Search Results (65)

Advances in geroscience suggest that aging is modulated by molecular pathways that are amenable to dietary and pharmacological intervention. We conducted an integrative critical review of caloric restriction (CR), intermittent fasting (IF), and caloric restriction mimetics (CR-mimetics) to compare shared mechanisms, clinical evidence, limitations, and translational potential. Across modalities, CR and IF consistently activate AMP-activated protein kinase and sirtuins, inhibit mTOR (mechanistic target of rapamycin) signaling, and enhance autophagy, aligning with improvements in insulin sensitivity, lipid profile, low-grade inflammation, and selected epigenetic aging measures in humans. CR-mimetics, such as metformin, resveratrol, rapamycin, and spermidine, partially reproduce these effects; however, long-term safety and efficacy in healthy populations remain incompletely defined. Methodological constraints—short trial duration, selective samples, intermediate (nonclinical) endpoints, and limited adherence monitoring—impede definitive conclusions on hard outcomes (frailty, disability, hospitalization, mortality). We propose the Active Management of Aging and Longevity (AMAL) model, a three-level biomarker-guided framework that integrates personalized diet, chrono-nutrition, exercise, and the selective use of CR-mimetics, along with digital monitoring and decision support. AMAL emphasizes epigenetic clocks, multi-omics profiling, inflammatory and microbiome metrics, and adaptive protocols to enhance adherence and clinical relevance. Overall, CR, IF, and CR mimetics constitute promising, complementary strategies to modulate biological aging; rigorous long-term trials with standardized biomarkers and clinically meaningful endpoints are needed to enable their scalable implementation. Full article

Background/Objectives: Bioactive peptides derived from animal venoms, toxins, and secretions demonstrate considerable pharmacological potential for use in the management of diabetes mellitus—a highly prevalent metabolic disorder of substantial global health significance. This integrative review systematically evaluated the current evidence regarding the pharmacological mechanisms underlying the antidiabetic properties of these bioactive peptides. Methods: This study was guided by the research question “What are the mechanisms of action of peptides derived from animal venoms in modulating parameters associated with diabetes?” developed using the PECo framework. A comprehensive literature search was executed across Scopus, PubMed, and Web of Science, focusing on studies from the last five years. Out of 190 identified articles, 17 satisfied the inclusion criteria. Results: Twenty-eight distinct peptides were characterized, exhibiting structural diversity with 7–115 amino acid residues and molecular weights of 900–13,000 Da. These compounds were sourced from venomous taxa including sea anemones, marine snails, spiders, centipedes, scorpions, and snakes. Their antidiabetic mechanisms encompassed glucagon-like peptide-1 (GLP-1) receptor agonism, insulin receptor activation, potassium channel inhibition, glucose transporter type 4 (GLUT4) upregulation, and α-amylase inhibition. Sequence analyses revealed substantial homology among peptides with analogous mechanisms—notably Con-Ins and ILP-Ap04, plus SpTx1 and SsTx-4—suggesting that structural determinants underlie their functional characteristics. Toxicological evaluations of nine peptides demonstrated low-toxicity profiles despite originating from toxic venom, crucial for therapeutic development. Conclusions: These peptides exhibited exceptional pharmacological potency with effective doses in nanogram-to-nanomole per kilogram ranges. Collectively, our findings underscore the therapeutic potential of venom-derived peptides as innovative candidates for use in diabetes management. Full article

The development of metallopharmaceuticals for diabetes treatment has garnered increasing attention due to its insulin-mimetic properties, particularly in vanadium complexes. In this study, we report the biophysical evaluation of a series of 3-hydroxy-4-pyridinone (3,4-HPO) vanadium complexes, designed to improve lipophilicity and biological cytocompatibility. Dynamic light scattering (DLS) was used to get insight on the size of the liposomes and Differential Scanning Calorimetry (DSC) was employed to investigate the interaction of these complexes with model biological membranes made from dimyristoylphosphatidylcholine (DMPC) unilamellar liposomes. The thermotropic phase behavior of the lipid bilayers was analyzed in the presence of vanadium complexes. The results reveal that the alkyl chain length of the 3,4-HPO ligands modulates membrane interaction of the respective vanadium compounds, with specific complexes inducing significant shifts in the lipid phase transition temperature (T_m), suggesting alterations in membrane fluidity and packing. These findings provide valuable insight into the membrane affinity of vanadium-based drug candidates and support their potential as next-generation antidiabetic agents. Full article

