Metabolically active compounds can cause toxicity which would otherwise be undetected using traditional in vitro assays with limited proficiency for xenobiotic metabolism. Introduction of liver microsomes to assay systems enables enhanced identification of compounds that require biotransformation to induce toxicity. Previously, metabolically active compounds from the Tox21 10 K compound library were identified using assays probing two targets, p53 and acetylcholinesterase (AChE), in the presence and absence of human or rat liver microsomes, due to the established roles of cytochrome P450 (CYP) enzymes in human drug metabolism. To further explore the role of metabolic activation, the activities of the identified metabolically active compounds were evaluated against five CYP enzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. CYP bioactivities were found to be highly predictive (>80 % accuracy) of compounds that required metabolic activation in these assays. Chemical features significantly enriched in metabolically active compounds, as well as chemical features that were specific for each of the five CYPs, were identified. Product use exposures of the metabolically active compounds were examined in this study, with "pesticides" appearing to be the largest category that may produce harmful metabolites. Additionally, the compound interactions with different CYPs were assessed and frequencies for both classes of compounds, drugs and environmental chemicals, were found to be proportionally similar across the five CYP isoforms.

The small GTPase Ran has emerged as a key player in cancer metastasis. Our previous studies demonstrated that Ran drives pancreatic cancer metastasis by modulating androgen receptor (AR) expression. However, the detailed mechanisms by which Ran regulates AR expression remain unclear. This study aimed to elucidate the regulatory mechanisms through which Ran influences AR expression in the context of pancreatic cancer metastasis. We observed elevated levels of Ran, osteopontin (OPN), and AR in metastatic lymph node tissues, with OPN positively correlated with either Ran or AR expression. Ran silencing led to decreased levels of OPN and AR, whereas Ran upregulation increased their expression. Notably, OPN overexpression restored AR levels in Ran-silenced cells, whereas OPN knockdown diminished the inductive effect of Ran on AR expression. Additionally, OPN knockdown decreased AR expression and was associated with reduced activation of the PI3K/AKT signaling pathway. Functional assays revealed that silencing OPN significantly impaired the mobility and invasion of pancreatic cancer cells and restricted hepatic metastasis. Conversely, OPN overexpression restored the impaired metastasis caused by Ran knockdown. Furthermore, inhibiting PI3K/AKT signaling abolished the promoting effects of either Ran or OPN on pancreatic cancer metastasis. Importantly, re-expressing AR reversed the inhibitory effects of Ran or OPN silencing on the mobility and invasion of pancreatic cancer cells. In summary, Ran induces AR expression through the regulation of the OPN-PI3K/AKT signaling cascade. The Ran-OPN-PI3K/AKT-AR signaling pathway is crucial for driving pancreatic cancer metastasis.

Waterpipe smoking (WPS) is associated with pulmonary inflammation and DNA damage. Tobacco use among diabetic patients adds substantial clinical and public health burden. This study aims to investigate the combined pulmonary effects of diabetes and smoking. To achieve this goal, type 1 diabetes (T1D) was induced in adult male rats by Streptozotocin (65 mg/kg) injection. Rats were then exposed either to fresh air or WPS for one hour daily over five weeks (five days/week). Lung remodeling was evaluated by histology. Changes affecting inflammation, oxidative stress, apoptosis and survival pathways were characterized by real-time quantitative PCR and Western blot. Our findings showed that T1D was associated with pulmonary remodeling characterized by increases in lung weight/BW ratio, exacerbated by WPS, and elevated alveolar count. Both T1D and WPS exposure led to an accumulation of alveolar foamy macrophages and decreased alveolar septal thickness. Upregulation in the transcript levels of pro-inflammatory cytokine, TNF-α and anti-inflammatory marker, IL-10, were reported in diabetic lungs irrespective of WPS exposure. Moreover, diabetic lungs also displayed significant changes in the expression of mitochondrial complexes III and IV and antioxidant enzyme, SOD2, irrespective of the exposure condition. We also noted significant downregulation in the expression of caspases 3 and 9, p-P53/P53 ratio and JNK protein in diabetic lungs compared to control irrespective of the exposure condition. Lastly, diabetes and WPS exposure triggered significant decreases in EGFR expression. In conclusion, we show for the first time pulmonary remodeling and damages caused by the combined effects of T1D and smoking. Our findings highlight the pressing need for future better management of waterpipe consumption among patients with diabetes.

