Catechins are a group of flavonoids found primarily in green tea, fruits, and berries; they play a significant role in the modulation of the gut microbiota, thereby having an impact on gut health and cancer prevention. Owing to their low bioavailability, catechins are transformed by the gut microbiota into various bioactive metabolites such as valerolactones and glucuronides, which support the growth of several beneficial bacterial species including Bifidobacterium and Lactobacillus while inhibiting harmful strains like Clostridium difficile and Escherichia coli. These interactions enhance metabolic balance, reduce inflammation, and help maintain gut homeostasis, which is critical for preventing gut dysbiosis. Dysbiosis is characterized by a shift from symbiotic to pathogenic microbial populations and is closely associated with cancer development, especially in the gut. This review explores how catechins, particularly epigallocatechin gallate (EGCG), contribute to cancer prevention by promoting a symbiotic microbial environment, supporting immune modulation, and inhibiting inflammatory pathways. By examining the role of catechins in both health and cancer, this paper aims to emphasize their therapeutic potential as dietary supplements in maintaining gut health and reducing cancer risk.
Ruta graveolens L. is widely used in traditional European, Asian, African, and South American medicine for digestive, nervous, cardiovascular, respiratory, and reproductive disorders. Despite its long-standing ethnomedical relevance, the translation into evidence-based phytotherapy remains limited due to fragmented pharmacological data and well-documented safety concerns. This review critically synthesizes ethnomedical use, phytochemical composition, pharmacological activities, and toxicological risks of R. graveolens, aiming to evaluate its therapeutic potential and identify key research gaps. A systematic search and critical analysis were conducted following PRISMA guidelines using PubMed, ScienceDirect, and Google Scholar. Ethnomedicinal data were reviewed without time limits, while phytochemical and pharmacological studies published between 2014 and 2025 were analysed in detail. More than 160 compounds (including furanocoumarins, alkaloids, flavonoids, and others) have been identified by HPLC, CC, GC-MS, and NMR methods, of which 38 are characteristic markers. The plant exhibits a wide spectrum of activity, from antimicrobial to antitumor. However, due to the content of furanocoumarins and alkaloids, the extracts have phototoxic, abortifacient, hepatotoxic, and nephrotoxic effects, which highlights safety concerns in the absence of dosage control. Although R. graveolens represents a chemically diverse source of bioactive compounds with promising pharmacological potential, its integration into modern phytotherapy requires rigorous toxicological evaluation, extract standardization, and well-designed preclinical and clinical studies. Future research should prioritize development of standardized extracts with defined phytochemical profiles, comprehensive dose-dependent toxicological assessment, and translational studies bridging experimental findings with clinical applications with particular attention to safe therapeutic windows and less toxic bioactive constituents.
Oxyfil is a dietary supplement including plant extracts from Epilobium angustifolium, Ptychopetalum olacoides (Muira puama), Ginkgo biloba, and Equisetum arvense and citrulline. The aim of the study was to investigate the protective effects on prostatic muscles of the Oxyfil formulation in an in vitro experimental model consisting of isolated mouse prostate specimens exposed to Escherichia coli lipopolysaccharide (LPS) as a pro-inflammatory stimulus. The study also assessed the tolerability and effectiveness of Oxyfil in alleviating lower urinary tract symptoms (LUTS) in patients with benign prostatic hyperplasia (BPH) when used in association with standard care. In the preclinical phase, Oxyfil was analysed via liquid chromatographic in order to identify and quantify phenolic compounds. Thereafter, the formulation was tested on isolated mouse prostate challenged with LPS in order to upregulate the gene expression of different pro-inflammatory and oxidative stress biomarkers, namely COX-2, i-NOS, TNFα, IL-6, VEGFA, HIF1α. The clinical trial was a retrospective, multicentre study. Fifty-nine patients were analyzed: 27 received Oxyfil, 18 Oxyfil + α-blocker, 7 Oxyfil + PDE5i, and 7 Oxyfil + 5-ARI. Key inclusion criteria were age 50-75 years, moderate to severe LUTS (IPSS), mild erectile dysfunction, and baseline Qmax 4-15 mL/s; exclusions were endocrine/hormonal erectile dysfunction, bladder-neck sclerosis, and urethral stricture. Treatment selection was non-randomized and left to the treating physician. The chromatographic analysis identified 25 phenolic compounds in the Oxyfil formulation. The total phenolic content can explain, albeit partially, the Oxyfil efficacy in blunting LPS-induced upregulation of the gene expression of all tested biomarkers in isolated prostate. The protective effects demonstrated in the preclinical phase also support, albeit partially, the clinical efficacy in ameliorating uroflowmetry and symptom outcomes in the patients' cohort. In conclusion, the present study demonstrated anti-inflammatory and antioxidant effects of the Oxyfil formulation in the prostate which corroborated the observed clinical outcomes.