Osteoblastogenesis plays a critical role in bone repair. Insulin and insulin-mimetic compounds, such as vanadium (IV) oxide acetylacetonate (VAC), have been reported to enhance bone healing in various models. This study aimed to evaluate the effects of vanadium compounds, VAC and vanadium (IV) oxide sulfate (VOSO₄), on osteoblast proliferation and function. MC3T3-E1 pre-osteoblast cells were treated with insulin, ascorbic acid, and varying concentrations of VAC or VOSO₄, and samples were collected at multiple time points over 21 days. We assessed cell proliferation, functional markers, and gene and protein expression. Our findings demonstrate that both VAC and VOSO₄ stimulate MC3T3-E1 proliferation, increase calcium and proteoglycan deposition, and enhance phosphorylation of Protein Kinase B (Akt) over time. Gene expression analysis revealed that VAC treatment upregulated RUNX2, BGLAP, and TWIST2 at Day 7 compared to controls, with sustained expression patterns observed at Day 10. These results align with existing literature, supporting that VAC and VOSO₄ promote osteoblastogenesis and may serve as effective adjuvants to accelerate bone regeneration during fracture healing. Full article

Regular physical activity induces a dynamic crosstalk between skeletal muscle and adipose tissue, modulating the key molecular pathways that underlie metabolic flexibility, mitochondrial function, and inflammation. This review highlights the role of myokines and adipokines—particularly IL-6, irisin, leptin, and adiponectin—in orchestrating muscle–adipose tissue communication during exercise. Exercise stimulates AMPK, PGC-1α, and SIRT1 signaling, promoting mitochondrial biogenesis, fatty acid oxidation, and autophagy, while also regulating muscle hypertrophy through the PI3K/Akt/mTOR and Wnt/β-catenin pathways. Simultaneously, adipose-derived factors like leptin and adiponectin modulate skeletal muscle metabolism via JAK/STAT3 and AdipoR1-mediated AMPK activation. Additionally, emerging exercise mimetics such as the mitochondrial-derived peptide MOTS-c and myostatin inhibitors are highlighted for their roles in increasing muscle mass, the browning of white adipose tissue, and improving systemic metabolic function. The review also addresses the role of anti-inflammatory compounds, including omega-3 polyunsaturated fatty acids and low-dose aspirin, in mitigating NF-κB and IL-6 signaling to protect mitochondrial health. The resulting metabolic flexibility, defined as the ability to efficiently switch between lipid and glucose oxidation, is enhanced through repeated exercise, counteracting age- and disease-related mitochondrial and functional decline. Together, these adaptations demonstrate the importance of inter-tissue signaling in maintaining energy homeostasis and preventing sarcopenia, obesity, and insulin resistance. Finally, here we propose a stratified treatment algorithm based on common age-related comorbidities, offering a framework for precision-based interventions that may offer a promising strategy to preserve metabolic plasticity and delay the age-associated decline in cardiometabolic health. Full article

Chlorophyll, the green pigment essential for photosynthesis, abundantly found in green vegetables and algae, has attracted growing scientific interest for its potential therapeutic effects, particularly in diabetes management. Recent research highlighted that chlorophyll and its derivatives may beneficially influence glucose metabolism and oxidative stress, key factors in diabetes. This review examines current knowledge on how chlorophyll compounds could aid diabetes control. Chlorophyll and its derivatives appear to support glucose regulation primarily through actions in the gastrointestinal tract. They modulate gut microbiota, improve glucose tolerance, reduce inflammation, and alleviate obesity-related markers. While chlorophyll itself does not directly inhibit digestive enzymes like α-glucosidase, its derivatives such as pheophorbide a, pheophytin a, and pyropheophytin a may slow carbohydrate digestion, acting as α-amylase and α-glucosidase inhibitors, reducing postprandial glucose spikes. Additionally, chlorophyll enhances resistant starch content, further controlling glucose absorption. Beyond digestion, chlorophyll derivatives show promise in inhibiting glycation processes, improving insulin sensitivity through nuclear receptor modulation, and lowering oxidative stress. However, some compounds pose risks due to photosensitizing effects and toxicity, warranting careful consideration. Chlorophyllin, a stable semi-synthetic derivative, also shows potential in improving glucose and lipid metabolism. Notably, pheophorbide a demonstrates insulin-mimetic activity by stimulating glucose uptake via glucose transporters, offering a novel therapeutic avenue. Overall, the antioxidant, anti-inflammatory, and insulin-mimicking properties of chlorophyll derivatives suggest a multifaceted approach to diabetes management. While promising, these findings require further clinical validation to establish effective therapeutic applications. Full article

