reduced blood glucose levels in ST2D mice. Although sustained HbA1c reduction was not observed, EAcFc improved lipid profiles, notably reducing triglyceride concentrations in ST2D males (from 156 ± 19.4 to 89.7 ± 3.3 mg/dL at week 4) and females (from 138 ± 2.0 to 77 ± 16.0 mg/dL at week 4). In oral sucrose and lactose tolerance tests (3 g/kg load), EAcFc (300 mg/kg) significantly attenuated postprandial hyperglycemia at 30, 60, and 120 min, an effect comparable to acarbose (50 mg/kg). No significant activity was observed during the oral glucose tolerance test (1.5 mg/kg load), suggesting the effect is not mediated by SGLT-1 inhibition. Preparative TLC and NMR analysis identified narcissin, nicotiflorin, and β-sitosterol. Thus, EAcFc possesses antihyperglycemic and lipid-modulating properties partially associated with α-glucosidase inhibition and bioactive flavonoids and phytosterol. Full article

Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, restores hyperglycemic conditions in patients with type 2 diabetes and has recently shown promising anti-inflammatory properties. In this study, we explored its potential to suppress osteoclast formation and bone loss triggered by lipopolysaccharide (LPS), an inflammatory agent. In animal models, the co-administration of liraglutide with LPS on the calvaria regions in mice markedly reduced osteoclast numbers and bone resorption areas relative to treatment with LPS alone. Furthermore, the expression levels of receptor activators of the NF-κB ligand (RANKL) and tumor necrosis factor (TNF)-α mRNA were notably lower in the group receiving liraglutide and LPS compared to treatment with LPS alone. Moreover, in vitro tests revealed that liraglutide has no direct inhibitory effect on RANKL-induced osteoclastogenesis and TNF-α-induced osteoclastogenesis. In addition, liraglutide had no direct inhibitory effect on LPS-stimulated RANKL expression in osteoblasts. Moreover, liraglutide effectively suppressed TNF-α mRNA expression in macrophages stimulated by LPS. These findings suggest that liraglutide prevents inflammatory bone destruction not by targeting osteoclast formation directly but by inhibiting the production of TNF-α within macrophages. Full article

This review aims to compare the biological properties of eleven fruits of the Prunus species, with the focus on their potential in the prevention and management of chronic diseases. The search spanned publications from 2000 to May 2026, only in English, and utilized databases such as PubMed, Web of Science, and Google Scholar, focusing on the in vitro and in vivo studies. The exclusion criteria included review articles, studies focusing exclusively on isolated phytochemicals or synthetic derivatives from Prunus species, and in silico or theoretical analyses. The fruits of Prunus species exhibited a broad spectrum of activities, including antioxidant, anti-inflammatory, anticancer, antihyperglycemic, or neuroprotective. Interestingly, sour cherries exhibited sleep-enhancing, and xanthine oxidase-inhibitory effects, while apricots showed promising hepatoprotective activity. Key species, including apricots, cherries, peaches, and plums, are widely recognized for their bioactive phytochemicals and potential health benefits, while some (e.g., bird cherry, blackthorn) are less examined, although promising. Prunus fruits revealed health-benefit potential, that at least partially supports their ethnopharmacological uses. However, further clinical and mechanistic studies are warranted to validate their efficacy and explore potential applications in pharmaceutical formulations. Full article

This study aimed to determine the absolute bioavailability of quercetin and quantitatively evaluate its pharmacokinetic–pharmacodynamic (PK-PD) relationship regarding acute glucose-lowering effects in normoglycemic and alloxan-induced diabetic rats, addressing whether its in vivo efficacy is driven by the free aglycone or its biotransformed intermediates. Healthy and diabetic rats received single doses of quercetin either orally (75 mg/kg) or intravenously (38 mg/kg). Plasma concentrations of free quercetin were quantified using a validated HPLC-DAD method, and temporal PK-PD relationships between systemic exposure and the percentage variation of glycemia were mathematically evaluated employing Pearson correlation analysis. The absolute bioavailability of free quercetin was significantly impaired by the pathophysiological state, dropping from 59.7% in healthy rats to 40.9% in diabetic subjects. Despite this diminished systemic exposure, oral administration elicited significant hypoglycemic responses. Crucially, the Pearson correlation analysis revealed a pronounced temporal dissociation: the onset of glycemic reduction occurred independently of the maximal circulating concentration of free quercetin. Furthermore, intravenous delivery bypassed first-pass barriers and induced a markedly faster and deeper hypoglycemic effect (up to −47% in diabetic rats). Finally, the diminished bioavailability under diabetic conditions and the stark PK-PD temporal dissociation strongly suggest that quercetin’s acute antihyperglycemic effect is driven by rapid hepatic Phase II biotransformation, implicating conjugated metabolites (rather than the free aglycone) as the principal pharmacological effectors. Full article