Search Results (300)

Diabetes mellitus (DM) is one of the leading causes of death and disability worldwide and its prevalence continues to rise. Chronic hyperglycemia exposes patients to severe complications. Among these, diabetic vascular lesions are the most destructive. Their primary driver is the synergistic interaction between hyperglycemia-induced oxidative stress and chronic inflammation. This review systematically elucidates how multiple pathological pathways—namely, metabolic dysregulation, mitochondrial dysfunction, endoplasmic reticulum stress, and epigenetic reprogramming—cooperate to drive oxidative stress and inflammatory cascades. Confronting this complex pathological network, natural products, unlike conventional single-target synthetic drugs, exert multi-target synergistic effects, simultaneously modulating several key pathogenic networks. This enables the restoration of redox homeostasis and the suppression of inflammatory responses, thereby improving vascular function and delaying both microvascular and macrovascular disease progression. However, the clinical translation of natural products still faces multiple challenges and requires comprehensive mechanistic studies and rigorous validation to fully realize their therapeutic potential. Full article

A dietary supplement, trans-resveratrol and hesperetin (tRES+HESP)—also known as GlucoRegulate—induces increased expression of glyoxalase 1 (Glo1) by activation of transcription factor Nrf2, countering accumulation of the reactive dicarbonyl glycating agent, methylglyoxal. tRES+HESP corrected insulin resistance and decreased fasting and postprandial plasma glucose and low-grade inflammation in overweight and obese subjects in a clinical trial. The aim of this study was to explore, for the first time, health-beneficial gene expression other than Glo1 induced by tRES+HESP in human endothelial cells and fibroblasts in primary culture and HepG2 hepatoma cell line and activity of cis-resveratrol (cRES) as a Glo1 inducer. We measured antioxidant response element-linked gene expression in these cells in response to 5 µM tRES+HESP by the NanoString method. tRES+HESP increases gene expression linked to the prevention of dicarbonyl stress, lipid peroxidation, oxidative stress, proteotoxicity and hyperglycemia-linked glycolytic overload. Downstream benefits were improved regulation of glucose and lipid metabolism and decreased inflammation, extracellular matrix remodeling and senescence markers. The median effective concentration of tRES was ninefold lower than cRES in the Glo1 inducer luciferase reporter assay. The GlucoRegulate supplement provides a new treatment option for the prevention of type 2 diabetes and metabolic dysfunction–associated steatotic liver disease and supports healthy aging. Full article

Diabetes mellitus (DM) is a global health challenge marked by chronic hyperglycemia, which can result in complications such as diabetic cardiomyopathy. Sitagliptin, an oral anti-hyperglycemic drug, has demonstrated efficacy in alleviating cardiovascular complications associated with DM. This study explored the impact of Sitagliptin’s potential as a therapeutic agent, functioning not only to control blood sugar levels but also to enhance vascular health and strengthen cardiac resilience in diabetes. The investigation focused on alterations in the vascular endothelial growth factor (VEGF) and its receptor-1 (FLT-1) signaling pathways, as well as its potential to suppress inflammation and oxidative stress. A number of rats received a single dose of streptozotocin (STZ) 55 mg/kg (i.p.) to induce DM. Sitagliptin was administered orally (100 mg/kg/90 days) to normal and diabetic rats, after which samples were collected for investigation. Sitagliptin significantly mitigated weight loss in diabetic rats. Its administration significantly reduced blood glucose levels and improved serum troponin I and CK-MB levels. Heart sections from diabetic rats showed a marked increase in mTOR, VEGF, and FLT-1 immune reaction, while sitagliptin-treated diabetic rats’ heart sections showed moderate immune reactions. Sitagliptin’s protective effect was also associated with reduced inflammation, and apoptotic markers. In conclusion, Sitagliptin is suggested to offer beneficial effects on the vascular health of cardiac blood vessels, thereby potentially reducing myocardial stress in diabetic patients. Full article

