Context Hepatocellular carcinoma (HCC), largely driven by chronic hepatitis B virus (HBV) infection, remains a major global health challenge with limited curative options in advanced stages. The hepatitis B virus X protein (HBx) is a multifunctional viral oncoprotein that plays a central role in HBV persistence and hepatocarcinogenesis by disrupting transcriptional regulation, DNA repair, apoptosis, and immune responses.Objective This review aims to evaluate the role of HBx in HBV‑related HCC progression and to examine the therapeutic potential of natural products that directly target HBx and indirectly modulate HBx‑driven antiviral and oncogenic pathways.Methods A comprehensive literature analysis was conducted focusing on studies published over the past decade, including in vitro, in vivo, and clinical evidence addressing HBx-mediated mechanisms and the pharmacological effects of bioactive natural products, including plant‑derived phytochemicals and non‑plant natural compounds.Results Accumulating evidence indicates that some natural products suppress HBV replication by reducing HBx expression, promoting HBx degradation, or limiting HBx‑dependent cccDNA transcription, whereas others primarily influence biological pathways associated with HBx‑driven hepatocarcinogenesis, including migration, invasion, fibrosis, metabolic reprogramming, and apoptosis resistance.Conclusion Natural products represent a promising multi-target therapeutic strategy for HBV-related HCC by intervening in HBx-driven oncogenic processes. Future studies should focus on mechanistic validation, standardization of bioactive compounds, and well-designed clinical trials to support their translational application as adjunctive or alternative therapies.
Context Safflower (Carthamus tinctorius L.) seeds have been reported to exert bone protective effects, but research on safflower leaves remains limited.Objective This study aimed to evaluate the inhibitory effects of safflower leaf and seed extracts on osteoclast differentiation, compare their chemical compositions, and identify anti-osteoclastogenic compounds from safflower leaves.Materials and methods The inhibitory effects on receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation were evaluated in bone marrow-derived macrophages (BMDMs). Compositional differences between safflower seeds and leaves were determined using liquid chromatography-mass spectrometry (LC-MS) analysis. Compounds from safflower leaves were isolated by medium-pressure liquid chromatography (MPLC) and identified using MS and nuclear magnetic resonance (NMR) analyses.Results Hot water and ethanol extracts of safflower leaves suppressed RANKL-induced osteoclast differentiation in BMDMs, with effects comparable to those of safflower seed extracts. These extracts also downregulated the expression of osteoclast-related genes, including nuclear factor of activated T cells 1 (NFATc1), tartrate-resistant acid phosphatase (TRAP), cathepsin K, and dendritic cell-specific transmembrane protein (DC-STAMP). LC-MS metabolite analysis detected quercetin and luteolin derivatives in safflower leaves, whose chemical composition differs from that of safflower seeds. Fourteen compounds, including a novel compound, 4-(2-nitroethyl)phenyl-O-rutinoside, were isolated and identified from safflower leaves. Seven quercetin and luteolin derivatives inhibited osteoclast differentiation and downregulated osteoclast-related gene expression.Discussion and conclusions These findings provide in vitro evidence supporting further in vivo investigation of safflower leaves as promising candidates for suppressing osteoclast differentiation, with quercetin and luteolin derivatives identified as potential bioactive markers.
CONTEXT:Mitragyna speciosa Korth, commonly known as kratom, has been used traditionally in Southeast Asia by chewing fresh leaves and brewing decoctions (tea) for its stimulant and sedative-like properties. Despite its widespread use, controlled clinical trials are limited and have monitored mitragynine only or a few other major alkaloids and metabolites. OBJECTIVE:The objective of the study was to develop and validate an ultra performance liquid chromatography-mass spectrometry (UPLC-MS/MS) method for the simultaneous quantification of 12 kratom alkaloids along with 5 metabolites of mitragynine in human plasma. MATERIALS AND METHODS:A sensitive UPLC-MS/MS based bioanalytical method for the simultaneous quantification of kratom alkaloids, including mitragynine, speciogynine, speciociliatine, mitraciliatine, paynantheine, isopaynantheine, corynantheidine, corynoxine-A, corynoxine-B, mitraphylline, speciofoline, and ajmalicine, along with five metabolites of mitragynine, 7-hydroxymitragynine, 9-hydroxycorynantheidine, mitragynine 16-carboxylic acid, mitragynine pseudoindoxyl, and 3-dehydromitragynine in human plasma was developed and validated following FDA guidelines. Chemically unstable metabolites, 7-hydroxymitragynine and 9-hydroxycorynantheidine, were stabilized in human plasma. The bioanalytical method was further used for the analysis of plasma samples collected during a clinical trial involving four regular kratom users. RESULTS:The method was linear over the concentration range of 1-250 ng/mL. A simple protein precipitation method was used to extract analytes. Upon oral administration of kratom products, most of the alkaloids were absorbed quickly and showed peak plasma concentrations within 1-2 h post-dose. DISCUSSION AND CONCLUSIONS:Mitragynine, speciociliatine, mitraciliatine, isopaynantheine, and paynantheine are major circulating alkaloids, with mitragynine 16-carboxylic acid and 9-hydroxycorynantheidine being the major circulating metabolites of mitragynine in plasma upon kratom oral administration.
