Search Results (494)

Oleanolic acid (OA) is readily modified at C-3 and C-28, but mechanistic studies of its derivatives often rely on downstream signaling readouts. This review examines compound series in which structural changes can be compared with quantitative enzyme data, receptor-level measurements, or functional target dependence, with emphasis on cancer pharmacology. PTP1B-directed studies show that potency and discrimination from the closely related TCPTP are separable SAR properties; later glycoside series changed the PTP1B/TCPTP selectivity profile, while cellular anticancer activity varied independently. Among RTKs, matched C-28 phenylurea derivatives have quantitative VEGFR2 inhibition data, whereas K73-03 has an EGFR-dependent cellular phenotype supported by molecular modeling, receptor phosphorylation, EGFR knockdown, and xenograft experiments. OA dimers show linker- and C-3-acetylation-dependent cellular SAR, while FAK remains a docking-derived target hypothesis without direct kinase validation. AKT/mTOR, AMPK/mTOR, JAK/STAT3, NF-κB, and Nrf2 responses are treated as downstream context unless supported by upstream target evidence. The compounds discussed here remain preclinical, and further development requires matched subtype profiling, direct receptor assays, functional target-dependence experiments, and compound-specific pharmacokinetic evaluation. Full article

Background/Objectives: Alzheimer’s disease (AD) is associated with impaired brain insulin signaling, oxidative stress, and neuroinflammation. This study investigated the effects of incensole acetate (IA) on sirtuin-associated insulin-signaling and cellular stress-response pathways using integrated computational and in vitro approaches. Methods: ADMET prediction, molecular docking, molecular dynamics simulations, and MM-PBSA analyses were performed for IA against SIRT1, SIRT3, and SIRT6 and compared with their corresponding reference ligands. An Aβ1–42-induced AD model was established in mesenchymal stem cell-derived neurons. The effects of IA on insulin-signaling components, sirtuins, Aβ, NF-κB, NRF2, and PPARα were evaluated using RT-qPCR, Western blotting, and immunofluorescence. Results: IA showed weaker docking affinities than the corresponding reference ligands for all three sirtuins, whereas trajectory-based analyses revealed target-dependent dynamic behavior. MM-PBSA-derived binding-energy estimates were −35.16 ± 3.32, −30.24 ± 3.63, and −38.26 ± 3.90 kcal/mol for IA with SIRT1, SIRT3, and SIRT6, respectively, with IA showing a more favorable relative energetic profile than 8L9 for SIRT6. In vitro, IA treatment was associated with reduced detectable Aβ levels and modulation of INSR, IRS, AKT, and AS160 expression. IA increased SIRT1 and SIRT6 expression, whereas SIRT3 protein levels were not significantly altered. IA also reduced NF-κB and increased NRF2 and PPARα expression. Conclusions: IA modulated insulin-signaling-related, sirtuin-associated, inflammatory, oxidative-stress, and metabolic markers in an Aβ1–42-induced cellular AD model. Computational analyses support potential IA–sirtuin interactions, particularly a favorable relative MM-PBSA energetic profile for SIRT6; however, direct sirtuin activation or causal sirtuin-mediated signaling was not established. Full article