Background/Objectives: Dendrobium nobile Lindl. (DNL), a traditional dietary supplement, exhibits therapeutic potential for type 2 diabetes mellitus (T2DM), yet its mechanisms remain unclear. Methods: T2DM was induced in db/db mice. DNL (10 g/kg/d) or metformin (65 mg/kg/d) was administered for 4 weeks. This study integrated pharmacodynamic evaluation and multi-omics to elucidate DNL’s anti-diabetic effects in db/db mice. Results: DNL intervention significantly ameliorated T2DM phenotypes, reducing hyperglycemia, insulin resistance, and renal dysfunction. Metabolomics analysis identified 39 differential metabolites (19 upregulated, 20 downregulated) linked to citrate cycle, oxidative phosphorylation, and glycerophospholipid metabolism, while proteomics revealed 113 differentially expressed proteins, with multi-omics integration highlighting DNL’s modulation of three proteins (Ckm, Ache, Selenbp1) and four metabolites (4-guanidinobutanoic acid, phosphorylcholine, homocysteine, succinic acid) across arginine/proline metabolism, glycerophospholipid metabolism, and sulfur metabolism. Pathway analysis demonstrated DNL’s restoration of dysregulated processes, including inflammation suppression via NF-κB and PI3K-Akt pathways, enhanced insulin sensitivity through glycerophospholipid balance, and mitigation of oxidative stress via sulfur metabolism. Key correlations between metabolites and proteins underscored DNL’s multi-target action. Conclusions: These findings systematically decode therapeutic mechanisms of Dendrobium nobile Lindl., emphasizing its role in rectifying metabolic disorders and inflammatory signaling, thereby providing a molecular basis for its clinical application in T2DM management. Full article

Diabetic retinopathy (DR), a leading cause of blindness in working-age adults, arises from chronic hyperglycemia-induced oxidative stress, inflammation, and vascular dysfunction. Current therapies such as laser photocoagulation, intravitreal anti-vascular endothelial growth factor (VEGF) agents, and steroids target advanced stages but fail to prevent early neuronal and microvascular damage. Emerging evidence highlights oxidative stress as a key driver of DR pathogenesis, disrupting the blood-retinal barrier (BRB), promoting neurodegeneration and angiogenesis. Advances in imaging, particularly optical coherence tomography angiography (OCTA), enable earlier detection of neurodegeneration and microvascular changes, underscoring DR as a neurovascular disorder. Polyphenols, such as resveratrol, curcumin, and pterostilbene, exhibit multitarget antioxidant, anti-inflammatory, and anti-angiogenic effects, showing promise in preclinical and limited clinical studies. However, their low bioavailability limits therapeutic efficacy. Nanotechnology-based delivery systems enhance drug stability, tissue targeting, and sustained release, offering potential for early intervention. Future strategies should integrate antioxidant therapies and precision diagnostics to prevent early irreversible retinal damage in diabetic patients. Full article

Background: Metabolic syndrome (MetS) is characterized by chronic inflammation, oxidative stress, and mitochondrial dysfunction. MetS is associated with increased intestinal permeability and dysbiosis. The objective of this study was to investigate the effects of peanut shell extract (PSE) and luteolin (LUT) on the kidneys, colon, and ileum in a MetS-like murine model. Methods: Thirty-six male Slc6a14^y/− mice were divided into four groups: low-fat diet (LFD), high-fat diet (HFD), HFD + 200 mg PSE/kg BW (PSE, p.o.), and HFD + 100 mg LUT/kg BW (LUT, p.o.) for 4 months. Outcome measures included glucose homeostasis, intestinal permeability, gut microbiome composition, and mRNA gene expression of mitochondrial homeostasis and inflammation/oxidative stress in the kidneys, colon, and ileum. Results: HFD resulted in glucose dysregulation with hyperglycemia and insulin resistance. PSE and LUT improved insulin tolerance and beta-cell function. PSE and LUT mitigated HFD-increased serum lipopolysaccharide-binding protein concentration. Perturbations in the gut microbiome were associated with HFD, and PSE or LUT reversed some of these changes. Specifically, Phocaeicola vulgatus was depleted by HFD and reverted by PSE or LUT. Relative to the LFD group, the HFD group (1) upregulated mitochondrial fusion (MFN1, MFN2, OPA1), mitophagy (TLR4, PINK1, LC3B), and inflammation (NFκB, TNFα, IL6), and (2) downregulated mitochondrial fission (FIS1, DRP1), biosynthesis (PGC1α, NRF1, NRF2, TFAM), electron transport chain (complex I), and antioxidant enzyme (SOD1) in the kidneys, colon, and ileum. Conclusions: PSE and LUT reversed such HFD-induced changes in the aforementioned gene expression levels. Full article

