Search Results (489)

Skin dullness contributes to a fatigued and aged appearance, often exceeding one’s biological age. It is a common dermatological concern influenced by aging and poor lifestyle habits, regardless of ethnicity or age. This study aimed to examine advanced glycation end products (AGEs) and their receptor (receptor for AGEs [RAGE]) as contributing factors to skin dullness. AGEs themselves have a yellowish hue, contributing to “yellow dullness.” Additionally, AGE–RAGE signaling promotes melanin production in melanocytes and impairs keratinocyte differentiation as a result of inflammation. Therefore, regulating the AGE–RAGE interaction may help reduce skin dullness. Through screening various natural ingredients, we found that peony root extract (PRE) inhibits AGE formation and blocks AGE–RAGE binding. Furthermore, the presence of PRE leads to the suppression of AGE-induced melanin production in melanocytes and the restoration of impaired keratinocyte differentiation in glycated basement membrane components. In a human clinical study, topical application of a 1% PRE-containing lotion for 2 weeks significantly reduced melanin content, with a trend toward decreased AGE accumulation and visible spots on the cheeks. These findings support the potential of PRE as a multifunctional cosmetic ingredient that comprehensively addresses skin dullness by modulating the AGE–RAGE interaction. Full article

Photoaging, predominantly induced by ultraviolet radiation, is a primary driver of premature skin aging, characterized by complex molecular mechanisms including oxidative stress, inflammation, matrix metalloproteinase activation, and extracellular matrix degradation. Consequently, there is growing scientific interest in identifying effective natural agents to counteract skin aging and photoaging. Djulis (Chenopodium formosanum), an indigenous Taiwanese pseudocereal from the Amaranthaceae family, has emerged as a promising candidate for skincare applications because of its rich phytochemicals and diverse bioactivities. This review describes the current understanding of the molecular mechanisms underlying photoaging and examines the therapeutic potential of djulis extract as a multifunctional agent for skin aging. Its mechanisms of action include enhancing antioxidant defenses, modulating inflammatory pathways, preserving the extracellular matrix, and inhibiting the formation of advanced glycation end products. Bioactive constituents of djulis extract, including phenolic compounds, flavonoids, and betanin, are known to exhibit potent antioxidant and photoprotective activities by modulating multiple molecular pathways essential for skin protection. The bioactivities of djulis in in vitro and animal studies, and four skin clinical trials of djulis extract products are presented in this review article. Ultimately, this review provides an overview that supports the potential of djulis extract in the development of evidence-based skincare formulations for the prevention and treatment of skin aging. Full article

