Toxicol. Appl. Pharmacol. [JOURNAL]
Sun
200 papers
Levistolide A induces endoplasmic reticulum stress-triggered apoptosis via ATF6 in triple-negative breast cancer.
Bai Y, Wang D, Guan H … +3 more , Guo Y, Zhu H, Chen Z
Toxicol Appl Pharmacol · 2026 Jun · PMID 41812734 · Publisher ↗
BACKGROUND: Levistolide A(LA), a bioactive constituent extracted from the herbal plant Ligusticum chuanxiong possesses anticancer properties. Nevertheless, its functions and underlying processes in triple-negative breast...
BACKGROUND: Levistolide A(LA), a bioactive constituent extracted from the herbal plant Ligusticum chuanxiong possesses anticancer properties. Nevertheless, its functions and underlying processes in triple-negative breast cancer (TNBC) are not well defined. METHODS: We evaluated how LA affects endoplasmic reticulum (ER) stress in TNBC cells by dosing in vitro models with different concentrations. Cellular viability and proliferation were evaluated through CCK-8 assays, colony formation assays, and immunofluorescence microscopy. Following this, tumor cells were pre-incubated with the ER stress inhibitor melatonin, and alterations in apoptosis were quantified by flow cytometry. Expression patterns of ER stress-associated markers were analyzed at both protein and transcript levels using Western blotting and quantitative reverse transcription PCR. These in vitro observations were further corroborated in tumor xenograft models via immunohistochemical staining and hematoxylin-eosin (HE) staining, thereby confirming the contribution of ER stress to LA's antitumor activity. RESULTS: Experimental findings revealed that LA markedly suppresses the proliferation of TNBC cells, triggers ER stress, and promotes cellular apoptosis. Conversely, when melatonin was administered to block ER stress, the ability of LA to both inhibit proliferation and stimulate apoptosis in TNBC cells was markedly restored. CONCLUSION: Our findings indicate that LA inhibits TNBC progression by activating ER stress. This discovery suggests promising directions for developing innovative therapeutic interventions against TNBC in clinical practice.
Phosphoethanolamine cytidylyltransferase 2 exerts an anti-tumor role in clear cell renal cell carcinoma by modulating the hippo/YAP1 signaling pathway in a PPP2R1A-dependent manner.
Nan N, Guo H, Huang Y … +2 more , Chen J, Qiang X
Toxicol Appl Pharmacol · 2026 Jun · PMID 41802576 · Publisher ↗
Recent studies have indicated that phosphoethanolamine cytidylyltransferase 2 (PCYT2) is aberrantly expressed in various tumors, influencing tumor progression, metastasis, and drug resistance. However, the role of PCYT2...
Recent studies have indicated that phosphoethanolamine cytidylyltransferase 2 (PCYT2) is aberrantly expressed in various tumors, influencing tumor progression, metastasis, and drug resistance. However, the role of PCYT2 in clear cell renal cell carcinoma (ccRCC) remains unexplored. The objective of this research is to explore the expression changes of PCYT2 in ccRCC and elucidate its potential regulatory effects on ccRCC biological functions, alongside the underlying molecular mechanisms. Through sequencing data analysis and clinical tissue assessments, we discovered a notable downregulation of PCYT2 in ccRCC tissues, with lower PCYT2 expression correlating with poorer patient prognosis. Gene overexpression and silencing experiments demonstrated that PCYT2 overexpression exerted notable anti-cancer effects, including inhibition of cell proliferation, migration, and invasion. Silencing PCYT2 produced opposite effects, which could be reversed by PCYT2 overexpression. Mechanistic studies revealed that PCYT2 promoted the phosphorylation of Yes-associated protein 1 (YAP1), preventing its nuclear translocation and thereby inhibiting YAP1 pathway activation. Further investigations indicated that the regulatory effect of PCYT2 on YAP1 phosphorylation was dependent on PPP2R1A. In vivo studies corroborated these findings, showing that PCYT2 overexpression significantly restrained tumor formation, accompanied by downregulation of the YAP1 pathway. Our findings offer substantial evidence that PCYT2 acts as a tumor suppressor in ccRCC, with its mechanism linked to the regulation of YAP1 pathway activation. This study offers fresh perspectives on the molecular pathogenesis of ccRCC and identifies PCYT2 as a potential candidate for therapeutic strategies in this disease.
Dermorphin blocks apneic response to intravenous bolus injection of fentanyl.
Zhuang J, Gao X, Shi S … +1 more , Xu F
Toxicol Appl Pharmacol · 2026 Jun · PMID 41802575 · Full text
BACKGROUND: Sudden death induced by intravenous bolus (IVb) injection of overdose fentanyl is the major cause of overdose opioid-induced deaths; however, the relevant countermeasure is lacking. IVb injection of overdose...