Hepatic ischemia-reperfusion injury (HIRI) is a major challenge in liver surgery, and effective pharmacological interventions are lacking. Salvianolic acid C (SaC) has shown protective effects in various pathologies, but its role in HIRI remains unclear. This study investigated whether SaC protects against HIRI and elucidated the underlying mechanisms. Bioinformatics analysis of GSE151648 identified differentially expressed heat shock proteins (HSPs) and associated pathways. Molecular docking predicted SaC binding to HSP90α and AKT. A murine HIRI model was established with SaC (10 mg/kg, i.p.) pretreatment for 7 days. Histology, serum transaminases, and oxidative stress markers assessed liver injury. HSP90α inhibition used 17-AAG; in vitro hypoxia/reoxygenation (H/R) experiments used AML12 hepatocytes. Clinical validation used paired liver tissues from patients undergoing ex vivo liver resection and autotransplantation. Twenty-one HSP genes were differentially expressed, with HSP90α as a core hub gene in the PI3K/AKT pathway. SaC showed high binding affinity for HSP90α (-8.7 kcal/mol) and p-AKT1 (-10.9 kcal/mol). In mice, SaC upregulated HSP90α, reduced necrosis and serum transaminases, decreased MDA and increased GSH and SOD, suppressed TNF-α, IL-1β, and IL-6, and reduced apoptosis (Bax/Bcl-2, cleaved caspase-3), while activating PI3K/AKT. These effects were abolished by 17-AAG and confirmed in H/R-treated AML12 cells. HSP90α was also upregulated in post-transplant human livers. SaC protects against HIRI by upregulating HSP90α and activating PI3K/AKT, thereby alleviating oxidative stress, inflammation, apoptosis, and necrosis. These findings support SaC as a potential therapeutic strategy for HIRI.
Heart failure (HF) and atrial fibrillation (AF) are among the most prevalent cardiovascular diseases, often coexisting and sharing common pathophysiological pathways such as systemic inflammation, oxidative stress, mitochondrial dysfunction, and endothelial impairment. Despite substantial progress in pharmacological treatment, including renin-angiotensin-aldosterone system (RAAS) inhibitors, beta-blockers, sodium-glucose cotransporter 2 (SGLT2) inhibitors, mineralocorticoid receptor antagonists (MRAs), diuretics, and antiarrhythmic drugs, many patients continue to experience residual symptoms and drug-related adverse effects. Nutraceuticals have emerged as potential adjuncts to conventional therapy due to their ability to modulate key biological processes involved in HF and AF. Polyphenols from Olea europaea, Hibiscus sabdariffa, Camellia sinensis, and Vitis vinifera (resveratrol) exhibit antioxidant, anti-inflammatory, and vasoprotective effects. Omega-3 fatty acids and astaxanthin contribute to inflammation control and redox balance, while Orthosiphon stamineus and Taraxacum officinale show mild diuretic activity. Moreover, anthocyanins, ursolic acid, and Rhodiola crenulata may exert antifibrotic and antiarrhythmic properties. This review provides a mechanistic comparison between pharmacological agents and nutraceuticals with overlapping mechanisms of action, highlighting their potential role in integrative cardiovascular care. While nutraceuticals are not substitutes for established therapies, emerging evidence supports their complementary use in improving treatment response, reducing side effects, and enhancing patient outcomes. Future research should focus on large-scale trials, improved bioavailability, standardized formulations, and the development of personalized therapeutic strategies. Challenges related to dosage consistency, clinical validation, and regulatory oversight are also addressed to guide innovation in integrative cardiology.