Adaptogens are natural substances proposed to enhance non-specific resistance to stress and support physiological homeostasis. This review critically evaluates the phytochemistry, molecular mechanisms, human-health relevance, and translational evidence for seven proposed next-generation adaptogens: Lepidium meyenii, Astragalus membranaceus, Cordyceps militaris, Rhaponticum carthamoides, Gynostemma pentaphyllum, Centella asiatica, and Glycyrrhiza glabra. Evidence from mechanistic studies, clinical trials, systematic reviews, and meta-analyses was critically synthesised with emphasis on chemically characterised preparations, molecular target engagement, human exposure, and the distinction between preclinical and clinical evidence. The most consistently supported mechanisms include fatty acid amide hydrolase (FAAH) inhibition by maca macamides; telomerase- and senescence-related effects of Astragalus constituents; and AMP-activated protein kinase (AMPK)-centred metabolic regulation by cordycepin and gypenosides. Other relevant pathways include oestrogen receptor beta (ERβ)-related and phosphoinositide 3-kinase/protein kinase B (PI3K/Akt)-dependent anabolic signalling by phytoecdysteroids; brain-derived neurotrophic factor/tropomyosin receptor kinase B (BDNF/TrkB)-associated neuroplasticity and nuclear factor erythroid 2-related factor 2 (NRF2)-dependent redox regulation by C. asiatica; and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) inhibition by glycyrrhetinic acid. However, evidence strength differs markedly among species and outcomes, and many mechanisms remain predominantly preclinical. Clinical translation is further limited by extract variability, incomplete pharmacokinetic characterisation, uncertain bioavailability, and safety concerns. The next-generation adaptogen concept should therefore be regarded as a pathway-oriented framework whose validation requires standardised preparations, mechanism-aligned biomarkers, clinically relevant endpoints, and rigorous safety assessment. Full article

Background: Cadmium (Cd) exposure impairs the autophagic response, a core mechanism for cell preservation and organismal homeostasis, eventually resulting in metabolic disturbances, mitochondrial dysfunction, and oxidative stress. L-theanine (LT) exhibits multiple health benefits with a high safety profile. However, the effects of LT on Cd exposure-induced impairments in autophagy and autophagy-related physiological functions remain unclear. Methods: This study investigated the effects of LT on the survival time of mice acutely exposed to Cd and the regulating effect of LT on autophagy and subsequent metabolic dysfunction in mice subjected to subchronic Cd exposure. Results: The results showed that acute Cd exposure resulted in 100% mortality within 8 h. However, LT treatment significantly prolonged the median survival time of mice from 4 h to 16 h and reduced the mortality to 60%. In the context of subchronic Cd exposure, autophagy was inhibited, as evidenced by the downregulation of the AMPK/mTOR signaling pathway mediated by DPP-4 and SIRT1. This exposure also promoted lipid peroxidation and ferroptosis, indicated by the inactivation of the AMPK/p-ACC axis and marked alterations in ferroptosis markers. Furthermore, mitochondrial dysfunction was suggested by the downregulation of the SIRT1/PGC-1α/Nrfs/TFAM signaling pathway and reductions in COX and SDH activities. Additionally, glucolipid metabolism was impaired, as indicated by the downregulation of the AMPK and PI3K/AKT signaling pathways and elevated lipid and glycogen accumulation in the liver of mice. LT significantly decreased the level of DPP-4 and upregulated SIRT1, leading to the activation of AMPK. This activation restored autophagy response by downregulating mTOR, promoted energy homeostasis by reducing lipid biosynthesis and enhancing fatty acid oxidation, blocked lipid peroxidation and ferroptosis through the phosphorylation of ACC at the serine 79 site and reducing the ubiquitination-mediated degradation of GPX4, and maintained mitochondrial function by upregulating the PGC-1α/Nrfs/TFAM signaling pathway. Conclusions: Collectively, LT effectively ameliorates mitochondrial dysfunction, ferroptosis and glucolipid dysmetabolism in Cd-exposed mice, and these effects are accompanied by findings consistent with modulation of autophagy-related signaling in the liver. Full article