BACKGROUND: Sudden death induced by intravenous bolus (IVb) injection of overdose fentanyl is the major cause of overdose opioid-induced deaths; however, the relevant countermeasure is lacking. IVb injection of overdose fentanyl in rats triggers a vagal mediated immediate sustained apnea via acting on mu1 opioid receptor (μ-OR), which becomes lethal if overdosed. Because dermorphin is a potent analgesic and can promote rapid desensitization of μ-ORs, we tested if dermorphin pretreatment would prevent/blunt the fentanyl-induced apnea. METHODS: We made three comparisons in anesthetized and spontaneously breathing rats: (1) the cardiorespiratory responses to IVb injection of dermorphin without and with naloxonazine (a μ-OR antagonist) pretreatment; (2) the reproducibility of the responses to IVb injection of dermorphin and fentanyl (each repeated three times within a 2-h period) and (3) the effects of dermorphin pretreatment on the fentanyl-induced apnea and fentanyl pretreatment on dermorphin-induced response. RESULTS: IVb injection of dermorphin triggered an immediate apnea followed by a brief bradypnea, depending on activating μ-ORs. Although dermorphin and fentanyl both elicited a similar immediate apnea, the recovery of respiratory response was much faster in the former than the latter (0.5 min vs. 30 min). Importantly, the apneic response was triggered only by the first dermorphin injection, but always evoked by the three trials of fentanyl injections. Dermorphin pretreatment blocked fentanyl-induced apnea, while fentanyl pretreatment failed to affect the dermorphin-induced apnea. CONCLUSION: Our results suggest that dermorphin pretreatment is able to block fentanyl-induced apnea likely via desensitization of μ-ORs in vagal afferents and/or their pathways. This pretreatment may be a potential therapeutic intervention in fentanyl abusers to prevent and minimize the fentanyl-induced apnea.
Unraveling the connection between PFOA and bladder cancer: A study integrating network toxicology, molecular docking, and experimental validation.
Yan H, Yin C, Xu F … +1 more , Li R
Toxicol Appl Pharmacol · 2026 Jun · PMID 41794187 · Publisher ↗
PFOA, an environmental pollutant linked to bladder cancer, has unclear molecular mechanisms. Integrating transcriptomic data with network toxicology and machine learning, we identified 125 shared genes related to PFOA an...
PFOA, an environmental pollutant linked to bladder cancer, has unclear molecular mechanisms. Integrating transcriptomic data with network toxicology and machine learning, we identified 125 shared genes related to PFOA and bladder cancer. Machine learning refined a 16-gene prognostic signature. Molecular docking revealed NUDT1 as the top candidate with strong PFOA binding affinity. Functional experiments showed PFOA upregulates NUDT1, enhancing bladder cancer cell proliferation and migration. NUDT1 knockdown attenuated these malignant effects and partially reversed PFOA's impact. Thus, PFOA promotes bladder cancer progression via NUDT1 interaction, positioning NUDT1 as a potential biomarker and therapeutic target for PFOA-associated carcinogenesis.
The critical role of HIBCH in pulmonary arterial hypertension.
Wu B, Tian T, Liu Y … +7 more , Qin S, Ma X, Zhang J, Liu C, Liu X, Li J, Qin Z
Toxicol Appl Pharmacol · 2026 Jun · PMID 41794186 · Publisher ↗
Lactate produced during glycolysis plays a critical role in pulmonary arterial hypertension (PAH) by mediating protein lactylation and other molecular effects. Targeting lactylation-related signaling holds significant pr...
Lactate produced during glycolysis plays a critical role in pulmonary arterial hypertension (PAH) by mediating protein lactylation and other molecular effects. Targeting lactylation-related signaling holds significant promise for the treatment of PAH. Therefore, we aimed to investigate lactylation-associated gene signatures and identify the critical role of hub genes. Transcriptomics analysis and mendelian randomization (MR) were applied to screen hub lactylation-related genes. 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) was identified as a hub lactylation-related gene. HIBCH was significantly upregulated in platelet-derived growth factor (PDGF) stimulated pulmonary arterial smooth muscle cells (PASMCs) and lung tissues in PAH. MR analysis revealed that HIBCH upregulation correlated with higher PAH risk. Subsequently, the cell viability, proliferation and migration were detected to elucidate the effects of HIBCH on PASMCs. HIBCH knockdown markedly reduced the PDGF-induced lactate production, proliferation and migration in PASMCs. Further, cyproheptadine was screened as a potential HIBCH inhibitor. Cyproheptadine suppressed PASMCs proliferation and alleviated the monocrataline-induced pulmonary hypertension in vivo. Together, we identified the lactylation-related gene HIBCH as a risk factor for PAH and provided a novel therapeutic candidate for the treatment of PAH.
Evaluation of liver toxicity in rats exposed to silver nanoparticles - Targeted metabolomics and histology based study.