Intracerebral hemorrhage (ICH) remains the most severe stroke subtype with high mortality and disability rates. Although apigenin has shown cerebroprotective potential in preclinical studies, its mechanism of action, particularly in hypertensive ICH, remains poorly understood. This study investigates the molecular pathway through which apigenin confers protection against hypertensive ICH. We employed a hypertensive ICH mouse model treated with varying apigenin doses. Through transcriptomic profiling, molecular docking, surface plasmon resonance (SPR), and pull-down assay, we identified peroxiredoxin 2 (PRDX2) as a direct target of apigenin. Prdx2-/- mice and recombinant human thioredoxin 1 (rhTrx1) rescue experiments were utilized to validate the signaling pathway. Histological analysis, western blot, immunofluorescence, and zymography were applied to assess hemorrhage, oxidative stress, inflammation, and extracellular matrix (ECM) remodeling. Apigenin administration significantly reduced ICH incidence, hemorrhage volume, and area while enhancing vascular integrity, independent of blood pressure changes. We identified PRDX2 as a direct binding partner of apigenin, with their interaction stabilizing PRDX2 expression. PRDX2 deficiency abolished apigenin's protective effects and exacerbated oxidative stress, neuroinflammation, and vascular damage. Furthermore, apigenin upregulated Trx1 expression via PRDX2, and rhTrx1 administration rescued the protective phenotype in Prdx2-/- mice by reducing oxidative damage, inflammatory cell infiltration, and vascular smooth muscle cell apoptosis. Our study elucidates a novel apigenin-PRDX2-Trx1 antioxidant signaling pathway that protects against hypertensive ICH through blood pressure-independent mechanisms. These findings not only provide a mechanistic foundation for developing apigenin-based therapeutics for cerebrovascular diseases, but also offer novel strategies and entry points for future clinical translation.
Brassinin, a phytoalexin compound derived mainly from Chinese cabbage, shows anticancer activity against several types of cancer. In this study, we aimed to investigate the role of brassinin in glioma progression and reveal the underlying mechanism. CCK8 assays were used to investigate the dose- and time-dependent effects of brassinin on the growth of different glioma cell lines, and then colony formation assays were employed to measure cell proliferation. Next, we used flow cytometry/Western blotting to assess cell cycle progression, apoptosis, and reactive oxygen species (ROS) production, and employed Western blotting/fluorescence staining for LC3, p62, and other signaling molecules to evaluate autophagy. Finally, we confirmed the in vitro findings in both the subcutaneous and intracranial glioma models using hematoxylin and eosin staining, immunohistochemistry, and immunofluorescence. Brassinin blocked cell cycle progression, inhibited proliferation, and promoted apoptosis in glioma cells. Brassinin inhibited autophagy, induced ROS overproduction, and suppressed the expression/activity of AMPKα-beclin1 signaling. The effect of brassinin on cell growth and survival was partially reversed by an ROS scavenger or an autophagy activator in glioma cells. Brassinin regulated the AMPKα/beclin1 signaling and autophagy via promoting ROS production in glioma cells. The anticancer role of brassinin was confirmed in subcutaneous and intracranial glioma models, and brassinin administration prolonged the survival of tumor-bearing mice. Brassinin inhibited cell survival and autophagy in glioma cells via modulation of ROS production and the AMPKα-beclin1 signaling pathway. Our study identified a promising botanical drug for the treatment of gliomas.