BACKGROUND:The United States Pharmacopeia (USP) Dietary Supplement Admission Evaluation and Labeling Expert Committee (DSAEL EC) routinely monitors safety‑related literature for dietary ingredients covered by USP monographs. Following multiple reports of hepatotoxicity associated with turmeric- or curcuminoid-containing products, the DSAEL EC conducted a comprehensive evaluation. OBJECTIVE:To assess the safety of turmeric and curcuminoids and determine whether cautionary labeling should be added to the USP monographs for these ingredients. METHODS:Following USP Guidelines, the DSAEL EC reviewed safety and toxicological information. RESULTS AND DISCUSSION:Hepatotoxicity has been observed with high-dose turmeric rhizome powder or extract in a few rodent toxicology studies. Numerous clinical trials involving turmeric- or curcuminoid-containing supplements have not reported organ toxicity or serious adverse events. Published case reports of clinically apparent liver injury often involve concomitant medications or supplements. Reported hepatotoxicity typically occurs after 1 to 4 months of use and generally resolves upon discontinuation; cases of acute liver failure have been reported albeit rarely. Proposed mechanisms include idiosyncratic, immune-mediated injury, and emerging evidence suggests possible genetic susceptibility. CONCLUSIONS:The USP DSAEL EC recommends adding the following cautionary statement to its turmeric and curcuminoids monographs: Liver problems have been reported very rarely in people taking supplements containing turmeric and/or curcuminoids. Consult your health-care practitioner before using this product if you have a history of liver problems. Stop using this product if you develop symptoms such as abdominal pain, dark urine, or jaundice (yellowing of the skin or eyes), and seek medical advice.
Context Zexie Decoction (ZXD) is a classical traditional Chinese medicine prescription that has long been used for the treatment of hyperlipidemia. However, its material basis and underlying mechanisms remain unclear.Objective This research aims to explore the effective compounds and lipid-lowering mechanism of ZXD in the treatment of hyperlipidemia by integrating serum pharmacochemistry, network pharmacology and targeted lipidomics.Materials and methods A high-fat diet-induced hyperlipidemia mouse model was established for evaluating the therapeutic efficacy of ZXD. The absorbed components of ZXD in serum were identified using ultra-high performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS/MS). Network pharmacology analysis based on in vivo absorbed components was subsequently performed to construct molecular networks and predict potential mechanisms. Furthermore, targeted lipidomics was employed to characterize lysophospholipid metabolic changes associated with ZXD treatment for hyperlipidemia.Results Pharmacodynamic evaluation demonstrated that ZXD exerted significant lipid-lowering effects on hyperlipidemic mice. Serum pharmacochemistry analysis identified twelve absorbed constituents, including 3 prototype compounds and 9 metabolites. Network pharmacology analysis demonstrated that ZXD primarily modulated lipid metabolism-associated pathways, particularly the peroxisome proliferator-activated receptor (PPAR) signaling pathway and the lipid and atherosclerosis pathways. Molecular docking further revealed strong binding affinities between the major bioactive compounds of ZXD and key targets PPARA and PPARG. In addition, targeted lipidomics identified 36 lysophospholipid biomarkers associated with ZXD-mediated amelioration of hyperlipidemia.Discussion and conclusions Integrated analysis indicates that ZXD alleviates hyperlipidemia in association with modulation of the PPAR signaling pathway and lysophospholipid metabolism, highlighting a potential lysophospholipid-PPAR regulatory mechanism.
Context Lavandula angustifolia Mill. is a widely used medicinal and aromatic plant with well-documented pharmacological activity, primarily attributed to its essential oil. However, the contribution of nonvolatile constituents and post-distillation biomass remains insufficiently characterized despite growing evidence of their biological relevance.Objective This study aimed to provide a structured narrative synthesis of the phytochemical composition, pharmacological properties, and translational relevance of L. angustifolia, with particular emphasis on polyphenol-rich aerial biomass as an underexplored bioresource.Methods A structured narrative review was conducted using ScienceDirect, Google Scholar, Scopus, PubMed, and SpringerLink databases through an iterative literature retrieval and refinement process. Priority was given to recent peer-reviewed English-language journal articles, particularly those published after 2015, with selective inclusion of earlier foundational studies where relevant. Eligible sources included studies reporting phytochemical characterization, mechanistic, experimental, translational, or clinical pharmacological data, as well as investigations addressing post-harvest or post-distillation biomass utilization. Literature was screened and synthesized using a thematic analytical approach.Results L. angustifolia demonstrates a dual pharmacological profile driven by both volatile and nonvolatile fractions. Essential oil is consistently associated with antimicrobial and anxiolytic effects, including evidence from clinical and mechanistic studies. In contrast, polyphenol-rich fractions exhibit pronounced antioxidant and anti-inflammatory activity through modulation of key signaling pathways. Post-distillation biomass was identified as a relevant and underutilized source of bioactive phenolics with potential for pharmaceutical and nutraceutical applications.Conclusion The findings establish L. angustifolia as a pharmacologically relevant dual-use plant system integrating essential oil production with biomass valorization. This approach supports circular bioeconomy strategies and highlights the translational potential of nonvolatile fractions in the development of value-added therapeutic products.
Background Gastrointestinal discomfort is a prevalent issue during spaceflight, yet targeted therapeutic strategies remain elusive. Existing research largely relies on single-factor modeling, limiting a comprehensive understanding of the underlying pathologies.Methods We established a composite mouse model combining simulated microgravity (hindlimb unloading) and low-dose radiation (Cobalt-60) to evaluate intestinal injury and the therapeutic potential of CB001. Mechanisms were investigated through histological analysis, in vitro co-culture assays, and flow cytometry assessment of B-cell dynamics and IgA/IgG secretion.Results The dual-factor model more effectively simulated spaceflight-induced injuries than single-factor models, showing significant intestinal inflammation and homeostasis disruption. Mechanistically, dual factors promoted CCR7+ B cells migration into the intestine by upregulating CXCR4 expression, subsequently enhancing leukocyte activation. CB001 treatment mitigated these intestinal perturbations by restoring tight junction proteins, suppressing excessive B-cell migration, and downregulating pro-inflammatory cytokines. Furthermore, in vitro assays confirmed that CB001 directly enhanced B-cell viability and augmented IgA/IgG secretion, thereby promoting mucosal repair.Conclusion CB001 is a promising candidate for mitigating spaceflight-induced intestinal dysfunction, as identified using a novel dual-factor mouse model. These data shed light on strategies for screening protective medicines to safeguard astronaut health during space missions.
BACKGROUND:Allergic rhinitis is a chronic non-communicable disease that adversely affects respiratory health and quality of life. Ginger-based formulations, owing to their anti-inflammatory and immunomodulatory properties, may offer a promising alternative therapeutic option. OBJECTIVE:To systematically review and meta-analyze evidence from animal studies and human randomized controlled trials assessing the efficacy of ginger-based formulations in allergic rhinitis. METHODS:A systematic search of the Cochrane Library, Embase, PubMed, and Scopus (April 2025) identified studies comparing ginger-based formulations with control interventions. Outcomes included clinical symptoms and relevant biomarkers. Risk of bias was assessed using the SYRCLE tool for animal studies and RoB2 for human studies. Meta-analyses were conducted using random-effects models, with results expressed as standardized mean difference (SMD) and 95% confidence intervals (CIs). RESULTS:Twenty-one studies (6 animal and 15 human studies) were included. In rodents, ginger-based formulations significantly reduced nasal rubbing (SMD = -1.99; 95%CI, -3.15 to -0.83), sneezing (SMD = -1.99; 95%CI, -2.78 to -1.20), and biomarkers (IL-4, IL-5, and OVA-specific IgE). In humans, ginger-based formulations significantly improved itching (SMD = -0.51; 95%CI, -0.79 to -0.24), runny nose (SMD = -0.59; 95%CI, -0.87 to -0.30), sneezing (SMD = -0.56; 95%CI, -0.75 to -0.37), total nasal symptom scores (SMD = -0.63; 95%CI, -1.00 to -0.26), and quality of life (SMD = -0.56; 95%CI, -0.87 to -0.24), and eosinophil levels. CONCLUSION:Ginger-based formulations improve symptoms and biomarkers of allergic rhinitis in both animal and human studies. As many interventions are multi-component, the observed effects are more appropriately attributed to the overall formulations rather than ginger alone. Further research is needed to explore mechanisms and clarify clinical applications.