Background: Sodium–glucose cotransporter 2 (SGLT2) inhibitors have transformed type 2 diabetes mellitus (T2DM) management by promoting glucosuria, lowering glycated hemoglobin (HbA1c), blood pressure, and weight; however, their use is limited by genitourinary infections and ketoacidosis. Phytocannabinoids—bioactive compounds from Cannabis sativa—exhibit multi-target pharmacology, including interactions with cannabinoid receptors, Peroxisome Proliferator-Activated Receptors (PPARs), Transient Receptor Potential (TRP) channels, and potentially SGLT2. Objective: To evaluate the potential of phytocannabinoids as novel modulators of renal glucose reabsorption via SGLT2 and to compare their efficacy, safety, and pharmacological profiles with synthetic SGLT2 inhibitors. Methods: We performed a narrative review encompassing the following: (1) the molecular and physiological roles of SGLT2; (2) chemical classification, natural sources, and pharmacokinetics/pharmacodynamics of major phytocannabinoids (Δ⁹-Tetrahydrocannabinol or Δ⁹-THC, Cannabidiol or CBD, Cannabigerol or CBG, Cannabichromene or CBC, Tetrahydrocannabivarin or THCV, and β-caryophyllene); (3) in silico docking and drug-likeness assessments; (4) in vitro assays of receptor binding, TRP channel modulation, and glucose transport; (5) in vivo rodent models evaluating glycemic control, weight change, and organ protection; (6) pilot clinical studies of THCV and case reports of CBD/BCP; (7) comparative analysis with established synthetic inhibitors. Results: In silico studies identify high-affinity binding of several phytocannabinoids within the SGLT2 substrate pocket. In vitro, CBG and THCV modulate SGLT2-related pathways indirectly via TRP channels and CB receptors; direct IC₅₀ values for SGLT2 remain to be determined. In vivo, THCV and CBD demonstrate glucose-lowering, insulin-sensitizing, weight-reducing, anti-inflammatory, and organ-protective effects. Pilot clinical data (n = 62) show that THCV decreases fasting glucose, enhances β-cell function, and lacks psychoactive side effects. Compared to synthetic inhibitors, phytocannabinoids offer pleiotropic benefits but face challenges of low oral bioavailability, polypharmacology, inter-individual variability, and limited large-scale trials. Discussion: While preclinical and early clinical data highlight phytocannabinoids’ potential in SGLT2 modulation and broader metabolic improvement, their translation is impeded by significant challenges. These include low oral bioavailability, inconsistent pharmacokinetic profiles, and the absence of standardized formulations, necessitating advanced delivery system development. Furthermore, the inherent polypharmacology of these compounds, while beneficial, demands comprehensive safety assessments for potential off-target effects and drug interactions. The scarcity of large-scale, well-controlled clinical trials and the need for clear regulatory frameworks remain critical hurdles. Addressing these aspects is paramount to fully realize the therapeutic utility of phytocannabinoids as a comprehensive approach to T2DM management. Conclusion: Phytocannabinoids represent promising multi-target agents for T2DM through potential SGLT2 modulation and complementary metabolic effects. Future work should focus on pharmacokinetic optimization, precise quantification of SGLT2 inhibition, and robust clinical trials to establish efficacy and safety profiles relative to synthetic inhibitors. Full article

Dietary advanced glycation end-products (dAGEs) contained in high-sugar/fat and ultra-processed foods of the “Western diet” (WD) pattern predispose to several diseases by altering protein function or increasing oxidative stress and inflammation via RAGE (receptor for advanced glycation end-products). Although elevated endogenous AGEs are associated with loss of muscle mass and functionality (i.e., muscle wasting; MW), the impact of dAGEs on MW has not been elucidated. Here, we show that the most common dAGEs or their precursor, methylglyoxal (MGO), induce C2C12 myotube atrophy as endogenous AGE-derived BSA. ROS production, mitochondrial dysfunction, mitophagy, ubiquitin–proteasome activation, and inhibition of myogenic potential are common atrophying mechanisms used by MGO and AGE-BSA. Although of different origins, ROS are mainly responsible for AGE-induced myotube atrophy. However, while AGE-BSA activates the RAGE-myogenin axis, reduces anabolic mTOR, and causes mitochondrial damage, MGO induces glycolytic stress and STAT3 activation without affecting RAGE expression. Among thirty selected natural compounds, Vaccinium macrocarpon (VM), Camellia sinensis, and chlorophyll showed a surprising ability in counteracting in vitro AGE formation. However, only the standardized VM, containing anti-glycative metabolites as revealed by UHPLC-HRMS analysis, abrogates AGE-induced myotube atrophy. Collectively, our data suggest that WD-linked dAGE consumption predisposes to MW, which might be restricted by VM food supplements. Full article

