Toxicol. Appl. Pharmacol. [JOURNAL]
Sun
200 papers
Icariin regulates osteogenic/adipogenic differentiation of bone marrow mesenchymal stem cells in postmenopausal osteoporosis, potentially via the AMPK-mTOR-autophagy pathway.
Zeng Y, Wang H, Hu J … +4 more , Ruan W, Yao Z, Jiang B, Deng S
Toxicol Appl Pharmacol · 2026 May · PMID 41702462 · Publisher ↗
BACKGROUND: Postmenopausal osteoporosis (PMOP) is a bone disease resulting from estrogen deficiency. This investigation explores the impact of icariin (Ica) on PMOP. METHODS: Bilateral ovariectomy was performed to establ...
BACKGROUND: Postmenopausal osteoporosis (PMOP) is a bone disease resulting from estrogen deficiency. This investigation explores the impact of icariin (Ica) on PMOP. METHODS: Bilateral ovariectomy was performed to establish an ovariectomized (OVX) mouse model, followed by Ica administration. Bone parameters were measured using micro computed tomography. Fat content was evaluated using hematoxylin-eosin staining. Osteogenic/adipogenic differentiation of mouse bone marrow mesenchymal stem cells (BMSCs) was analyzed by Alkaline Phosphatase, Alizarin Red S, and Oil Red O staining. Reverse transcription-quantitative polymerase chain reaction measured bone and lipid marker gene expression. Transcriptome sequencing and cell counting kit-8 were conducted, and the expression of AMPK-mTOR-autophagy pathway proteins and bone and lipid marker proteins was detected by immunohistochemistry and Western blot. Autophagy inhibitor 3-Methyladenine (3-MA) and AMPK inhibitor dorsomorphin were employed to validate the role of autophagy and AMPK in Ica treatment of PMOP. RESULTS: Ica treatment raised bone mass while reducing fat content in OVX mice in a dose-dependent manner. Ica promoted osteogenesis and inhibited adipogenesis in BMSCs from OVX mice. Transcriptome sequencing showed that autophagy and mTOR pathways were involved in PMOP. Ica reduced mTOR and p62 expression and increased LC3 expression in OVX mice and their BMSCs, and 3-MA reversed this phenomenon. The AMPK pathway was downregulated in OVX mice and their BMSCs, but was activated following Ica treatment. The application of dorsomorphin altered the expression of AMPK-mTOR-autophagy pathway in Ica-treated BMSCs. CONCLUSION: Ica alleviates PMOP by regulating osteogenic/adipogenic differentiation of BMSCs, which may involve the AMPK-mTOR-autophagy pathway.
Network toxicology, molecular docking, and multi-level bioinformatics integration reveal the targets and mechanisms linking benzo[a]pyrene exposure to ischemic stroke.
Wu J, Jiang K, Qi M … +1 more , Wu D
Toxicol Appl Pharmacol · 2026 May · PMID 41692077 · Publisher ↗
This study aims to clarify the potential mechanisms of ischemic stroke (IS) induced by benzo[a]pyrene (BaP) through integrated network toxicology, molecular docking, and multi-level bioinformatics analyses. Targets of Ba...
This study aims to clarify the potential mechanisms of ischemic stroke (IS) induced by benzo[a]pyrene (BaP) through integrated network toxicology, molecular docking, and multi-level bioinformatics analyses. Targets of Bap were obtained from STITCH and ChEMBL databases, while IS-related targets were sourced from GeneCards, OMIM, and TTD databases. Differential gene expression was analyzed using combined datasets (GSE58294 and GSE22255 from GEO database), and key genes were validated using RT-qPCR on peripheral blood of IS patients. A nomogram was constructed for risk prediction, and molecular docking simulations were conducted for BaP-target interactions. 21 common targets for BaP and IS were identified, and a molecular regulatory network of BaP, targets, and IS was constructed. Functional enrichment revealed involvement in inflammatory and lipid metabolic pathways. MMP9 and PTGS2 were selected as key genes, showing significant upregulation in IS samples (P < 0.001). These genes exhibited moderate diagnostic accuracy, reflected by area under the curve (AUC) values of 0.716 and 0.718, respectively. Immune infiltration analyses showed that key genes were significantly correlated with neutrophils and eosinophils. Molecular docking demonstrated strong interaction between BaP and MMP9 and PTGS2, yielding docking scores of -9.9 kcal/mol and - 10.9 kcal/mol, respectively. The nomogram demonstrated robust predictive performance (AUC = 0.753) and was externally validated using the GSE16561 dataset (AUC = 0.906). BaP may promote IS pathogenesis by modulating MMP9 and PTGS2, affecting inflammatory response, immune infiltration, and lipid metabolism. These findings provide new insights into environmental toxicants in IS and suggest potential biomarkers for IS diagnosis and therapy.
Ethyl gallate attenuates 5-fluorouracil induced hepatic injury via MAPK/NF-κB downregulation in rats.
Thetchana Priya M, Sanjay S, Sharmila M … +4 more , Karthick M, Shree Harini K, Langeswaran K, Ezhilarasan D
Toxicol Appl Pharmacol · 2026 May · PMID 41687884 · Publisher ↗
BACKGROUND AND AIM: 5-Fluorouracil (5-FU) is known to cause liver injury in cancer patients. Experimental studies have reported that administration of 5-FU induces oxidative stress and inflammation in liver tissue. Ethyl...