GLP-1RAs improve glycemia and body weight, but their effects extend beyond insulin secretion and appetite suppression. Experimental evidence indicates that GLP-1 receptor signaling can relieve lipotoxic stress by reducing lipid influx, restoring lipid trafficking, promoting cholesterol efflux, improving mitochondrial and endoplasmic reticulum homeostasis, and suppressing inflammatory and apoptotic signaling. In pancreatic beta cells, saturated fatty acids, oxidized low-density lipoprotein and excess free cholesterol disrupt membrane microdomains, insulin-granule trafficking, calcium signaling, autophagic flux and beta-cell identity. Preclinical studies with individual GLP-1RAs, principally exendin-4 and liraglutide, implicate cAMP/PKA, PI3K/Akt, ERK1/2, AMPK, Nrf2 and autophagy-related pathways in these protective responses. A relevant mechanism is induction of ATP-binding cassette transporter A1 (ABCA1): exendin-4 stimulates ABCA1 transcription through the CaMKK/CaMKIV/PREB axis, linking incretin signaling to cholesterol export and preservation of glucose-stimulated insulin secretion. Recent work indicates spatially organized GLP-1R signaling at endoplasmic reticulum–mitochondria contact sites. Preclinical genetic evidence in mouse metabolic dysfunction-associated steatohepatitis (MASH) models indicates that pericentral liver sinusoidal endothelial GLP-1 receptors contribute to weight-loss-independent semaglutide-mediated improvements in steatosis, fibrosis and immune remodeling; whether an analogous causal mechanism operates in human MASH remains unknown. This review integrates systemic nutrient unloading, beta-cell cholesterol homeostasis and intrahepatic endothelial signaling as complementary mechanisms of metabolic protection. Full article

With increasing global life expectancy, there is a growing need for strategies to mitigate age-related declines in fitness and health. Withania somnifera (WS), commonly known as ashwagandha, has been traditionally recognized by ayurvedic medicine for its benefits in promoting healthy aging. More recently, it has also emerged as a potential treatment option for age-related diseases such as Alzheimer’s disease (AD), Parkison’s disease, and Huntington’s disease. WS has been shown to improve sleep quality, has adaptogenic and antioxidant properties, and enhances exercise performance by improving muscle strength and recovery. However, the molecular mechanisms underlying the effects of WS on aging are poorly understood. Therefore, we used Drosophila melanogaster flies to assess the impact of analytically characterized water (WSAq) extracts of WS root. To test effects during aging, the flies were treated at middle-age (4 weeks from eclosion) for two weeks. We found that WSAq reduced Akt phosphorylation in fly heads and that Akt is required to improve fitness in the fast phototaxis assays. We also determined that the effects of WSAq treatment depended on the Akt downstream pathways Tsc/mTOR, FOXO, and NRF. This supports that WS provides resilience to the age-related decline in fitness by modifying Akt signaling and affecting downstream pathways connected to aging and longevity. Full article

Wheat (Triticum aestivum L.) is among the most widely consumed cereal grains worldwide and is essential for global food security. This review critically examines current evidence on wheat bioactive compounds, nutritional composition, and health-promoting properties. Wheat contains diverse nutritional and bioactive compounds, including phenolic acids, flavonoids, lignans, alkylresorcinols, phytosterols, and bioactive peptides. This review systematically evaluates evidence across multiple levels, from chemical characterization and cell-based studies to animal models and human clinical trials, with explicit differentiation of evidence quality. Wheat-derived compounds demonstrate antioxidant, antidiabetic, anti-obesity, anti-inflammatory, anticancer, antimicrobial, and gut microbiota-modulating activities in preclinical models. Identified molecular mechanisms converge on Nrf2-mediated antioxidant defense, NF-κB inflammatory pathway inhibition, AMPK metabolic regulation, and PI3K/AKT insulin signaling. Recent advances in artificial intelligence (AI) and machine learning provide new tools for identifying wheat bioactive molecules, predicting biological targets, and assessing flour quality through hyperspectral imaging. AI-integrated multi-omics approaches offer potential for personalized wheat-based nutrition strategies by matching individual genetic, metabolic, and microbiome profiles to specific wheat varieties or bioactive extracts. This review concludes that wheat-derived bioactive compounds show significant nutraceutical potential; however, clinical translation requires rigorous human studies, and safety considerations for gluten-sensitive populations must be addressed. Full article

Oxidative stress is caused by the imbalance between the generation of free reactive oxygen species (ROS)/reactive nitrogen species (RNS) and the antioxidant defense systems, which participate in animal growth, development, disease pathogenesis, and aging. This review summarizes endogenous and exogenous triggers of ROS/RNS overproduction, as well as model animals and cell models together with oxidative stress biomarkers and detection methods. We further dissect the three-layered redox regulatory network, focusing on crosstalk among four core pathways (Nrf2-ARE, NF-κB, MAPK, PI3K/Akt) that govern cell fate via oxidative eustress or distress. Excessive ROS/RNS trigger irreversible DNA damage and metabolic disorders, leading to inflammation and apoptosis. Finally, we prospect integrating non-model animals and multi-omics to advance oxidative stress research. This work provides a comprehensive theoretical framework for animal redox biology studies. Full article

