Toxicol. Appl. Pharmacol. [JOURNAL]
Sun
200 papers
Effect of naringin and prednisolone treatment on blood-testis barrier in experimental rheumatoid arthritis model.
Kaya G, Çoşkun G, Şaker D … +3 more , Öztürk ÖG, Polat S, Sencar L
Toxicol Appl Pharmacol · 2026 Jul · PMID 42119708 · Publisher ↗
Rheumatoid arthritis (RA) is a systemic autoimmune disorder that not only affects joints but also causes substantial impairment in male reproductive functions. This study aimed to evaluate the protective effects of Narin...
Rheumatoid arthritis (RA) is a systemic autoimmune disorder that not only affects joints but also causes substantial impairment in male reproductive functions. This study aimed to evaluate the protective effects of Naringin and Prednisolone, both alone and in combination, on testicular damage and blood-testis barrier (BTB) integrity in a murine model of adjuvant-induced arthritis. Thirty-six male Swiss albino mice were divided into six groups. RA was induced using Complete Freund's Adjuvant, followed by treatment with Naringin (150 mg/kg, oral) and/or Prednisolone (10 mg/kg, intraperitoneal). Histopathological, biochemical, immunohistochemical, and ultrastructural analyses were performed. RA led to significant testicular degeneration, reduced serum testosterone and LH levels, and suppressed expression of BTB-related proteins Connexin-43 and Occludin. Naringin treatment effectively alleviated these alterations by reducing TNF-α and IL-6 expression, restoring seminiferous tubule architecture, and preserving BTB integrity. Although Prednisolone reduced inflammatory markers, it did not reverse testicular structural damage. The addition of prednisolone did not enhance the histological protective effects observed with naringin monotherapy. These findings indicate that Naringin exhibits potent anti-inflammatory and antioxidant properties, attenuating RA-induced testicular injury and potentially safeguarding reproductive function. Further studies are warranted to elucidate its molecular mechanisms and therapeutic utility in RA-associated male infertility.
Regionally specific dysregulation of gut microbiota and host-metabolite interface in podophyllotoxin-induced enterotoxicity based on the toxicological evidence chain concept.
Jiang T, Sun J, Liu C … +7 more , Sun Y, Chen H, Liu D, Chen R, Wang Y, Ru Y, Duan J
Toxicol Appl Pharmacol · 2026 Jul · PMID 42114568 · Publisher ↗
Podophyllotoxin (PPT) induces enterotoxicity through gut microbiota dysbiosis; however, the influence of intestinal regional specificity on toxicity remains unclear. This study investigated segment-specific alterations i...
Podophyllotoxin (PPT) induces enterotoxicity through gut microbiota dysbiosis; however, the influence of intestinal regional specificity on toxicity remains unclear. This study investigated segment-specific alterations in PPT-induced enterotoxicity using a toxicological evidence chain framework. Male Sprague-Dawley rats received oral PPT (10, 15, or 20 mg/kg) daily for 4 days. Intestinal toxicity was evaluated using histopathology and quantitative real-time polymerase chain reaction analysis of tight junction proteins and pro-inflammatory cytokines. 16S rRNA sequencing and metabolomic profiling were performed on the contents of the small intestine, cecum, and colon. Microbe-metabolite interactions were analyzed using Spearman's correlation and K-means clustering. The results demonstrated that PPT exposure induced significant enterotoxicity, as evidenced by diarrhea, villus damage, goblet cell loss, barrier impairment, and inflammation. 16S rRNA sequencing revealed a consistent depletion of beneficial genera Romboutsia, Lombactobacillus, and Turicibacter, alongside an expansion of pathogenic Escherichia-Shigella across all gut segments. Metabolomic analysis revealed profound disturbances in key metabolic pathways. Notably, a putative co-regulated protective axis encompassing vitamin B6, histidine, and tryptophan metabolism was altered, with central metabolites such as 4-pyridoxic acid and β-alanyl-L-histidine being significantly downregulated. Critically, these microbial and metabolic alterations exhibited distinct spatial patterns. Network analysis indicated that the correlations between depleted beneficial bacteria and downregulated protective metabolites were stronger in the cecum and colon than in the small intestine. Collectively, these findings provide systematic evidence that PPT-induced enterotoxicity is associated with region-specific disturbances in the gut microbiota-metabolite network, which may serve as a potential target for mitigating PPT-induced intestinal damage.
Structural determinants of paraben-mediated 11β-hydroxysteroid dehydrogenase 1 inhibition: Integrated mechanistic, kinetic and in silico approaches to cortisol metabolism.
Li L, Chen H, Zhu Y … +3 more , Ge RS, Chen C, Chen S
Toxicol Appl Pharmacol · 2026 Jul · PMID 42114567 · Publisher ↗
Parabens are extensively employed as antimicrobial preservatives in cosmetics, personal care items, and pharmaceuticals. However, their potential metabolism regulating effects, particularly regarding the inhibition of hu...