BACKGROUND AND AIM: 5-Fluorouracil (5-FU) is known to cause liver injury in cancer patients. Experimental studies have reported that administration of 5-FU induces oxidative stress and inflammation in liver tissue. Ethyl gallate (EG), a plant-derived phytocompound, has been shown to possess antioxidant and anti-inflammatory properties. Therefore, in this study, we evaluated the protective effect of EG against 5-FU-induced acute liver injury in rats. METHODS: Rats were intraperitoneally injected with a single dose of 5-FU (150 mg/kg) to induce acute liver injury. In separate groups, rats were concurrently treated with EG (10 and 20 mg/kg) or silymarin (SIL) daily once for 7 days. At the end of an experimental period, serum transaminase activities, oxidative stress markers, inflammatory markers, and histopathological changes were assessed in liver tissue. RESULTS: A single dose of 5-FU caused a significant increase of transaminases in serum and oxidative stress, and DNA fragmentation in liver tissue. 5-FU administration also decreased the mRNA expression of its catabolizing enzyme, dihydropyrimidine dehydrogenase. At the molecular level, 5-FU upregulated apoptosis signal-regulating kinase 1, c-Jun N-terminal kinase 1, and extracellular signal-regulated kinase 1 mRNA expressions in liver tissue. It also downregulated nuclear factor erythroid 2-related factor 2 and upregulated its inhibitor Kelch-like ECH-associated protein 1, indicating oxidative stress. Similarly, 5-FU administration increased tumor necrosis factor-α and nuclear factor kappa B (NF-κB) expression while reducing its inhibitor, inhibitor of κB, confirming the activation of inflammation cascade. These abnormalities were significantly prevented in rats treated concurrently with EG or SIL. Histopathological analysis revealed reduced necrosis and better preservation of liver architecture in the 5-FU + EG and 5-FU + SIL groups. CONCLUSION: Our study demonstrates that EG and SIL treatments effectively alleviate 5-FU-induced acute liver injury by modulating 5-FU catabolism and suppressing the mitogen-activated protein kinase and NF-κB signaling pathways in rats.
Neuroprotective potential of orphenadrine in focal cerebral ischemia: A neurobehavioral and mechanistic study.
Balhara P, Ahmed S, Vasudeva N … +2 more , Jangir BL, Sharma S
Toxicol Appl Pharmacol · 2026 May · PMID 41679394 · Publisher ↗
Ischemic stroke is a leading cause of mortality and disability globally, with limited therapeutic options. This study hypothesized that orphenadrine, an NMDA antagonist with neuroprotective, anti-inflammatory and analges...
Ischemic stroke is a leading cause of mortality and disability globally, with limited therapeutic options. This study hypothesized that orphenadrine, an NMDA antagonist with neuroprotective, anti-inflammatory and analgesic properties would attenuate reperfusion brain injury in a rat middle cerebral artery occlusion (MCAO) model of focal cerebral ischemia. Male rats underwent 90-min MCAO followed by reperfusion, then received orphenadrine intraperitoneally (10 and 30 mg/kg) immediately 1 h post-reperfusion and daily for 21 days. Primary outcomes included neurological deficit scores, beam walk latency, locomotor activity, infarct volume, oxidative stress (MDA, glutathione, catalase), cytokines (IL-6, TNF-α), blood-brain barrier (BBB) integrity, and expression of HIF-1α, TFAM (mitochondrial functions), caspase-3, iNOS, and Nrf-2/HO-1. Orphenadrine administration significantly improved neurological functions, muscle strength, and locomotor activity (days 1, 7, 14 and 21), reduced infarct volume, lowered MDA and nitrite, while increased antioxidants (glutathione and catalase), and decreased neuroinflammation by lowering IL-6 and TNF-α levels. It preserved BBB integrity, enhanced mitochondrial genes, hypoxia-inducing factor 1 alpha (HIF-1α) and Transcription factor A, mitochondrial (TFAM), suppressed caspase-3 and enhanced nitric oxide synthase gene expression, and nuclear factor erythroid 2-related factor 2/ Heme oxygenase-1 (Nrf-2/HO-1) expression. These findings highlight Orphenadrine as a promising multi-target neuroprotective agent via antioxidative, anti-inflammatory, and mitochondrial preservation mechanisms in ischemic stroke, warranting further investigation for clinical translation.
Protective effect of Florfenicol against DSS-induced ulcerative colitis by inhibiting cellular senescence and reducing inflammation via the AMPK signaling pathway.
Lian W, Hou Q, Liu J … +6 more , Chen C, Wang Z, Song S, Zhou M, He F, Wang X
Toxicol Appl Pharmacol · 2026 Apr · PMID 41666985 · Publisher ↗
Ulcerative colitis (UC) is a chronic inflammatory disorder of unclear etiology. Senescence-related signs have been detected in the intestinal tissue of UC patients. Senescence is known to amplify the body's inflammatory...
Ulcerative colitis (UC) is a chronic inflammatory disorder of unclear etiology. Senescence-related signs have been detected in the intestinal tissue of UC patients. Senescence is known to amplify the body's inflammatory response, potentially accelerating UC progression. However, the precise relationship between UC and senescence remains elusive. Florfenicol (FLO) is a broad-spectrum antibiotic characterized by potent antibacterial activity and low toxicity. To date, no studies have reported on the potential of FLO in mitigating intestinal damage and senescence. In this study, we discovered that DSS can induce cellular and colon tissue senescence. Interestingly, we found that FLO can effectively counteract DSS-induced cellular senescence and alleviate DSS-induced ulcerative colitis and colon senescence in C57BL/6j mice. Moreover, we provide strong evidence that FLO effectively inhibits colon senescence and treats DSS-induced colitis by activating the AMPK signaling pathway. Consequently, FLO's anti-senescence properties may represent a novel therapeutic approach for UC management.