Metabolic-associated fatty liver disease (MAFLD), formerly known as non-alcoholic fatty liver disease (NAFLD) has caused a significant health burden. Glycyrrhiza uralensis Fisch. is a traditional Chinese medicinal herb used to prevent and treat numerous diseases. Liquiritigenin (LQ), a flavonoid isolated from Glycyrrhiza uralensis Fisch., has shown potential benefits in regulating lipid metabolism. This study aimed to analyze whether LQ was involved in ameliorating hepatic steatosis and elucidate the specific molecular mechanisms. A high-fat diet (HFD) model of male C57BL/6J mice was established to evaluate the effects of LQ on regulating hepatic steatosis. The potential molecular mechanisms of LQ on promoting lipid droplet catabolism were assessed in vitro using HepG2 cells treated with palmitic acid (PA) and/or LQ. The impact of the PLIN2-ATGL signaling in lipid droplet catabolism was elucidated by treating HepG2 cells with NG-497 (an ATGL inhibitor), the inhibitor of ATGL, and by constructing Plin2-overexpressed HepG2 cell lines. Both in vivo and in vitro experiments demonstrated that LQ alleviated excessive lipid accumulation, enhanced lipolysis and lipophagy, down-regulated PLIN2 expression and up-regulated CGI-58 expression. Further, inhibiting lipolysis with NG-497, the inhibitor of ATGL, attenuated the effects of LQ on increasing the phosphorylation of HSL and promoting lipophagy. The results also showed that transfecting HepG2 cells with a Plin2-overexpressing vector reduced the effects of LQ on up-regulating the expression of CGI-58, as well as proteins related to lipolysis and lipophagy. LQ promoted lipid droplet catabolism through the activation of lipolysis and lipophagy by regulating PLIN2-ATGL signaling, which provided evidence for developing LQ as a functional compound in food for ameliorating hepatic steatosis.
Tumor-associated macrophages (TAMs), particularly the M2-like subtype, contribute to an immunosuppressive tumor microenvironment and promote tumor progression. Melittin, a natural bioactive peptide derived from bee venom, has been reported to exert anticancer and immunomodulatory effects; however, the cellular targets and molecular mechanisms underlying its selective action on TAMs remain incompletely defined. This study aimed to investigate the immunomodulatory effects of melittin on TAM subsets and to identify the molecular determinant responsible for its selectivity toward M2-like macrophages. Macrophage subsets were analyzed following melittin treatment using flow cytometry, gene expression analysis, and immunofluorescence. Binding interactions were assessed by biochemical and biophysical approaches. Tumor growth and immune cell composition were examined in wild-type and CD18-deficient mice. Melittin treatment selectively reduced M2-like TAM populations while increasing infiltration of CD8+ cytotoxic T cells in tumor tissues. Mechanistic analyses revealed that melittin preferentially binds to the integrin subunit CD18 (ITGB2), which is enriched in M2-polarized macrophages, leading to disruption of M2-associated phenotypes in vitro. Notably, genetic deletion of CD18 abolished the M2-suppressive and antitumor effects of melittin in vivo. These findings demonstrate that CD18 is functionally required for the immunomodulatory and antitumor activities of native full-length melittin. This study provides mechanistic insight into the selective action of a natural bioactive peptide and supports its potential as a lead compound for natural product-based immunomodulatory strategies.
Hypertension remains a major global risk factor for cardiovascular diseases, yet current treatments face challenges such as suboptimal blood pressure control and inadequate organ protection. Plant-derived bioactive ingredients (PDBIs), with their multi-target and multi-pathway properties, offer novel strategies for hypertension management. This review systematically examines the mechanisms of major PDBIs (flavonoids, terpenoids, alkaloids) in hypertension, focusing on their regulation of vascular function, renin-angiotensin-aldosterone system and sympathetic nervous system, water-salt homeostasis, and target organ protection. Key signaling pathways involved (NF-κB, TGF-β, MAPK, PI3K/Akt) are analyzed. Clinical translation challenges, including low bioavailability and response heterogeneity, are discussed. Future research should integrate systems pharmacology, smart delivery systems, and precision medicine to advance PDBIs from traditional use to evidence-based therapy, providing a theoretical basis for developing novel antihypertensive and organ-protective strategies.