Osimertinib is a third-generation Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI) widely used to treat advanced non-small cell lung cancer with EGFR mutations. However, resistance to osimertinib frequently develops, limiting its long-term effectiveness.

N6-methyladenosine (m6A) modification of pleckstrin homology domain and leucine rich repeat protein phosphatase 2 (PHLPP2), mediated by methyltransferase-like enzyme 14 (METTL14), plays a critical role in regulating PHLPP2 expression across various pathological conditions. This study aims to ascertain whether METTL14 influences m6A methylation of PHLPP2 in diabetic retinopathy (DR) and to delineate the precise function of the METTL14/PHLPP2 axis in disease progression. METTL14 levels were observed to be elevated in retinas of DR rats and in HG-stimulated RGCs, coinciding with an increase in PHLPP2 m6A modification. Knockdown of METTL14 resulted in significant reductions in PHLPP2 expression and its m6A modification. Silencing METTL14 mitigated HG-induced damage in RGCs, which was linked to the inhibition of apoptosis, oxidative stress and inflammation. This protective effect could be negated through the restoration of PHLPP2. METTL14 knockdown modulated the AKT/GSK-3β/Nrf2 signal cascade through PHLPP2. Silencing METTL14 resulted in the downregulation of METTL14 and PHLPP2 in the retinas of DR rats, ameliorated visual function impairment and reduced the pathological alterations. These protective effects of METTL14 silencing against DR were also weakened when PHLPP2 was restored. Overall, these results suggest that suppressing METTL14 improves HG-induced damage in RGCs and protects against DR by downregulating PHLPP2 through m6A modification.

Drug-induced toxicity is considered a crucial clinical affair, as some adverse effects could be severe or life threatening. Drugs may have adverse effects by altering biological pathways that aren't always involved in the drug's reaction. From this perspective, the purpose of the current study was to assess the impacts of paricalcitol, a synthetic, active, and selective vitamin D receptor activator, on dexamethasone-induced liver injury, and discover the probable implicated signaling pathways as well. Male Wistar rats were treated with paricalcitol at a dose of 0.2 μg/kg, daily, i.p for 12 days and injected with 8 mg/kg dexamethasone i.p daily over the last 6 days. Administration of paricalcitol improved liver function markers, lipid profile, reduced histopathologic changes in hepatic sections, and restored normal oxidative status. Moreover, paricalcitol markedly decreased hepatic collagen deposition as confirmed by Masson's trichrome staining. Paricalcitol effectively inhibited endoplasmic reticulum stress through decreasing expression of tissue PERK and Chop, increasing hepatic Nrf2, and HO-1 activity. Besides, paricalcitol decreased levels of NLRP3 and IL-1β as well as decreased expression of active caspase-1 p20, GSDMD-N-terminal indicating suppression of NLRP3/caspase-1/GSDMD pyroptosis pathway. Paricalcitol can protect against dexamethasone-induced liver injury showing a promising therapeutic value in drug-induced liver injuries.