Diabetes mellitus is a chronic metabolic disease that has a significant impact on public health and is becoming more and more common worldwide. Although effective, conventional therapies are often limited by high cost, adverse effects, and issues with patient compliance. As a result, there is growing interest in complementary and alternative therapies. Medicinal plants have played an essential role in diabetes treatment, especially in regions such as Romania, where biodiversity is high and traditional knowledge is well preserved. The pathophysiology, risk factors, and worldwide burden of diabetes are examined in this review, with an emphasis on the traditional use of medicinal plants for glycemic control. A total of 47 plant species were identified based on ethnopharmacological records and recent biomedical research, including both native flora and widely cultivated species. The bioactive compounds identified, such as flavonoids, triterpenic saponins, polyphenols, and alkaloids, have hypoglycemic effects through diverse mechanisms, including β-cell regeneration, insulin-mimetic action, inhibition of α-glucosidase and α-amylase, and oxidative stress reduction. A systematic literature search was conducted, including in vitro, in vivo, and clinical studies relevant to antidiabetic activity. Among the species reviewed, Urtica dioica, Silybum marianum, and Momordica charantia exhibited the most promising antidiabetic activity based on both preclinical and clinical evidence. Despite promising preclinical results, clinical evidence remains limited, and variability in phytochemical content poses challenges to reproducibility. This review highlights the potential of Romanian medicinal flora as a source of adjunctive therapies in diabetes care and underscores the need for standardization and clinical validation. Full article

Background: Incretin mimetics, including glucagon-like peptide-1 receptor agonists (GLP-1 receptor agonist) and dipeptidyl peptidase-4 (DPP-4) inhibitors, have been increasingly utilized for glycemic control in patients with type 2 diabetes (T2D). Studies have demonstrated additional improvements in weight loss, cardiovascular health, and renal outcomes. Animal studies have shown an association between GLP-1 receptor agonists and C-cell proliferation and elevated calcitonin, resulting in an FDA black box. Insulin resistance in patients with T2D, along with the use of other glucose control medications, confounds the relationship between incretin mimetics and thyroid cancers. The true effect of incretin mimetics on thyroid cancer remains uncertain and speculative due to this confounding. Methods: This retrospective cohort study compared patients with T2D, who were new users of incretin mimetics, to new users of metformin. Study patients used no other anti-diabetes medications beyond the study medications. The risks of incident thyroid cancer and subsequent thyroidectomy were quantified using Cox proportional hazards regression models fitted with adjustments for demographic and medical covariates over a three-year study period. Medullary thyroid cancer (MTC) and multiple endocrine neoplasia type II (MEN2) cases were quantified. Results: Of the 91,394 patients, 28 incretin mimetic users had a diagnosis of thyroid cancer, and nine of these patients underwent a subsequent thyroidectomy procedure. No incretin mimetic user was diagnosed with MTC or MEN2. There was no statistically significant effect on the overall incretin mimetic category (1.28 aHR, 0.83–1.96), the incretin mimetic subcategories of GLP-1 receptor agonists (1.35 aHR, 0.80–2.29), or DPP-4 inhibitor (0.62 aHR, 0.33–1.17) users in developing thyroid cancer within three years of drug initiation. Similarly, no association was found between the overall incretin mimetic category (1.02 aHR, 0.49–2.10), the subcategories of GLP-1 receptor agonists (1.26 aHR, 0.54–2.96), or DPP-4 inhibitors (0.32 aHR, 0.08–1.37) and a subsequent thyroidectomy. Conclusions: In this real-world cohort study, exposure to incretin mimetics overall or through the incretin mimetic subcategories of GLP-1 receptor agonists and DPP-4 inhibitors was not associated with risks of thyroid cancer or thyroidectomy compared to metformin users. Full article

We explore the structural and electronic properties of representative insulin-mimetic oxovanadium and zinc complexes as computed in vacuum, in water clusters and upon binding to PTEN and PTP1B phosphatases. Albeit diverse, the enzymes’ active sites represent evolutionary variant choices of the same type of biochemistry. Though different in respect to covalency and the orbital nature of bonding, theory predicts comparable ionic radii, bond lengths and square pyramidal coordination for the considered vanadyl and zinc systems when in an aqueous environment. Employing docking, DFT and quantum mechanics/molecular mechanics methods, we address possible polar interactions in the protein environments and compute infrared/Raman modes and optical electronic properties, which may be suitable for the structural analysis of the specific chemical moieties in binding studies. Accounting for how protein embedding may alter the electronic states of metal centres, we discuss artificial intelligence-assisted protein field engineering to assist biomedical and quantum information applications. Full article

Quinones, one of the oldest organic compounds, are of increasing interest due to their abundant presence in a wide range of natural sources and their remarkable biological activity. These compounds occur naturally in green leafy vegetables, fruits, herbs, animal and marine sources, and fermented products, and have demonstrated promising potential for use in health interventions, particularly in the prevention and management of type 2 diabetes (T2DM). This review aims to investigate the potential of quinones as a health intervention for T2DM from the multidimensional perspective of their sources, types, structure–activity relationship, glucose-lowering mechanism, toxicity reduction, and bioavailability enhancement. Emerging research highlights the hypoglycemic activities of quinones, mainly driven by their redox properties, which lead to covalent binding, and their structural substituent specificity, which leads to their non-covalent binding to biocomplexes. Quinones can improve insulin resistance and regulate glucose homeostasis by modulating mitochondrial function, inflammation, lipid profile, gastrointestinal absorption, and by acting as insulin mimetics. Meanwhile, increasing attention is being given to research focused on mitigating the toxicity of quinones during administration and enhancing their bioavailability. This review offers a critical foundation for the development of quinone-based health therapies and functional foods aimed at diabetes management. Full article

Background/Objectives: This study evaluated the effects of a novel Astragalus extract (Keyfobell powder [KFB]) composed of Astragalus membranaceus, red ginseng (Panax ginseng C. A. Meyer), and Cervi Parvum Cornu as a potential growth hormone (GH) alternative. The primary focus was placed on its impact on longitudinal bone growth through the upregulation of circulatory insulin-like growth factor (IGF)-1. Methods: We performed in vitro and in vivo experiments using a hypothalamic cell line and Sprague–Dawley (SD) rats. Quantitative RT-PCR was performed to determine growth hormone-releasing hormone (GHRH) and ghrelin mRNA expressions in GT1-7 cells. The treatment groups were administered KFB at various dosages, and the positive controls received recombinant human GH. Body weight, bone length, and density were assessed, along with serum levels of insulin-like growth factor binding protein (IGFBP)-3 and IGF-1. Results: KFB and somatropin exhibited no cytotoxic effect in GT1-7 cells and increased GHRH and ghrelin mRNA levels in a dose-dependent manner. KFB administration resulted in a significant dose-dependent increase in body weight and bone growth (femur and tibia). Changes in IGF-1 and IGFBP-3 levels were comparable to those observed in the GH-treated group. Based on network pharmacological analysis, multiple compounds in KFB ((20S)-20-hydroxypregn-4-en-3-one, 2-isopropyl-3-methoxypyrazine, caproic acid, daidzein, furfuryl alcohol, lauric acid, octanal, and salicylic acid) may synergistically regulate the PI3K-Akt, Ras, and Rap1 signaling pathways linked to growth control and cartilage formation, leading to a possible increase in height. Conclusions: Our results suggest that KFB can function as a GH-mimetic agent that promotes bone growth through IGF-1 upregulation. Full article

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes in both Type 1 (T1D) and Type 2 (T2D). While there are no specific medications to prevent or treat DPN, certain strategies can help halt its progression. In T1D, maintaining tight glycemic control through insulin therapy can effectively prevent or delay the onset of DPN. However, in T2D, overall glucose control may only have a moderate impact on DPN, although exercise is clearly beneficial. Unfortunately, optimal exercise may not be feasible for many patients with DPN because of neuropathic foot pain and poor balance. Exercise has several favorable effects on health parameters, including body weight, glycemic control, lipid profile, and blood pressure. We investigated the impact of an exercise mimetic, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), on DPN. AICAR treatment prevented or reversed experimental DPN in mouse models of both T2D and T1D. AICAR in high-fat diet (HFD-fed) mice increased the phosphorylation of AMPK in DRG neuronal extracts, and the ratio of phosphorylated AMPK to total AMPK increased by 3-fold (HFD vs. HFD+AICAR; p < 0.001). Phospho AMP increased the levels of dynamin-related protein 1 (DRP1, a mitochondrial fission marker), increased phosphorylated autophagy activating kinase 1 (ULK1) at Serine-555, and increased microtubule-associated protein light chain 3-II (LC3-II, a marker for autophagosome assembly) by 2-fold. Mitochondria isolated from DRG neurons of HFD-fed had a decrease in ADP-stimulated state 3 respiration (120 ± 20 nmol O₂/min in HFD vs. 220 ± 20 nmol O₂/min in control diet (CD); p < 0.001. Mitochondria isolated from HFD+AICAR-treated mice had increased state 3 respiration (240 ± 30 nmol O₂/min in HFD+AICAR). However, AICAR’s protection in DPN in T2D mice was also mediated by its effects on insulin sensitivity, glucose metabolism, and lipid metabolism. Drugs that enhance AMPK phosphorylation may be beneficial in the treatment of DPN. Full article

Diabetes mellitus is a spreading global pandemic. Type 2 diabetes mellitus (T2DM) is the predominant form of diabetes, in which a reduction in blood glucose uptake is caused by impaired glucose transporter 4 (GLUT4) translocation to the plasma membrane in adipose and muscle cells. Antihyperglycemic drugs play a pivotal role in ameliorating diabetes symptoms but often are associated with side effects. Hence, novel antidiabetic compounds and nutraceutical candidates are urgently needed. Phytogenic therapy can support the prevention and amelioration of impaired glucose homeostasis. Using total internal reflection fluorescence microscopy (TIRFM), 772 plant extracts of an open-access plant extract library were screened for their GLUT4 translocation activation potential, resulting in 9% positive hits. Based on commercial interest and TIRFM assay-based GLUT4 translocation activation, some of these extracts were selected, and their blood glucose-reducing effects in ovo were investigated using a modified hen’s egg test (Gluc-HET). To identify the active plant part, some of the available candidate plants were prepared in-house from blossoms, leaves, stems, or roots and tested. Acacia catechu (catechu), Pulmonaria officinalis (lungwort), Mentha spicata (spearmint), and Saponaria officinalis (common soapwort) revealed their potentials as antidiabetic nutraceuticals, with common soapwort containing GLUT4 translocation-activating saponarin. Full article

Type 2 diabetes mellitus (T2DM) stands as a prevalent global public health issue caused by deficiencies in the action of insulin and/or insulin production. In the liver, insulin plays an important role by inhibiting hepatic glucose production and stimulating glycogen storage, thereby contributing to blood glucose regulation. Kaempferitrin (KP) and kaempferol (KM), flavonoids found in Bauhinia forficata, exhibit insulin-mimetic properties, showing promise in managing T2DM. In this study, we aimed to assess the potential of these compounds in modulating the insulin signaling pathway and/or glucose metabolism. Cell viability assays confirmed the non-cytotoxic nature of both compounds toward HepG2 cells at the concentrations and times evaluated. Theoretical molecular docking studies revealed that KM had the best docking pose with the IR β subunit when compared to the KP. Moreover, Langmuir monolayer evaluation indicated molecular incorporation for both KM and KP. Specifically, KM exhibited the capability to increase AKT phosphorylation, a key kinase in insulin signaling, regardless of insulin receptor (IR) activation. Notably, KM showed an additional synergistic effect with insulin in activating AKT. In conclusion, our findings suggest the potential of KM as a promising compound for stimulating AKT activation, thereby influencing energy metabolism in T2DM. Full article

Stable analogues of the adipokine apelin-13 have shown promising therapeutic potential via APJ receptor activation in isolated β-cells and in animal models of obesity-related diabetes. Incretin mimetics such as exenatide that bind to GLP-1 receptors are well-established Type 2 diabetes treatment options. We developed novel hybrid co-agonist peptide analogues incorporating both exendin-4(1-30) covalently linked to apelin (ELA). The dose-dependent (10⁻¹² to 10⁻⁶ M) actions of ELA and component peptides were tested on acute (20 min) insulin secretion from cultured pancreatic BRIN-BD11 β-cells at 5.6 mmol/L glucose. In addition, separate tests were performed in the presence or absence of specific APJ and GLP-1 receptor antagonists. The co-agonist ELA peptide showed markedly greater insulinotropic actions (1.6 to 3.3-fold) than equimolar concentrations of either component peptide alone or in combination (p < 0.001). ELA and related acylated analogues (25 nmol/kg i.p. injection) were also tested on cumulative food intake in trained 21 h-fasted adult mice (n = 8), with food intake measured at 30 min intervals up to 180 min. The ELA co-agonist peptides significantly reduced food intake (3.1-fold by 180 min) in mice (p < 0.001) versus saline-treated controls. ELA peptides showed marked improvements in both insulin secretion and appetite control, raising interest in their therapeutic potential. Full article