Rui S, Yueyang W, Zezhou H … +2 more , Yunlong C, Jianguo L
Toxicol Appl Pharmacol · 2026 Jun · PMID 41794185 · Publisher ↗
Silver nanoparticles (AgNPs) while providing beneficial applications may also pose risks, making it essential to investigate their potential toxicity in living systems. In this study, we examined the impact of Ag NPs on...
Silver nanoparticles (AgNPs) while providing beneficial applications may also pose risks, making it essential to investigate their potential toxicity in living systems. In this study, we examined the impact of Ag NPs on the liver metabolomes, as the liver is the body's primary homeostatic organ. Twenty-four Sprague-Dawley (SD) rats were divided into four groups and fed either silver nitrate, low-dose Ag NPs, high-dose Ag NPs, or a basal diet (control). Serum samples were analyzed using an LC-ESI-MS/MS system for metabolomic profiling. The analysis identified 32 differential metabolites, including organic acids and their derivatives, amino acids and related metabolites, hormones and hormone-related substances, bile acids, nucleotides and their metabolites, lipids, and various heterocyclic compounds. These metabolomic changes were consistent with biochemical findings, which showed elevated alkaline phosphatase (ALP) levels in both low- and high-dose AgNPs groups. Histological examination further revealed inflammatory cell infiltration in the confluent areas and mild fibrous tissue proliferation in the livers of AgNP-treated rats, indicating notable toxic effects of AgNP exposure on liver morphology. This study will help to understand the hazardous effects of AgNPs on histology and metabolism of the live. It may also initiate new research to make strategies to avoid from the side effects of the AgNPs if their use is inevitable.
MiR-29a/DNMT3A axis participates in Dihydroartemisinin's suppression on lung adenocarcinoma: Implications for overcoming acquired resistance to EGFR-TKIs.
Zhu Y, Qiu P, Tang J … +5 more , Chen R, Liu Y, Ling H, Liu Y, Chen L
Toxicol Appl Pharmacol · 2026 Jun · PMID 41791429 · Publisher ↗
Dihydroartemisinin (DHA), the traditional antimalarial agent, has attracted significant interest as potential anticancer drug, yet its underlying mechanisms are incompletely understood. Herein, we showed that DNA methylt...
Dihydroartemisinin (DHA), the traditional antimalarial agent, has attracted significant interest as potential anticancer drug, yet its underlying mechanisms are incompletely understood. Herein, we showed that DNA methyltransferase 3 alpha (DNMT3A), a de novo DNA methyltransferase was substantially inhibited by DHA in both in vitro and in vivo lung adenocarcinoma settings. Overexpression of DNMT3A effectively counteracted DHA's inhibition on the proliferation of HCC827 and A549 cells. Intriguingly, DNMT3A was observed to be up-regulated in Gefitinib-resistant HCC827 (HCC827/GR) cells as compared with parental Gefitinib-hypersensitive HCC827 cells. DNMT3A overexpression effectively counteracted the inhibition of Gefitinib on HCC827 cells. Conversely, si-RNA mediated DNMT3A knockdown generated considerable inhibitory effects on HCC827/GR cells, and further increased Gefitinib sensitivity. Furthermore, combination of DHA and Gefitinib generated significant synergistic effects on the suppression of cell viability and induction of apoptosis of both HCC827 and HCC827/GR cells. Finally, our results showed that DHA effectively up-regulated the expression of miR-29a. Transfection with miR-29a mimics substantially suppressed DNMT3A expression whereas with miR-29a inhibitor effectively up-regulated DNMT3A in HCC827 and A549 cells. Furthermore, miR-29a inhibitor effectively restored DHA's suppression on DNMT3A expression in both cell lines. Overall, these data demonstrate that DHA has therapeutic effects on lung adenocarcinoma by down-regulating DNMT3A through miR-29a. Understanding of this mechanism will have implications for overcoming acquired resistance in epidermal growth factor receptor (EGFR) - targeted therapy by using tyrosine kinase inhibitors (TKIs).
Clarification on the interpretation of TCGA-SARC data in the prognostic evaluation of MMP13 in osteosarcoma.
Ichikawa J, Wako M, Kawasaki T
Toxicol Appl Pharmacol · 2026 Jun · PMID 41791428 · Publisher ↗
Abstract loading — click title to view on PubMed.
Lysine succinylation-mediated energy metabolism imbalance drives brain injury in acute diquat poisoning.
Wang C, Yang H, Wang Z … +2 more , Liu J, Du Y
Toxicol Appl Pharmacol · 2026 Jun · PMID 41791427 · Publisher ↗
Neurological damage induced by diquat (DQ) poisoning has garnered significant attention from researchers in recent years. This study represents the first systematic investigation into the molecular mechanisms underlying...