Excessive stress is a known contributor to cardiovascular diseases (CVD), and ferulic acid (FA), a natural phenolic compound, has demonstrated significant antioxidant and anti-inflammatory properties. This study investigates the protective effects of FA against stress-induced myocardial injury (SIMI) and elucidates the underlying mechanisms. An acute SIMI model was established in mice using low-temperature water immersion restraint. Cardiac function was assessed via cardiac index and histopathological analysis. Serum levels of corticosterone (CORT), lactate dehydrogenase (LDH), and brain natriuretic peptide (BNP) were quantified using enzyme-linked immunosorbent assay (ELISA), along with inflammatory markers TNF-α and IL-1β. The oxidative stress parameters, including malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), and reactive oxygen species (ROS), were analyzed using colorimetric methods and fluorescent probes. Immunohistochemistry (IHC) and Western Blot were used to analyze the expression of proteins related to TNF, MAPK, PPAR-α/PGC-1α, and Nrf2 signaling pathways. Results indicated that FA pretreatment improved cardiac index, myocardial structural integrity, and reduced inflammatory cell infiltration. Serum levels of LDH, BNP, CORT, TNF-α, and IL-1β were significantly decreased in FA-treated SIMI mice. Elevated MDA and ROS levels, along with decreased GSH and SOD levels in the SIMI group, were reversed by FA pretreatment, likely through activation of the PPARα/PGC-1α and Nrf2 signaling pathways. Additionally, FA inhibited the TNF-α/TNFR1 and ERK/JNK MAPK pathways, contributing to its protective effects. In conclusion, FA mitigates SIMI by alleviating oxidative stress and inflammatory responses.

Cholestasis arises as a clinical syndrome triggered by the accumulation and aggregation of bile acids. Currently, there are only a few treatment options available for cholestasis. Therefore, it is necessary to explore novel therapeutic strategies. β-sitosterol (SIT), the phytosterol most abundantly found in plants, exhibits diverse pharmacological activities. This study examined SIT's protective role against hepatotoxicity and cholestasis induced by lithocholic acid (LCA). LCA was administered twice a day to male C57BL/6 mice for four days to cause hepatotoxicity and cholestasis. Assessment of the improvement in cholestasis following SIT treatment used H&E staining and serum biomarkers. Mice hepatocyte culture, real-time PCR, immunofluorescence staining, and Western blot were utilized to clarify the mechanisms of SIT hepatoprotection. Furthermore, molecular docking and dual-luciferase reporter gene analysis were utilized to show that SIT would activate the farnesoid X receptor (FXR). In vivo, SIT reduced bile acid accumulation by inducing the bile salt export pump (Bsep), multidrug resistance-related protein 2 (Mrp2), and reduced hepatic uptake of bile acids by inhibiting Na+/taurocholate co-transporting polypeptide (Ntcp), and cholesterol 7α-hydroxylase (Cyp7a1) and oxysterol 12α-hydroxylase (Cyp8b1) while in vitro, it restored FXR expression and transcriptional activity. Besides, SIT decreased hepatic inflammation by suppressing the inflammatory genes NF-κB p65 and p-NF-κB p65, TNF-α, IL-6, and IL-1β. However, the hepatoprotective effects of SIT were abolished by the FXR antagonist guggulsterone in vivo and FXR siRNA in vitro, confirming FXR-dependent mechanisms. In conclusion, SIT protects against LCA-induced hepatotoxicity and cholestasis via FXR activation. These findings highlight SIT as a promising therapeutic candidate for cholestasis.

Idiopathic pulmonary fibrosis (IPF), a progressive interstitial lung disease of unknown etiology, remains a therapeutic challenge with limited treatment options. This study investigates the therapeutic potential and molecular mechanisms of Tryptanthrin, a bioactive indole quinazoline alkaloid derived from Isatis tinctoria L., in pulmonary fibrosis. In a bleomycin-induced murine IPF model, Tryptanthrin administration (5 and 10 mg/kg/day for 28 days) significantly improved pulmonary function parameters and attenuated histological evidence of fibrosis. Mechanistic analysis revealed dual pathway modulation: Tryptanthrin suppressed MAPK/NF-κB signaling through inhibition of phosphorylation events, subsequently reducing pulmonary levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). Concurrently, it attenuated TGF-β1/Smad pathway activation by decreasing TGF-β1 expression and Smad2/3 phosphorylation, thereby downregulating fibrotic markers including COL1A1, α-smooth muscle actin (α-SMA), and fibronectin in lung tissues. Complementary in vitro studies using Lipopolysaccharide (LPS) or TGF-β1-stimulated NIH3T3 fibroblasts confirmed these anti-inflammatory and anti-fibrotic effects through analogous pathway inhibition. Our findings demonstrate that Tryptanthrin exerts therapeutic effects against pulmonary fibrosis via coordinated modulation of both inflammatory (MAPK/NF-κB) and fibrotic (TGF-β1/Smad) signaling cascades, suggesting its potential as a novel multi-target therapeutic agent for IPF management.