Infertility is a significant global health concern, and incorporating antioxidants into sperm preparation media is one strategy to enhance sperm quality and decrease infertility rates. This study aimed to investigate the phytochemical compounds of red cotton stamen extracts and their effects as antioxidants in improving the quality of bull frozen semen. Among the extracts, RCU contained the highest levels of total phenolics, total tannins, and total monomeric anthocyanins along with the strongest ABTS free radical scavenging activity and protein denaturation inhibition. Exposing sperm to FeSO₄-induced oxidative stress resulted in significantly reduced motility, viability, and normal morphology. However, treatment with RCD, RCU, and RCM improved these parameters. Additionally, the FeSO₄-induced group showed elevated levels of reactive oxygen species (ROS) and advanced glycation end products (AGEs) compared to the normal control, whereas all red cotton stamen extracts effectively reduced these levels. In conclusion, red cotton stamen extracts, rich in phenolic bioactive compounds, demonstrated strong free radical scavenging capacity and improved sperm motility, viability, and morphology by neutralizing free radicals and enhancing antioxidant defenses. These findings suggest that the red cotton stamen extracts, particularly RCD and RCU, offer benefits for sperm preservation. Full article

This study investigated the functional potential of Campomanesia xanthocarpa leaf and fruit infusions through phytochemical profiling, simulated gastrointestinal digestion, enzyme inhibition assays, and in vivo evaluation of glycemic markers. Leaf infusions exhibited a more diverse phenolic profile, higher total phenolic content, and greater antioxidant capacity compared to fruit infusions. Simulated digestion confirmed the bioaccessibility of key phenolic compounds, particularly glycosylated flavonoids such as quercetin-3-glucoside and kaempferol derivatives, with leaf extracts showing superior gastrointestinal stability. In vitro assays revealed a strong inhibitory activity of leaf infusions against α-amylase and β-glucosidase. In a 32-day trial with healthy dogs, the consumption of biscuits enriched with leaf infusion did not alter fasting glucose or amylase levels but resulted in a significant treatment × time interaction for serum fructosamine, indicating a delayed modulation of glycemic control, potentially associated with antioxidant or anti-glycation activity. These findings highlight the potential of C. xanthocarpa leaves as a functional ingredient in foods aimed at supporting glycemic regulation and metabolic health. Full article

Alzheimer’s disease (AD) and schizophrenia are traditionally considered distinct clinical entities, yet growing evidence highlights substantial overlap in their molecular and neuroinflammatory pathogenesis. This review explores current insights into the shared and divergent mechanisms underlying these disorders, with emphasis on neuroinflammation, autophagy dysfunction, blood–brain barrier (BBB) disruption, and cognitive impairment. We examine key signaling pathways, particularly spleen tyrosine kinase (SYK), the mechanistic (or mammalian) target of rapamycin (mTOR), and the S100 calcium-binding protein B (S100B)/receptor for advanced glycation end-products (RAGE) axis, that link glial activation, excitatory/inhibitory neurotransmitter imbalances, and impaired proteostasis across both disorders. Specific biomarkers such as S100B, matrix metalloproteinase 9 (MMP9), and soluble RAGE show promise for stratifying disease subtypes and predicting treatment response. Moreover, psychiatric symptoms frequently precede cognitive decline in both AD and schizophrenia, suggesting that mood and behavioral disturbances may serve as early diagnostic indicators. The roles of autophagic failure, cellular senescence, and impaired glymphatic clearance are also explored as contributors to chronic inflammation and neurodegeneration. Current treatments, including cholinesterase inhibitors and antipsychotics, primarily offer symptomatic relief, while emerging therapeutic approaches target upstream molecular drivers, such as mTOR inhibition and RAGE antagonism. Finally, we discuss the future potential of personalized medicine guided by genetic, neuroimaging, and biomarker profiles to optimize diagnosis and treatment strategies in both AD and schizophrenia. A greater understanding of the pathophysiological convergence between these disorders may pave the way for cross-diagnostic interventions and improved clinical outcomes. Full article

Background: Cancer stem cells (CSCs) are a subpopulation of cancer cells known for their self-renewal capacity, tumorigenicity, and resistance to treatment. Toll-like receptor 3 (TLR3) plays a complex role in cancer, exhibiting both pro-apoptotic and pro-tumorigenic effects. This study investigates the pro-tumorigenic role of TLR3, specifically its impact on CSCs in head and neck cancer. Methods: We have investigated Detroit 562, FaDu and SQ20B cell lines, the latter being stably transfected with a plasmid containing inducible shRNA for TLR3, by cultivating them to form tumor spheres in order to study CSCs. Results: Our findings demonstrate that TLR3 activation promotes stemness in head and neck cancer cell lines. This is evidenced by increased tumor sphere formation, promotion of epithelial-to-mesenchymal transition (EMT), upregulated stemness gene expression, and elevated aldehyde dehydrogenase (ALDH) activity. Conditional TLR3 knockdown abolished tumor sphere formation, confirming its important role. Furthermore, TLR3 activation triggers the secretion of damage-associated molecular patterns (DAMPs) into the tumor microenvironment, leading to increased cancer cell migration. This was inhibited by DAMP inhibitors. In patient tissue samples, we observed co-localization of TLR3 with stemness markers CD133 and ALDH1, as well as with heat shock protein 70 (HSP70) and receptor for advanced glycation end products (RAGE). We then explored potential CSC-targeted therapies, initially combining the apoptosis inducer poly (I:C) with DAMP inhibitors and γ-irradiation. While this combination proved effective in adherent cells, it failed to eliminate tumor spheres. Nevertheless, we discovered that proton radiotherapy, particularly when combined with aspirin (HMGB1 inhibitor) and poly (I:C), effectively eliminates CSCs. Conclusions: This novel combination holds promise for the development of new therapeutic strategies for head and neck cancers, particularly given the promising results of proton therapy in treating this disease. Full article

Thermal-processed foods like baked, smoked, and fried products are popular for their unique aroma, taste, and color. However, thermal processing can generate various contaminants via Maillard reaction, lipid oxidation, and thermal degradation, negatively impacting human health. This review summarizes the formation pathways, influencing factors, and tracing approaches of potential hazards in thermally processed foods, such as polycyclic aromatic hydrocarbons (PAHs), heterocyclic aromatic amines (HAAs), furan, acrylamide (AA), trans fatty acids (TFAs), advanced glycation end-products (AGEs), sterol oxide. The formation pathways are explored through understanding high free radical activity and multiple active intermediates. Control patterns are uncovered by adjusting processing conditions and food composition and adding antioxidants, aiming to inhibit hazards and enhance the safety of thermal-processed foods. Full article

In the present study, the primary by-products of the hemp-seed oil process—hemp seed cake flour and hemp seed protein concentrate—underwent enzymatic hydrolysis using proteases and carbohydrases, either individually or in combination. The effectiveness of these enzymatic treatments in releasing bioactive compounds was evaluated by assessing the antioxidant and anti-inflammatory properties of the aqueous extracts of both hydrolysed and untreated hemp by-products. The aim was to explore their potential senotherapeutic properties and promote their application as dietary supplements. Secondary metabolites such as flavonoids, phenolic acids, and catechins were analysed using high-performance liquid chromatography. Total phenolic, flavonoid, and protein contents were determined using spectrophotometric methods. Scavenging activity (2,2-Diphenyl-1-picrylhydrazyl scavenging assay (DPPH assay)), antioxidant power (Ferric reducing antioxidant power assay (FRAP assay)), and lipid peroxidation-reducing activity (thiobarbituric acid-reactive substance analysis) were assessed through in vitro assays. Possible anti-inflammatory effects were evaluated by assessing haemolysis inhibition. The impact of extracts on albumin glycation induced by exposure to fructose was also determined. To assess the toxicity of extracts, a zebrafish larvae model was employed. All extracts contained significant amounts of phenolic compounds, flavonoids, and proteins, and they exhibited notable activities in reducing lipid peroxidation and stabilising erythrocyte cell membranes. However, they did not significantly influence protein glycation (the glycation inhibition was only in the range of 15–40%). Our research demonstrates the substantial health-promoting potential, including senescence delay, of aqueous extracts from by-products of the hemp-seed oil process, which are available in large quantities and can serve as valuable supplements to support the health of animals, including humans, rather than being discarded as waste from oil production. Full article