Neurological damage induced by diquat (DQ) poisoning has garnered significant attention from researchers in recent years. This study represents the first systematic investigation into the molecular mechanisms underlying acute DQ-induced brain injury by integrating quantitative proteomics with lysine succinylation proteomics in male C57BL/6 J SPF mice exposed to 200 mg/kg DQ dibromide via a single oral gavage. The study revealed that DQ poisoning significantly downregulated lysine succinylation levels in mouse brain tissue, thereby inhibiting key mitochondrial energy metabolism pathways and disrupting glycine-serine-threonine metabolism and the one‑carbon folate pool pathway. These alterations led to energy metabolism disorders, exacerbated oxidative stress, and enhanced neuroinflammation, ultimately triggering neuronal apoptosis and neurological dysfunction. This study reveals the central regulatory role of abnormal lysine succinylation in DQ neurotoxicity, providing a novel potential target for clinical intervention.
Aloperine alleviates lung ischemia-reperfusion injury by modulating ferroptosis via the STAT-1 pathway.
Xiao J, Wei S, Huang D … +4 more , Cheng Y, Li H, Cao H, Hu Z
Toxicol Appl Pharmacol · 2026 Jun · PMID 41785917 · Publisher ↗
Lung ischemia-reperfusion injury (LIRI) is a severe complication of lung transplantation and acute respiratory distress syndrome, leading to significant pulmonary dysfunction. Aloperine, a natural alkaloid derived from S...
Lung ischemia-reperfusion injury (LIRI) is a severe complication of lung transplantation and acute respiratory distress syndrome, leading to significant pulmonary dysfunction. Aloperine, a natural alkaloid derived from Sophora alopecuroides, has demonstrated promising pharmacological effects on various ischemia-reperfusion injuries. However, its role in LIRI remains underexplored. Our experimental results revealed that aloperine significantly alleviated bilateral lung tissue damage induced by ipsilateral ischemia-reperfusion, with a mechanism closely linked to the regulation of inflammatory responses and apoptosis-related proteins. Further studies demonstrated that aloperine specifically activated the STAT-1 signaling pathway, as evidenced by markedly increased STAT-1 phosphorylation levels in lung tissue damage in the ipsilateral (ischemic) and contralateral (non-ischemic) lung, thereby inhibiting ferroptosis. Notably, the STAT-1 inhibitor AG490 completely reversed the lung-protective effects of aloperine, confirming the protective effects of STAT-1. These findings provide critical experimental evidence for the potential clinical application of aloperine in LIRI intervention.
RUNDC3A-AS1 is an adverse prognostic factor for triple-negative breast cancer which mediates the Warburg effect and Adriamycin resistance by targeting miR-224-3p/COL5A2.
Kong L, Liu X, Zhang H … +1 more , Liu J
Toxicol Appl Pharmacol · 2026 Jun · PMID 41765289 · Publisher ↗
Breast cancer has become the most common malignant tumor among women worldwide, among which triple-negative breast cancer (TNBC) is a subtype with the worst prognosis. Although the function of long non-coding RNA (lncRNA...
Breast cancer has become the most common malignant tumor among women worldwide, among which triple-negative breast cancer (TNBC) is a subtype with the worst prognosis. Although the function of long non-coding RNA (lncRNA) RUNDC3A-AS1 in other cancers has been revealed, it has not been reported in TNBC. To explore the functional mechanism of RUNDC3A-AS1 in TNBC by regulating miR-224-3p/COL5A2, the predictive value of RUNDC3A-AS1 for disease prognosis was evaluated by using its serum level in TNBC patients. miR-224-3p/COL5A2, as a potential downstream of RUNDC3A-AS1, was predicted by the lncRNASNP-human and miRDB databases. Their binding relationships were verified through RNA pull-down experiment. The function of this signaling axis in aerobic glycolysis of TNBC cells was evaluated by detecting glucose uptake, ATP production, and extracellular acidification rate (ECAR). The Adriamycin (ADR)-resistant TNBC cell lines were introduced to explore the function of RUNDC3A-AS1/miR-224-3p/COL5A2 axis in chemotherapy resistance. TNBC patients with high RUNDC3A-AS1 expression showed lower survival rates and shorter overall survival time. RUNDC3A-AS1 competed with COL5A2 mRNA in binding to miR-224-3p, and it increased COL5A2 expression by negatively regulating miR-224-3p. The overexpression of RUNDC3A-AS1 promoted aerobic glycolysis in TNBC cells, which was reversed by the miR-224-3p agonist. Meanwhile, COL5A2 overexpression reversed the inhibitory function of miR-224-3p agonist on aerobic glycolysis. Silencing RUNDC3A-AS1/COL5A2 or upregulating miR-224-3p reduced lactic acid production in ADR-resistant cells and increased their sensitivity to ADR. In conclusion, as a sponge of miR-224-3p, RUNDC3A-AS1 mediated the Warburg effect and chemotherapy resistance in TNBC by up-regulating COL5A2.