Intranasal exposure of poly (I:C) exacerbates OVA-induced allergic asthma by causing a major shift in the immune response.
Sandhu A, Naura AS
Toxicol Appl Pharmacol · 2026 Apr · PMID 41655797 · Publisher ↗
Viral respiratory infections are the major cause of exacerbation of allergic asthma, often resulting in increased emergency visits and hospitalizations. However, the understanding of the immune pathways at the cellular/m...
Viral respiratory infections are the major cause of exacerbation of allergic asthma, often resulting in increased emergency visits and hospitalizations. However, the understanding of the immune pathways at the cellular/molecular level under the conditions is lacking. Therefore, the present work was designed to elucidate the complex interplay of immune response under the settings mimicking exacerbation of allergic asthma upon viral infection using mouse model of the condition. Mice were sensitized & challenged with Ovalbumin (OVA) to induce allergic asthma, and subsequently subjected to intranasal administration of poly(I:C), a viral mimetic. Poly(I:C) administration at a dose of 200 μg in OVA sensitized & challenged mice resulted in shift of airway inflammation from eosinophils to neutrophils and was accompanied by enhanced airway hyper-responsiveness. Interestingly, down-regulation of Th2 cytokines (IL-4/IL-5/IL-13), and steep production of pro-inflammatory cytokines (TNF-α/IL-6/KC/MCP-1) upon poly(I:C) exposure in allergic mice indicates a switch of immune response from adaptive to innate type. Further, poly(I:C) exposure exaggerated the OVA induced oxidative stress along with over-activation of MAPK/NF-κB in lung tissue. Such changes were accompanied with Th17/Treg imbalance. Despite the proven efficacy of corticosteroids in controlling eosinophilic inflammation in OVA-induced allergic asthma, failure of dexamethasone, a steroid class of drug to mitigate neutrophil-driven inflammation upon poly(I:C) exposure in allergic mice, suggests that innate immune mediators may contribute considerably during viral infection mediated exacerbation of allergic asthma. Overall, our study highlights the complexity of the immune response during viral induced exacerbation of allergic asthma and may provide new insights to tackle such steroid insensitive conditions.
The effects of tungsten inhalation and continuous administration of angiotensin II on cardiac injury and pulmonary outcomes.
MazloumiBakhshayesh M, Hunter RP, Baird B … +12 more , Liu R, Jimenez-Campos AG, Goitom S, Barr EB, Herbert GW, Lucas SN, McVeigh CM, Moreno J, Zhu Y, Bleske BE, Campen MJ, Bolt AM
Toxicol Appl Pharmacol · 2026 Apr · PMID 41654231 · Full text
Tungsten exposure is associated with multiple cardiovascular diseases, but limited information exists on the mechanistic underpinnings of these relationships. The current study investigated the individual and combined ef...
Tungsten exposure is associated with multiple cardiovascular diseases, but limited information exists on the mechanistic underpinnings of these relationships. The current study investigated the individual and combined effects of angiotensin II (AT-II) treatment, as a model of accelerated cardiovascular disease risk, and tungsten (W) exposure on cardiac function, to provide insights into potential mechanisms involved in tungsten-mediated cardiac injury. Mice received AT-II (0.73 mg/kg/d) or saline (Veh) for 24 days through osmotic mini-pumps. The final 2-weeks of treatment, mice were exposed 4 times (4 h each) to filtered air (FA) or 1.50 ± 0.22 mg/m W particles by whole-body inhalation. Laser ablation and bulk inductively-coupled plasma mass spectrometry (ICP-MS) of lung samples indicated an accumulation of iron in AT-II treatment groups and confirmed the deposition of W and decreases in essential elements zinc, magnesium, and molybdenum in exposure groups. Echocardiographic data showed W exposure decreased cardiac output and stroke volume; however treatment with AT-II did not further exacerbate W's effects. The A'/E' ratio was significantly elevated in the AT-II + W group compared to the W + Veh group and trending significant compared to the FA + AT-II group. Blood cardiac troponin I was elevated in the W + AT-II group compared to either FA + Veh or W + Veh groups. Results suggest an interactive effect of both W and AT-II to drive cardiac injury following exposure. However, neither W exposure nor AT-II treatment resulted in pulmonary inflammation at the terminal endpoint of the study. Data illustrate pathophysiological effects of inhaled W and AT-II that contribute to cardiac injury.
Iatrogenic plasticizer Di(2-ethylhexyl) phthalate (DEHP) exposure increases Sepsis mortality risk: Machine learning implicates monocyte-driven immune dysregulation.
Gao JJ, Huang LZ, Wang T … +4 more , Zhang YL, Ye K, Lu WH, Zhang PH
Toxicol Appl Pharmacol · 2026 Apr · PMID 41651080 · Publisher ↗
Sepsis poses a significant global health burden, and ICU patients are disproportionately exposed to di(2-ethylhexyl) phthalate (DEHP), an immunotoxic plasticizer that leaches from PVC medical devices; however, whether th...