Adrenergic receptors (AR) are manipulated therapeutically for the treatment of pulmonary and cardiovascular diseases; however, their role in air pollutant-induced respiratory effects is poorly understood. We examined the contribution of AR-subtypes in acrolein-induced respiratory effects through selective receptor inhibition. We pre-treated 12-week-old male Wistar-Kyoto rats intraperitoneally daily for 9-days with subtype-specific AR antagonists prazosin (PRZ, α1-AR antagonist; 2-mg/kg-day), yohimbine (YOH, α2-AR antagonist; 5-mg/kg-day), or propranolol (PROP, β-AR antagonist; 10-mg/kg-day). On day-8 and day-9 of treatment, rats were exposed nose-only to air or acrolein (1.6 or 3.2 ppm), ∼4 h/day. Head-out plethysmography during exposure on Day-9 revealed overall concentration-dependent acrolein-related reduced ventilatory capacity, which was exacerbated in PRZ- and YOH-treated animals. Nasal (NALF) and bronchoalveolar lavage fluid (BALF), and blood samples were collected on day-9. Plasma epinephrine levels did not change; however, corticosterone decreased in YOH- and PROP-treated air-exposed animals. Adrenal and spleen weights were higher in PRZ-treated animals. Acrolein, 3.2-ppm depleted circulating lymphocytes in saline-treated and increased neutrophils in PRZ- and YOH-treated animals. NALF and BALF analysis indicated 3.2-ppm acrolein-induced neutrophilic and lymphocytic inflammation (NALF>BALF), which was exacerbated in lung of PRZ- and YOH-treated rats and slightly dampened in PROP-treated rats. However, acrolein-induced vascular protein leakage and increases in inflammatory cytokines in NALF were reduced by PROP-treatment. In conclusion, this study highlights sympathetically-mediated adrenoreceptor influence on acrolein-indued respiratory health effects, and AR subtype-specific modulation of breathing, hemodynamic, and inflammatory responses. These results have broader translational implications, as those receiving adrenergic agonistic/antagonistic therapies might experience variable air pollution-related respiratory health effects.

This study was designed to analyze the potential mechanism of action of solasodine by which solasodine suppresses airway remodeling and autophagy in allergic asthma. Human bronchial smooth muscle cells (HBSMCs) were induced by 10 ng/mL of transforming growth factor (TGF)-β1 for 24 h and treated with a series of solasodine (10, 20, 40 μM) for another 24 h. In the TGF-β1-induced HBSMCs, solasodine treatment downregulated the α- smooth muscle actin (α-SMA) level but upregulated the glucocorticoid receptor (GR) level compared with the vehicle treatment (P < 0.05). The binding of solasodine to GR was analyzed using molecular docking and MST measurement. As a result, a direct interaction between solasodine and GR was found. RU486, a GR antagonist, was used to verify that solasodine attenuates TGF-β1-induced fibrosis and autophagy by regulating GR. The RU486 treatment suppressed the effects of solasodine on the TGF-β1-induced FOXO3A, fibrosis and autophagy in the HBSMCs. Subsequently, C57BL/6 J mice were induced with ovalbumin (OVA) and treated with 10 mg/kg/d of solasodine or 2.5 mg/kg/d of dexamethasone (Dex). In the OVA-induced mice, solasodine or Dex treatment attenuated airway inflammation, airway remodeling, and abnormal autophagy compared with the vehicle treatment (P < 0.05). Moreover, the solasodine or Dex treatment increased the expression of GR and FOXO3A in the OVA-induced mice compared with the vehicle treatment (P < 0.01). This study showed that solasodine ameliorated airway remodeling and abnormal autophagy by binding to GR in the allergic model, presenting a possible therapeutic agent for the allergic asthma.

Fine particulate matter (PM2.5) has been reported to exacerbate chronic airway inflammation, contributing to progression and acute exacerbation of chronic obstructive pulmonary disease (COPD). Persistent activated endoplasmic reticulum (ER) stress-related PERK/eIF2α/ATF4/CHOP pathway is critical in driving inflammation and cell death in a variety of inflammatory diseases. Melatonin (MEL) is well-recognized for its broad biological activities, such as anti-oxidative and anti-inflammatory effects However, the exact role of ER stress-related pathway and MEL in PM2.5-induced airway inflammation and apoptosis in COPD has not yet been elucidated. Therefore, we constructed the COPD mice model by cigarette smoke (CS) exposure to evaluate the mechanism by which PM2.5 exacerbate the development of COPD and the protective role of MEL. Results indicated that PM2.5 significantly impair lung function, disrupt emphysema, exacerbate inflammation and apoptosis and intensify the PERK/eIF2α/ATF4/CHOP pathway in COPD mice. Moreover, these changes caused by PM2.5 could be mitigated by MEL. In vitro, PM2.5 exposure notably reduced cell viability and triggered inflammation and apoptosis in BEAS-2B cells induced by cigarette smoke extract (CSE). These effects were reversed by the ER stress inhibitor 4-phenylbutyric acid (4-PBA), with MEL demonstrating similar effect. These findings demonstrate that PM2.5 aggravates airway inflammation and apoptosis via activating ER stress-related PERK/eIF2α/ATF4/CHOP pathways in COPD, which could be significantly restored by MEL.

Exposure to arsenic (As) from drinking water is a global public health concern, as As is a recognized carcinogen. Groundwater in South Texas, particularly in areas with Gulf Coast aquifers, contains high levels of As. Private wells are neither regulated nor regularly monitored, leaving residents vulnerable to arsenic exposure. This study aimed to investigate potential biomarkers of health effects for long-term, low-level As exposure among private well users in South Texas and to cross-validate findings using an in vitro model. Among 74 private well users, the association between urinary As levels and urinary LDH and 16 cytokine levels was assessed. After adjusting for covariates, linear regression analysis showed weak but significant associations between urinary total inorganic As levels and LDH (β = 0.37, p < 0.01, R = 0.23) and PDGF-BB (β = 0.22, p = 0.02, R = 0.17). However, no significant associations were found with other cytokines. To compare findings from the population study, SV-HUC-1 uroepithelial cells were exposed to 0.1 or 0.5 μM NaAsO₂ subchronically for 5 weeks, corresponding to total arsenic levels of 7.5 and 37.5 μg/L in drinking water. As exposure was not cytotoxic at either dose, as indicated by lactate dehydrogenase (LDH) activity. However, platelet-derived growth factor (PDGF)-BB protein levels showed a statistically significant increase at a lower concentration of 0.1 μM. These findings suggest that PDGF-BB may serve as a potential biomarker for low-level As exposure, but further studies are required for confirmation.

Ulcerative colitis (UC) is a persistent intestinal disorder featuring periodic flare-ups of the colon's inner lining inflammation. Current therapeutic strategies, while effective in managing symptoms, are often limited by side effects and high costs. This study investigates the potential of pectin-loaded ferulic acid (PC-FA) nanoparticles as a novel therapeutic approach for UC, focusing on their ability to modulate the cGAS-STING pathway, a key mediator in the inflammation associated with UC. PC-FA nanoparticles were prepared and characterized for their physicochemical properties, antioxidant capacity, biocompatibility, and influence on the cGAS-STING pathway. In vitro experiments demonstrated that PC-FA nanoparticles enhanced the solubility and bioavailability of ferulic acid (FA), reduced oxidative stress, and protected colon epithelial cells from damage caused by the administration of dextran sulfate sodium (DSS). In vivo studies in a DSS-induced colitis mouse model showed that PC-FA nanoparticles mitigated weight reduction, lowered disease activity index (DAI) scores, and sustained colon length, and ameliorated histopathological changes. Additionally, PC-FA nanoparticles effectively targeted DNA damage and inhibited the cGAS-STING pathway, leading to a significant reduction in pro-inflammatory cytokines. Pharmacokinetic studies revealed rapid absorption of PC-FA in the bloodstream, with a predominant distribution in the intestines. The study concludes that PC-FA nanoparticles are a promising therapeutic strategy for UC, offering targeted drug delivery, enhanced bioavailability, and anti-inflammatory effects.