PM-induced ferroptosis via the miR-188-3p/GPX4 axis disrupts renal erythropoietin production.
Chen W, Chen S, Bai L … +5 more , Zhang M, Dong C, Fan L, Zan Q, Li R
Toxicol Appl Pharmacol · 2026 May · PMID 41734873 · Publisher ↗
Exposure to fine particulate matter (PM) is a significant environmental risk factor for renal pathologies, including chronic kidney disease and acute kidney injury. Ferroptosis is increasingly implicated in kidney pathol...
Exposure to fine particulate matter (PM) is a significant environmental risk factor for renal pathologies, including chronic kidney disease and acute kidney injury. Ferroptosis is increasingly implicated in kidney pathology or PM-induced toxicology. However, the direct mechanistic link between PM and renal ferroptosis, particularly within an endocrine context, remains elusive. In this study, pathological injury, kidney fibrosis, lipid peroxidation (LPO), iron ions, and ferroptosis effects were measured in in vivo and in vitro experiments following PM exposure. Ferroptosis was visualized by confocal microscopy of glutathione (GSH)/reactive oxygen species (ROS). Next, the glutathione peroxidase-4 (GPX-4) function and its regulation by miR-188-3p were verified. EPO and aldosterone levels were also measured. Results showed that PM exposure induced renal pathological injury and fibrosis, along with the abnormal changes in the levels of related factors (IL-6, TNF-α, Fibronection, Col4A2, TGF-β, and KIM-1). At the same time, PM caused ferroptosis, as evidenced by iron overload, elevated ROS and LPO, reduced GSH levels, and dysregulation of ferroptosis-related proteins (GPX-4 and Acsl4). The critical role of GPX-4 was confirmed by the ferroptosis inhibitor ferrostatin-1, which attenuated these injurious effects. The miR-188-3p mimic and inhibitor experiments validated miR-188-3p regulation of GPX-4. Of note, PM significantly reduced EPO levels compared with controls and was linked to ferroptosis. Our findings elucidate a novel miR-188-3p/GPX-4/ferroptosis pathway of PM-induced kidney injury, accompanied by renal EPO endocrine disruption. These also reveal potential therapeutic targets for combating air pollution-related kidney diseases.
Cinnamaldehyde inhibits the progression of gastric cancer by regulating glycolysis through PTP1B/PI3K/AKT/mTOR signaling pathway.
Qiao X, Xue D, Hu Z … +2 more , Wang H, Mu L
Toxicol Appl Pharmacol · 2026 May · PMID 41724216 · Publisher ↗
Gastric cancer (GC) is a prevalent malignancy for which novel therapeutic approaches are urgently needed. Cinnamaldehyde (CA), a natural compound with anti-tumor potential, has an unclear mechanism of action in GC. This...
Gastric cancer (GC) is a prevalent malignancy for which novel therapeutic approaches are urgently needed. Cinnamaldehyde (CA), a natural compound with anti-tumor potential, has an unclear mechanism of action in GC. This study aimed to investigate whether CA suppresses GC progression by modulating the PTP1B/PI3K/Akt/mTOR signaling pathway and its downstream glycolytic metabolism. The effects of CA on GC cell proliferation, migration, and invasion were evaluated through functional assays. Western blotting and metabolite detection were employed to analyze its impact on the PTP1B/PI3K/Akt/mTOR pathway and glycolysis. The critical role of PTP1B in mediating CA's effects was determined using lentivirus-mediated knockdown and overexpression. Finally, a nude mouse xenograft model was used to validate the anti-tumor efficacy of CA in vivo. In vitro, CA significantly inhibited the proliferation, migration, and invasion of GC cells, concurrently suppressing the activation of the PTP1B/PI3K/Akt/mTOR pathway and reducing glycolytic activity. PTP1B knockdown potentiated the anti-tumor and glycolytic-inhibitory effects of CA, whereas PTP1B overexpression partially reversed them. In vivo, CA markedly suppressed the growth of xenograft tumors. Collectively, these findings demonstrate that CA inhibits GC progression by targeting the PTP1B/PI3K/Akt/mTOR-glycolysis axis, revealing a novel mechanism and a potential therapeutic strategy.
Alleviation of cigarette smoke-induced cellular senescence in BALB/c mice by the Lipoxin A4 receptor agonist BML-111 is associated with mitophagy.
Li X, Xu H, Shi M … +2 more , Liu K, Liu X
Toxicol Appl Pharmacol · 2026 May · PMID 41724215 · Publisher ↗
Cigarette smoke (CS) significantly accelerates age-associated pulmonary pathologies by promoting cellular senescence. BML-111, a synthetic lipoxin A4 analog, exhibits therapeutic potential in inflammatory diseases owing...