Saffron, branded as Repron^®, is effective in slowing the progression of several neurodegenerative diseases. Its production, however, requires specific cultivation techniques and procedures that, together with low yields, make it expensive. To address this challenge, hydroponic cultivation has been adopted. Previous studies have shown that hydroponically cultivated saffron and Repron^® share comparable chemical compositions and neuroprotective effects under oxidative stress conditions. In this study, we evaluated the protective properties of extracts derived from Crocus sativus L. waste, compared with those of saffron derived from stigmas. Human retinal pigment epithelium (ARPE-19) cells were pre-treated with extracts of various plant waste fractions before being subjected to three stress conditions: H₂O₂-induced oxidative stress (500 μM, 3 h), lipopolysaccharide (LPS; 0.25 mg/mL, 24 h), and hyperglycemia (25 mM glucose, 96 h). Saffron Repron^® served as a positive control. The results revealed that the extract derived from C. sativus waste had superior protective effects against oxidative stress and inflammation by preserving the state of the mitochondria and tight junctions (ZO-1); conversely, the tepal extract alone was more effective under hyperglycemic conditions by also modulating acrolein levels. These results suggest that different plant fractions contain bioactive compounds with specific protective actions, which together lead to increased cell survival. Full article

Type 2 diabetes, a widespread metabolic disorder, is characterized by hyperglycemia and insulin resistance. Xylose-oligosaccharide, a functional oligosaccharide, has shown potential in mitigating hyperglycemia. This study established a type 2 diabetes mouse model via a high-fat diet and streptozotocin administration to investigate the effects of two xylose-oligosaccharide doses (20 and 60 mg/kg/day). Both doses were observed to regulate lipid metabolism, decrease inflammation, and alleviate damage to the liver, kidneys, and islets. Additionally, xylose-oligosaccharide corrected diabetes-induced intestinal microbiota imbalances by increasing Bacteroides and Proteobacteria while decreasing Firmicutes. Notably, the 60 mg/kg/day dose was more effective in enhancing glucose tolerance and reducing insulin resistance compared to the 20 mg/kg/day dose. These results suggested that xylose-oligosaccharide had hypoglycemic effects, reduced insulin resistance and oxidative stress, possessed anti-inflammatory properties, and modulated intestinal microbiota. Thus, xylose-oligosaccharide shows promise as a functional food for managing type 2 diabetes. Full article

Cataracts, characterized by the opacification of the eye lens, remain a leading cause of reversible blindness globally. Age and diabetes are key risk factors, and with the increasing aging and diabetic population, the global burden of cataracts is projected to rise significantly. Current treatment is predominantly surgical; however, pharmacological strategies could offer a non-invasive alternative with the potential to delay, prevent, or even reverse cataract progression. Recent research has enhanced our understanding of cataractogenesis, emphasizing oxidative stress as a key underlying mechanism, but also including other processes such as calcium dysregulation and altered lens homeostasis or specific events induced by hyperglycemia in diabetic cataracts. New therapeutic approaches have emerged considering the molecular mechanisms involved in cataracts, most of which focus on pharmacological agents with antioxidant properties. Additionally, small-molecule chaperones, aldose reductase inhibitors, and protein aggregation inhibitors have also demonstrated potential in stabilizing or restoring lens protein structure and transparency. While experimental results have shown encouraging results, further research is needed to optimize drug delivery systems to the lens, assess long-term safety, and confirm the clinical efficacy of these treatments. This article reviews current progress in pharmacological treatments for cataracts, outlining challenges and prospects for future integration into clinical practice. Full article

Background: This study aimed to explore the therapeutic potential of a dietary regimen of banaba leaf extract (BNB), policosanol (PCO, Raydel^®), and their combination (BNB+PCO), to mitigate high cholesterol (HC) and high galactose (HG) diet-induced dyslipidemia, hyperglycemia, oxidative stress, senescence, and organ damage in zebrafish (Danio rerio). Methodology: Zebrafish (n = 28/group) were fed with HC (4% w/w)+HG (30% w/w) or HC+HG supplemented either with BNB (0.1% w/w) or PCO (0.1% w/w) or BNB+PCO (0.1% w/w each). Following 6 weeks of dietary intervention, biochemical and histopathological examinations across the groups were performed. Results: Post 6 weeks of consumption, the BNB+PCO group exhibited a significant 40% decrease in body weight (BW) relative to the BW of the HC+HG group, while the BNB or PCO groups displayed nonsignificant changes in BW. Both BNB and PCO reduced HC+HG-induced dyslipidemia and hyperglycemia; however, co-administration (BNB+PCO) demonstrated a significantly greater therapeutic effect in countering these conditions compared to either BNB or PCO alone. A similar effect of the BNB+PCO combination was observed on the elevation of plasma sulfhydryl content, paraoxonase (PON), and ferric ion reduction activity (FRA), with notably ~1.2-times (p < 0.01) higher levels compared to their corresponding values observed in the BNB or PCO groups. Significantly diminished plasma AST, ALT, hepatic interleukin 6 (IL-6) levels, and fatty liver changes were observed in response to BNB+PCO, compared to either BNB or PCO alone. Also, BNB+PCO displayed a higher curative effect against HC+HG-induced impairment of tissue regeneration than BNB or PCO alone. A notable effect of BNB+PCO was perceived in protecting kidneys, testis, and ovary damage. Consistently, BNB+PCO showed a profound impact on mitigating HC+HG elevated reactive oxygen species (ROS) generation, apoptosis, cellular senescence, and accumulation of brain-binding lipid proteins (BLBPs) and 4-hydroxynoneal (4-HNE) in the brain. Conclusions: The findings highlight the synergistic effects of the BNB and PCO combination to mitigate the adversity posed by the consumption of the HC+HG diet. Full article