CONTEXT:Skin photoaging induced by chronic ultraviolet B (UVB) exposure is primarily driven by oxidative stress. Emerging evidence suggests that ferroptosis contributes to UVB-induced skin damage. Sauchinone, a phenolic lignan derived from Saururus chinensis, possesses potent antioxidant and anti-inflammatory properties; however, its protective effects and underlying mechanisms against UVB-induced skin damage remain unclear. OBJECTIVE:This study aimed to investigate the potential photoprotective effects and underlying mechanisms of sauchinone against UVB-induced skin damage in dermal fibroblasts. MATERIALS AND METHODS:UVB-induced HFFs were used as an in vitro model of photoaging. Cellular senescence, extracellular matrix (ECM) degradation, oxidative stress, and ferroptosis were evaluated using fluorescence staining, flow cytometry, qPCR, ELISA, and western blot analysis. RESULTS:Sauchinone significantly attenuated cellular senescence and ECM degradation in UVB-induced HFFs, as evidenced by reduced SA-β-gal activity and decreased expression of p16 and p21, increased COL1A1 levels, and decreased MMP1 levels. Sauchinone also alleviated oxidative stress by reducing intracellular ROS and MDA levels while restoring GSH content and antioxidant enzyme activity. In addition, sauchinone attenuated ferroptosis-related features, including reduced lipid ROS and Fe2+ accumulation, and normalized ACSL4, GPX4, FTH1, and SLC7A11 expression. Mechanistically, sauchinone was associated with activation of the Keap1-Nrf2 pathway, as evidenced by decreased Keap1 levels, enhanced nuclear translocation of Nrf2, and upregulation of downstream antioxidant genes. Importantly, pharmacological inhibition of Nrf2 using ML385 partially reversed the protective effects of sauchinone on oxidative stress, ferroptosis, cellular senescence, and ECM degradation. DISCUSSION AND CONCLUSIONS:Our findings revealed that sauchinone protected fibroblasts against UVB-induced photoaging by inhibiting oxidative stress and ferroptosis, potentially through activation of the Keap1-Nrf2 pathway.
BACKGROUND:Commercial herbal teas marketed as Epilobium herb are widely consumed in Europe for prostate-related and anti-inflammatory effects. However, they are often sold under generic names without clear species differentiation or quality specifications, raising concerns about chemical consistency and therapeutic equivalence. OBJECTIVE:To evaluate the chemical equivalence of commercial Epilobium products and refine the framework for quality marker selection by integrating pharmacological relevance with structural assessment. MATERIALS AND METHODS:Sixteen commercial tea samples labeled as E. angustifolium, E. parviflorum, E. hirsutum, from eight European countries were analyzed using high-performance thin-layer chromatography (HPTLC) and validated by HPLC-DAD. Candidate markers were prioritized using the Herbal Chemical Marker Ranking System (Herb MaRS) and further assessed via Pan-Assay Interference Compounds (PAINS) structural filters. RESULTS:Significant qualitative and quantitative heterogeneity was observed across all samples, including those labeled as the same species. Oenothein B was the dominant compound but exhibited high variability (7.9-48.7 mg/g DW; CV >50%) and was significantly higher in E. hirsutum (p < 0.05). Flavonol glycosides (e.g., hyperoside, isoquercitrin) also varied substantially. Although species identity influenced phenolic profiles, overlapping concentration ranges indicated a lack of chemical equivalence among products. Geographic origin contributed additional but secondary variability. DISCUSSION:Oenothein B, hyperoside, and isoquercitrin were identified as priority quality markers based on abundance and analytical suitability. Structural reassessment demonstrated that pharmacological ranking alone may be misleading for polyphenol-rich matrices due to redox-related interference. CONCLUSION:Commercial Epilobium teas differ chemically and are not interchangeable. A structure-informed approach is essential for reliable quality assessment and for aligning commercial products with pharmacopeial standards.
Context Premature ovarian insufficiency (POI), defined as ovarian activity cessation before age 40, significantly impacts both fertility and long-term health, with currently inadequate treatment options available. Wubie Fanchun Formula (WBFC) has been clinically used for over 20 years, showing benefits in TCM symptoms and hormone levels in POI patients with liver-kidney deficiency. However, its active components and mechanistic basis are still largely unknown.Objective To characterize the active ingredients and delineate the pharmacological basis of WBFC’s action in managing POI.Materials and methods LC-TOF-MS was used to identify WBFC’s chemical constituents. Network pharmacology analysis pinpointed candidate mechanisms, which were tested in a 4-VCD-induced POI mouse model. Metabolic dysfunction was characterized via pyruvate tolerance tests, liver glycogen staining, and untargeted metabolomics. Key metabolites regulated by WBFC in model mice, phosphatidylinositol 38:5 (PI) and glutamine (GLN), were supplemented to validate their roles in POI pathology.Results 25 bioactive constituents in WBFC were found by LC-TOF-MS analysis. WBFC ameliorated ovarian dysfunction and activated the PI3K/AKT/FOXO3a pathway in parallel with simultaneously improving systemic metabolic parameters. Metabolomics identified PI and GLN among the top 30 most significantly altered metabolites, both showing marked depletion in POI mice and substantial restoration following WBFC treatment. Functional validation through exogenous supplementation demonstrated that combined PI and GLN administration effectively rescued ovarian dysfunction and specifically reactivated the ovarian PI3K-AKT pathway in 4-VCD induced POI mice.Discussion and conclusion Amino acids, saponins, anthraquinones, and carbohydrates are the main chemical components of WBFC. WBFC ameliorated POI and activated PI3K/AKT/FOXO3a signaling through metabolic regulation, with PI and GLN identified as critical therapeutic mediators.
CONTEXT:Wound healing requires coordinated keratinocyte and fibroblast migration, extracellular matrix (ECM) deposition, and growth factor signaling. Disruption of these processes delays repair and impairs skin integrity. Bombax ceiba flower contains phenolic compounds with antioxidant and anti-inflammatory properties; however, its role in wound healing has not been elucidated. OBJECTIVE:This study aimed to investigate the phytochemical profile, antioxidant capacity, and wound-healing potential of B. ceiba flower extract (BCFE) in human keratinocytes (HaCaT) and fibroblasts (Detroit 551). MATERIALS & METHODS:BCFE was prepared by ethanolic extraction and tentatively profiled using LC-QTOF/MS. Total phenolic and flavonoid contents and antioxidant capacity were determined using chemical assays, and intracellular ROS levels were measured in H2O2-stimulated HaCaT and Detroit 551 cells. Wound closure and collagen production were evaluated as indicators of wound repair in both cell types. RESULTS:LC-QTOF/MS tentatively identified gallic acid, epicatechin, rutin, quercetin, hesperetin, apigenin, and luteolin in BCFE. The extract had high phenolic (140.2 mg GAE/g) and flavonoid (8.3 mg QE/g) contents. BCFE exhibited DPPH and ABTS radical-scavenging capacity (IC50 values of 48.0 μg/mL and 33.4 μg/mL, respectively) and attenuated H2O2-induced intracellular ROS levels in HaCaT and Detroit 551 cells. Furthermore, BCFE enhanced wound closure in keratinocytes and fibroblasts, as well as promoted collagen production in a dose-dependent manner. CONCLUSIONS:Collectively, BCFE promoted key cellular processes involved in wound repair, including antioxidant activity, wound closure, and collagen synthesis. These results support the potential role of B. ceiba flowers in skin wound repair.
BACKGROUND:Xeroderris stuhlmannii is a medicinal plant, widely used in Cameroonian folk medicine to treat hypertension. OBJECTIVE:This study aimed to investigate the beneficial effect of X. stuhlmannii in hypertensive rats and to explore the vasorelaxant mechanisms of its hydroalcoholic extract and to determine the compounds responsible of the activities. MATERIALS AND METHODS:Hydroalcoholic extract, fractions, subfractions and isolated compounds were screened for the antihypertensive activity in Wistar rat of either sex using a noninvasive method to record blood pressure (BP) and heart rate (HR). At the end of the treatment, the level of nitrite in the tissues and the histological analysis of the heart and aorta were determined. Vasorelaxant activity of the plant was carried out in vitro, on the contractile responses of aortic rings induced by phenylephrine (10-6 M) or KCl (60 mM). Mechanisms involved vasorelaxation effect of X. stuhlmannii were assessed using various antagonists. RESULTS:Treatment of Cadmium-hypertensive rats with extract significantly (p ˂ 0.001) reduced BP and HR, improved nitrite level, ameliorated heart and aorta alterations. Moreover, the hydroalcoholic extract, fractions, subfraction and odoratin-induced vasorelaxant effect. The preincubation with NG-nitro-L-arginine methyl ester, methylene blue and tetraethylammonium partially inhibited hydroalcoholic extract/fraction-induced relaxation. The extract completely inhibited the effects on CaCl2-induced contracted rings and reduced the contraction induced by phenylephrine in a Ca2+-free solution. CONCLUSION:These results support the traditional use of X. stuhlmannii in the treatment of hypertension. This effect may be due in part to the plant's vasorelaxant activity and the presence of compounds such as phenol in plant extracts.
Context Psoriasis is a relapsing autoimmune disease exacerbated by aberrant interleukin (IL)-17 A activity. Majoon Ushba, a unani polyherbal formulation implicated in clinical cases of psoriasis lacks immunopharmacological validation.Objective The study aims to investigate the pre-clinical efficacy of Majoon Ushba and its therapeutic role in mitigating IL-17A-induced keratinocytes ferroptosis via ablation of JAK-2/STAT-3 pathway.Materials and Methods HaCaT cells were stimulated with IL-17A to assess the activation of the JAK-2-STAT-3 pathway. The STAT-3 inhibitor, S3I-201, was used to confirm the role of the STAT-3 axis in keratinocyte ferroptosis. Majoon Ushba pretreatment was assessed to determine its efficacy in alleviating keratinocyte ferroptosis. An imiquimod (IMQ)-induced psoriasis mouse model was used to evaluate the pre-clinical efficacy of Majoon Ushba. Furthermore, prior high-performance liquid chromatography (HPLC) profiling was leveraged for in-silico docking analysis to identify the binding affinities of key phytoconstituents with IL-17RA and STAT-3.Results Majoon Ushba alleviated the IL-17A/JAK-2-STAT-3 axis, improved GPX4 expression, and regulated lipid peroxidation. Subsequently, Majoon Ushba also reversed the expression of pathogenic mediators and led to a reduction in serum cytokine levels of IL-17A, IL-23, and IFN-γ. An in-silico docking analysis suggested favorable binding affinities for key phytoconstituents of Majoon Ushba against IL-17RA and STAT-3. Aligned with pre-clinical and in vitro results, the computational findings offer initial evidence that the polyherbal formulation may influence the IL-17A/JAK-2-STAT-3 signaling pathway.Discussion and Conclusion In conclusion, our preliminary findings reveal a plausible mechanistic basis for the anti-psoriatic efficacy of Majoon Ushba, warranting larger clinical trials in psoriasis patient cohorts.
Context Ginkgolic acid (GAC), one of the major active constituents of Ginkgo biloba L. (Ginkgoaceae) extract, has been reported as a potential anticancer agent.Objective To investigate the effect of GAC on the viability of human hepatocellular carcinoma (HCC) cells and to identify its primary target and underlying mechanism.Materials and methods Human HCC cell lines and an orthotopic HCC mouse model were employed. The mechanism of GAC was elucidated through integrated analyses of cell viability, RNA sequencing, and biomarkers. The primary target of GAC was identified by drug affinity responsive target stability (DARTS) coupled with LC-MS/MS and further validated using molecular docking (MD), cellular thermal shift assay (CETSA), and microscale thermophoresis (MST) assay. Mechanistic roles were confirmed using genetic approaches, including gene knockdown and the construction of mutant plasmids. A KFERQ reporter system was used to detect the activity of chaperone-mediated autophagy (CMA).Results GAC effectively inhibits the viability of HCC by triggering ferroptosis. HSPA8 was identified as the direct target of GAC. The binding of GAC with HSPA8 enhances its interaction with glutathione peroxidase 4 (GPX4), which leads to the degradation of GPX4 via CMA. This process depleted glutathione (GSH) and caused lipid peroxidation, finally inducing ferroptosis in HCC cells. Furthermore, GAC suppressed tumor growth in an orthotopic HCC model, increased lipid peroxidation, and GPX4 degradation in tumor tissues.Discussion and conclusions Our results revealed a novel mechanism by which GAC induces ferroptosis in HCC cells through direct targeting of HSPA8 and promoting CMA-dependent GPX4 degradation. These findings suggest GAC-mediated ferroptosis as a potential therapeutic strategy against HCC and expand the pharmacological application of CMA-targeted cancer therapies.