Cigarette smoke (CS) significantly accelerates age-associated pulmonary pathologies by promoting cellular senescence. BML-111, a synthetic lipoxin A4 analog, exhibits therapeutic potential in inflammatory diseases owing to its antioxidant and anti-inflammatory properties, yet its impact on CS-induced senescence remains undefined. This study investigated the effect and mechanism of BML-111 on CS-induced cellular senescence using a BALB/c mouse model and the murine alveolar macrophage cell line MH-S. Our findings indicate that BML-111 attenuated CS-induced histopathological damage and senescence markers in murine lungs, while substantially suppressing cigarette smoke extract-triggered senescence in MH-S cells. In addition, BML-111 inhibited mitochondrial damage, and promoted autophagosome formation and mitophagy-related protein expression in both in vivo and in vitro models. Crucially, the mitophagy inhibitor Mdivi-1 abrogated BML-111's effects on cellular senescence, mitochondrial damage restoration, and mitophagy. Taken together, BML-111 may mitigate CS-induced cellular senescence in the lung by promoting processes associated with mitophagy initiation, highlighting its potential as a therapeutic strategy against CS-associated lung pathologies.
Dexmedetomidine regulates fatty acid oxidation through the AMPK/PGC-1α/CPT1A pathway to mitigate renal ischaemia-reperfusion injury.
Zhang CL, Yan Y, Wang K … +10 more , Ma JJ, Xu WJ, Liu G, Zhu XC, Zhu ZG, Ding HF, Ke ZR, Yao K, Fan FT, Ren L
Toxicol Appl Pharmacol · 2026 Jun · PMID 41722785 · Publisher ↗
OBJECTIVE: This study aimed to investigate whether dexmedetomidine (Dex) attenuates renal ischaemia-reperfusion injury (RIRI) by regulating fatty acid oxidation and to explore its underlying mechanisms. METHODS: A renal...
OBJECTIVE: This study aimed to investigate whether dexmedetomidine (Dex) attenuates renal ischaemia-reperfusion injury (RIRI) by regulating fatty acid oxidation and to explore its underlying mechanisms. METHODS: A renal ischaemia-reperfusion (I/R) model was established in Sprague-Dawley rats, and a hypoxia/reoxygenation model was established using human proximal renal tubule epithelial cells. Renal function was evaluated by measuring serum creatinine and blood urea nitrogen. Oxidative stress markers malondialdehyde (MDA) and superoxide dismutase (SOD), lipid accumulation free fatty acids (FFA), triglycerides (TG) and apoptosis were assessed. Protein and mRNA expression levels of adenosine monophosphate-activated protein kinase (AMPK), peroxisome proliferator-activated receptor γ coactivator 1 alpha (PGC-1α) and carnitine palmitoyl transferase 1 A (CPT1A) were analysed by Western blot, quantitative real-time polymerase chain reaction and immunohistochemistry. Mitochondrial ultrastructure and intracellular lipid droplets were examined by transmission electron microscopy (TEM). Molecular docking was performed to predict the interaction between Dex and AMPK, and functional validation was performed using the AMPK inhibitor Compound C. RESULTS: Dexmedetomidine significantly improved renal function and ameliorated histopathological damage in rats with I/R. It reduced oxidative stress (decreased MDA, increased SOD activity) and attenuated lipid accumulation (reduced FFA and TG levels)， enhancing adenosine triphosphate production in both in vivo and in vitro models. Furthermore, Dex upregulated the phosphorylation of AMPKα, the expression of PGC-1α and CPT1A at both protein and mRNA levels. The TEM revealed that Dex preserved mitochondrial integrity and reduced lipid droplet accumulation in renal tubular cells. Molecular docking indicated a strong binding affinity between Dex and AMPK, and the protective effects of Dex were reversed by Compound C. CONCLUSION: Dexmedetomidine alleviates RIRI by reducing oxidative stress and promoting fatty acid oxidation through the AMPK/PGC-1α/CPT1A pathway. This study provides a potential therapeutic mechanism for the use of Dex in mitigating RIRI.
Alterations in the jejunal 5-hydroxytryptamine synthesis and turnover in septic mice induced by cecal ligation and puncture.
Kuroda A, Machida T, Hiraide S … +8 more , Yamamoto T, Abe Y, Kumagai H, Tsuda S, Hamaue N, Iizuka K, Hattori Y, Matsuda N
Toxicol Appl Pharmacol · 2026 May · PMID 41722784 · Publisher ↗
Recent studies have shown that endogenous 5-hydroxytryptamine (5-HT) facilitates in the progression of sepsis pathology. We aimed to characterize the impact of sepsis induced by cecal ligation and puncture (CLP) surgery...