Pancreatic cancer, especially pancreatic ductal adenocarcinoma, is known for its aggressive nature, late diagnosis, and resistance to standard treatments. This review demonstrates the therapeutic potential of phytochemicals as multitarget agents in pancreatic cancer, emphasizing their molecular mechanisms, pharmacological properties, and translational relevance. Important carcinogenic signaling pathways, such as KRAS/MAPK, PI3K/Akt, NF-κB, STAT3, Hedgehog, and Wnt/β-catenin, are modulated by phytochemicals like curcumin, quercetin, resveratrol, and others. These substances demonstrate anticancer effects by suppressing epithelial-mesenchymal transition, inducing apoptosis, reducing proliferation and angiogenesis, and modulating oxidative stress. Preclinical research indicates consistent multipathway targeting and potential enhanced efficacy with traditional chemotherapeutics, although evidence from clinical studies remains limited and inconsistent. New strategies to improve drug stability, target tumors more effectively, and enhance treatment outcomes involve the use of combination medicines and nanotechnology-based delivery systems. The gap between preclinical effectiveness and clinical translation continues due to insufficient large-scale trials, diverse study designs, and a lack of standardized dosing strategies. Phytochemicals show potential as multitarget treatments for pancreatic cancer, but their clinical application is inhibited by pharmacokinetic challenges and insufficient validation.
Withania somnifera (L.) Dunal (WS), commonly known as Ashwagandha, is a prominent medicinal herb in Ayurveda, with extensive therapeutic potential attributed to its diverse phytochemical profile. This review critically examines the immunomodulatory properties of WS, focusing on innate immune cell populations, including neutrophils, eosinophils, macrophages, dendritic cells, and natural killer (NK) cells. Bioactive constituents, particularly withanolides and withaferin A derived mainly from roots and leaves, orchestrate immune responses through modulation of cytokine networks, enhancement of phagocytic activity, and attenuation of oxidative stress. WS constituents regulate key signaling pathways, including ERK, NF-κB, and JAK/STAT, at transcriptional and translational levels. WS exhibits a dual immunoregulatory role by enhancing innate immune cell functionality while suppressing pathological inflammation in allergic and chronic inflammatory disorders. However, critical gaps persist in elucidating its molecular mechanisms, establishing phytochemical standardization, and defining context-specific dosing regimens. Collectively, current evidence positions WS as a promising candidate for the management of autoimmune, infectious, and inflammatory diseases. However, it further highlights the need for rigorous mechanistic studies and well-designed clinical trials to enable its integration into evidence-based therapeutics.
Irritable bowel syndrome (IBS) is a common disorder of brain-gut interaction that presents with abdominal pain, bloating associated with variable stool consistency. Many IBS patients prefer plant-based preparations to pharmacological therapy; however, the utility of this approach is not well established. To address this issue, a systematic review with meta-analysis to assess the efficacy and safety of plant-based therapy in IBS patients was performed. Literature search with 3 electronic databases (Medline via PubMed, Embase via Ovid, and Web of Science Core Collection) from inception to May 2024. Efficacy was assessed using dichotomous ratings of change in IBS symptoms. A random effects model with 95% confidence intervals was used. Through the screening process, 60 eligible studies were identified (6329 patients). Meta-analysis was performed for fiber (8 studies, RR = 1.22; 95% CI: 1.00-1.49), peppermint oil (7 studies, RR = 1.63; 95% CI: 1.33-2.00), Aloe vera (3 studies, RR = 1.25; 95% CI: 0.76-2.06), and Chinese herbal medicine (7 studies, RR = 1.56; 95% CI: 1.27-1.92). For other plant-based substances investigated in at least one randomized controlled trial (RCT) (e.g., St. John's wort, Anise oil), there were insufficient data for a meta-analysis. The quality of many studies was limited. The findings demonstrate that the treatment of IBS patients with peppermint oil and Chinese herbal medicine were more effective than placebo and had a good safety profile. Dietary fiber showed effects that approached significance. Further, well-powered RCTs are needed to establish the place of plant-based preparations in IBS treatment.