Advanced glycation end-products (AGEs) and oxidative stress are recognized as central contributors to the pathogenesis of age-related or diabetic cataracts, diabetic retinopathy (DR), and age-related macular degeneration (AMD). These glycation-related diseases are characterized by impaired redox balance and decreased glutathione (GSH) levels. This review aims to examine the mechanistic links between AGEs and GSH depletion across ocular tissues by integrating in vitro, ex vivo, in vivo, and clinical studies relevant to this topic. The multiple levels of evidence highlight GSH homeostasis as both a biomarker and therapeutic target in glycation-related ocular disorders. Therapeutic strategies aimed at restoring GSH homeostasis under glycation stress are categorized into four mechanistic domains: (I) promoting GSH supply and synthesis, (II) enhancing GSH recycling, (III) mitigating glycation stress, and (IV) reducing oxidative and nitrosative stress. Most of these strategies have been explored via different approaches, and experimental findings with various interventions have shown promise in restoring GSH balance and mitigating AGE-induced damage. A pathological link between GSH depletion and vascular endothelial growth factor (VEGF) overexpression is observed in DR and wet AMD. GSH-centered interventions act upstream to modulate redox homeostasis while anti-VEGF therapies target downstream angiogenesis. This study supports the rationale for a dual-targeting strategy that combines redox-based interventions with VEGF inhibition in glycation-related ocular diseases. Full article

Glycation is known as an important factor inducing human diseases, including diabetic complications. As oxidative stress contributes to procedures of glycation, antioxidants may inhibit glycation and delay the progression of diabetic complications. Our previous investigation of human aqueous humor after the intake of a lutein-containing supplement demonstrated increases in antioxidative activities and decreases in peroxidative products. This study enrolled 25 patients with diabetes (DM group) and 100 age-matched controls. Aqueous humor samples were collected during cataract surgery before and after 6 weeks of oral intake of the lutein-containing antioxidant supplement, Ocuvite + Lutein^®. The carboxymethyl-lysine level (CML) was measured as an indicator of glycation. Levels of superoxide dismutase activities (SOD) and total hydroperoxide (TH) were measured as indicators of oxidation. Changes after intake and the differences between age-matched controls and the DM group were evaluated. CML decreased after intake among the DM group, while there were no changes among the age-matched controls. SOD was significantly lower and TH was significantly higher in the DM group as compared to the age-matched controls, both before and after intake. In line with the decreases in glycation, the intake of lutein-containing antioxidant supplements may inhibit diabetic complications in diabetic patients. Full article

In this study, the ranking of the multifaceted activity of rutin (Ru), quercetin (Q), and quercetin’s glucosides (Q3G, Q4′G and Q3,4′G) was addressed. The antioxidant potency was determined by electrochemical methods, whereas the ability of these compounds to inhibit angiotensin-converting enzyme (ACE) activity, acetylcholinesterase (AChE) activity, and advanced glycation endproduct (AGE) formation was examined in bovine serum albumin (BSA)/glucose and BSA/methylglyoxal (MGO) model systems to show their importance against hypertension, Alzheimer-type dementia, and diabetic complication, respectively. Then, the relationship between the biological activities of these compounds and their antioxidant potential provided by the cyclic voltammetry (CV) method was evaluated. The ranking of the ACE inhibitory activity was Q > Q3,4′G > Ru > Q3G > Q4′G. The correlation coefficient between ACE enzyme inhibitory activities and antioxidant potentials had a value of r = −0.68, thus clearly indicating the impact of antioxidant potential and chemical structure on ACE inhibitory activity. The ranking of the AChE enzyme inhibitory activity was Q ≈ Q3G ≈ Q4′G ≈ Ru > Q3,4′G, and the correlation between their antioxidant potentials and AChE inhibitory activities (r = −0.77) also indicated the impact of chemical structure. The quercetin glucosides displayed strong inhibitory capacity on AGE formation, as the ranking of anti-AGE activity in the BSA/MGO model system was Q3,4′G ≈ Q4′G ≈ Q3G > Ru ≈ Q > AG. The anti-AGE activity of rutin, quercetin, and quercetin’s glucosides was negatively correlated with their IC₅₀ values for ACE inhibition (r = −0.67) and AChE inhibition (r = −0.81), whereas no correlation was found between their ACE and AChE inhibition activities. These effects of rutin, quercetin, and quercetin’s glucosides expand our knowledge of the multifunctional activity of biologically active compounds of plant origin. Full article