Andrographolide, a diterpene compound derived from the medicinal plant Andrographis paniculata, possesses anti-inflammatory, antioxidant, antitumor, and antiviral properties. Injectable formulations containing andrographolide, such as Potassium Sodium Dehydroandrographolide Succinate for Injection (PSDS), are widely used in clinical practice to treat various diseases, including upper respiratory tract infections. However, clinical reports have highlighted that andrographolide-based herbal injections may induce acute kidney injury and other renal adverse effects, thereby restricting its clinical application. Despite these concerns, the molecular mechanisms underlying andrographolide-induced nephrotoxicity remain poorly understood. In this study, we demonstrated that andrographolide induces inflammation and fibrosis in renal tubular epithelial cells and mouse kidneys. Notably, we identified for the first time that andrographolide promotes cellular senescence in renal tubular epithelial cells and mouse kidneys while downregulating the expression and enzymatic activity of SIRT3. Mechanistic investigations revealed that andrographolide mediates kidney injury and senescence through inhibition of the SIRT3/p53 signaling pathway. Furthermore, andrographolide was found to disrupt the interaction between SIRT3 and p53, resulting in increased acetylation of p53 and upregulation of its downstream target genes involved in inflammation, fibrosis, and senescence. These findings elucidate the molecular mechanisms of andrographolide-induced nephrotoxicity and provide a scientific basis for developing strategies to reduce its toxic effects.

The poor prognosis of patients with acute myeloid leukemia (AML) is largely ascribed to the deficiency of persistently effective therapies. Despite the recent approval of targeted drugs such as the BCL-2 inhibitor venetoclax, the clinical benefit is limited due to the development of resistance. The use of natural products is emerging as a feasible strategy to treat malignant diseases including AML. Flavokawain A (FKA) is a naturally occurring chalcone isolated from the root of kava and possesses extensive antitumor activities. The therapeutic potential of FKA in AML remains unknown. In the present study, we found that treatment with FKA reduced the viability in four AML cell lines in dose- and time-dependent manners. The anti-AML activity of venetoclax was significantly potentiated by FKA. Mechanistically, FKA induced G1 phase arrest in AML cells along with CDT1 downregulation and p27 upregulation. Knockdown of CDT1 increased the expression of p27, leading to the inhibition on cell viability. Both p27 upregulation and viability inhibition caused by FKA was partially rescued by CDT1 overexpression. The therapeutic effect of FKA alone or in combination with venetoclax was verified in primary blasts from AML patients, further strengthening the clinical relevance of the current study. Therefore, our data suggest that FKA can be considered as a potential therapeutic agent in the treatment of AML.

This study aims to investigate the effects of continuous renal replacement therapy (CRRT) combined with ulinastatin on cytokine levels and prognosis in patients with sepsis. The control and study groups (40 cases each) were established. The control group received CRRT alone, while the study group received CRRT plus ulinastatin treatment, with both groups being treated for 7 days. We compared the following parameters before and after treatment between the two groups: Sequential Organ Failure Assessment (SOFA) scores, Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, renal function indicators [cystatin C (CysC), blood urea nitrogen (BUN), and serum creatinine (SCr)], inflammatory factors [tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), and procalcitonin (PCT)], and immune function parameters (CD4+, CD8+, CD4+/CD8+ ratio). Additionally, we recorded adverse reactions and 28-day mortality rates in both groups. After 7 days of treatment, the study group showed significantly lower SOFA scores, APACHE II scores, serum levels of CysC, BUN, Scr, TNF-α, CRP, PCT, and peripheral blood CD8+ compared to the control group, while demonstrating higher peripheral blood CD4+ and CD4+/CD8+ ratio. During the treatment period, there was no significant difference in the incidence of adverse reactions between the two groups. However, the 28-day mortality rate was significantly lower in the study group compared to the control group. For patients with sepsis, the combination of CRRT and ulinastatin therapy can significantly improve disease severity, inflammatory factors, renal function, and immune function, while reducing mortality rate.