Diabetic foot ulcers (DFUs) are a leading cause of lower-limb amputation, with oxidative stress and ferroptosis playing critical roles in impaired wound healing. This study aimed to evaluate the therapeutic potential of luteolin (LU), a naturally occurring plant-derived flavonoid, in DFU repair and to elucidate its underlying molecular mechanisms. A DFU rat model was established using a high-fat/high-glucose diet combined with streptozotocin injection, followed by full-thickness skin wounding. LU was topically administered at different concentrations. Wound closure was monitored macroscopically, while histopathological changes, inflammatory cytokines, and growth factor levels were assessed by microscopy and ELISA. Network pharmacology and molecular docking analyses were performed to identify potential targets and signaling pathways, which were subsequently validated in vitro using human umbilical vein endothelial cells (HUVECs). LU significantly accelerated wound closure in a dose-dependent manner, accompanied by reduced oxidative stress and pro-inflammatory cytokine production, enhanced collagen deposition, increased angiogenesis, and upregulated expression of key growth factors. Bioinformatics analysis identified ferroptosis inhibition and activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway as central mechanisms, which were confirmed experimentally. LU reduced intracellular reactive oxygen species levels and lipid peroxidation and promoted HUVEC migration and viability. Notably, pharmacological inhibition of Nrf2 with ML385 markedly reversed the protective effects of LU, indicating a pivotal role for Nrf2 signaling. Collectively, these findings demonstrate that LU promotes DFU healing through activation of Nrf2 signaling and suppression of ferroptosis, supporting its potential as a therapeutic candidate for the management of diabetic wounds.
To investigate the effects and targets of cordycepin (COR) in alleviating non-alcoholic fatty liver disease (NAFLD). High-fat diet was used to induce NAFLD in mice, and after COR gavage administration, changes in liver function, glucose and lipid metabolism, and ferroptosis-related signaling were detected. In vitro, palmitic acid (PA) and oleic acid (PSA) were combined to induce hepatocyte lipid injury. The effect of COR on hepatocyte ferroptosis was examined. GCH1 conditional knockout mice (GCH1-CKO) and hepatocyte models were constructed, and AAV9-GCH1 was used to construct GCH1 overexpression mouse models to verify the effect of GCH1 on NAFLD. CETSA-WB, co-immunoprecipitation, and DARTS were employed in the COR-GCH1 interaction and mechanism studies to validate the targeted binding relationship between COR and GCH1. Animal-level studies showed that COR could improve glucose and lipid metabolism and liver function damage in mouse NAFLD, inhibit ferroptosis occurrence and lipid peroxidation injury. Cell-level results showed that COR could inhibit hepatocyte ferroptosis. The ferroptosis-inhibiting effect of GCH1 is independent of GPX4 and other signals; GCH1 directly inhibits reactive oxygen free radicals and suppresses lipid metabolism peroxidation damage. COR's effects are not related to classical anti-ferroptosis signals such as GPX4 and Nrf2, but only related to GCH1. COR can target the GCH1 K155 site, stabilize protein levels by inhibiting GCH1 ubiquitination degradation, and when GCH1 is knocked out, COR's effects are antagonized. GCH1 has a protective role in NAFLD, and this effect is independent of classical GPX4 signaling. COR can target the GCH1 K155 site, inhibit GCH1 ubiquitination thereby preventing protein degradation and exerting protein stabilization. COR elevates GCH1 levels to inhibit ferroptosis. COR is a small molecule with potential for treating NAFLD.
Various pharmacological properties and therapeutic effects were shown for Allium cepa L. (Liliaceae), (A. cepa) or onion and its derivatives including their effects on oxidative stress in different conditions. In this article, an update and comprehensive review of antioxidant effects of A. cepa and A. cepa-associated phytochemicals as well as the underlying molecular mechanisms are provided. The literature on antioxidant effects of A. cepa published between 2015 and the end of July 2025 was searched on database like PubMed, WOS, Science direct and Scopus. A. cepa and its constituents showed antioxidant in various conditions such as cardiovascular, endocrine and metabolic, gastrointestinal and liver, immunological, hematological and autoimmune, urogenital, neurologic and respiratory disorders as well as cancer and neoplasia. The antioxidant effects of A. cepa and its derivatives were achieved by decreasing lipid peroxidation (LPO), malondialdehyde (MDA), nitric oxide (NO), and endothelial nitric oxide synthase (eNOS), inhibiting NADPH oxidase (NOX) activity but enhancing antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GSH-Px), glutathione peroxidase omega (GSPO), thioredoxin reductase (TrxR), glutathione-S-transferase (GST) and glutathione reductase (GR) activities and thiol levels. Therefore A. cepa and A. cepa-associated phytochemicals showed potent antioxidant effects indicating their possible therapeutic value for treatment of disorders associated with oxidative stress.
Endothelial cell ferroptosis drives atherosclerosis. Salvianolic acid A (SAA), a polyphenol from Salvia species, was tested for its ability to inhibit ferroptosis and attenuate atherosclerosis, and its molecular mechanism was investigated. Screening of 124 natural compounds identified SAA as the most potent inhibitor of RSL3-induced ferroptosis in human umbilical vein endothelial cells (HUVECs). Cellular/mitochondrial lipid peroxidation, Fe2+ content, ROS, and mitochondrial function were assessed with or without SAA. AMPK signaling was probed using pharmacological inhibitors. The AdipoR1 axis was examined via siRNA knockdown. In vivo, ApoE-/- mice on a Western diet were treated with SAA to evaluate atherosclerosis and ferroptotic damage. SAA was identified as the most potent inhibitor of (1S,3R)-RSL3-induced ferroptosis in HUVECs among the screened natural compounds. SAA inhibited the ferroptotic response by restoring GPX4-dependent antioxidant capacity and preventing lipid peroxidation at both the cellular and mitochondrial levels. It improved mitochondrial function by restoring homeostasis of the mitochondrial quality control system, inhibiting mitochondrial reactive oxygen species generation, reducing ferrous iron accumulation, limiting mitochondrial lipid peroxidation, and preserving mitochondrial ultrastructure. The protective effects of SAA against ferroptosis were abolished by AMPK inhibitors, which disrupted cellular lipid metabolism and mitochondrial function regulation. The deleterious effects of AMPK inhibition were reversed by co-treatment with the mitochondrial reactive oxygen species inhibitor MitoTempol. Knockdown of AdipoR1 and experiments with the AMPK agonist AICAR confirmed that salvianolic acid A restores mitochondrial homeostasis and inhibits ferroptosis specifically through activation of the AdipoR1-AMPK signaling pathway. In vivo, treatment with SAA significantly ameliorated Western diet-induced atherosclerosis and ferroptosis-like cell damage in ApoE-/- mice. SAA has strong therapeutic potential against endothelial ferroptosis and atherosclerosis by restoring mitochondrial homeostasis through AdipoR1-AMPK pathway activation. These findings support further clinical investigation of SAA for treating atherosclerosis and other endothelium-related cardiovascular diseases.
Obesity is a major risk factor for type 2 diabetes. Some traditional Chinese medicine (TCM) compounds can improve obesity by increasing energy consumption. This study aimed to identify and verify TCM compounds that promote adipose thermogenesis to alleviate obesity via transcriptomic analysis, molecular docking, network pharmacology, and Connectivity Map (CMap) analysis. Thirty-six TCMs related to adipose tissue thermogenesis were first collected to generate transcriptomic data. Then a ranking method based on integrated transcriptomic data was used to select emodin from the TCM Da Huang for network pharmacology to explore its potential mechanisms and further experimental validation. CMap analysis of thermogenesis signature genes from ProFAT and GEO datasets identified triptolide as another compound for improving obesity through enhanced thermogenesis. In vitro experiments with 3T3-L1 cells and in vivo experiments with zebrafish were conducted. The results showed that both emodin and triptolide could upregulate the NAD+/NADH ratio, increase AMPK and SIRT1 expression, suppress lipid accumulation, and promote lipolysis, as verified by both in vitro and in vivo experiments. They also upregulated thermogenesis-related genes (e.g., UCP1, PGC1α, and PRDM16), lipolysis-related genes (e.g., PKA, ATGL, and HSL), mitochondrial biogenesis-related genes (e.g., NRF1, NRF2, and TFAM), and β-oxidation-related genes (e.g., CPT1α and CPT1β). Meanwhile, they downregulated lipogenesis-related genes such as FASN, SREBP1, and ACC. These results provide a basis for understanding the effects of emodin and triptolide on obesity. The findings highlight the effectiveness of combined screening approaches in exploring compounds with beneficial metabolic effects.