Diabetes and its complications, including impaired wound healing, present a critical clinical challenge and burden for the U.S. healthcare system, with costs of over USD 13 billion annually. Hyperglycemia and chronic inflammation in diabetic wounds increase reactive oxygen species (ROS) production, inducing oxidative stress and perpetuating inflammation, which delays healing. This study investigates inflammation, oxidative stress, and the roles of cellular populations in a diabetic wound healing mouse model (db/db). Given that diabetes leads to persistent inflammation and impaired fibroblast function, we also examined how diabetes influences superoxide production in dermal fibroblasts. Blood, dermal fibroblasts, and wound tissue were collected from 12-week-old female diabetic (Db) and heterozygous (Hz) mice. Electron paramagnetic resonance (EPR) spectroscopy revealed higher superoxide levels in diabetic blood, dermal fibroblasts, and wounds compared to controls. In diabetic wounds, immunohistochemistry and flow cytometry showed increased leukocyte infiltration and reduced macrophage presence, with a higher proportion of pro-inflammatory Ly6C^hi macrophages. These results suggest that elevated superoxide production and persistent inflammation contribute to impaired fibroblast function and delayed wound healing in diabetes. By identifying the contributions of ROS and Ly6C^hi macrophages to oxidative stress and chronic inflammation, this study offers insights into therapeutic strategies. These findings highlight the importance of addressing systemic oxidative stress alongside localized inflammation to improve wound healing outcomes in diabetic patients and advance diabetic wound care strategies. Full article

Diabetes mellitus is a chronic metabolic disorder characterized by persistent hyperglycemia, leading to endothelial dysfunction and accelerated atherosclerosis. Mitochondrial dysfunction, oxidative stress, and dysregulated lipid metabolism contribute to endothelial cell (EC) injury, promoting plaque formation and increasing cardiovascular disease risk. Current lipid-lowering therapies have limited effectiveness in restoring endothelial function, highlighting the need for novel strategies. Mitochondrial uncoupling has emerged as a promising approach, with BAM15—a newly identified mitochondrial uncoupler—showing potential therapeutic benefits. BAM15 enhances fatty acid oxidation (FAO), reduces reactive oxygen species, and protects ECs from hyperglycemia-induced apoptosis. Unlike conventional uncouplers, BAM15 demonstrates improved tolerability and efficacy without severe off-target effects. It restores mitochondrial function, improves endothelial survival, and supports metabolic homeostasis under hyperglycemic conditions. This review uniquely integrates emerging evidence on mitochondrial dysfunction, endothelial metabolism, and FAO to highlight the novel role of BAM15 in restoring vascular function in diabetes. We provide the first focused synthesis of BAM15’s mechanistic impact on EC bioenergetics and position it within the broader landscape of mitochondrial-targeted therapies for diabetic vascular complications. Further research is needed to elucidate the molecular mechanism through which BAM15 modulates EC metabolism and to evaluate its long-term vascular effects in diabetic models. Full article