Sepsis poses a significant global health burden, and ICU patients are disproportionately exposed to di(2-ethylhexyl) phthalate (DEHP), an immunotoxic plasticizer that leaches from PVC medical devices; however, whether this exposure causally influences sepsis outcomes remains unclear. To investigate this relationship, we conducted a prospective cohort study comparing 90 ICU sepsis patients with 50 controls, quantifying urinary DEHP metabolites using LC-MS/MS. Sepsis patients demonstrated significantly elevated DEHP metabolite levels (p < 0.001), and high exposure (≥341.58 μg/g creatinine) was independently associated with reduced 28-day survival (35% vs 55%, p = 0.04; HR = 1.92, 95%CI:1.01-3.65). To identify the molecular mechanisms underlying this association, we integrated seven sepsis transcriptomic datasets with predicted DEHP targets, revealing 46 overlapping genes. Subsequently, machine learning algorithms (LASSO, SVM-RFE, and Random Forest) prioritized seven core genes, with SHAP analysis identifying MAPK14 as the predominant contributor. Molecular docking further confirmed high-affinity binding between DEHP and these target proteins. To establish causality, Mendelian randomization analysis using cis-eQTLs and FinnGen GWAS data demonstrated that genetically predicted higher MAPK14 expression increases sepsis susceptibility (OR = 1.18, p = 0.045). In conclusion, these findings provide converging evidence that high iatrogenic DEHP exposure is associated with increased sepsis mortality, potentially through MAPK14-mediated pathways, suggesting that DEHP exposure represents a modifiable risk factor in critical care settings and supporting the evaluation of DEHP-free alternatives for high-leach medical devices.
Multi-omics reveal the key role of gut microbiota metabolism in adenine-induced chronic kidney disease.
Xin Y, Ma H, Li X … +3 more , Sun R, Fang L, Pan L
Toxicol Appl Pharmacol · 2026 Apr · PMID 41651079 · Publisher ↗
The gut microbiota plays a crucial role in the progression of chronic kidney disease (CKD). The adenine-induced CKD mouse model is widely employed in preclinical research, yet the effects of adenine on the composition an...
The gut microbiota plays a crucial role in the progression of chronic kidney disease (CKD). The adenine-induced CKD mouse model is widely employed in preclinical research, yet the effects of adenine on the composition and metabolic function of the gut microbiota remain to be elucidated. This study aimed to test the hypothesis that adenine-induced alterations in the structure and function of the gut microbiota are significantly associated with the onset and progression of CKD. To this end, a mouse CKD model was established by alternating feeding with 0.15% and 0.20% adenine for 7 weeks. Multi-omics analysis (untargeted metabolomics, metagenomics, and spatial metabolomics) was performed to compare the adenine-induced CKD group with a standard diet-fed normal control group. Integrated analysis of plasma metabolomics and intestinal content metabolomics identified 94 differentially co-regulated metabolites: among these, indolelactic acid was significantly upregulated, while indole-3-propionic acid was significantly downregulated. The bile acid metabolic pathway also underwent marked perturbations: taurochenodeoxycholic acid and tauro-β-muricholic acid (two taurine-conjugated bile acids) were significantly elevated, whereas nordeoxycholic acid and norcholic acid were notably reduced. Integrated metabolomics-metagenomics analysis further demonstrated that Lactobacillus exhibited a significant positive correlation with a subset of upregulated metabolites (including indolelactic acid), while Taurinivorans muris showed a strong negative correlation with the taurine-conjugated bile acids. Additionally, renal spatial metabolomics revealed that phospholipid metabolic disorders in the adenine-induced CKD group directly contributed to the aggravation of renal inflammatory responses. Collectively, these findings reveal a gut microbiota-metabolite-kidney axis perturbed by adenine, providing novel insights into the pathogenesis of CKD and potential targets for metabolic intervention.
Targeting aryl hydrocarbon receptor signaling attenuates hypertension programmed by maternal Di-2-ethylhexylphthalate exposure.
Hsu CN, Liu HY, Hou CY … +4 more , Chen YW, Chang-Chien GP, Lin SF, Tain YL
Toxicol Appl Pharmacol · 2026 Apr · PMID 41643944 · Publisher ↗
Adverse early-life conditions can predispose offspring to long-term health risks. Phthalate exposure, particularly to di-2-ethylhexylphthalate (DEHP), during pregnancy and lactation has been implicated in programming off...
Adverse early-life conditions can predispose offspring to long-term health risks. Phthalate exposure, particularly to di-2-ethylhexylphthalate (DEHP), during pregnancy and lactation has been implicated in programming offspring hypertension via aryl hydrocarbon receptor (AHR) activation, renin-angiotensin system (RAS) dysregulation, nitric oxide (NO) deficiency, and gut microbiota alterations. Using a maternal DEHP exposure rat model, we investigated whether blockade of AHR signaling-directly with the AHR inhibitor CH223191 or indirectly with the indoleamine 2,3-dioxygenase (IDO) inhibitor INCN-024360-prevents offspring hypertension. Pregnant rats received DEHP (10 mg/kg/day) by oral gavage throughout pregnancy and lactation, with or without CH223191 (10 mg/kg/day) or INCN-024360 (50 mg/kg/day). Maternal DEHP exposure induced sustained systolic hypertension in adult male offspring, accompanied by upregulation of renal AHR signaling and RAS components. This effect was attenuated by the IDO inhibitor (approximately 10 mmHg reduction in systolic blood pressure) and more effectively by the AHR inhibitor (approximately 16 mmHg reduction). Mechanistically, the IDO inhibitor reduced asymmetric dimethylarginine (an endogenous nitric oxide synthase inhibitor), renin, and CYP1A1 expression while increasing angiotensin-converting enzyme 2 (ACE2), whereas the AHR inhibitor suppressed renal AHR, renin, angiotensin-converting enzyme (ACE), and angiotensin II type 1 receptor (AT1R) expression and significantly enhanced short-chain fatty acid receptor expression. Both interventions were associated with distinct alterations in gut microbiota composition. These findings identify AHR as a key mechanistic link between early-life environmental phthalate exposure and programmed hypertension and support early-life AHR blockade as a potential preventive strategy for offspring cardiometabolic-kidney risk.