Lung cancer remains an aggressive and highly prevalent disease worldwide, causing an estimated 1.8 million deaths in 2022 and becoming a leading cause of cancer-related mortality. Resistance to current therapies necessitates novel approaches that target the tumour immune microenvironment (TIME), which is crucial for disease progression. Studies suggest that certain phytochemicals can enhance antitumour immunity by modulating the TIME. This systematic review aimed to elucidate and synthesise the mechanisms by which phytochemicals exert antitumour immunomodulatory effects in lung cancer and to assess their therapeutic potential and translational challenges. We comprehensively reviewed the literature from PubMed, Web of Science, and China National Knowledge Infrastructure (CNKI) until December 2025. Phytochemical mechanisms were analysed and classified based on their chemical structures and specific targets within the TIME. Phytochemicals effectively reprogrammed the immunosuppressive TIME using multi-target strategies. Key actions include the inhibition of immunosuppressive cells-such as myeloid-derived suppressor cells (MDSCs), Treg cells, and M2-polarised macrophages (e.g., via STAT3 downregulation by dihydroisotanshinone I)-activation of effector cells (e.g., NK cells, CD8+ T cells, and M1 macrophages), and the reversal of T helper cell drift (e.g., panaxan and aesculetin). This multipronged modulation offers superior efficacy by enhancing CD8+ T cell responses and overcoming functional exhaustion. This review validates the significant potential of phytochemicals as novel multi-target therapeutic agents for TIME-targeted therapy in lung cancer. Future research should prioritise addressing pharmacological challenges to accelerate rational clinical integration.
Type 2 diabetic osteoporosis (T2DOP) significantly impairs bone health, partially through ferroptosis triggered by glucolipotoxicity. However, therapeutic strategies targeting this process remain largely unexplored. Broussonin A (BRA), a natural antioxidant compound, shows potential for treating bone metabolic disorders, yet its specific effects on T2DOP are unclear. This study aimed to examine whether BRA inhibits ferroptosis and restores bone quality under type 2 diabetic conditions. A rat model of T2DOP was established by administering streptozotocin (STZ) combined with a high-fat dietary regimen. Additionally, an in vitro model was developed through the exposure of bone marrow mesenchymal stem cells (BMSCs) to high-glucose/high-lipid (HGHF) conditions. Intracellular Fe2+ and lipid peroxidation levels were determined using FerroOrange and C11-BODIPY staining techniques separately. Mitochondrial integrity and function were assessed via JC-1 staining and ultrastructural examination. Furthermore, assays for osteogenic differentiation, Western blotting (WB), and immunofluorescence (IF) analyses were performed. The results showed that BRA markedly reduced cytotoxicity induced by high-glucose/high-lipid exposure, decreased lipid peroxidation and Fe2+ overload, restored mitochondrial integrity and antioxidant enzyme activities, and rescued impaired osteogenic function in BMSCs. In vivo administration of BRA maintained femoral trabecular microarchitecture without observable toxicity to major organs. Network pharmacology analysis and cellular thermal shift assays identified the JAK2/STAT3 signaling pathway as the direct molecular target. Treatment with BRA effectively restored the phosphorylation states of JAK2 and STAT3, leading to an elevation in GPX4 protein expression. Importantly, knockdown of STAT3 through siRNA interference abolished these protective effects. Taken together, these findings indicate that BRA mitigates T2DOP by reactivating the JAK2/STAT3 signaling axis, thereby suppressing ferroptosis.