Parabens are extensively employed as antimicrobial preservatives in cosmetics, personal care items, and pharmaceuticals. However, their potential metabolism regulating effects, particularly regarding the inhibition of human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), remains unknown. This study assessed 4-hydroxybenzoic acid and 9 parabens for their ability to inhibit human and rat liver 11β-HSD1, investigating their mechanism of action, structure-activity relationship (SAR), molecular interactions (via in silico docking), and influence on cortisol metabolism in LX-2 cells. Nonylparaben emerged as the most potent inhibitor, demonstrating the lowest IC values (human: 6.29 μM) and strongest binding affinity (ΔG: human: -6.84 kcal/mol). The inhibitor trend followed nonyl > heptyl (IC = 11.37 μM) > hexyl (15.32 μM) > benzyl (29.99 μM) > phenyl (53.27 μM) > butyl (58.87 μM) paraben. Short-chain parabens (<C4) and 4-hydroxybenzoic acid exhibited no inhibition at 100 μM, indicating activity dependent on alkyl chain length. Furthermore, these effective parabens suppressed cortisol metabolism in intact human LX-2 liver cells at concentrations below 100 μM. SAR analysis revealed lipophilicity and molecular weight as primary factors governing inhibitory efficacy, with higher values associated with enhanced activity. A 3D-QSAR pharmacophore model confirmed the essential role of hydrophobic interactions and aromatic ring in inhibition. For rat 11β-HSD1, only two aryl parabens (benzyl and phenyl) moderately inhibited this enzyme activity (81.93 μM for benzyl and 98.61 μM for phenyl paraben). Observed species-specific differences in binding mechanisms underscore the necessity for caution in extrapolating animal model data to humans. These findings provide valuable mechanistic insights into the metabolism-regulating potential of parabens, highlighting their structure- and species-dependent capacity to disrupt glucocorticoid metabolism.
Shared inflammatory targets of phthalate plasticizers in MODS-related syndromes: An integrative network toxicology study with representative DEHP in vitro validation.
Song L, He A, Jiang W … +6 more , Liu K, Ma J, Wang J, Shi K, Yu J, Zheng R
Toxicol Appl Pharmacol · 2026 Jul · PMID 42107545 · Publisher ↗
Phthalate esters (PAEs) are widely used in medical-grade polyvinyl chloride materials and may contribute to inflammatory injury under medical-device-relevant exposure conditions. However, the shared molecular targets lin...
Phthalate esters (PAEs) are widely used in medical-grade polyvinyl chloride materials and may contribute to inflammatory injury under medical-device-relevant exposure conditions. However, the shared molecular targets linking different phthalates to multiple organ dysfunction syndrome (MODS)-related pathological processes remain unclear. Here, an integrative network toxicology approach was used to identify shared candidate inflammatory targets of diethyl phthalate (DEP), dimethyl phthalate (DMP), and dioctyl phthalate (DOP) within a MODS framework, with focused analyses of three clinically relevant MODS-related syndromes: sepsis, acute kidney injury (AKI), and acute respiratory distress syndrome (ARDS). Compound- and disease-associated targets were integrated to construct interaction networks, identify hub genes, and perform pathway enrichment and molecular docking analyses. To provide representative experimental support, di- (2-ethylhexyl) phthalate (DEHP) was selected for in vitro validation in A549, HK-2, and RAW264.7 cells. Network analysis identified recurrent candidate inflammation-related targets, with STAT3, PTGS2, and TLR4 repeatedly prioritized across the MODS-related syndrome analyses. Acute 24 h DOP/DEHP exposure reduced cell viability, increased apoptosis, elevated IL-6, TNF-α, IL-1β, and IL-18 secretion, and was associated with increased expression of TLR4, STAT3, and PTGS2 in all three cell models. These findings identify shared candidate inflammatory targets networks of representative phthalate plasticizers in MODS-related syndromes and provide hypothesis-generating evidence supporting conserved inflammatory responses to representative DOP/DEHP exposure.
Inhibitory effects and kinetics of Sudan dyes on human carboxylesterases.
Fan YZ, Liao CY, Gong JM … +4 more , Yang YX, Ma YL, Liu ZZ, Du Z
Toxicol Appl Pharmacol · 2026 Jul · PMID 42107544 · Publisher ↗
Sudan dyes, widely used as industrial colorants and occasionally added illegally to foods, have been reported to act as environmental endocrine disruptors with adverse effects on metabolic processes. This study investiga...
Sudan dyes, widely used as industrial colorants and occasionally added illegally to foods, have been reported to act as environmental endocrine disruptors with adverse effects on metabolic processes. This study investigated the inhibitory effects of Sudan dyes on the predominant human carboxylesterases CES1 and CES2 using an in vitro system based on human liver microsomes, aiming to elucidate the mechanisms underlying Sudan dye-related metabolic toxicity. All Sudan dyes significantly inhibited CES1 and CES2 activities, with CES1 strongly inhibited by Sudan II, Para Red, and Sudan Red 7B, and CES2 by Sudan III, Sudan IV, and Sudan Red G, showing inhibition ratios exceeding 70%. Kinetic analyses combined with in vitro-in vivo extrapolation suggested potential interference of Sudan dyes with CES-mediated hydrolytic metabolism in vivo. Molecular docking revealed hydrophobic interactions and azo-group-mediated hydrogen bonding as key determinants of binding, and molecular dynamics simulations confirmed the formation of stable and compact enzyme-dye complexes. These findings provide new experimental evidence for understanding the toxicity of Sudan dyes mediated through CES inhibition and indicate a potential contribution to metabolic disorders, particularly in relation to lipid metabolism.
Curcumol induces autophagy-dependent hepatic stellate cell death through methionine metabolism disruption.
Gao YJ, Zhou Y, Li YN … +10 more , Yang KY, Xia SW, Hu MR, Li Y, Chen L, Wang FX, Lu S, Lian NQ, Zheng SZ, Zhang F
Toxicol Appl Pharmacol · 2026 Jul · PMID 42107543 · Publisher ↗
Hepatic stellate cell (HSC) activation is a key driver of extracellular matrix (ECM) accumulation and liver fibrosis. Autophagy plays an essential role in regulating HSC activation, yet its metabolic regulation remains l...