Human umbilical cord mesenchymal stem cells-derived exosomes restore lung architecture and reduce the susceptibility to asthma of offspring in maternal asthma.
Li X, Wu Y, Mao M … +5 more , Xu H, Liu C, Liu Y, Zhang H, Liu H
Toxicol Appl Pharmacol · 2026 Apr · PMID 41638506 · Publisher ↗
Asthma is a heterogeneous disorder driven by inflammatory processes that promote pathogenic airway remodeling. Human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-Exos) emerge as a compelling therapeutic...
Asthma is a heterogeneous disorder driven by inflammatory processes that promote pathogenic airway remodeling. Human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-Exos) emerge as a compelling therapeutic candidate to disrupt this disease cycle, with potential intergenerational benefits. In a chronic OVA-induced asthma model using C57BL/6 mice, hucMSC-Exos were delivered via serial injections during the sensitization phase. Airway structural changes were evaluated through histological analysis (H&E staining, Masson's trichrome) and immunofluorescence for key remodeling markers including α-SMA, CC-10, and the proliferation marker Ki67. Molecular pathway analyses specifically targeted the TGF-β/Smad and STAT6 signaling cascades. We found that hucMSC-Exos intervention effectively ameliorated the core pathological features of asthma-induced lung injury and significantly reduced the levels of IL-6 and TNF-α in bronchoalveolar lavage fluid (BALF) in a dose-dependent manner. Additionally, this treatment reduced asthma susceptibility in offspring of mothers with chronic asthma. Compared to the OVA group, the Exos group showed restored CC-10 expression and decreased pulmonary Ki67 levels. In offspring, Hopx (but not SPC) expression was significantly elevated at PN1 and PN4 relative to the OVA group, though these differences lost statistical significance at PN14, consistent with Western blotting (WB) validation. Notably, unlike maternal findings, both CC-10 and Ki67 expression in the lungs of treated offspring were lower than in controls. Furthermore, we observed that OVA-induced activation of PECAM-1, α-SMA, p-ROCK1, and Caspase-8 was attenuated by hucMSC-Exos treatment. RNA sequencing of hucMSC-Exos identified asthma-associated miRNAs, including let7a-5p and miR-125a-5p. The therapeutic efficacy of hucMSC-Exos against asthma was partially abolished when these miRNA inhibitors were applied, underscoring their critical regulatory role in exosome-based asthma therapy. In conclusion, hucMSC-Exos have demonstrated significant efficacy in the treatment of asthma, capable of alleviating airway remodeling and related symptoms. What is particularly important is that they have a cross-generational protective effect, which can reduce the asthma susceptibility of children born to asthmatic mothers. Mechanistically, this benefit may be achieved through the transfer of asthma-related miRNAs. These findings elucidate the key molecular pathways of the cross-generational therapeutic effect mediated by hucMSC-Exos, providing a scientific basis for their clinical application in the management of maternal and offspring asthma.
Thiophene-based styrene derivative improves colitis symptoms in DSS-induced BALB/C mice through AhR-mediated gut barrier function and inflammatory responses.
Yang AK, Li YL, Chen YY … +5 more , Liu Y, Du ZY, Dong CZ, Meunier B, Chen HX
Toxicol Appl Pharmacol · 2026 Apr · PMID 41638505 · Publisher ↗
Worldwide incidence and prevalence of ulcerative colitis (UC) has been rising in recent years, which can occur at any age, with a high frequency seen in young children and people aged 40 to 50. The aryl hydrocarbon recep...
Worldwide incidence and prevalence of ulcerative colitis (UC) has been rising in recent years, which can occur at any age, with a high frequency seen in young children and people aged 40 to 50. The aryl hydrocarbon receptor (AhR) activation axis is well known for its important role in the regulation of intestinal inflammation, intestinal homeostasis, intestinal immune system and improvement of colitis outcomes. This study investigated the therapeutic efficacy of the thiophene-based styrene derivative (TBSD), a novel AhR agonist against UC in vitro and in vivo. TBSD decreased FITC-dextran hyperpermeability, upregulated the tight junction (TJ)-related protein expression levels and regulated the inflammatory mediators including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-22 and cyclooxygenase 2 (COX-2) in the Caco-2/RAW264.7 co-culture system and in DSS-induced UC-like mice. Overall, TBSD may be considered as a promising therapeutic agent to improve UC severity through mitigating inflammation, maintaining intestinal mucosal homeostasis and enhancing the intestinal barrier integrity.
Long-term exposure to Di(2-ethylhexyl) phthalate induced uterine histopathologic alterations in female mice.
