Search Results (171)

Monascin, a yellow azaphilone pigment derived from Monascus fermentation, undergoes significant photo-degradation that limits its applications. This study reveals that free radical formation, particularly hydroxyl radicals (·OH) generated via H₂O₂ photolysis, is the primary mechanism driving monascin photo-degradation. Dissolved oxygen synergistically accelerates degradation, whereas deoxygenation reduces radical yield by 68% and lowers the degradation to 5%. Enzymatic scavengers confirmed H₂O₂ as the critical ·OH precursor: catalase reduced radicals by 61% and suppressed degradation to 7%, while superoxide dismutase exhibited moderate effects. Natural antioxidants ascorbic acid and α-lipoic acid (ALA) protected monascin concentration-dependently, with ALA showing superior photo-protection (68% degradation reduction) due to its broad ROS-scavenging capacity. These findings establish H₂O₂-derived ·OH as the primary destructive species and identify oxygen exclusion, H₂O₂ decomposition, and radical scavenging as effective photo-stabilization strategies. Full article

Background: Multiple symmetric lipomatosis (MSL) is an orphan disease characterized by pathological expansion of lipomatous tissue (LT) in the subcutaneous adipose tissue (SAT) areas, causing severe deformities and compression of vital organs. To date, the only treatment options available are either lifestyle modification or surgical excision/liposuction. Since sex hormones play an important role in adipose tissue (AT) expansion, they may represent an opportunity for pharmacological treatment. Methods: LT and control SAT were collected from eight MSL patients. Both tissues and derived stromal vascular fraction (SVF) were compared in terms of aromatase (hCYP19A1) and 5-α-reductase isoform (hSRD5A1, -2 and -3) mRNA expression. Primary cultures obtained from one MSL patient were exposed to an aromatase inhibitor, 5-α-reductase inhibitor and DL-α-Lipoic Acid and assayed for cell viability, proliferation and adipogenic differentiation. Results: hCYP19A1, hSRD5A1 and hSRD5A3 were expressed in both MSL-affected and MSL-spared tissues at different levels. Cell viability and proliferation of LT-derived SVF cells were slightly increased by treatment with DL-α-Lipoic Acid and the aromatase inhibitor. Adipogenesis was slightly reduced by Finasteride and strongly reduced by Exemestane (more in LT- than in SAT- derived primary cultures). Conclusions: These preliminary results pave the way for the use of aromatase and 5-α-reductase inhibition as a potential pharmacological approach to tackling dysfunctional adipogenesis in MSL. Therefore, the reported study should be interpreted as exploratory and further experiments are recommended in a larger number of patients to validate these promising results. Full article

Among cardiovascular diseases, myocardial infarction (MI) has become one of the leading causes of mortality worldwide, and the prevalence is anticipated to rise considerably in the coming years. Within non-surgical procedures, chemical drugs, including diuretics, vasodilators, calcium channel blockers, ꞵ blockers, angiotensin converting enzyme inhibitors, are now a well-established option to treat MI progression. However, these drugs are not developed to mitigate oxidative stress directly, which has been recently proven to contribute to MI advancement. Naturally occurring antioxidant compounds possess promising cardioprotective properties and have the potential to be used both as lead compounds for finding novel drugs and complementary therapy to manage MI. While some of them, namely quercetin, puerarin, α-lipoic acid, and curcumin, have already made their way up to clinical trials, numerous compounds have not been sufficiently investigated clinically. To develop and formulate natural antioxidant compounds as drugs against MI, it is crucial to comprehend their underlying mechanisms of cardio-protective activities and structure–activity relationships (SARs). This comprehensive review sheds light on the contribution of oxidative stress in the pathogenesis and progression of Myocardial Infarction, and highlights the cardio-protective roles of 51 natural antioxidant compounds along with their mechanistic insights and SAR. Full article