Hepatic stellate cell (HSC) activation is a key driver of extracellular matrix (ECM) accumulation and liver fibrosis. Autophagy plays an essential role in regulating HSC activation, yet its metabolic regulation remains largely undefined. Curcumol, a bioactive compound derived from Curcuma longa, possesses potent antifibrotic activity, but the underlying metabolic mechanisms are unclear. In this study, we found that curcumol suppressed HSC activation and induced autophagy-dependent cell death, together with inhibition of methionine metabolism. Curcumol treatment reduced LX-2 cell viability and downregulated profibrogenic markers α-smooth muscle actin (α-SMA) and collagen type I (COL1A1) in a dose-dependent manner. Mechanistically, curcumol enhanced LC3-II accumulation, diminished p62 levels, and promoted autophagic vacuole formation, effects that were reversed by the autophagy inhibitor 3-methyladenine (3-MA). Silencing of ATG7 attenuated curcumol-induced autophagy-associated changes and cell death, supporting the involvement of ATG7 in this process. Furthermore, curcumol significantly reduced the expression of key methionine cycle enzymes MAT2A and AHCY. Supplementation with S-adenosylmethionine (SAM) partially reversed curcumol-associated changes in methionine metabolism and autophagy-related markers, and improved HSC viability, supporting a functional link between methionine metabolism and the observed phenotype. Collectively, these findings suggest that curcumol promotes autophagy-dependent death of HSCs in association with disrupted methionine metabolism, providing new insight into the metabolic basis of its antifibrotic action.
Isoliquiritigenin suppresses ER stress-driven epithelial apoptosis to preserve barrier integrity in colitis.
Xu C, Wang H, Zhu M … +1 more , Fan Z
Toxicol Appl Pharmacol · 2026 Aug · PMID 42105812 · Publisher ↗
Ulcerative colitis (UC) is an inflammatory bowel disease characterized by epithelial barrier disruption and chronic mucosal inflammation, and its underlying mechanisms remain incompletely understood. Increasing evidence...
Ulcerative colitis (UC) is an inflammatory bowel disease characterized by epithelial barrier disruption and chronic mucosal inflammation, and its underlying mechanisms remain incompletely understood. Increasing evidence suggests that endoplasmic reticulum (ER) stress contributes to epithelial injury and apoptosis and plays an important role in the development of UC. Isoliquiritigenin (ISL), a natural flavonoid derived from licorice, has been reported to exert anti-inflammatory and antioxidant effects. However, whether ISL alleviates UC by regulating ER stress-associated apoptosis and the underlying mechanisms remain unclear. This study aimed to determine whether ISL alleviates dextran sulfate sodium (DSS)-induced colitis by regulating ER stress-associated apoptosis and to explore the underlying molecular mechanisms. A DSS-induced colitis model was established in mice, and ER stress was induced in Caco-2 cells using tunicamycin. Disease severity was evaluated by disease activity index scoring, histological examination, mucus production assessment, and intestinal permeability analysis, and inflammatory cytokine levels were measured. Quantitative proteomics was performed to identify altered pathways. ER stress signaling and apoptosis-related proteins were further examined. In addition, the ER stress inhibitor 4-phenylbutyric acid (4-PBA) was used to verify the involvement of ER stress. The results showed that ISL markedly alleviated DSS-induced colitis, as evidenced by improved epithelial structure, mucus production, and barrier function, along with reduced levels of IL-6, IL-1β, TNF-α, and IL-17 A. Proteomic analysis revealed enrichment of ER protein processing and apoptosis-related pathways in DSS-treated tissues, which were partially reversed by ISL. DSS induced ER stress, as indicated by increased GRP78 (BiP) expression and activation of the PERK-eIF2α-ATF4-CHOP pathway, and promoted epithelial apoptosis, evidenced by Bax upregulation, caspase-3 activation, Bcl-2 reduction, and increased TUNEL-positive cells. ISL inhibited activation of this pathway and restored apoptotic balance. Consistently, ISL suppressed tunicamycin-induced ER stress, barrier dysfunction, and apoptosis in Caco-2 cells, whereas pharmacological inhibition of ER stress with 4-PBA produced similar protective effects. Collectively, these findings suggest that ISL attenuates DSS-induced colitis by inhibiting ER stress-mediated epithelial apoptosis, potentially through modulation of the PERK signaling pathway, thereby providing experimental evidence for its therapeutic potential in UC.
Ginsenoside Rb1 attenuates hyperoxia-induced lung injury in neonatal rats by inhibiting ferroptosis via the system Xc pathway.
Lian H, Zhou H, Dong J … +6 more , Qian J, Cheng Y, Lou J, Zheng X, Lin W, Jia D
Toxicol Appl Pharmacol · 2026 Jul · PMID 42103085 · Publisher ↗
BACKGROUND: Hyperoxia-induced lung injury (HALI) is a common and severe complication in neonatal intensive care units, and there is currently no effective therapy available. Ferroptosis, a newly recognized form of iron-d...