Glycation in biological systems contributes to the development of chronic diseases, particularly under conditions of hyperglycemia and oxidative stress. This study evaluated the antiglycation and methylglyoxal (MGO)-trapping capacities of aqueous and methanolic extracts of carob flour. The methanolic extract exhibited significantly higher bioactive compounds, containing 1.4-fold more total phenolics and 1.6-fold more flavonoids than the aqueous extract, as well as 1.2- and 1.8-fold-higher antioxidant activity. Antiglycation activity was assessed using bovine serum albumin (BSA)–glucose and BSA–MGO in vitro models, where the methanolic extract consistently outperformed the aqueous extract. At 25 mg/mL, the formation of advanced glycation end-products was inhibited by 81.0% in the BSA–glucose model and nearly 70% in the BSA–MGO model. These findings were supported by lower IC₅₀ values for the methanolic extract (6.6 vs. 10.8 mg/mL and 9.4 vs. 16.6 mg/mL). MGO-trapping capacity was also higher for the methanolic extract, reaching 97% with 25 mg/mL after 168 h. The superior antiglycation and MGO-trapping activities of the methanolic extract are attributed to its higher content of gallic acid and other phenolic compounds with known bioactivities. These results highlight the potential of carob-based formulations as functional ingredients with preventive applications against glycation-associated pathologies. Full article

Background/Objectives: Metformin inhibits secretory function of overactive thyrotrophs, gonadotrophs, and lactotrophs. The clinical significance of an excess of high-molecular-weight prolactin (macroprolactinemia) remains unclear. The aim of the current study was to investigate for the first time whether macroprolactinemia determines the pituitary effects of this drug. Methods: This single-center prospective case–control study included two groups of postmenopausal women with subclinical hypothyroidism, who were matched for age, insulin sensitivity, and plasma concentrations of gonadotropins and TSH. Group A enrolled women with normal prolactin status, while group B included women with macroprolactinemia. Owing to concomitant type 2 diabetes or prediabetes, all the participants received metformin for six months. The outcomes of interest included glucose homeostasis markers (fasting glucose, glycated hemoglobin, and HOMA-IR), plasma prolactin (total and monomeric), macroprolactin, other pituitary hormones (FSH, LH, TSH, and ACTH), and peripheral hormones (estradiol, free thyroid hormones, and IGF-1). Results: Before metformin treatment, the study groups differed only in concentrations of total prolactin and macroprolactin. Metformin decreased FSH and TSH and tended to decrease LH only in group A, and the strength of this effect showed correlations with the baseline levels of these hormones, the degree of improvement in insulin sensitivity, and the macroprolactin content (only in group B). The decrease in fasting glucose, glycated hemoglobin, and HOMA-IR was more pronounced in group A than group B. There were no differences between the pretreatment and posttreatment values of total prolactin, monomeric prolactin, macroprolactin, ACTH, estradiol, free thyroid hormones, and IGF-1. Conclusions: The obtained results suggest that macroprolactinemia may counteract the pituitary effects of metformin. Full article