Neutrophils are essential for antimicrobial defense through reactive oxygen species (ROS) production, tumor necrosis factor-alpha (TNF-α) release, and neutrophil extracellular trap formation. Lipoic acid, a redox-active antioxidant, modulates activation in human neutrophils. Neutrophils isolated from healthy donors were pretreated with lipoic acid and then exposed to lipopolysaccharide (LPS) or whole Escherichia coli, according to the specific assay. ROS production, NET formation, TNF-α release, bacterial killing, metabolic activity, and cell death were assessed using fluorometric assays, enzyme-linked immunosorbent assay, colony-forming unit assays, MTT reduction, and Annexin V-FITC/propidium iodide flow cytometry. Lipoic acid significantly reduced ROS production and NET formation induced by LPS and Escherichia coli. at 0.5 mM, lipoic acid also reduced E. coli-induced NET formation by approximately 50% and attenuated TNF-α release at early stimulation times. In colony-forming unit assays, lipoic acid did not significantly reduce neutrophil-mediated killing of Escherichia coli or Staphylococcus aureus. Although only neutrophil preparations with high baseline viability were used, Escherichia coli challenge markedly reduced cell viability during the assay; under this condition, lipoic acid pretreatment limited bacteria-induced necrosis and preserved a higher proportion of viable neutrophils. These findings indicate that lipoic acid dampens excessive oxidative and inflammatory neutrophil responses while maintaining measurable bactericidal capacity in vitro. Full article

Background/Objectives: Malignant melanoma is characterized by constitutive PI3K/Akt/mTOR and MAPK activation, driving aggressive behavior and therapeutic resistance. Alpha-lipoic acid (αLA), a naturally occurring dithiol compound with an established clinical safety profile, has shown anticancer potential; however, its integrated molecular mechanisms in melanoma remain poorly defined. This study aimed to comprehensively evaluate the cytotoxic and mechanistic effects of αLA in B16F10 murine melanoma cells. Methods: Antiproliferative effects were assessed by MTT assay at four concentrations (250, 500, 750, 1000 µM) over 48 h. Protein levels of apoptotic markers (Bax, Bcl-2, Caspase-3, AIF), kinase signaling components (p-Akt, p-mTOR, p-ERK, p-JNK), ER stress markers (GRP78, GADD153/CHOP), and cell cycle regulator Wee1 were quantified by ELISA at a specifically selected sub-lethal concentration of 750 µM (inducing ~38% growth inhibition). Results: αLA dose-dependently inhibited B16F10 proliferation. At 750 µM, it triggered robust intrinsic apoptotic signaling, evidenced by a nearly 10-fold shift in the Bax/Bcl-2 ratio and greater than 9-fold Caspase-3 activation. Elevated AIF suggested profound mitochondrial stress and the potential priming of concurrent caspase-independent cell death mechanisms. αLA suppressed survival signaling by reducing p-Akt (44%), p-mTOR, p-ERK, and p-JNK. Treatment triggered lethal ER stress via GRP78 and GADD153/CHOP upregulation and upregulated Wee1, suggesting the induction of stress-responsive checkpoint signaling. The simultaneous CHOP upregulation and p-Akt suppression highlight a concurrent dysregulation of stress and survival pathways, suggesting a potential pro-apoptotic interplay. Conclusions: αLA exerts potent multi-target anticancer effects by inducing a broad spectrum of associated molecular changes, including the suppression of PI3K/Akt/mTOR and MAPK networks, induction of ER stress, engagement of cell cycle checkpoints, and activation of the mitochondrial Bax/Bcl-2/Caspase-3 axis. Importantly, these correlative findings do not establish proven pathway dependencies. Nevertheless, this concurrent dysregulation positions αLA as a potential disruptor of inter-pathway resilience underlying drug resistance. Full article