Morchella polysaccharides are commonly labeled as antioxidants because they quench radicals in chemical assays, yet this designation does not establish biological redox efficacy. This critical narrative review reframes these fungal polymers as candidate redox-modulating biomacromolecules. A structured search of PubMed and OpenAlex through 17 August 2026 yielded 84 unique records after deduplication; 31 core Morchella-polysaccharide reports with redox-relevant experimental evidence were mapped, supplemented by five mechanistically adjacent studies. Evidence was graded from chemical assays (E1) to human intervention (E5), with a separate causality score (M0–M2). Structure-resolved studies indicate that molecular weight, branching, charge, conformation, source, and acetylation or degradation can modify activity, but process-related co-variation and incomplete purity controls preclude universal structure–activity rules. Cellular and animal studies repeatedly implicate PI3K/Akt–Nrf2/HO-1, AMPK/Sirt1, mitochondrial apoptosis, NF-κB/NLRP3, and gut-mediated pathways, although most reported links remain associative. Within the databases and search strategy used, no eligible human intervention study was identified. We propose a translational roadmap requiring identity-controlled materials, orthogonal redox endpoints, causal pathway perturbation, exposure and microbiota studies, and standardized early-phase trials. The field should move beyond DPPH-positive claims toward reproducible mechanisms and biologically credible redox protection. Full article

Background: Obesity is a multifaceted metabolic disorder characterized by systemic disturbances, particularly impaired energy homeostasis, chronic low-grade inflammation, and mitochondrial dysfunction across the brain, gut, adipose tissue, and liver axes. Objectives: This review aims to examine the metabolic properties and molecular mechanisms of six key phytochemicals (berberine, resveratrol, catechins, capsaicin, thymoquinone, and phycocyanin) and the exercise-induced myokine irisin, and their roles in mitochondrial signaling and metabolic reprogramming. Sources of Evidence: A comprehensive literature search was conducted across major electronic databases, including PubMed, Web of Science, and Scopus, to identify relevant mechanistic, in vivo, and in vitro studies. Results: Both the selected phytochemicals and irisin act as multi-target regulators that modulate key signaling pathways, including AMPK, PI3K/Akt/mTOR, SIRT1, Nrf2, and PPARγ. These phytochemicals and irisin can drive cell- and tissue-specific metabolic reprogramming, promoting the browning of white adipocytes, suppressing de novo lipogenesis in hepatocytes, and enhancing fatty acid oxidation in skeletal myocytes. This synergistic metabolic reprogramming enhances thermogenesis and increases energy expenditure. Conclusions: Co-targeting redox signaling and metabolic pathways via phytochemicals and irisin offers a powerful strategy against obesity. This integrative framework restores multi-organ homeostasis, laying the groundwork for targeted metabolic therapies. Full article