Tetrabromobisphenol A (TBBPA), a commonly utilized flame retardant, presents potential risks to both environmental and human health, with particular concern regarding its impact on embryonic development.This study employed zebrafish embryos as a model organism to investigate the comprehensive toxicological effects of TBBPA exposure, integrating metabolomics analysis with molecular and biochemical approaches. Embryos exposed to TBBPA concentrations ranging from 0.5 to 1.5 mg/L exhibited significant dose-dependent developmental abnormalities, including pericardial edema, yolk sac enlargement, and body axis curvature. At 96 h, we observed 50 % mortality at 1 mg/L. At 144 h of exposure to 0.1 mg/L TBBPA, automated behavioral analysis revealed significant changes in larval swimming patterns, characterized by reduced total distance moved, shortened active swimming time, impaired acceleration parameters, and abnormal spatial distribution. UHPLC-Q-TOF-MS-based metabolomics analysis revealed substantial perturbations in multiple biochemical pathways, particularly affecting neurotransmitter metabolism, energy homeostasis, and oxidative stress responses. TBBPA exposure significantly disrupted dopamine and serotonin metabolism, evidenced by altered enzyme expression and metabolite levels. Notable changes in oxidative stress markers, including GSH, MDA, and SOD, indicated significant cellular damage, while inflammatory responses showed dysregulation of both pro- and anti-inflammatory cytokines. Energy metabolism was comprehensively affected, with disruptions in glycolysis, TCA cycle, and amino acid metabolism pathways. The study identified key metabolic signatures of TBBPA toxicity and elucidated the interconnected mechanisms underlying its developmental impacts, providing valuable insights for environmental risk assessment and regulatory considerations. These findings emphasize the complex nature of TBBPA toxicity and highlight the need for careful evaluation of its environmental impact, particularly concerning early developmental exposure.

Progestin use as a contraceptive has increased exponentially in the last few decades, as has its disposal in the environment. These synthetic hormones can impair the physiology and behavior of non-target organisms, such as fish. In this study, we evaluated the effects of exposure to an environmentally relevant concentration of etonogestrel (ETO, 3.2 ng L) on the behavior and endocrine system of zebrafish (Danio rerio) larvae. We found that ETO caused anxiogenic-like behavior in larvae, as demonstrated by the open-field and light-dark tests. The exposed larvae also presented an increase in whole-body cortisol levels. These changes may lead to an ecological imbalance, emphasizing the risk of early exposure to progestins in the environment.

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI), including brigatinib, are widely used to treat ALK-positive non-small cell lung cancer. However, severe adverse effects associated with brigatinib, such as interstitial pneumonia and liver dysfunction, may involve immune system activation. The precise mechanisms underlying these immune-related adverse effects remain unclear. In this study, we evaluated the direct activation of inflammasomes by brigatinib and other ALK TKI (crizotinib, alectinib, ceritinib) in differentiated THP-1 cells. Additionally, we analyzed the inflammasome-activating potential of supernatants from functional liver cell (FLC)-4 cells treated with these drugs. Our results demonstrate that brigatinib directly activates inflammasomes in THP-1 cells, inducing the production of interleukin-1β and the activation of caspase-1. In contrast, no inflammasome activation was observed with the other ALK TKIs. Furthermore, supernatants from FLC-4 cells, characterized by high drug-metabolizing activity, were shown to activate inflammasomes in differentiated THP-1 cells following treatment with brigatinib. Brigatinib treatment significantly increased the levels of damage-associated molecular patterns (DAMPs), including heat shock protein 90 and S100A6, in the supernatants of FLC-4 cells. These findings suggest that brigatinib induces the release of DAMPs from hepatocytes, which subsequently activate inflammasomes. This mechanism may be essential for brigatinib-induced immune system activation and the development of immune-related adverse events.