Background/Objectives: α-lipoic acid (ALA) shows therapeutic potential but faces poor aqueous solubility (BCS Class II), gastric instability, and low oral bioavailability (~30%). This work investigated the formulation of cyclodextrin (CD) inclusion complexes of ALA to overcome the aforementioned limitations and improve nutraceutical applications. Methods: Phase solubility studies in simulated gastric and intestinal fluids screened for optimal CD, followed by molecular dynamics simulations and MM-PBSA binding free energy calculations. Inclusion complexes of choice were prepared by grinding, spray-drying, and lyophilization, followed by solid-state characterization (DSC/XRPD/FTIR). Further analysis was performed using pH-shift dissolution (USP II), permeability (PermeaPad^®, Caco-2), and (photo)stability according to ICH. Results: Hydroxypropyl-β-cyclodextrin (HPβCD) emerged as the optimal host due to favorable complexation, as confirmed by phase solubility studies and supported by molecular modeling, which revealed a favorable balance between inclusion complex stability and pH-triggered drug release. Formulations based on spray-dried and lyophilized HPβCD–ALA complexes (HPβALA-sd and HPβALA-lyo), in which ALA was fully amorphized, achieved near-complete dissolution within five minutes under biorelevant pH-shift conditions. This performance markedly exceeded that of free ALA (approximately 66% dissolution at pH 7.4) while maintaining moderate permeability (Papp 8–9 × 10⁻⁶ cm/s). Storage stability was enhanced markedly (88–90% ALA retention after 6 months at 40 °C/75% RH vs. 36% for free ALA) while UV stability was not improved through CD-complexation, probably due to interaction of UV-VIS light with the exposed portion of ALA. Conclusions: Even though the permeability of ALA–CD inclusion complexes remained medium (Papp ~ 8–9 × 10⁻⁶ cm/s) and unaffected by complexation, a significantly improved dissolution profile indicates better expected bioavailability compared to pure ALA. Full article

Background: Cytarabine (Ara-C) remains the cornerstone of remission-induction and consolidation chemotherapy for acute myeloid leukemia (AML) and related hematological malignancies. Despite more than six decades of clinical use, its multi-organ toxicity continues to be managed almost exclusively through dose attenuation and supportive care, with no approved upstream pharmacological prevention strategy available. Objectives: This scoping review aimed to systematically map the breadth and nature of pharmacological agents tested in vivo for their capacity to mitigate cytarabine-induced multi-organ toxicity, to characterize their mechanisms of action and organ targets, and to identify evidence gaps and agents with translational potential. Methods: The review was designed and reported in accordance with the PRISMA-ScR checklist. A structured electronic search was conducted across PubMed/MEDLINE, Scopus, Cochrane Library and Embase, and Web of Science from database inception to 15 July 2025. Eligible studies were restricted to full-text, peer-reviewed, English-language research involving in vivo mammalian models administered cytarabine as the principal toxin, with at least one pharmacological co-intervention and at least one quantitative or histopathological organ-injury outcome. Results: From 5701 retrieved records, 36 eligible in vivo mammalian studies (spanning 1964–2024) were identified. Included studies addressed neurotoxicity (n = 6), gastrointestinal mucositis (n = 9), ocular toxicity (n = 3), hepatotoxicity (n = 3), bone marrow suppression (n = 4), chemotherapy-induced alopecia (n = 5), and reproductive and developmental toxicity (n = 4). Five recurring mechanistic strategies were identified across the heterogeneous agents tested: redox buffering (N-acetylcysteine, α-lipoic acid, rutin, swertiamarin, α-tocopherol), mitochondrial preservation (betanin, thymoquinone, vitamin D, sodium zinc dihydrolipoylhistidinate [DHLHZn]), tissue-microenvironment reprogramming (apraglutide, BADGE, plerixafor, short-chain fatty acids, β-glucan), molecular antagonism (deoxycytidine, dCMP), and immunomodulation (lienal peptide, IL-1β, AHCC). Conclusions: This scoping review provides the first systematic cartography of pharmacological mitigation strategies for cytarabine-induced multi-organ toxicity. Five mechanistic pathways converge across eight organ systems, with apraglutide and N-acetylcysteine representing the most clinically translatable candidates. Plerixafor and PPARγ blockade by BADGE constitute high-priority candidates for bone marrow niche protection, while the deoxycytidine antagonism principle warrants formal pharmacokinetic evaluation. The complete absence of cardiotoxicity mitigation data defines the most critical gap for future research. Full article

Diabetic wounds are characterized by persistent hyperglycemia, excessive ROS accumulation, sustained inflammation, and impaired angiogenesis, yet current treatments remain suboptimal. To address these challenges, we developed a mild heat stimulating and microenvironment reprogramming hydrogel (termed C-4-N) via a green synthetic strategy. L-Arginine (L-Arg) triggered the spontaneous self-polymerization of protocatechuic aldehyde (PA) into poly (protocatechuic aldehyde) (PPA) nanoparticles, onto which ginsenoside Compound K (CK) was subsequently loaded, yielding CK/L-Arg/PPA nanoparticles. These nanoparticles were then uniformly embedded into a dynamic disulfide network composed of α-lipoic acid (LA)-modified chitosan (CS-LA) and 4-arm-PEG-SH under UV irradiation without toxic photo-initiators, forming the C-4-N hydrogel. The C-4-N hydrogel reprogrammed the diabetic wound microenvironment through three synergistic mechanisms, lowering blood glucose and scavenging ROS via the coordinated actions of LA, CK and PPA, promoting M1-to-M2 macrophage polarization via downregulation of pro-inflammatory cytokines (TNF-α, IL-6) and upregulation of anti-inflammatory cytokines (IL-10, TGF-β1), further amplified by mild photothermal stimulation of 40–43 °C. In a diabetic rat model, the C-4-N hydrogel achieved a near-complete wound closure rate of 99.49 ± 0.10% on day 13 upon mild photothermal stimulation, accompanied by enhanced re-epithelialization, organized collagen deposition, vascular maturation, and systemic glucose regulation. In summary, this green synthesized, mild heat-stimulating hydrogel establishes a synergistic microenvironment reprogramming paradigm for chronic diabetic wound managements. Full article

Tuberculosis (TB) treatment is severely hampered by the rise in multi-drug-resistant strains and the prevalence of drug-induced toxicities. Host-Directed Therapies (HDTs) have emerged as a promising strategy to overcome these challenges by modulating innate immunity and circumventing Mycobacterium tuberculosis (Mtb) evasion mechanisms. A hallmark of Mtb pathogenesis is the arrest of phagosome maturation and the induction of host cell necrosis over protective apoptosis. In this study, we investigated the potential HDT effects of α-Lipoic acid (α-LA), a well-known antioxidant and metabolic cofactor, within an in vitro model of Mtb-infected THP-1 macrophages. Our findings indicate that α-LA treatment modulates the macrophage redox state and selectively promotes apoptosis in infected cells without increasing necrotic lysis. Furthermore, α-LA administration led to a significant, dose-dependent restoration of phagolysosome acidification, effectively reversing the maturation blockade imposed by Mtb. Notably, this enhanced acidification inversely correlated with intracellular bacterial survival. These results suggest that α-LA might act as a multifaceted HDT agent capable of restoring both host-protective cell death and phagosomal microbicidal mechanisms. Given its established safety profile and its ability to complement standard anti-TB drugs like Bedaquiline (BDQ), α-LA represents a highly promising candidate for adjunct therapy to improve TB treatment outcomes and mitigate the impact of antibiotic resistance. Full article

Methylglyoxal (MG) is a reactive dicarbonyl compound generated mainly as a byproduct of glycolysis. Excess accumulation of MG can promote protein glycation and the formation of advanced glycation end-products (AGEs), which have been associated with oxidative stress, inflammation, mitochondrial dysfunction, and cellular damage. These processes are implicated in the development of several chronic conditions, including diabetes, neurodegenerative disorders, cardiovascular disease, and age-related decline. The glyoxalase system, comprising Glyoxalase I (Glo1) and Glyoxalase II (Glo2), serves as a key cellular defense mechanism that detoxifies MG and helps maintain dicarbonyl homeostasis. Among these enzymes, Glo1 catalyzes the conversion of MG into less reactive intermediates in a glutathione (GSH)-dependent manner. A range of natural compounds and dietary phytochemicals, including sulforaphane, resveratrol, α-lipoic acid, selenium, vitamin D3, and N-acetylcysteine, have been reported to modulate Glo1 activity through transcriptional regulation, antioxidant effects, or support of intracellular GSH levels. Evidence from preclinical and limited human studies suggests that these compounds may help reduce MG burden and AGE formation, although their effects are often indirect and context-dependent. However, several challenges remain, including variable bioavailability, dose-dependent responses, disease-specific differences in Glo1 regulation, and the lack of standardized biomarkers and adequate clinical validation. This review examines the MG–Glo1 axis as a mechanistic framework linking metabolic stress to disease and evaluates natural compounds as context-dependent modulators of this pathway. By integrating mechanistic insights with emerging in vivo and clinical evidence, this work highlights the potential, while acknowledging the limitations, of targeting Glo1 as a translational strategy for managing glycation-associated disorders. Full article

Background: Neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis, represent a major global health burden and share convergent pathogenic mechanisms, such as mitochondrial dysfunction, oxidative stress, neuroinflammation, calcium imbalance, and neuronal loss. Despite advances in symptomatic management, effective disease-modifying therapies remain limited. Objectives: This review aims to critically synthesize mechanistic, preclinical, and clinical evidence on α-lipoic acid and biotin as candidate neuroprotective agents in neurodegenerative diseases, with emphasis on shared signaling pathways, therapeutic potential, generally favorable safety profiles, and translational limitations. Methods: A narrative and integrative review was conducted, encompassing mechanistic studies, preclinical experimental models, and clinical trials and observational studies evaluating ALA and biotin in neurodegenerative diseases. The evidence was qualitatively analyzed with attention to biological plausibility, consistency across models, and clinical relevance. Results: ALA and biotin modulate key cellular pathways implicated in neurodegeneration, including mitochondrial metabolism, redox homeostasis, inflammatory signaling, and neurovascular function. Preclinical studies consistently report beneficial effects on mitochondrial efficiency, oxidative stress, and neuroinflammatory markers. In contrast, clinical evidence remains heterogeneous, with more extensive evaluation of biotin in progressive multiple sclerosis and more limited or exploratory findings for ALA across neurodegenerative disorders. Conclusions: ALA and biotin exhibit mechanistic convergence across pathways relevant to neurodegeneration and generally favorable safety profiles. Although current evidence supports their biological plausibility as adjunctive or exploratory therapeutic strategies, clinical outcomes remain inconsistent and appear to be influenced by dosing regimens, disease stage at intervention, and endpoint selection. Well-designed clinical studies are required to define their efficacy, optimal dosing, and disease-specific applicability. Full article

The programmed death-ligand 1 (PD-L1) plays a critical role for promoting cancer immune evasion. However, the resistance to PD-L1-targeted immunotherapy greatly limits its application. α-lipoic acid (ALA) is an endogenous antioxidant, while whether ALA affects PD-L1 expression remains unknown. In IFN-γ-stimulated castration-resistant prostate cancer (CRPC)-mimicking PC3 and DU145 cells, the expression of PD-L1 and its regulatory genes was determined by Western blotting, RT-PCR, and immunofluorescence. The T-cell-mediated tumor-killing activity was evaluated in a co-culture system of cancer cells and Jurkat T cells. ALA significantly inhibits IFN-γ-induced PD-L1 protein and mRNA expression without affecting its degradation. The upstream genes accounting for PD-L1 induction, including JAK1/STAT1/IRF-1 cascade, c-Myc, HIF-1α, and GSK3β activity, were markedly suppressed by ALA. The decreased expression of PD-L1 and these regulators by ALA is also modulated by attenuation of mTOR/p70S6K/4EBP1-dependent protein translation and ROS production. In the co-culture system, ALA markedly increased T-cell-mediated tumor-killing activity compared to that of ALA treatment alone, suggesting that ALA may augment the antitumor immunity. Collectively, we demonstrated that ALA-mediated inhibition of PD-L1 expression is regulated by multiple mechanisms, which indicates that ALA may be a potential agent to enhance cancer immunotherapy, particularly in CRPC. Full article

Background/Objectives: This exploratory study (n = 6 per group) investigated the associations between supplementation with α-lipoic acid (AL), betaine (BT), and L-carnitine (LC) and gut microbiota composition in a high-fat diet (HFD)-induced obesity mouse model. Methods: Four-week-old male C57BL/6J mice were fed a control diet (10% fat), HFD (60% fat), or HFD supplemented with AL, BT, or LC (300 mg/kg BW/day) for nine weeks. Results: All three compounds were associated with shifts in microbial composition compared to the HFD-only group. While AL and BT supplementation moderately modulated specific Firmicutes and Bacteroidetes taxa, LC supplementation was linked to a more pronounced reduction in the Firmicutes/Bacteroidetes ratio and a decreased abundance of genera such as Christensenellaceae, Lachnospiraceae, and Coprococcus 3. These microbial changes were correlated with obesity-related metabolic and adiposity markers, including leptin and lipid parameters. Furthermore, functional profiling via PICRUSt suggested potential alterations in amino acid metabolism; however, these findings represent inferred metabolic potential rather than direct metagenomic measurements. Conclusions: Collectively, these results indicate differential associations between dietary supplementation and gut microbiota composition in HFD-fed mice. Although this study was conducted within an exploratory framework and utilized a modest sample size, the observed microbial shifts consistently paralleled metabolic alterations, supporting biologically plausible associations that warrant further mechanistic investigation. Full article

Diabetic neuropathy is a frequent and disabling complication of diabetes, encompassing distal symmetric polyneuropathy and cardiovascular autonomic neuropathy, both associated with reduced quality of life and increased cardiovascular risk. Beyond its traditional interpretation as a direct consequence of chronic hyperglycaemia, oxidative stress has emerged as a central integrative mechanism linking metabolic overload, inflammation, mitochondrial dysfunction, and microvascular injury to progressive neural damage. These processes converge within the neurovascular unit, promoting a self-perpetuating cycle of axonal degeneration, impaired nerve perfusion and altered neuronal excitability. This narrative review synthesises experimental and clinical evidence on oxidative stress-related pathways implicated in diabetic neuropathy, including hyperglycaemia-activated metabolic routes, mitochondrial dysfunction, endoplasmic reticulum stress, and chronic inflammatory signalling. Classical antioxidant and mitochondrial-supportive interventions are evaluated alongside pleiotropic glucose-lowering agents, with particular emphasis on sodium–glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, integrating mechanistic insights with biomarker and clinical outcome data. Conventional antioxidant strategies, such as α-lipoic acid, acetyl-L-carnitine, coenzyme Q10 and N-acetylcysteine, show reproducible benefits on neuropathic symptoms and oxidative stress markers, but evidence for sustained structural or disease-modifying effects remains limited. In contrast, incretin-based therapies and sodium–glucose cotransporter-2 inhibitors exert broader pleiotropic actions by attenuating oxidative and inflammatory signalling, improving mitochondrial homeostasis and endothelial function, with emerging evidence for modest but consistent neurophysiological and autonomic benefits. Overall, oxidative stress emerges as a key mechanistic hub in diabetic neuropathy. Future progress will depend on mechanism-aligned, neuropathy-specific clinical trials incorporating multidimensional endpoints and validated biomarkers. Full article

The citric acid cycle disruptions are implicated in the pathogenesis of chronic diseases, including diabetes, obesity, cancer, and cardiovascular conditions. Numerous publications link TCA cycle disorders to oncological, neurodegenerative, and osteoporotic diseases, and specific single-nucleotide polymorphisms have been proposed as potential markers. Nevertheless, lifestyle and diet have been strongly linked to risk factors for mitochondrial dysfunction; thus, preventive measures that minimize these risks are a relevant field of research. This review summarizes 45 years of relevant publications on the TCA cycle, its genetics and epigenetics, and the restorative potential of certain nutrients. The review includes articles in English and Russian, registered in PubMed, Elsevier, eLIBRARY.RU. The genes encoding the TCA cycle enzymes have been collected and presented. Information is provided that a number of changes in the expression of these genes, for example, Arg18Trp, Ser87Leu, Ala252Thr, and Leu357Val of the ACO2 gene, leads to the development of neurodegenerative diseases; mutations rs121913499, rs121913500 in the IDH1, IDH2 genes, rs1270341616 and the DLST gene lead to the development of cancer. There is evidence that through epigenetic modifications, nutrition affects the activity of the TCA cycle. Niacin, α-lipoic acid, succinic acid, resveratrol, curcumin, arginine, leucine, quercetin, ursolic acid, and alternol affect the regulation of the TCA cycle at the genetic level. Further research into the effects of plant metabolites, vitamins, and bioactive supplements on the TCA cycle may improve the existing preventative and therapeutic diets. Full article