Background/Objectives: Oxidative stress, chronic inflammation, disrupted apoptosis, and altered autophagy are biological processes implicated in colorectal tumor development. Morin is a plant-derived flavonoid with antioxidant and anti-inflammatory properties, but its limited solubility and bioavailability may limit its biological activity. This study evaluated the effects of free morin and morin-loaded liposomes (MOR-Lips) on 1,2-dimethylhydrazine (DMH)-associated colonic biochemical, molecular, and histopathological alterations in rats. Methods: Rats were randomly assigned to six groups—vehicle control, MOR, MOR-Lips, DMH, DMH + MOR, and DMH + MOR-Lips—and treated for 10 weeks. Serum and colonic tissues were evaluated for cancer-associated biomarkers (CEA, CA19-9, CA125, HMG-CoA reductase), oxidative stress and antioxidant indices, nitrosative and oxidative DNA-damage markers (MDA, NO, 8-OHdG), inflammatory mediators (TLR4/NF-κB/COX-2, cytokines, MPO), proliferative indices (Ki-67, PCNA), apoptotic and autophagy-related regulators (Bax, caspase-3, p53, cytochrome c, BCL-2, p-AKT, LC3-II, Beclin-1, p62), and histopathological and immunohistochemical changes. Results: DMH exposure was associated with increased CEA, CA19-9, CA125, HMG-CoA reductase, MDA, NO, 8-OHdG, TLR4/NF-κB/COX-2, cytokines, MPO, Ki-67, and PCNA. DMH also reduced NRF2/HO-1 signaling and antioxidant defenses, shifted apoptosis-related markers toward a pro-survival profile, altered autophagy-related markers, and produced marked colonic histopathological abnormalities. Both free MOR and MOR-Lips attenuated several of these DMH-associated alterations, with MOR-Lips generally producing greater effects than free MOR. MOR-LIP treatment was associated with restoration of antioxidant marker profiles, reduced levels of inflammatory and proliferative markers, a shift toward a pro-apoptotic marker profile, partial normalization of autophagy-related markers, and improved colonic histopathological appearance. Conclusions: In DMH-exposed rats, MOR-Lips were associated with more favorable redox, inflammatory, proliferative, apoptosis-related, autophagy-related, and histopathological profiles than free MOR. These findings support further investigation of MOR-Lips as a formulation strategy for improving the biological activity of morin. Because quantitative preneoplastic and neoplastic endpoints were not measured, the results do not establish inhibition of colorectal carcinogenesis or chemopreventive efficacy. Full article

Population aging has intensified the search for natural compounds capable of promoting healthy aging and preventing age-related diseases. Among medicinal plants, species of the genus Crataegus (hawthorn) have attracted increasing attention because of their rich phytochemical composition and broad spectrum of biological activities. This review summarizes and critically evaluates current evidence on the geroprotective potential of Crataegus species, integrating data from phytochemical, pharmacological, and mechanistic studies. Particular attention is given to the major bioactive constituents of Crataegus, including flavonoids, oligomeric proanthocyanidins, phenolic acids, and triterpenoids, which exhibit antioxidant, anti-inflammatory, cardioprotective, neuroprotective, metabolic, and anticancer properties. We discuss the growing evidence that these phytochemicals target multiple hallmarks of aging by modulating oxidative stress, chronic low-grade inflammation (inflammaging), mitochondrial dysfunction, cellular senescence, and the senescence-associated secretory phenotype (SASP). Their biological effects are mediated through key signaling pathways involved in cellular homeostasis and longevity, including Nrf2/ARE, NF-κB, PI3K/Akt/mTOR, AMPK, and SIRT1. The review also critically examines findings from in vitro, in vivo, and available clinical studies, highlighting both the therapeutic potential and current limitations of Crataegus-based interventions for age-related disorders. Although preclinical evidence strongly supports the multi-target geroprotective properties of Crataegus species, clinical validation remains limited. Overall, Crataegus represents a promising source of natural geroprotective agents with the potential to promote healthy aging through the modulation of multiple aging-related molecular pathways. Future well-designed clinical studies are essential to establish their efficacy, safety, optimal dosage, and long-term therapeutic value in humans. Full article

Uveitis comprises a heterogeneous group of intraocular inflammatory diseases that differ in anatomical location, etiology, clinical course, and immune mechanisms. Despite this diversity, evidence derived predominantly from experimental autoimmune uveitis (EAU) suggests that oxidative stress may act as a context-dependent amplifier linking immune activation, ocular barrier dysfunction, and tissue injury. Excess reactive oxygen species (ROS) disrupt redox homeostasis and activate redox-sensitive inflammatory signaling, thereby amplifying cytokine production, mitochondrial dysfunction, leukocyte recruitment, and retinal damage. This review summarizes current evidence on oxidative stress in uveitis, focusing on major ROS-generating systems, NF-κB-driven inflammation, Nrf2/HO-1-mediated antioxidant responses, MAPK and PI3K-Akt signaling, and immune–metabolic pathways involved in autoimmune ocular inflammation. Cell-specific responses in retinal and immune cells further illustrate how redox imbalance may contribute to local tissue injury and immune-mediated disease progression. The role of oxidative stress in blood–ocular barrier dysfunction, particularly blood–retinal barrier disruption during posterior segment inflammation, is also discussed. Overall, preclinical studies support an active role for oxidative stress in inflammatory amplification and ocular tissue injury, whereas evidence from patients with defined uveitic entities remains limited, heterogeneous, and largely associative. Redox-directed treatments should therefore currently be regarded as investigational adjunctive strategies rather than established therapies for uveitis. Full article