BACKGROUND: Hyperoxia-induced lung injury (HALI) is a common and severe complication in neonatal intensive care units, and there is currently no effective therapy available. Ferroptosis, a newly recognized form of iron-dependent regulated cell death, has recently been implicated in the pathogenesis of this disease. Ginsenosides are bioactive components extracted from ginseng. Among them, ginsenoside Rb1 (GsRb1) belongs to the protopanaxadiol-type saponins, and its molecular structure is CHO. This study aimed to investigate the protective effects and underlying mechanisms of GsRb1 in neonatal rats with hyperoxia-induced lung injury. METHODS: A neonatal rat model of hyperoxia-induced lung injury and an in vitro alveolar epithelial cell model of hyperoxic damage were established. Histopathological changes, inflammatory cytokines, oxidative stress, and key ferroptosis-related proteins like the solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression were assessed using hematoxylin-eosin staining, enzyme-linked immunosorbent assay, Western blotting, transmission electron microscopy, and immunofluorescence. The ferroptosis inhibitor, liproxstatin-1(Lip-1), and the system Xc inhibitor, erastin, were used for mechanistic validation. RESULTS: GsRb1 significantly alleviated hyperoxia-induced alveolar structural disruption, pulmonary edema, and elevated levels of inflammatory cytokines (interleukin (IL)-1β, IL-6, and tumor necrosis factor-α(TNF-α)). Moreover, GsRb1 reversed the characteristic features of hyperoxia-induced ferroptosis, including decreased intracellular ferrous iron and malondialdehyde levels, improved mitochondrial morphology, and regulation of ferroptosis-associated proteins, i.e., upregulating SLC7A11, GPX4, and Ferritin heavy chain 1 (FTH1) while downregulating Transferrin receptor protein (TFR). The protective effects of GsRb1 were comparable to those of the classical ferroptosis inhibitor Lip-1. Molecular docking analysis revealed that GsRb1 could directly and stably bind to the active pocket of the SLC7A11. Furthermore, GsRb1 reversed erastin-induced pulmonary injury and ferroptosis, confirming that its protective effects depend on system Xc pathway activation. CONCLUSION: GsRb1 exerts protective effects against hyperoxia-induced lung injury in neonatal rats by targeting SLC7A11 to activate the system Xc pathway, thereby inhibiting ferroptosis in alveolar epithelial cells.
Activation of TGF-β/ALK5/SMAD signaling alleviates behavioral and neurochemical deficits in tramadol withdrawal.
Wani SN, Grewal AK, Sharma O … +7 more , Kumar A, Singh V, Khan H, Singh TG, Singh T, Ahmad SF, Al-Mazroua HA
Toxicol Appl Pharmacol · 2026 Jul · PMID 42097514 · Publisher ↗
Opioid withdrawal state poses profound neurobiological and clinical complications characterized by neuroinflammation, oxidative stress, and neurotransmitter imbalance. Tramadol, a widely used synthetic opioid, induces a...
Opioid withdrawal state poses profound neurobiological and clinical complications characterized by neuroinflammation, oxidative stress, and neurotransmitter imbalance. Tramadol, a widely used synthetic opioid, induces a distinct withdrawal syndrome with poorly understood mechanisms, limiting targeted therapeutic options. The current investigation evaluated the neuroprotective potential of SRI-011381 hydrochloride, a selective TGF-β receptor agonist, against neurobehavioral and biochemical changes in mice induced by tramadol withdrawal. Male albino mice were administered tramadol (50 mg/kg, s.c.) twice daily for 56 days to induce dependence; on day 57, only the morning dose was administrated followed by administration of naloxone (5 mg/kg) by intraperitoneal (i.p) route to precipitate the withdrawal symptoms. Behavioral parameters, including jumping frequency, withdrawal severity score (WSS), and hyperalgesia, were assessed. Biochemical evaluations measured oxidative stress (TBARS, GSH), inflammatory mediators (IL-1β, IL-6, TNF-α, NF-κB), and neurotransmitters (glutamate, serotonin, dopamine). Treatment with SRI-011381 hydrochloride (15 and 30 mg/kg, i.p.) significantly mitigated behavioral signs of withdrawal and restored biochemical homeostasis by enhancing antioxidant defenses, reducing lipid peroxidation, normalizing neurotransmitter levels, and attenuating inflammatory mediators. Co-administration of the SMAD4 inhibitor galnusertib (150 mg/kg, i.p.) reversed these effects, confirming the involvement of a SMAD-dependent mechanism. The standard drug clonidine (0.1 mg/kg, i.p.) exhibited comparable protective effects. These findings suggest that pharmacological activation of the TGF-β/ALK5/SMAD signaling pathway by SRI-011381 hydrochloride effectively ameliorates the neurobehavioral and biochemical disturbances associated with opioid withdrawal, highlighting this pathway as a potential therapeutic target for the treatment of opioid dependence and withdrawal syndromes.
Onalespib enhances antitumor immunity through coordinated catalytic and chaperone-dependent regulation of tryptophan metabolism.
Yang L, Zhang R, Li L … +4 more , Ji M, Xi R, Wang F, Sheng Y
Toxicol Appl Pharmacol · 2026 Jul · PMID 42097513 · Publisher ↗
Tryptophan metabolism via the kynurenine (Kyn) pathway represents a central mechanism of tumor immune tolerance. Although HSP90 inhibitors have been extensively investigated as anticancer agents, their role in metabolic...
Tryptophan metabolism via the kynurenine (Kyn) pathway represents a central mechanism of tumor immune tolerance. Although HSP90 inhibitors have been extensively investigated as anticancer agents, their role in metabolic immune regulation remains incompletely unknown. Here, we identify the HSP90 inhibitor onalespib as a potent suppressor of IDO1-dependent tryptophan metabolism in breast cancer. Mechanistically, onalespib suppresses the tryptophan-kynurenine pathway through coordinated catalytic modulation of IDO1 and interference with HSP90 chaperone-associated regulation of IDO1, accompanied by attenuation of IFN-γ-induced JAK-STAT and NF-κB signaling programs. In vivo, onalespib remodels the tumor immune microenvironment, promotes CD8 effector T-cell infiltration, and enhances the antitumor efficacy of cisplatin without compromising tolerability. Collectively, these findings define a functional HSP90-IDO1 regulatory axis and provide a mechanistic rationale for combination strategies targeting metabolic immune tolerance.
An innovative label-free approach for investigating epithelial-mesenchymal transition: pharmacological characterization of TGF-β1 effects in A549 cells.
Djeujo FM, Negrini MS, Ferri P … +7 more , Mion A, Ruscitti F, Pitozzi V, Malfacini D, Trevisani M, Marchini G, Calò G
Toxicol Appl Pharmacol · 2026 Aug · PMID 42097512 · Publisher ↗
Epithelial-mesenchymal transition (EMT) is a fundamental biological process involved in normal functions such as embryonic development and tissue repair, as well as in pathological conditions including cancer progression...
Epithelial-mesenchymal transition (EMT) is a fundamental biological process involved in normal functions such as embryonic development and tissue repair, as well as in pathological conditions including cancer progression, metastasis, and fibrosis. TGF-β1 is a key inducer of EMT, activating pathways that alter cell morphology and gene expression (e.g., downregulation of E-cadherin, upregulation of α-smooth muscle actin (α-SMA)). EMT contributes to fibrotic tissue remodeling in idiopathic pulmonary fibrosis (IPF), a chronic and progressive lung disease characterized by excessive scarring of lung tissue. To achieve a comprehensive evaluation of EMT in respiratory epithelial cells (A549), we employed the standard Operetta CLS platform to assess morphological changes and protein expression of key biomarkers (E-cadherin, α-SMA), alongside an advanced approach that monitored cellular dynamics using the xCELLigence Real-Time Cell Analysis (RTCA) system and quantified biomarker gene expression via RT-qPCR. In Operetta experiments, TGF-β1 reduced cell roundness and E-cadherin protein levels, while it increased cell length and α-SMA protein levels. In xCELLigence RTCA experiments, TGF-β1 reduced the cellular index and E-cadherin gene expression while increasing α-SMA expression. SB-525334 blocked all effects of TGF-β1, whereas nintedanib was more effective in counteracting the stimulatory effects of TGF-β1 on cell length and α-SMA. Interestingly, nintedanib, per se, evoked small but consistent effects opposite to those of TGF-β1. In conclusion, integrating these experimental approaches provides a powerful platform for detailed investigation of EMT mechanisms and for the identification of novel drug candidates that counteract EMT.
RAD23A promotes multiple myeloma cell survival through DNA damage response, proteostasis and enhanced metabolic activity.
Liu H, Wang Y, Liu X … +6 more , Yang N, Wang S, Zhao J, Shi Y, Wang H, Ma Y
Toxicol Appl Pharmacol · 2026 Jul · PMID 42092462 · Publisher ↗
Multiple myeloma (MM) remains incurable and is characterized by the abnormal proliferation of malignant plasma cells in the bone marrow. RAD23A is a multifunctional protein involved in the ubiquitin-proteasome system (UP...
Multiple myeloma (MM) remains incurable and is characterized by the abnormal proliferation of malignant plasma cells in the bone marrow. RAD23A is a multifunctional protein involved in the ubiquitin-proteasome system (UPS) and DNA damage repair; however, its role in MM remains unclear. Here, we analyzed RAD23A expression and its prognostic relevance across multiple MM cohorts. The biological functions of RAD23A in MM cells were predicted using bulk RNA-seq and single-cell RNA-seq data. Experimental validation was performed in H929 and RPMI8226 MM cell lines. Flow cytometry was used to assess cell cycle progression and apoptosis. Oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and glucose uptake assays were performed to evaluate mitochondrial respiration, glycolytic activity, and glucose uptake, respectively, and RNA sequencing was conducted to further verify the role of RAD23A in MM. Our results showed that RAD23A is upregulated in MM and that high RAD23A expression is associated with greater disease burden and more advanced disease stage. Bioinformatics analyses revealed that RAD23A high MM cells exhibited elevated metabolic activity and increased protein transport. RAD23A knockdown suppressed MM cell growth both in vitro and in vivo, induced DNA damage and endoplasmic reticulum stress, and caused G2/M cell cycle arrest and apoptosis. Moreover, RAD23A knockdown enhanced the sensitivity of MM cells to bortezomib (BTZ) and impaired mitochondrial respiration, glycolytic activity, and glucose uptake. These findings suggest that RAD23A may serve as a multifunctional regulator and potential therapeutic target in MM.
Efficient pulmonary-targeted therapy and mechanistic insights of a novel glutathione dry powder inhaler in a model of radiation-induced lung injury.
Zhi Y, Yang Y, Wu B … +6 more , Chen Z, Huang H, Wang Q, Hong J, Xu Y, Chen C
Toxicol Appl Pharmacol · 2026 Jul · PMID 42086150 · Publisher ↗
Radiation-induced lung injury (RILI) remains a serious complication of thoracic radiotherapy, with limited treatment options. While reduced glutathione (GSH) has therapeutic potential, its efficacy is hindered by poor pu...
Radiation-induced lung injury (RILI) remains a serious complication of thoracic radiotherapy, with limited treatment options. While reduced glutathione (GSH) has therapeutic potential, its efficacy is hindered by poor pulmonary bioavailability via systemic administration. This study developed a novel glutathione dry powder inhaler (GSH-DPI) through rational formulation optimization. The optimized GSH-DPI exhibited excellent aerosol performance, with a fine particle fraction of 84.48% and sustained release in simulated lung fluid. In a murine RILI model, GSH-DPI (50 mg/kg, intrapulmonary administration) demonstrated superior efficacy in alleviating histopathological damage, restoring immune homeostasis, and reducing oxidative stress and pro-inflammatory cytokine expression compared to equimolar liquid GSH or high-dose oral administration. Mechanistically, analyses of single-cell RNA sequencing data revealed that RILI involves substantial alveolar type II epithelial cell (AT2) loss, compensatory oxidative stress (Nrf2/HO-1 activation), and progressive pyroptosis. GSH-DPI improved the survival of AT2 cells, simultaneously enhancing Nrf2 response and suppressing GSDMD-N-mediated pyroptosis, thereby interrupting the "oxidative stress-pyroptosis-inflammation" vicious cycle. This study highlights GSH-DPI as a promising pulmonary-targeted strategy for RILI, leveraging dual antioxidative and antipyroptotic mechanisms.
Diacerein protects against thioacetamide-induced acute liver injury via modulating HMGB1/TLR4/MyD88/NF-κB signaling pathway.
El Redeny RM, Samaha MM, El-Kashef DH
Toxicol Appl Pharmacol · 2026 Jul · PMID 42070712 · Publisher ↗
Acute liver injury (ALI) is a serious disease which happens suddenly in people with or without previous liver disease. In this experiment, thioacetamide (TAA) was utilized to induce ALI. The experimental design was condu...
Acute liver injury (ALI) is a serious disease which happens suddenly in people with or without previous liver disease. In this experiment, thioacetamide (TAA) was utilized to induce ALI. The experimental design was conducted using forty-eight adult male Sprague-Dawley rats, which were randomly divided into six groups (n = 8 per group). The control group received no treatment, Dia 100 group received diacerein (100 mg/kg, orally) only once daily for six consecutive days, TAA group received a single intraperitoneal injection of TAA at a dose of 500 mg/kg. For the treatment groups, rats were pretreated orally for six days prior to TAA administration; NAC + TAA group received N-acetylcysteine (50 mg/kg), followed by a single intraperitoneal injection of TAA (500 mg/kg) on day 6. Dia 50 + TAA group received diacerein (50 mg/kg) and Dia 100 + TAA group received diacerein (100 mg/kg) for six consecutive days, followed by TAA injection on day 6. Twenty-four hours after TAA administration, all rats were euthanized. Blood samples were collected for serum separation, and liver tissues were harvested for the assessment of biochemical parameters. Pretreatment with diacerein conferred hepatoprotective effects as evidenced by considerable (p ≤ 0.05) decrease in liver enzymes; ALT, AST, ALP, GGT concomitant with profound (p ≤ 0.05) elevation in serum level of albumin besides improvement in hepatic architecture when compared to TAA group. Diacerein also showed antioxidant properties as evidenced by the significant (p ≤ 0.05) decline in MDA content and substantial (p ≤ 0.05) increment in GSH level. Moreover, diacerein markedly (p ≤ 0.05) reduced inflammation by down-regulating HMGB1/TLR4/MYD88/NF-κB signaling pathway. Collectively, diacerein might be a potential therapeutic candidate for treatment of ALI pending further clinical studies to confirm this notion.
Non-clinical pharmacology, pharmacokinetics, and safety evaluation of TAX2, a first-in-class peptide targeting the TSP-1/CD47 matricellular axis.
Henry A, Etiennot M, Ghoula M … +4 more , Poli S, Dedieu S, Jeanne A, Moniot A
Toxicol Appl Pharmacol · 2026 Jul · PMID 42069155 · Publisher ↗
Thrombospondin-1 (TSP-1) is a matricellular glycoprotein involved in the regulation of angiogenesis, immune responses, and extracellular matrix remodeling within the tumor microenvironment. Its overexpression and interac...
Thrombospondin-1 (TSP-1) is a matricellular glycoprotein involved in the regulation of angiogenesis, immune responses, and extracellular matrix remodeling within the tumor microenvironment. Its overexpression and interaction with receptor CD47 have been associated with tumor progression and resistance to therapy. In contrast to CD47/SIRPα blockade, which is constrained by hematological and immunotoxic adverse effects, selective inhibition of the TSP-1/CD47 interaction axis may represent a mechanistically distinct and potentially safer therapeutic approach. TAX2, a 12-amino-acid cyclic peptide, was designed as an orthosteric antagonist of this interaction. Its non-clinical profile was characterized through cross-species binding assays, receptor selectivity profiling, pharmacokinetic and biodistribution analyses in rodents and dogs, in vitro off-target and cytokine release assays, and GLP-compliant toxicology studies. Human pharmacokinetics were predicted using multiple-species allometric scaling. TAX2 demonstrated binding to TSP-1 from human, rodent, and canine origin, without measurable interference with CD47/SIRPα signaling under the conditions tested. The peptide exhibited rapid plasma clearance (1-4 h), dose-proportional exposure, and detectable signal in TSP-1-rich tissues and tumor-associated regions in biodistribution studies. No relevant off-target activity or unexpected immunostimulatory effects were observed. TAX2 was well tolerated at doses up to 400 mg/kg in rats and 100 mg/kg in dogs, with no hematological or systemic toxicity, and exposures exceeding the projected clinical range. Overall, these findings establish a translational non-clinical framework for TAX2 as a first-in-class TSP-1/CD47 antagonist with cross-species reactivity and a favorable pharmacokinetic and safety profile.
Scoparone inhibits the progression of gastric cancer by regulating the PIN1/STING/TBK1/IRF3 signaling pathway.
Zhao N, Wang P
Toxicol Appl Pharmacol · 2026 Jul · PMID 42069154 · Publisher ↗
Gastric cancer (GC) remains a prevalent malignancy with poor outcomes in advanced stages. This study investigated the anti-GC effect of Scoparone (SCO) and elucidated its underlying mechanism involving the PIN1/STING/TBK...
Gastric cancer (GC) remains a prevalent malignancy with poor outcomes in advanced stages. This study investigated the anti-GC effect of Scoparone (SCO) and elucidated its underlying mechanism involving the PIN1/STING/TBK1/IRF3 signaling pathway. GC cell lines (AGS and HGC-27) were treated with increasing concentrations of SCO, and subsequent assessments of proliferation, migration, and invasion were performed using colony formation, EdU, wound healing, and Transwell assays. Mechanistically, molecular docking was performed to predict the binding between SCO and PIN1. and Western blot analysis was further employed to evaluate the phosphorylation levels of key proteins in the PIN1/STING/TBK1/IRF3 axis. While stable knockdown and overexpression models were established in vitro to validate the pivotal role of PIN1, a subcutaneous xenograft model in nude mice was utilized to independently assess the in vivo antitumor efficacy of SCO. Our results demonstrated that SCO concentration-dependently inhibited GC cell proliferation, migration, and invasion. Mechanistically, SCO downregulated PIN1 expression and promoted the phosphorylation of STING, TBK1, and IRF3. Notably, PIN1 knockdown recapitulated and enhanced SCO-mediated suppression of malignant phenotypes as well as activation of the STING/TBK1/IRF3 pathway, whereas PIN1 overexpression partially reversed these effects. In vivo, SCO significantly suppressed tumor growth through regulation of the PIN1/STING/TBK1/IRF3 pathway. Collectively, these findings elucidate a novel mechanism by which SCO suppresses GC progression via the PIN1/STING/TBK1/IRF3 axis, providing a preclinical rationale for developing SCO as a promising therapeutic candidate for GC.
Tetramethylpyrazine promotes spinal cord injury repair by modulating macrophage M1/M2 polarization via inhibition of the IL-6/JAK2/STAT3 pathway.
Bai H, Huo L, Yu R … +6 more , Deng B, Yue J, Jiang Y, Zhou Y, Zhao Y, Mu X
Toxicol Appl Pharmacol · 2026 Jul · PMID 42069153 · Publisher ↗
Spinal cord injury (SCI) induces a detrimental secondary inflammatory cascade driven largely by pro-inflammatory M1 macrophages, which impedes neural repair. Tetramethylpyrazine (TMP), a bioactive alkaloid from Ligusticu...
Spinal cord injury (SCI) induces a detrimental secondary inflammatory cascade driven largely by pro-inflammatory M1 macrophages, which impedes neural repair. Tetramethylpyrazine (TMP), a bioactive alkaloid from Ligusticum chuanxiong, has shown promise in modulating neuroinflammation. In this study, Sprague-Dawley rats subjected to thoracic contusion SCI received daily intraperitoneal TMP at 60 mg/kg or 80 mg/kg for 7 days. TMP treatment significantly improved hindlimb motor function, as evidenced by higher Basso-Beattie-Bresnahan (BBB) locomotor scores from day 7 through day 28 post-injury and increased motor evoked potential (MEP) amplitudes at day 28, confirming enhanced motor pathway conduction. Histological analyses (HE and Nissl staining) revealed reductions in lesion cavitation, preservation of neuronal architecture, and attenuated glial scar formation in TMP-treated groups. Immunofluorescence demonstrated increased NeuN, MAP2, and NF200 and decreased GFAP expression, while double staining for iNOS/CCR2 and Arg1/CCR2 indicated a shift from M1 to M2 macrophage polarization. ELISA showed significant reductions in IL-6 and TNF-α and elevation of IL-10, and both WB and RT-qPCR confirmed TMP-mediated suppression of IL-6/JAK2/STAT3 phosphorylation and gene transcription. In vitro, TMP reversed LPS-induced M1/M2 polarization imbalance in RAW 264.7 cells, meanwhile suppressing IL-6/JAK2/STAT3 phosphorylation and gene transcription, reduced pro-inflammatory cytokine release in TMP groups. Furthermore, rescue experiments demonstrated that co-treatment with recombinant IL-6 reversed TMP-mediated suppression of JAK2/STAT3 phosphorylation and M1-to-M2 polarization shift, confirming the IL-6/JAK2/STAT3 pathway as a direct mechanistic target of TMP. These results indicate that TMP fosters histopathological and functional recovery after SCI by reshaping macrophage polarization via inhibition of the IL-6/JAK2/STAT3 pathway, highlighting its potential as an anti-inflammatory neuroprotective therapy.
ADAMTS7 selective inhibitor BAY-9835 alleviates acute myocardial infarction by suppressing the NF-κB-mediated pyroptosis.
Ling Y, Lyu Y, Chen H … +9 more , Lin B, Zhou G, Chen S, Weng T, Ruan Z, Zhu Y, Zhu Z, Guo Y, Lin K
Toxicol Appl Pharmacol · 2026 Aug · PMID 42061659 · Publisher ↗
BACKGROUND: Cardiomyocyte death and functional loss following acute myocardial infarction (AMI) are major causes of post-MI heart dysfunction, yet effective drug treatments remain limited. Previous studies have suggested...
BACKGROUND: Cardiomyocyte death and functional loss following acute myocardial infarction (AMI) are major causes of post-MI heart dysfunction, yet effective drug treatments remain limited. Previous studies have suggested that plasma ADAMTS7 levels may correlate with poor outcomes in ST-segment elevation MI, but the underlying molecular mechanisms are unclear, and whether pharmacological inhibition of ADAMTS7 can improve AMI symptoms is unknown. METHOD: AMI was induced in C57BL/6 mice via ligation of the left anterior descending (LAD) coronary artery. For in vitro studies, AC16 cells were subjected to oxygen-glucose deprivation (OGD) to establish a cellular injury model. Mice were treated with BAY-9835 at doses of 0.1, 0.3, or 0.9 mg/kg/day via intraperitoneal injection. Transcriptomic analysis was performed to identify potential molecular mechanisms. RESULTS: Both in vivo and in vitro experiments demonstrated a significant upregulation of ADAMTS7 levels following MI or OGD. BAY-9835 treatment significantly improved left ventricular systolic function and reduced infarct size in mice, while non-cytotoxic concentrations of the compound alleviated OGD-induced cardiomyocyte injury in a dose-dependent manner. Transcriptomic analysis identified the NF-κB-pyroptosis pathway as a key regulatory mechanism. Specifically, BAY-9835 effectively inhibited P65 phosphorylation and reduced the expression of pyroptosis marker proteins. Notably, pharmacological activation of NF-κB abolished the protective effects of BAY-9835 in both experimental systems. CONCLUSION: This study revealed that ADAMTS7 promotes myocardial injury and cardiac dysfunction following AMI by activating NF-κB-mediated pyroptosis. These effects can be mitigated by the selective ADAMTS7 inhibitor BAY-9835. Therefore, ADAMTS7 may serve as a promising therapeutic target for the treatment of MI.
Thioacetamide-induced hepatotoxicity in rats: Hepatoprotective role of ethyl gallate in association with the regulation of Nrf2/MAPK/NF-κB signaling pathway.
Karthick M, Shree Harini K, Sanjay S … +2 more , Sharmila M, Ezhilarasan D
Toxicol Appl Pharmacol · 2026 Jul · PMID 42061658 · Publisher ↗
Acute liver injury (ALI) is characterized by the rapid onset of liver dysfunction, which may progress to acute liver failure within a short period. Thioacetamide (TAA) is widely known to induce hepatotoxicity through mec...
Acute liver injury (ALI) is characterized by the rapid onset of liver dysfunction, which may progress to acute liver failure within a short period. Thioacetamide (TAA) is widely known to induce hepatotoxicity through mechanisms involving oxidative stress, cell death, inflammation, fibrosis, and cirrhosis. Ethyl gallate (EG), a polyphenolic compound, is recognized for its potent antioxidant and free radical scavenging properties. The present study investigated the hepatoprotective role of EG on TAA-induced ALI through the Nrf2/MAPK/NF-κB associated signaling pathways in rats. Female Wistar rats were divided into six groups (n = 6) as control, TAA (350 mg/kg, i.p.,), TAA + EG (10 & 20 mg/kg, p.o.,), TAA + silymarin (SIL) (100 mg/kg, p.o.,) and EG (20 mg/kg, p.o.,). TAA, EG, and SIL were administered as a single dose, and animals were euthanized 24 h after treatment. TAA administration caused a significant elevationof liver marker enzymes in serum, as well as oxidative stress and inflammatory markers in liver tissue, indicating the onset of ALI. Co-treatment with EG and SIL significantly reduced elevated liver enzymes and oxidative stress markers, while restoring hepatic antioxidant status. Both treatments downregulated MAPK and NF-κB, and upregulated Nrf2 signaling pathways. Notably, high-dose EG (20 mg/kg) markedly prevented hepatocellular damage in TAA-induced rats. Overall, the findings of this study demonstrate the hepatoprotective potential of EG against TAA-induced acute liver injury through modulation of Nrf2 (sMaf, NQO1, Keap1, and Cul3), MAPK (JNK1, c-Jun, ERK1, ASK1, p38, and Bcl2), and NF-κB signaling pathways in rats.
Emerging contaminant fluorinated liquid crystal monomer 1-ethoxy-2,3-difluoro-4-(trans-4-propylcyclohexyl) benzene (EDPrB)-induced hepatotoxicity: Insights from combined transcriptomics and metabolomics approaches.
Li W, Wang S, Wang Z … +2 more , Fan H, You H
Toxicol Appl Pharmacol · 2026 Jul · PMID 42031323 · Publisher ↗
Fluorinated liquid crystal monomers (FLCMs) are widely used in liquid crystal display (LCD) panels. However, as emerging contaminants, FLCMs have been detected in various environments and proven to be toxic to humans. Th...
Fluorinated liquid crystal monomers (FLCMs) are widely used in liquid crystal display (LCD) panels. However, as emerging contaminants, FLCMs have been detected in various environments and proven to be toxic to humans. This study aimed to investigate the molecular mechanisms underlying the hepatotoxicity of a typical FLCM, 1-ethoxy-2,3-difluoro-4-(trans-4-propylcyclohexyl) benzene (EDPrB), in HepG2 cells. EDPrB exposure (25 mg/L) induced oxidative stress, evidenced by reduced CAT activity (1.87-fold) and increased MDA content (2.12-fold) (p < 0.05). 25 mg/L EDPrB disrupted the metabolism, significantly elevating the levels of TC (1.65-fold, p < 0.001), TG (1.47-fold, p < 0.01), and GLU (1.44-fold, p < 0.05), respectively. Comprehensive analysis of transcriptomics and metabolomics revealed that EDPrB affected lipid and glucose metabolisms, antioxidant defense-related pathways, and PI3K/AKT/mTOR signaling pathways. Additionally, the altered expression of metabolism-related genes confirmed the promotion of fatty acid synthesis and glycolysis. The altered expression of PI3K, AKT, and mTOR proteins, coupled with their strong binding affinity to EDPrB, collectively revealed the dysregulation of PI3K/AKT/mTOR pathways. Protein-protein interaction (PPI) analysis further verified the interaction between lipid and glucose metabolism disorders, oxidative stress, and PI3K/AKT/mTOR pathways dysfunction, contributing to EDPrB-induced hepatotoxicity. Our findings provide valuable insights into the potential health risks of FLCMs.
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