Type 1 diabetes (T1D) is a chronic metabolic disease defined by sustained hyperglycemia, leading to oxidative stress (OS) and systemic complications, including male subfertility. This study investigates the potential impact of T1D-induced OS on microtubule (MTs) dynamics and microtubule-associated proteins (MAPs) in the testis and spermatozoa (SPZ). Using a streptozotocin-induced T1D rat model, we examined the expression and localization of key MAPs, including Microtubule Affinity-Regulating Kinase 4 (MARK4), Microtubule-Associated Protein 1A (MAP1A), Dynein Light Chain LC8-Type 1 (DYNLL1), Prolyl Endopeptidase (PREP), and Radial Spoke Head 6 Homolog A (RSPH6A), alongside sperm functional parameters. Our findings showed that T1D significantly impaired the expression and distribution of these proteins, which may affect MTs organization and be associated with cytoskeletal disorganization, and impaired germ cell differentiation. Moreover, T1D rats exhibited reduced sperm count, viability, and motility, accompanied by increased DNA fragmentation and chromatin defects. Elevated levels of 4-hydroxy-2-nonenal (4-HNE), a marker of OS, were detected in SPZ, particularly in the acrosome and flagellum, correlating with mitochondrial dysfunction and ATP depletion. Additionally, decreased intracellular Ca²⁺ levels, downregulation of Cation Channel of Sperm (CATSPER) and Voltage-Dependent Anion Channel 3 (VDAC3), and altered tubulin acetylation, possibly due to imbalanced Alpha-Tubulin N-Acetyltransferase 1 (ATAT1) and Histone Deacetylase 6 (HDAC6) expression, were also associated with impaired sperm motility. The combined data suggest that T1D-induced OS is linked to disrupted MTs dynamics, which may contribute to testicular dysfunction and reduced sperm quality, potentially affecting male fertility. A better understanding of these associations may support the development of therapeutic strategies to mitigate the reproductive consequences of T1D and improve male fertility outcomes. Full article

Diabetic peripheral neuropathy (DPN) is a debilitating complication of diabetes, characterized by mechanical allodynia, neuroinflammation, and oxidative stress. Current treatments offer limited efficacy and are often associated with systemic side effects. Emerging evidence suggests that activation of cannabinoid receptor type 2 (CB₂) may represent a promising target for managing neuropathic pain and inflammation. This study investigates the therapeutic potential of intraplantar β-Caryophyllene (BCP), a selective CB₂ receptor agonist, administered as a topical intervention in a streptozotocin (STZ)-induced DPN mouse model. Hyperglycemia was induced by STZ injections, and diabetic mice received intraplantar BCP (9, 18, or 27 µg) daily for 21 days. Mechanical allodynia was assessed using von Frey filaments, and levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and oxidative stress markers (MDA, SOD, CAT) were quantified in hind paw tissues. BCP dose-dependently alleviated STZ-induced mechanical allodynia, with the 27 µg dose producing the most pronounced effect (p < 0.001). The anti-allodynic effects of BCP were mediated through CB₂ receptor activation, confirmed by reversal with the CB₂ antagonist AM630 (p < 0.001), while the CB₁ antagonist AM251 had no significant impact. In addition, BCP significantly reduced pro-inflammatory cytokines (p < 0.01) and oxidative stress markers (p < 0.001) while restoring antioxidant enzyme activities (p < 0.05). A control group treated with a clinically available topical analgesic cream containing capsaicin 0.075% exhibited limited efficacy. These findings position topical BCP administration as a novel therapeutic strategy for DPN, offering sustained pain relief and modulation of neuroinflammatory and oxidative pathways with minimal systemic exposure. Further clinical studies are warranted to validate its potential for translation into therapeutic practice. Full article

Type 2 Diabetes (T2D) is a complex metabolic disorder that affects multiple organs, leading to severe complications in the pancreas, kidneys, liver, and heart. Prolonged hyperglycemia, along with oxidative stress and chronic inflammation, plays a crucial role in accelerating tissue damage, significantly increasing the risk of diabetic complications such as nephropathy, hepatopathy, and cardiovascular disease. This review evaluates the protective effects of various antidiabetic treatments on organ tissues affected by T2D, based on findings from experimental animal models. Metformin, a first-line antidiabetic agent, has been widely recognized for its ability to reduce inflammation and oxidative stress, thereby mitigating diabetes-induced organ damage. Its protective role extends beyond glucose regulation, offering benefits such as improved mitochondrial function and reduced fibrosis in affected tissues. In addition to traditional therapies, new classes of antidiabetic drugs, including sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists not only improve glycemic control but also exhibit nephroprotective and cardioprotective properties by reducing glomerular hyperfiltration, oxidative stress, and inflammation. Similarly, GLP-1 receptor agonists have been associated with reduced hepatic steatosis and enhanced cardiovascular function. Preclinical studies suggest that tirzepatide, a dual GLP-1/gastric inhibitory polypeptide receptor agonist may offer superior metabolic benefits compared to conventional GLP-1 agonists by improving β-cell function, enhancing insulin sensitivity, and reducing fatty liver progression. Despite promising preclinical results, differences between animal models and human physiology pose a challenge. Further clinical research is needed to confirm these effects and refine treatment strategies. Future T2D management aims to go beyond glycemic control, emphasizing organ protection and long-term disease prevention. Full article