Objective This study aims to evaluate the renoprotective effects of QGDD in a DKD model exhibiting metabolic memory features and to explore its potential mechanism involving the regulation of ferroptosis via the SIRT1/Nrf2 signaling pathway.Methods A DKD rat model was induced using streptozotocin (STZ). The rats were assigned to the Blank Control Group (C), Model Group (M), Metformin group (Met), and low-, medium-, and high-dose QGDD groups (QGDD-L/M/H). Intervention effects were assessed by monitoring body weight, fasting blood glucose, renal function markers (24-UTP, BUN, Scr, Cys-C, β2-MG), renal histopathology (HE/Masson staining), oxidative stress markers (Fe2+, MDA, GSH, SOD), cell death indicators (TUNEL, ROS), and expression of genes and proteins associated with the SIRT1/Nrf2 pathway (RT-qPCR, Western blot).Results All QGDD dose groups decreased 24-hour urinary protein excretion and serum levels of BUN, Scr, Cys-C, and β2-MG. The medium-dose QGDD group notably reduced renal Fe2+ and MDA levels, increased GSH and SOD activity, and inhibited ROS accumulation and cellular apoptosis. QGDD activated the SIRT1/Nrf2 pathway, significantly upregulating the mRNA and protein expression of Nrf2, HO-1, and GPX4, while suppressing the accumulation of AGEs and Ferritin.Conclusion QGDD mitigated the persistent elevation of AGEs, a hallmark of metabolic memory in DKD by activating the SIRT1/Nrf2 signaling pathway to inhibit ferroptosis-associated lipid peroxidation and oxidative stress. Its multi-target synergistic effects provide a solid experimental foundation for the use of Chinese herbal formulations in treating DKD. The medium-dose group demonstrated optimal therapeutic efficacy, emphasizing the significance of dose optimization.
Context Endoscopic submucosal dissection (ESD) is the standard treatment for early gastrointestinal cancers but is often complicated by delayed healing and stenosis. Current therapies like proton pump inhibitors primarily suppress acid without actively promoting mucosal regeneration. Asiaticoside (AS), a triterpenoid from Centella asiatica, shows promise in tissue repair.Objective This review evaluates the therapeutic potential of AS for ESD-induced wound healing, focusing on its pharmacological mechanisms and emerging delivery strategies.Methods A comprehensive literature search was conducted using databases such as PubMed, Web of Science, and China National Knowledge Infrastructure (CNKI). Relevant in vitro, preclinical, and clinical studies regarding AS, wound healing, fibrosis, and drug delivery systems were selected and synthesized to analyze efficacy and safety.Results AS accelerates healing through multifaceted mechanisms: it exerts anti-inflammatory effects via NF-κB and MAPK pathways, reduces oxidative stress through Nrf2/HO-1 signaling, and inhibits fibrosis by modulating TGF-β/Smad axes. Additionally, AS promotes angiogenesis and collagen synthesis. While clinical data supports its use in skin wounds, its gastrointestinal application is hindered by poor bioavailability. Novel delivery systems, including hydrogels and microneedles, are identified as solutions for localized, sustained release.Conclusion AS offers a promising therapeutic evolution, moving from reliance on passive acid suppression toward a synergistic model that integrates acid control with active mucosal regeneration for ESD management. Future research should focus on optimizing endoscope-compatible delivery platforms to facilitate clinical translation and reduce postoperative complications.
Context Rabdosin B (RB), an active compound derived from the Chinese herb Isodon japonicus (Burm. f.) H. Hara, has demonstrated inhibitory effects on non-small cell lung cancer (NSCLC) cell proliferation in prior studies. However, its precise mechanism of action remains unclear.Objective To investigate the mechanism of RB against NSCLC and its synergistic effect with cisplatin (CDDP) via the SRC/PI3K/AKT signaling pathway.Materials and methods In vitro assays, CCK-8, colony formation, flow cytometry, scratch, Transwell, and Western blot assessed proliferation, apoptosis and migration. Network pharmacology, molecular docking, molecular dynamics simulation (MDS) and cellular thermal shift assay (CETSA) were employed to validate molecular targets. King’s formula was used to evaluate the combined effect of RB and CDDP, with xenograft models confirming in vivo efficacy.Results In vitro, RB significantly suppressed NSCLC proliferation, migration, and invasion while inducing apoptosis. Mechanistically, network pharmacology predicted SRC as a core target. MDS and CETSA subsequently confirmed the direct and stable binding of RB to SRC. Western blot analysis revealed that RB exerted its effect by inhibiting SRC/PI3K/AKT signaling. Notably, RB synergistically enhanced CDDP sensitivity by blocking SRC/PI3K/AKT pathway activation, thereby potentiating apoptosis. Finally, in vivo experiments validated that RB effectively suppressed tumor growth with favorable safety.Discussion and Conclusions RB inhibits NSCLC progression and sensitizes cells to CDDP by directly targeting SRC to inactivate the PI3K/AKT pathway. These findings identify a novel mechanism of RB against NSCLC and suggest its potential as a therapeutic strategy.
Background/objectives Curcumin, a dietary polyphenol derived from turmeric, has been widely studied for its anti-cancer properties, yet its effects at clinically relevant concentrations remain unclear. This study investigates the anti-cancer effects of curcumin at low in vitro concentrations selected based on reported plasma ranges using in vitro lung and CRC models, with a focus on underlying cellular mechanisms.Methods Curcumin was tested at 4, 10, 20, and 50 µg/mL in two CRC cell lines (Caco-2 and HT29) and two lung cancer cell lines (A549 and H460).Results MTS assays showed that at a low concentration of Curcumin 4 µg/mL, cell viability remained above 100% across all cell lines (A549: 102.1%, H460: 101.1%, Caco-2: 103.6%, HT29: 104.9%, n = 3, p > 0.05) and had no significant effect on cell death. Immunofluorescence analysis showed increased nuclear Cyclin D1 levels at 4 µg/mL curcumin in H460 and HT29 cells (p < 0.001), and no change in Caco-2 cells (p = 0.17), and a significant reduction in A549 cells (p < 0.001), suggesting promotion of cell cycle progression in H460 and HT29 cells only. Western blotting analysis showed higher levels of procaspase-3 without evidence of cleavage at 4 µg/mL, indicating the absence of apoptosis. A reduction in procaspase 3 levels were observed at 20 µg/mL (Caco-2, p < 0.05) and 50 µg/mL (H460, p < 0.05; A549, and HT29, p > 0.05).Conclusions These findings suggest that at low. plasma level-informed concentrations, curcumin may support cancer cell survival rather than induce cytotoxicity. This study highlights the need for further pre-clinical evaluation of polyphenols at clinically relevant concentrations.
Agrimonia pilosa Ledeb. (AP), a traditional herbal medicine rich in flavonoids, phenolics, triterpenoids, and glycosides, has been widely used for hepatic injury and metabolic disorders. This study integrated in vivo and in vitro experiments, UHPLC-HRMS profiling, network pharmacology, and molecular simulation to elucidate the bioactive constituents and mechanisms of AP against metabolic dysfunction-associated steatohepatitis (MASH). Therapeutic efficacy was evaluated using a MASH mouse model, AML12 hepatocytes, and RAW264.7 macrophages. Active constituents were identified by UHPLC-HRMS, and potential targets were predicted via SwissTargetPrediction and GEO databases, followed by PPI network construction, GO/KEGG enrichment analysis, molecular docking, and molecular dynamics simulation. AP markedly reduced body weight, liver index, and serum AST, ALT, TG, TC, and LDL-c levels, and attenuated hepatic steatosis, inflammation, and fibrosis. In AML12 cells, AP suppressed lipogenesis by downregulating SREBP-1c, FASN, and SCD1, while promoting fatty acid β-oxidation through CPT1A upregulation. In RAW264.7 macrophages, AP inhibited LPS-induced expression of TNF-α, IL-1β, and IL-6. A total of 83 active constituents and 25 key targets were identified, with HMGCR and AXL emerging as hub nodes. Agrimol B (AGB) exhibited favorable binding affinity and structural stability toward both targets. Mechanistically, AGB inhibited HMGCR, reduced SREBP-2 nuclear translocation, and enhanced LXRα/β-mediated cholesterol efflux, maintaining hepatic cholesterol homeostasis. These findings demonstrate that AP ameliorates MASH through coordinated regulation of lipid metabolism, inflammatory suppression, and collagen deposition, with AGB representing a promising bioactive candidate warranting further investigation.