Bioactive polyphenols have emerged as multi-target regulators of cellular processes involved in the pathogenesis of skin diseases. Skin disorders, including inflammatory conditions, photoaging, and skin cancers, are characterized by complex pathogenic mechanisms associated with oxidative stress, mitochondrial dysfunction, dysregulated signaling pathways, and metabolic imbalance. Excessive production of reactive oxygen species (ROS) and persistent inflammatory signaling contribute to disease progression and cellular adaptation under stress conditions. Unlike conventional agents that typically target a single pathway, polyphenols act on interconnected signaling and metabolic networks. These compounds regulate key signaling pathways, including phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), AMP-activated protein kinase (AMPK), nuclear factor-κB (NF-κB), and nuclear factor erythroid 2-related factor 2 (Nrf2), thereby regulating cell survival, proliferation, inflammatory responses, antioxidant defense, and metabolic adaptation. Polyphenols also influence mitochondrial function by maintaining redox homeostasis, regulating energy metabolism, and affecting apoptosis-related signaling pathways. This review provides a mechanistic overview of the effects of polyphenols on oxidative stress, mitochondrial function, and cell survival signaling in skin diseases. In addition, the therapeutic implications and current limitations of polyphenol-based approaches are discussed, with particular emphasis on the translational gap between experimental findings and physiological relevance. Factors such as concentration, bioavailability, and cellular microenvironment are highlighted as major determinants of polyphenol activity and key challenges for clinical translation. Finally, the need for further in vivo and clinical investigations is emphasized to support the development of effective polyphenol-based therapeutic strategies for skin diseases. Full article

Cirsium japonicum Fisch. ex DC. has long been used in traditional East Asian medicine and has attracted increasing attention because of its diverse pharmacological activities, including antioxidant, anti-inflammatory, antifibrotic, metabolic regulatory, and anticancer effects. Although numerous studies have investigated its phytochemical composition and biological activities, current evidence has largely been organized according to individual compounds or disease categories, providing limited insight into the shared molecular mechanisms underlying its pleiotropic actions. In this review, we critically re-evaluate the molecular pharmacology of C. japonicum using an evidence-oriented framework that distinguishes experimentally supported mechanisms from pharmacological associations and emerging hypotheses. Rather than accepting changes in signaling proteins or downstream biomarkers as sufficient evidence of mechanism, we assess the strength of evidence based on reproducibility, pathway-specific interventions, genetic or pharmacological validation, and direct target engagement. Current evidence indicates that nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant responses and nuclear factor kappa B (NF-κB)-associated inflammatory responses represent the most consistently observed pathway associations, although direct molecular targets and causal pathway dependency remain insufficiently established. Evidence for AMPK/PI3K-Akt-associated metabolic regulation and TGF-β/Smad-associated antifibrotic responses is comparatively more limited. In contrast, modulation of apoptosis and autophagy is currently supported primarily by indirect or context-dependent observations. We further discuss how multiple phytochemicals converge on interconnected signaling networks regulating oxidative stress, inflammation, metabolism, tissue remodeling, and cell fate, thereby providing a systems-level explanation for the broad therapeutic potential of C. japonicum. Finally, we highlight the need for standardized phytochemical characterization, rigorous target validation, multi-omics integration, and artificial intelligence-assisted systems biology to establish causal molecular mechanisms and accelerate the translational development of evidence-based phytopharmaceuticals. Full article