Recent studies have shown that endogenous 5-hydroxytryptamine (5-HT) facilitates in the progression of sepsis pathology. We aimed to characterize the impact of sepsis induced by cecal ligation and puncture (CLP) surgery on 5-HT synthesis and the metabolic system in mice jejunum at multiple pathological stages. The jejunal tissue were isolated at 3, 6, 12, 24 and 48 h after the surgical procedure of CLP. We found that the sepsis induced by the CLP procedure leads to significant body weight loss and intestinal injury, including villus atrophy associated with pro-inflammatory cytokine expression. We also demonstrated that sepsis alters intestinal 5-HT synthesis and degradation at distinct phases, an increase in 5-hydroxyindoleacetic acid, a final metabolite of 5-HT, at 3-6 h and a rise in 5-HT levels at 24 h. Tryptophan hydroxylase 1 and serotonin transporter expression increased at specific time points following CLP procedure. Additionally, MAO-A protein expression showed a rise at 12 h, while MAO activity significantly suppressed between 12 and 48 h. These findings offer valuable insight into the regulation of 5-HT synthesis and degradation at various stages of sepsis, potentially informing therapeutic strategies aimed at modulating 5-HT metabolism.
Isopropylated phenyl phosphate, an organophosphorus flame retardant, induces depressive- and anxiety-like behaviors in mice.
Inoue Y, Chiba S, Maeda H … +1 more , Nakajima A
Toxicol Appl Pharmacol · 2026 May · PMID 41713619 · Publisher ↗
Isopropylated phenyl phosphate (IPP), commonly used as a flame retardant in a number of consumer products and construction materials, has been detected in human biological samples, raising concerns about human health. Li...
Isopropylated phenyl phosphate (IPP), commonly used as a flame retardant in a number of consumer products and construction materials, has been detected in human biological samples, raising concerns about human health. Limited information is currently available on the neurotoxicity of IPP. Therefore, we herein investigated the effects of IPP on emotional- and memory-related behaviors in juvenile mice. IPP (1, 10, or 100 mg/kg body weight) was orally administered to 3-week-old mice daily for two weeks. In a series of behavioral analyses, treatment with 100 mg/kg IPP induced anxiety-like behavior in the open-field test. Furthermore, treatment with 1-100 mg/kg IPP dose-dependently induced depressive-like behavior in the forced swimming test. An RNA sequencing analysis showed that 145 genes (119 up-regulated and 26 down-regulated) in the hippocampus were differentially expressed between 100 mg/kg IPP-treated mice and vehicle-treated Control mice. The representative enriched terms in the top two clusters were "ensheathment of neurons" and "myelin sheath", suggesting that IPP modified the expression of genes related to these biological processes and cellular components. Real-time PCR confirmed changes in the expression of several oligodendrocytic marker genes in these clusters. These results demonstrate that IPP may induce abnormal emotional behavior through oligodendrocyte dysfunction.
Schisandrol A induces cardiac developmental toxicity in zebrafish (Danio rerio) via disruption of calcium homeostasis, oxidative stress, and apoptosis.
Liu W, Chu Y, Li Q … +6 more , Wang F, Zhang X, Ma C, Zhou H, Ji Z, Wu D
Toxicol Appl Pharmacol · 2026 May · PMID 41713618 · Publisher ↗
Schisandrol A (SA) is a major lignan component of Schisandra chinensis with anti-inflammatory and antioxidant activities, yet its developmental and cardiac safety profile remains unclear. In this study, a zebrafish (Dani...
Schisandrol A (SA) is a major lignan component of Schisandra chinensis with anti-inflammatory and antioxidant activities, yet its developmental and cardiac safety profile remains unclear. In this study, a zebrafish (Danio rerio) embryo model was used to evaluate the toxicity of SA and its underlying mechanisms following exposure to different concentrations of SA (ranging from 0 to 160 μg/mL, with safe concentrations of 10, 20, and 40 μg/mL for mechanistic studies from 6 to 96 h post-fertilization (hpf). SA induced a dose-dependent increase in mortality, with an LC₅₀ of 62.5 μg/mL at 96 hpf. SA induced concentration-dependent developmental abnormalities, characterized by reduced body length, pericardial edema (PE), delayed yolk sac absorption, and spinal curvature, accompanied by decreased heart rate, indicating evident cardiotoxicity. Transcriptomic analysis showed that differentially expressed genes were mainly enriched in pathways related to oxidative stress, apoptosis and calcium signaling. Consistent with this, fluorescence staining and qPCR demonstrated that SA induced Ca accumulation and increased ROS and AO signals in the cardiac region, along with dysregulated expression of genes involved in calcium handling, antioxidant defense and apoptosis. In conclusion, SA induces developmental and cardiac toxicity in zebrafish embryos, at least in part by disrupting calcium homeostasis, promoting oxidative stress and activating apoptotic pathways, suggesting that its potential safety risks should be carefully considered in future development and application.