Lee JY, Kim JS, Zaheer J … +6 more , Chang SH, Choi K, Hwang DW, Lee J, Kim YA, Cho YH
Toxicol Appl Pharmacol · 2026 Apr · PMID 41617092 · Publisher ↗
OBJECTIVE: To investigate the effects of long-term Di(2-ethylhexyl) phthalate (DEHP) exposure on the female reproductive system, employing different dosages and durations of exposure. METHODS: Pregnant female CD-1 mice (...
OBJECTIVE: To investigate the effects of long-term Di(2-ethylhexyl) phthalate (DEHP) exposure on the female reproductive system, employing different dosages and durations of exposure. METHODS: Pregnant female CD-1 mice (F0) were orally exposed to DEHP at doses of 0, 100, and 500 mg/kg/day during gestation. Following birth, the female offspring (F1) were allocated into three groups as F0 mice. Both F0 and F1 mice were consequently subjected to ongoing DEHP exposure until they were sacrificed. Body weight, anogenital distance, anogenital index (AGI), and histopathologic outcomes of the uterus were examined at 21 and 35 weeks for F0 mice and at 10 and 24 weeks for F1 mice. RESULTS: Both low and high DEHP exposures significantly decreased body weight in F0 at 21 weeks and in F1 at 10 and 24 weeks, while AGI was not significantly changed in response to DEHP exposure in both F0 and F1 mice. DEHP exposure induced endometrial stromal fibrosis, endometrial hyperplasia, and myometrial atrophy in the uterus of F1mice, while cystic hyperplasia and endometrial stromal sarcoma (ESS) were seen in the F0 after DEHP exposure at 35 weeks. CONCLUSIONS: Long-term Exposure to DEHP significantly reduced body weight and induced pathological alterations in the uterus of both F0 and F1 mice. Dams exposed to high doses of DEHP developed ESS, suggesting that DEHP may have carcinogenic potential in the uterus. However, further research is necessary to confirm this finding.
Angelicin attenuates sepsis-associated splenic injury by targeting NF-κB/JAK2/STAT3 and PI3K/Akt pathways to inhibit inflammation and apoptosis.
Pan E, Sun H, Ma Z … +7 more , Zhang S, Liu Y, Xu Z, Li Y, Jin X, Wang H, Dong J
Toxicol Appl Pharmacol · 2026 Mar · PMID 41605309 · Publisher ↗
Sepsis represents a clinical syndrome characterized by maladaptive host immune dysregulation in response to infection, leading to potentially fatal multiorgan dysfunction. As the largest secondary lymphoid organ in mamma...
Sepsis represents a clinical syndrome characterized by maladaptive host immune dysregulation in response to infection, leading to potentially fatal multiorgan dysfunction. As the largest secondary lymphoid organ in mammals, spleen tissue plays a fundamental role in immune defense. Angelicin (ANG), the main active ingredient in the traditional Chinese medicine Psoralea corylifolia Linn., possesses biological activities such as anti-inflammation and anti-apoptosis. This study established a mouse sepsis-associated splenic injury model using cecal ligation and puncture (CLP) to systematically analyze the protective effects of ANG and its underlying mechanisms. Additionally, the J774A.1 cell model stimulated with lipopolysaccharide (LPS) was used to further validate the pathway regulation phenomena observed in vivo. The results showed that ANG treatment significantly attenuated sepsis-associated splenic injury in mice. qPCR results showed that ANG downregulated pro-inflammatory and upregulated anti-inflammatory cytokine transcripts. TUNEL results showed that ANG treatment inhibited the ratio of TUNEL-positive cells. Further studies demonstrated that ANG suppressed inflammatory responses by inhibiting the NF-κB and JAK2/STAT3 pathways, and alleviate apoptosis by activating the PI3K/Akt pathway. Notably, the suppressive effect of ANG on JAK2/STAT3 pathway was dependent on the inhibition of the NF-κB pathway.
Transcription factor TFAP2A drives EMT progress by activating BDKRB1 transcription: The potential mechanism by which TFAP2A promotes idiopathic pulmonary fibrosis.
Zhang J, Jin X, Sun Y … +2 more , Xia R, Chen F
Toxicol Appl Pharmacol · 2026 Apr · PMID 41587695 · Publisher ↗
Epithelial-mesenchymal transition (EMT)-inducing signals trigger the accumulation of extracellular matrix, thereby contributing to organ pathology, including idiopathic pulmonary fibrosis (IPF). Transcription factor AP-2...
Epithelial-mesenchymal transition (EMT)-inducing signals trigger the accumulation of extracellular matrix, thereby contributing to organ pathology, including idiopathic pulmonary fibrosis (IPF). Transcription factor AP-2 alpha (TFAP2A) has been reported to facilitate the EMT process, but its function in IPF remain unknown. A mouse IPF model was established via single intratracheal instillation of bleomycin (BLM). Adenovirus carrying shRNA specifically targeting TFAP2A was administered 24 h prior to BLM challenge to achieve TFAP2A silencing. For in vitro studies, human bronchial epithelial cells (BEAS-2B) underwent lentivirus infection for 48 h to achieve TFAP2A silencing, followed by BLM treatment. We found that the expression of TFAP2A at both mRNA and protein levels was significantly upregulated in fibrotic lung tissue. TFAP2A knockdown alleviated BLM-induced lung injury and fibrosis, as evidenced by reduced collagen deposition and decreased expression of the fibrotic biomarkers α-SMA and Collagen I. Furthermore, TFAP2A silencing inhibited BLM-induced EMT in in the lungs of fibrotic mice, characterized by the upregulation of epithelial markers (Cytokeratin-8 and E-cadherin) and downregulation of mesenchymal markers (Fibronectin, Vimentin, and N-cadherin). In vitro assays demonstrated that BLM exposure increased α-SMA protein expression and promoted the EMT process in BEAS-2B cells, which were reversed by TFAP2A knockdown. Interestingly, TFAP2A significantly upregulated the RNA level of bradykinin receptor B1 (BDKRB1), a fibrosis-inducing factor. Mechanistically, TFAP2A activated BDKRB1 transcription by binding to the promoter of BDKRB1. Overexpression of BDKRB1 abrogated the protective effects of TFAP2A knockdown against lung fibrosis. Overall, our findings demonstrate that TFAP2A drives EMT progression and promotes IPF development by transcriptionally activating BDKRB1, identifying the TFAP2A/BDKRB1 axis as a potential therapeutic target in IPF.
Expression of drug transporters in human allogenic transplanted kidneys in acute rejection.
Łapczuk-Romańska J, Hybiak J, Piotrowska K … +5 more , Marchelek-Myśliwiec M, Wilk A, Słojewski M, Urasińska E, Droździk M
Toxicol Appl Pharmacol · 2026 Mar · PMID 41581572 · Publisher ↗
Kidney drug transporters, primarily located in the basolateral and apical membranes of proximal tubule cells, play a key role in the secretion and reabsorption of drugs and endogenous compounds. Recent studies have demon...
Kidney drug transporters, primarily located in the basolateral and apical membranes of proximal tubule cells, play a key role in the secretion and reabsorption of drugs and endogenous compounds. Recent studies have demonstrated that kidney diseases can alter transporter expression; however, the expression of these transporters in human transplanted kidneys, with and without rejection, remains unclear. Therefore, the aim of this study was to investigate the mRNA expression (qRT-PCR) and immunolocalization (via immunohistochemistry) of key ABC (ATP-binding cassette) (n = 14) and SLC (solute carriers) (n = 33) transporters in glomeruli and proximal tubule cells from human normal kidney (CTRL, n = 8), non-rejected transplanted kidney (AR-0, n = 7) and transplanted kidney under rejection process (AR-I, n = 8) from patients receiving immunosuppressive drugs. Our study shows that mRNA expression level of SLC22A4, SLC22A6, SLC22A7, SLC22A8, SLC28A1, SLC47A1, SLC22A11, SLC15A2, SLC16A1, ABCC2, ABCC5 and ABCC6 are statistically significantly downregulated, while SLC22A2, SLCO4A1 and ABCB1 are statistically upregulated in proximal tubule cells from rejected transplanted kidneys compared to controls. Immunohistochemistry revealed that OAT1, OAT3, OCT2, MATE1, MRP2, MRP6 and P-gp were primarily expressed in proximal tubule cells, with significantly lower protein expression of OAT1, OAT3, P-gp in AR-I and AR-0 biopsies compared to CTRL sections. These preliminary data suggest that the expression profile of kidney transporters may be altered in transplanted kidneys from patients treated with immunosuppressive drugs.
Cardamonin attenuates osteoporosis progression and promotes osteogenic differentiation of bone mesenchymal stem cells by upregulating TCF4 expression.
Sun H, Hu R, Wu J
Toxicol Appl Pharmacol · 2026 Mar · PMID 41581571 · Publisher ↗
BACKGROUND: Osteoporosis is a common skeletal metabolic disorder. Cardamonin (CAR) is a natural chalcone compound with multiple activities. However, the role and mechanism of CAR in osteoporosis progression remain largel...
BACKGROUND: Osteoporosis is a common skeletal metabolic disorder. Cardamonin (CAR) is a natural chalcone compound with multiple activities. However, the role and mechanism of CAR in osteoporosis progression remain largely unknown. METHODS: Mice underwent ovariectomy (OVX) to establish a model of osteoporosis, and bone loss was analyzed. Osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs) was induced by culturing in osteoblast medium, and evaluated by determining ALP, OCN, RUNX2, and OSX levels using qRT-PCR and western blotting. Bioinformatics analysis was conducted using the SEA server, DisGeNet database, and GSE35959 GEO dataset. TCF4 protein expression was examined using western blotting. RESULTS: CAR mitigated OVX-induced bone loss in mice and promoted osteogenic differentiation of hBMSCs by increasing the expression levels of ALP, OCN, RUNX2, and OSX. TCF4 expression was reduced in osteoporosis, and CAR upregulated TCF4 level. TCF4 overexpression promoted osteogenic differentiation of hBMSCs, while its silencing weakened the promoting effect of CAR on osteogenic differentiation. CONCLUSION: CAR attenuates bone loss in an OVX-induced mouse model of osteoporosis and promotes osteogenic differentiation of hBMSCs via increasing TCF4 expression, indicating the therapeutic potential of CAR in osteoporosis.
Identification of key targets and mechanisms of isoorientin in osteoporosis treatment through integrated network pharmacology and experimental validation.
Guo J, Xie J, Xu A … +4 more , Wang W, Fu Z, Zhou K, Hong S
Toxicol Appl Pharmacol · 2026 Apr · PMID 41580162 · Publisher ↗
Osteoporosis is a prevalent metabolic bone disorder characterized by diminished bone mineral density and elevated fracture susceptibility. Although isoorientin (ISO) has emerged as a promising candidate for osteoporosis...
Osteoporosis is a prevalent metabolic bone disorder characterized by diminished bone mineral density and elevated fracture susceptibility. Although isoorientin (ISO) has emerged as a promising candidate for osteoporosis treatment, its molecular mechanisms remain unclear. In this study, a comprehensive network pharmacology approach was employed to identify potential therapeutic targets by systematically mining the GeneCards and DisGeNET databases. ISO-target interactions were predicted through an integrated analysis of multiple chemoinformatic platforms, including Super-Pred, SwissTargetPrediction, PharmMapper, and ChemMapper. Hub targets were identified via protein-protein interaction (PPI) network analysis, complemented by functional enrichment assessments and molecular docking simulations. The computational findings were experimentally validated using an ovariectomy (OVX)-induced osteoporotic murine model. Network pharmacological analysis revealed 332 putative ISO targets, 45 of which significantly overlapped with 610 osteoporosis-associated targets. Functional enrichment analysis highlighted the critical involvement of these genes in hormone-mediated signaling pathways and cellular responses to nutrient levels. KEGG pathway analysis further implicated these targets in key regulatory cascades, including the MAPK, relaxin signaling, and lipid metabolism-associated atherosclerosis pathways. Molecular docking simulations demonstrated strong binding affinities between ISO and pivotal targets, including MAPK14, TLR4, and ESR1. In vivo validation using OVX mice confirmed ISO's capacity to attenuate bone loss by suppressing osteoclast activation, as evidenced by micro-CT analysis and histomorphometric quantification. Further in vitro studies demonstrated that ISO inhibits RANKL-induced osteoclastogenesis via suppression of the MAPK pathway. This study elucidates the key targets and pathways through which ISO exerts anti-osteoporotic effects, highlighting its therapeutic potential in osteoporosis management.
Nab-paclitaxel inhibits angiogenesis via the CYR61/integrin αβ Axis: Exosomal proteomics insights into breast cancer chemoprevention.
Zhang Y, Wang J, Deng Z … +5 more , Zhuang H, Chen X, Zhou X, Huang W, Yu S
Toxicol Appl Pharmacol · 2026 Apr · PMID 41580161 · Publisher ↗
Albumin-bound paclitaxel (Nab-PTX), a nanoparticle albumin-bound formulation in which paclitaxel is conjugated to human serum albumin, has emerged as a pivotal agent in cancer therapy. Its significance stems not only fro...
Albumin-bound paclitaxel (Nab-PTX), a nanoparticle albumin-bound formulation in which paclitaxel is conjugated to human serum albumin, has emerged as a pivotal agent in cancer therapy. Its significance stems not only from direct cytotoxic effects on cancer cells but also from multifaceted interactions with angiogenesis, a critical driver of tumor progression and metastasis. Nevertheless, the underlying mechanism of its anti-angiogenesis in breast cancer remains elusive. In the present study, we employed the iTRAQ (isobaric tags for relative and absolute quantification) technique to assess the effect of Nab-PTX on Triple-negative breast cancer cells (MDA-MB-231). A total of 5145 exosomal proteins were identified, of which 941 exhibited significant differences between Nab-PTX-treated cells and the control group (P-value<0.05). Notably, we found that CYR61 (Cysteine-rich angiogenic inducer 61), a secreted matricellular protein belonging to the CCN family, was significantly inhibited by Nab-PTX. Furthermore, our study demonstrated for the first time that Nab-PTX inhibits angiogenesis via the CYR61/Integrin αβ signaling pathway. These findings elucidate a potential anti-angiogenesis mechanism of Nab-PTX and highlight CYR61's promise as a therapeutic target in human breast cancer.
Cyclomulberrin represses renal cell carcinoma progression via ferroptosis activation.
Yi X, Xie Z, Jin T … +6 more , Ji Y, Zhu W, Lu D, Eman S, Liu S, Tian J
Toxicol Appl Pharmacol · 2026 Mar · PMID 41580160 · Publisher ↗
Renal cell carcinoma (RCC) is one of the most common malignancies in the genitourinary system. Cyclomulberrin (CyM), a natural prenylated flavonoid, has shown anti-tumor potential. However, the efficacy and potential mec...
Renal cell carcinoma (RCC) is one of the most common malignancies in the genitourinary system. Cyclomulberrin (CyM), a natural prenylated flavonoid, has shown anti-tumor potential. However, the efficacy and potential mechanisms of this treatment in RCC remain unclear. This study employed MTT, wound-healing, colony-formation, Transwell, and xenograft mouse models to demonstrate that CyM effectively suppresses RCC cell proliferation and migration. To figure out the possible mechanism, untargeted metabolomic and transcriptomic analyses found CyM induced ferroptosis by disrupting the cellular oxidative defense system. Subsequent experiments confirmed key ferroptotic events, including increased lipid peroxidation, accumulation of intracellular Fe, depletion of glutathione, and mitochondrial dysfunction. Ferroptosis inhibitor Ferrostatin-1 (Fer-1) reversed these events, underscoring the central role of ferroptosis in its anti-tumor activity. In summary, this study first demonstrates that CyM exerts anti-RCC effects by triggering ferroptosis through impairment of the oxidative defense system, induction of mitochondrial damage, and lipid peroxidation. These findings identify a promising therapeutic candidate for RCC.
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