Interference with IL-13/JAK1/STAT6 inflammatory signaling by dipalmitoyl phosphoethanolamine-polyethylene glycol (DPPE-PEG); A CD1d-dependent antagonist to iNKT cells; contributes to retarding the advancement of oxazolone colitis.
Abdel-Razek EA, Mahmoud HM, Azouz AA
Toxicol Appl Pharmacol · 2026 May · PMID 41707991 · Publisher ↗
Ulcerative colitis-associated immune dysregulation necessitates an appropriate and effective therapy to suppress its progression and achieve sustained remission. The current research was designed to examine the prospecti...
Ulcerative colitis-associated immune dysregulation necessitates an appropriate and effective therapy to suppress its progression and achieve sustained remission. The current research was designed to examine the prospective anti-colitis mechanism of dipalmitoyl phosphoethanolamine-polyethylene glycol (DPPE-PEG); a CD1d-dependent antagonist to invariant natural killer T (iNKT) cells with previously reported potent anti-inflammatory activity. Colitis was induced in BALB/c mice by cutaneous pre-sensitization with 3% oxazolone, followed 5 days later by intra-colonic injection of 1% oxazolone to evaluate the therapeutic effect of DPPE-PEG (250 μg; i.p.). DPPE-PEG substantially ameliorated the decrease in body weight, disease activity index (DAI), histological alterations induced by oxazolone, and almost normalized colon length. Our findings revealed that DPPE-PEG down-regulated CD1d expression. In addition, DPPE-PEG greatly attenuated the colonic inflammatory response and apoptosis, that was evidenced by significantly diminished colon myeloperoxidase (MPO) activity, interleukin-13 (IL-13) and tumor necrosis factor-alpha (TNF-α) contents, along with down-regulated relative protein expressions of p-JAK1 (phosphorylated-Janus kinase 1) and phosphorylated-signal transducer and activator of transcription 6 (p-STAT6), as well as the pro-apoptotic Bax and the apoptotic effector cleaved caspase-3. Collectively, the interference of DPPE-PEG with iNKT cells activation evidenced by reduced CD1d expression and IL-13 cytokine, with subsequently retarded activation of JAK1/STAT6 inflammatory signaling and preserved intestinal mucosa could, at least partly, contribute to impeding the progression of colitis. These findings reinforce our suggestion that DPPE-PEG could be an effective and promising candidate for retarding the advancement of ulcerative colitis.
Tussilagone inhibits MRGPRX2-mediated mast cell degranulation and suppresses pseudo-allergic reactions.
Yan PP, Huang TT, Attiogbe MKI … +2 more , Mi YN, Cao YX
Toxicol Appl Pharmacol · 2026 May · PMID 41707990 · Publisher ↗
Mas-related G protein-coupled receptor X2 (MRGPRX2) is a crucial target in pseudo-allergic reactions. Tussilagone (Tus), the main bioactive component derived from Tussilago farfara, has anti-inflammatory effects, but its...
Mas-related G protein-coupled receptor X2 (MRGPRX2) is a crucial target in pseudo-allergic reactions. Tussilagone (Tus), the main bioactive component derived from Tussilago farfara, has anti-inflammatory effects, but its potential inhibitory effects on pseudo-allergic responses remain unclear. This research aimed to evaluate the inhibitory role of Tus on pseudo-allergic reactions and its underlying mechanism. In vivo Systemic pseudo-allergic reactions and passive cutaneous anaphylaxis (PCA) models were established to assess the effects of Tus. In vitro, mast cell (LAD2) degranulation, inflammatory cytokine release, and signaling pathway protein expression were assessed. Calcium influx was measured in MRGPRX2-expressing HEK293 cells. The results showed that Tus significantly attenuated Tween 80- and substance P (SP)-induced systemic pseudo-allergy and PCA reactions. It also suppressed mast cell degranulation and decreased production of tumor necrosis factor-alpha (TNF-α), Interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1). In MRGPRX2-expressing HEK293 cells, Tus suppressed Tween 80- and SP-induced Ca influx. Mechanistically, Tus inhibited tolimidone-induced Lyn kinase activation and suppressed SP-and Tween 80-induced β-hexosaminidase release, exhibiting an inhibitory profile comparable to that of the Lyn/Btk antagonist bosutinib. Additionally, Tus attenuated the phosphorylation levels of MRGPRX2 downstream signal molecules, including Btk, PLCγ1, PKC, p38 MAPK, IκB-α and NF-κB (p65). In conclusion, Tus attenuates SP-and Tween 80-induced mast cell activation and pseudo-allergic reactions by targeting the Lyn/Btk/PLCγ1 and p38/NF-κB pathways, highlighting its therapeutic potential for pseudo-allergy.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe