BMC Pharmacology & Toxicology
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2025
·Vol. 26
·期 1
·1-12
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IF 2.7
Yang Lili,Liu Xiaotian
Section
Background
To evaluate the effects of tyrosine kinase inhibitors (TKIs) Dovitinib, Lapatinib, and Telatinib on angiogenesis in zebrafish, and to explore the regulatory mechanism of PI3K/AKT pathway activator SC79 on these inhibitory effects.
Section
Methods
Transgenic Fli-1:EGFP zebrafish embryos were used to observe the development and morphological changes of intersegmental vessels (ISVs) by fluorescence microscopy. Real-time fluorescence quantitative PCR was employed to detect the expression of angiogenesis-related genes including kdrl, flt1, vegfaa, akt2, and pik3r1. After determining the maximum tolerated concentration (MTC) of each compound, the effects of single-drug treatment and SC79 co-treatment on vascular development and gene expression were observed.
Section
Results
Dovitinib (0.488 µM) and Telatinib (0.031 µM) significantly reduced the number (by 16.9% and 33.8%, respectively, P < 0.001) and length (by 14.9% and 23.3%, respectively, P < 0.001) of complete ISVs, while Lapatinib (1.95 µM) showed no significant inhibitory effect. Gene expression analysis revealed that Dovitinib mainly downregulated flt1 expression ( P < 0.01), whereas Telatinib more broadly downregulated kdrl ( P < 0.05), flt1 ( P < 0.001), and akt2 ( P < 0.01) expression. SC79 (2.44 nM) promoted angiogenesis, increasing ISV number ( P < 0.01) and length ( P < 0.05), while upregulating kdrl (2.03-fold, P < 0.001), flt1 (1.31-fold, P < 0.05), vegfaa (1.45-fold, P < 0.01), akt2 (1.64-fold, P < 0.01), and pik3r1 (1.48-fold, P < 0.05) expression. Co-treatment experiments showed that all three TKIs could counteract SC79’s pro-angiogenic effects to varying degrees, with Telatinib showing the strongest effect. Under SC79 co-treatment conditions, all TKIs significantly downregulated kdrl expression ( P < 0.001), but had differential effects on other genes: Dovitinib mainly downregulated flt1 ( P < 0.05), Lapatinib specifically downregulated vegfaa ( P < 0.01), akt2 ( P < 0.05), and pik3r1 ( P < 0.05), while Telatinib simultaneously downregulated flt1 ( P < 0.01), akt2 ( P < 0.05), and pik3r1 ( P < 0.01).
Section
Conclusions
Dovitinib and Telatinib exhibit significant anti-angiogenic effects, while Lapatinib is less effective. Different TKIs inhibit angiogenesis by regulating different signaling molecules: Dovitinib primarily targets VEGF receptors, Telatinib targets both receptors and the downstream PI3K/AKT pathway, and Lapatinib shows inhibitory effects on VEGF ligand expression in the SC79 background. SC79 promotes angiogenesis by activating the PI3K/AKT pathway and partially reverses the inhibitory effects of TKIs. These findings provide new insights for targeted therapy of abnormal angiogenesis in ophthalmic diseases, suggesting that precise regulation of angiogenesis may be achieved by modulating the balance between TKIs and the PI3K/AKT signaling pathway.
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PHYTOMEDICINE
·
2025
·
IF 8.3
Chenying Zeng,Linjian Chen,Jiajie Lin,Zipeng Xiao,Qingqiang Tu,Wenhui Yu,Weihao Zhang,Qibo Li,Yanfeng Wu,Zhongyu Xie,Ziji Zhang
Background The shift in BMSC differentiation potential toward adipogenesis at the expense of osteogenesis is a critical mechanism underlying reduced bone formation in osteoporosis. Necroptosis has been implicated as a key driver of bone-fat imbalance in osteoporosis, though its mechanisms remain unclear. Taraxasterol (TAX), a bioactive triterpenoid derived from Taraxacum officinale , exhibits antitumor, antioxidant, and immunomodulatory properties. However, its potential role in osteoporosis has not yet been explored. Objective This study aimed to investigate whether TAX alleviates osteoporosis by regulating necroptosis and osteogenic–adipogenic differentiation in BMSCs, and to elucidate the underlying molecular mechanisms. Methods An ovariectomized (OVX) mouse model of osteoporosis was established for in vivo evaluation. Treatment groups received daily oral administration of TAX (5 or 20 mg/kg), with estradiol (E₂, 10 μg/kg) serving as a positive control. Bone microarchitecture and therapeutic response were assessed via micro-CT and immunohistochemistry, while femoral necroptosis and differentiation markers were evaluated by immunostaining. For in vitro studies, BMSCs isolated from osteoporosis patients were treated with the necroptosis inducer TSZ (TNF-α, SM-164, Z-VAD-FMK), with or without TAX. Flow cytometry was used to analyze the phenotype of MSCs. To identify molecular targets and mechanisms, an integrated approach combining network pharmacology, RNA sequencing, SPR assays, and molecular docking was employed. Subsequent analyses included western blotting, PI staining, and RNA interference to assess TAX-regulated necroptosis and PI3K/AKT/PPARγ pathway activity. ARS and ORO staining were employed to analyze osteogenic and adipogenic differentiation, respectively, and mitochondrial function was evaluated with TMRE and MitoSOX Red probes. Results TAX (20 mg/kg) significantly ameliorated bone loss in OVX mice, suppressed femoral necroptotic signaling, and reversed osteogenic–adipogenic imbalance in OVX-derived BMSCs. In vitro , TAX pretreatment attenuated TSZ-induced differentiation imbalance and necroptosis in patient-derived BMSCs and mitigated mitochondrial damage. Integrated network pharmacology and RNA sequencing revealed that TAX targets the PI3K/AKT/PPARγ axis. Immunohistochemical analysis demonstrated upregulation of the PI3K/AKT/PPARγ axis in the femurs of OVX mice following TAX administration. Molecular docking and SPR assays confirmed effective binding between TAX and PI3K. The protective effects of TAX were abolished by the PI3K inhibitor LY294002. Furthermore, TAX enhanced the rebalancing of osteogenic–adipogenic differentiation in PPARγ-silenced BMSCs. Conclusion Our study reveals for the first time that TAX restores osteogenic-adipogenic equilibrium in OP-BMSCs and promotes bone regeneration through PI3K/AKT/PPARγ activation and mitochondrial protection-mediated suppression of necroptosis. These results position TAX as a promising therapeutic candidate for osteoporosis.
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FEBS Open Bio
·
2025
·
IF 2.3
Wenheng Gao,Yunlong Li,Lihua Chen,Wenshuo Yang,Yong He,Ye Yang,Dengke Yin,Song Tan
Hyperlipidemia is a common chronic disease characterized by elevated levels of lipids in the blood. There is some evidence that suggests that berberine (BBR) might be beneficial for the treatment of hyperlipidemia. However, its low intestinal bioavailability limits its potential therapeutic action. In the present study, we explored the effect and the underlying mechanism of berberine–cinnamic acid co-crystal (BBR-CA), which is self-assembled from CA and BBR and displays a high intestinal bioavailability. In mice, BBR-CA showed the ability to decrease body weight gain and hepatic lipid accumulation in animals fed a high-fat diet. To further characterize the molecular basis of this effect, we established a hyperlipidemia cell model by treating human hepatocellular carcinoma cells (HepG2) with free fatty acids. Similarly to our in vivo experiments, lipid accumulation in free fatty acids-induced HepG2 cells was also reduced by BBR-CA. We hypothesized that BBR-CA might act through the regulation of sterol regulatory element-binding proteins-1 (SREBP-1), a key factor regulating lipid synthesis, and, indeed, SREBP-1 protein expression was inhibited by BBR-CA treatment, resulting in the decreased expression of its downstream proteins stearoyl-CoA desaturase 1 and acetyl-CoA carboxylase. Furthermore, the phosphorylation of phosphatidylinositol 3-kinase (PI3K), AKT and mammalian target of rapamycin (mTOR) was inhibited by BBR-CA, contributing to decreased active SREBP-1 in the nucleus, and was reversed and enhanced by the PI3K agonist recilisib and inhibitor LY294002, respectively. Taken together, our results suggest that BBR-CA could function by modulating the PI3K/AKT/mTOR signaling pathway, resulting in decreased nuclear expression of SREBP-1, as well as reduced expression of stearoyl-CoA desaturase 1 and acetyl-CoA carboxylase, thus alleviating hyperlipidemia. Further experimental validation is required to confirm these results.
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Advanced Science
·
2024
·
IF 14.3
Qun Cui,Xiaona Zheng,Yunyang Bai,Yaru Guo,Shuo Liu,Yanhui Lu,Lulu Liu,Jia Song,Yang Liu,Boon Chin Heng,Fuping You,Mingming Xu,Xuliang Deng,Xuehui Zhang
Regulation of the immune response is key to promoting bone regeneration by electroactive biomaterials. However, how electrical signals at the micro- and nanoscale regulate the immune response and subsequent angiogenesis during bone regeneration remains to be elucidated. Here, the distinctly different surface potential distributions on charged poly(vinylidene fluoridetrifluoroethylene) (P(VDF-TrFE)) matrix surfaces are established by altering the dimensions of ferroelectric nanofillers from 0D BaTiO 3 nanoparticles (homogeneous surface potential distribution, HOPD) to 1D BaTiO 3 nanofibers (heterogeneous surface potential distribution, HEPD). Compared to HOPD, HEPD is significantly better at inducing the M2 polarization of macrophages and promoting neovascularization, which results in accelerated bone regeneration in vivo. The transcriptomic analysis reveals that macrophages modulated by HEPD display high expression levels of pro-angiogenic genes, which is corroborated by tube-formation assays, RT-qPCR, and western blot analyses in vitro. Mechanistic explorations elucidate activation of the PI3K-Akt signaling pathway, which in turn induces the polarization of macrophages toward a pro-angiogenic phenotype. This study elucidates the cascade of biological processes by which heterogeneous electrical signals at the micro- and nanoscale modulate macrophage functions to promote vascularization and bone regeneration. Hence, this study provides new insights into how the micro- and nanoscale distribution characteristics of electrical signals facilitate bone regeneration.
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MOLECULAR BIOLOGY REPORTS
·
2021
·Vol. 49
·期 2
·1223-1232
·
IF 2.316
Su Qi,Wu Qing,Chen Kun,Wang Jingjing,Sarwar Ammar,Zhang Yanmin
Background Female breast cancer has become the most commonly diagnosed cancer worldwide. As a tumor suppressor, estrogen receptor β (ERβ) can be potentially targeted for breast cancer therapy. Methods and results TAD1822-7 was evaluated for ERβ-mediated autophagy and cell death using cell proliferation assay, Annexin V/PI staining, immunofluorescence, western blotting, ERβ siRNA, ERβ plasmid transfection and hypoxia cell models. TAD1822-7 upregulated ERβ causing cell death and induced mitochondrial dysfunction and autophagy companied with mitochondrial located ERβ. Enhanced levels of microtubule associated protein1 light chain 3 (LC3)-II and p62/SQSTM1 (p62) indicated that TAD1822-7 blocked the late-stage autolysosome formation, leading to cell death. Mechanistically, TAD1822-7-induced cell death was mediated by phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathways. Moreover, TAD1822-7 modulated hypoxia inducible factor (HIF) functions and autophagy via the inhibition of HIF-1β in the context of hypoxia-induced autophagy. ERβ overexpression and ERβ agonist showed similar effects, whereas ERβ siRNA abrogated TAD1822-7-induced cell death, the inhibition of PI3K/AKT pathway and autophagy. The involvement of PI3K/AKT pathway and autophagy was also demonstrated in TAD1822-7-treated hypoxic breast cancer cells. Conclusions These findings provide new insight into the mechanism underlying the inhibitory effects of TAD1822-7 via ERβ-mediated pathways in breast cancer cells.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
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HEREDITAS
·
2025
·Vol. 162
·期 1
·232
·
IF 2.5
Xiaohui Yu,Jie Li,Jiangqiao Zhou
Background Coptisine (COP) is a natural compound extracted from Rhizoma Coptidis , and it represses the malignant biological behaviors of bladder cancer cells. However, the underlying molecular mechanism has not been fully elucidated. The aim of this study was to clarify the downstream mechanism by which COP treats bladder cancer. Materials and methods SwissTargetPrediction, STITCH, SymMap, ETCM, TCMSP, CTD databases were used to collect the related targets of COP. GeneCards, DisGeNET, TTD and OMIM databases were used to obtain the related targets of bladder cancer. A Venn diagram was used to identify the potential targets of COP in bladder cancer treatment. The protein-protein interaction network was constructed using STRING database, and Cytoscape 3.9.0 software was used to screen the hub targets. The binding relationship between COP and the hub targets was verified by molecular docking and molecular dynamics simulation. After the bladder cell lines T24 and BIU-87 were treated with different doses of COP, the regulatory effects of COP on PI3K/AKT pathway were investigated with western blotting. Additionally, the tumor-suppressive properties of COP on bladder cancer cells were validated with tumorigenesis model and metastasis model in nude mice. Results RAC-alpha serine/threonine-protein kinase 1 (AKT1), glycogen synthase kinase 3 beta (GSK3B), caspase-3 (CASP3), tumor necrosis factor (TNF) and cyclin D1 (CCND1) were identified as the main hub targets of COP in bladder cancer treatment. PI3K/AKT pathway was predicted to be a crucial pathway regulated by COP. The binding affinities between COP and AKT1, GSK3B, CASP3, TNF and CCND1 were high. COP treatment markedly repressed the phosphorylation level of ERK1/2, AKT1, PI3K p85 and mTOR in T24 and BIU-87 cells, and repressed the tumorigenesis and lung/liver metastasis of T24 cells in vivo. Conclusion COP may be a natural inhibitor for AKT1, GSK3B, CASP3, TNF and CCND1. COP represses PI3K/AKT pathway to suppress the progression of bladder cancer.
研究领域:
药理学
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肿瘤学
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计算生物学
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分子生物学
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天然产物研究
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
·
IF 5.6
Lei Zhu,Guan Zhang,Jiasai Kang,Xinru Xu,Haoshu Zhang,Yingying Pu,Yong Huang,Dewen Tong,Qian Du
Background Folium Isatidis (Da Qing Ye), a traditional Chinese medicine, exhibits broad-spectrum antiviral and immunomodulatory properties and has been widely used in treating respiratory diseases. Porcine circovirus type 2 (PCV2), a widespread swine virus, causes respiratory disease complex in piglets and leads to substantial economic losses in the global swine industry. This study aimed to evaluate the anti-PCV2 activity of Folium Isatidis . Materials and methods The anti-PCV2 activity of Folium Isatidis was first validated through both in vivo and in vitro experiments. Potential targets of Folium Isatidis were identified using TCMSP, BATMAN-TCM, and SwissTargetPrediction databases, and intersected with PCV2-related targets. Mechanism exploration involved PPI network analysis, GO annotation, and KEGG enrichment. Molecular docking analyzed component-target interactions, followed by experimental validation of the core component. Finally, the anti-PCV2 effect of the core component was verified through in vitro and in vivo experiments. Results A total of 135 overlapping targets between Folium Isatidis components and PCV2-related disease targets were identified. Key targets, including AKT1 and TNF-α, were implicated in the therapeutic effects of Folium Isatidis against PCV2. Isovitexin was identified to be the core component that directly binds to AKT1 and TNF-α, thereby inhibiting the PI3K/AKT signaling pathway and regulating TNF-α expression and activity to suppress PCV2 replication and alleviate PCV2-induced lung injury. Conclusions Our study reveals that Isovitexin, the core anti-PCV2 component of Folium Isatidis , exerts its effect by inhibiting the PI3K/AKT pathway and modulating TNF-α, thereby outlining a novel therapeutic strategy for combating PCV2 infection and associated respiratory injuries.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Zhun Li,Sixia Yang,Wei Liu,Long Ling,Hailan Hu,Yanming Cao,Shouyu Xiang
Salidroside, one of the main active compounds extracted from Rhodiola, has shown promising potential for the treatment of osteoporosis. Our previous study demonstrated that salidroside alleviated cognitive dysfunction in senescence-accelerated mouse prone 8(SAMP8) mice. In this study, we further investigated the effect of salidroside on osteoporosis in SAMP8 mice and explored the mechanism. The results of micro-computed tomography(micro-CT) and histology showed that salidroside significantly increased trabecular bone formation and improved bone microstructure in senile osteoporotic SAMP8 mice, and upregulated the protein expression levels of phosphatidylinositol-3-kinase(PI3K), glutathione peroxidase 4(GPX4), and Runt-related transcription factor 2(RUNX2) in the distal femur. Cell-based assays, including the Cell Counting Kit-8(CCK-8) assay, senescence-associated β-galactosidase (SA-β-galactosidase) staining, alkaline phosphatase (ALP) staining, Alizarin Red staining, and lipid peroxide detection, demonstrated that salidroside significantly promoted the proliferation and osteogenic differentiation of senile osteoporotic bone marrow stromal cells (BMSCs) and decreased lipid peroxide levels. Furthermore, real-time polymerase chain reaction (RT-PCR) and Western blotting analysis showed that salidroside increased protein and gene expression levels of solute carrier family 7 member 11(SLC7A11), GPX4, and ferroptosis suppressor protein 1(FSP1). Additionally, salidroside also increased the phosphorylation of PI3K, AKT, and mTOR, an effect reversed by LY294002.In conclusion, our investigation showed that salidroside could prevent ferroptosis, promote proliferation, and enhance osteogenic differentiation in senile osteoporotic BMSCs, thereby alleviating senile osteoporosis in SAMP8 mice. The PI3K/AKT/mTOR signaling pathway might play a crucial role in this mechanism. These findings suggest that salidroside has the potential to prevent senile osteoporosis and may serve as a candidate for therapeutic development.
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JOURNAL OF MICROBIOLOGY AND BIOTECHNOLOGY
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2026
·
IF 3.4
Yanliang Li,Siqiang Niu,Haipeng Wang,Jianhua Li
Gemcitabine (GEM) resistance remains a major challenge in the treatment of gallbladder cancer (GBC). This study investigated the synergistic effect of curcumin (CUR) combined with the probiotic Lactobacillus rhamnosus GG (LGG) in reversing chemoresistance through modulation of the gut microbiota. In GEM-resistant GBC-SD cells, the CUR–LGG combination significantly inhibited cell proliferation, suppressed migration and invasion, and induced apoptosis, as demonstrated by CCK-8, wound healing, Transwell, and flow cytometry assays. Western blot analysis revealed corresponding regulation of proliferation markers (Ki67, PCNA), apoptosis-related proteins (Bcl-2, Bax, cleaved Caspase-3), and epithelial–mesenchymal transition markers. In xenograft models, the combined treatment markedly suppressed tumor growth and altered gut microbial composition, increasing beneficial bacteria ( Lactobacillus , Bifidobacterium ) while reducing pathogenic taxa. LC–MS analysis further demonstrated restoration of bile acid homeostasis, characterized by elevated primary bile acids (GCA, CDCA) and decreased secondary bile acids (DCA, LCA). Mechanistically, the intervention significantly inhibited PI3K/AKT signaling, as confirmed by Western blot and immunohistochemistry. Bioinformatic analysis further identified PI3K/AKT as a central regulatory pathway. These findings indicate that probiotic-assisted CUR therapy reverses GEM resistance by remodeling the gut microbiota and its metabolic outputs, thereby suppressing oncogenic signaling pathways. This strategy provides a promising microbiota-based approach for improving therapeutic outcomes in GBC.
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BIOCHEMICAL PHARMACOLOGY
·
2026
·
IF 6.5
Huimin Qiu,Xinqi Tan,Quan Sheng,Na Yang,Chunming Jiang,Lulu Wang
Metabolic dysfunction-associated steatohepatitis (MASH) frequently induces renal injury, forming a “liver-kidney axis” vicious cycle. Current therapies primarily target hepatic lesions, failing to interrupt the cross-organ injury cascade, creating an urgent need for novel strategies. To explore dapagliflozin’s therapeutic efficacy and core mechanism in MASH and associated renal injury, we utilized in vitro models (free fatty acid [FFA]-induced HepG2 hepatocyte MASH model, HK2 renal tubular epithelial cell injury model, Transwell co-culture system) and an in vivo MASH mouse model induced by a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). Results showed dapagliflozin dose-dependently improved dysregulated lipid metabolism, suppressed inflammation, and alleviated fibrosis in vitro and in mouse liver/kidney tissues, while upregulating SIRT1/PPARα and downregulating SREBP-1c to restore lipid homeostasis. Molecularly, dapagliflozin specifically bound to ferroptosis key regulator solute carrier family 7 member 11 (SLC7A11), upregulated its abnormally reduced expression, and inhibited PI3K/AKT pathway hyperactivation—an effect mediated via a “liver-kidney axis” paracrine mechanism with β-hydroxybutyrate (β-HB) as the key mediator. Additionally, SLC7A11 knockdown in cells conversely confirmed that the lipid-lowering effect of dapagliflozin is mediated by SLC7A11.Collectively, dapagliflozin forms hydrogen bonds with SLC7A11, modulates the SIRT1/PPARα/SREBP-1c axis, and inhibits PI3K/AKT, thereby exerting therapeutic effects on MASH and associated renal injury.
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Journal of Oleo Science
·
2022
·
IF 1.628
Runzhou Sun,Ruixin Xiao,Pengfei Lv,Feifei Guo,Yanling Gong,Meixing Yan
Pink lotus essential oil (PLEO) is the volatile components extracted from lotus flowers and there are few relevant research. The purpose of this study was to observe the effect of PLEO on NAFLD in vitro model and its possible mechanism. The ingredients of PLEO were determined by gas chromatography-mass spectrometry (GS-MS) and its lipid-lowering and hepatoprotective activities were investigated. HepG2 cells were treated with free fatty acid (FFA) to establish a cell model of NAFLD. Cell viability was evaluated by 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method. Total cholesterol (TC), triglyceride (TG), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) were determined by Enzyme-Linked Immune Sorbent Assay (ELISA). Oil red O staining was performed to observe the lipid accumulation in the HepG2 cells. Lipid metabolism enzymes including fatty acid synthase (FAS), acetyl-coA carboxylase (ACC), stearoyl-CoA desaturase 1 (SCD-1), and carnitine palmitoyltransferase-1 (CPT-1), insulin signaling pathways including phosphatidylinositol 3 kinase (PI3K) and protein kinase B Akt, inflammatory signaling pathways such as nuclear factor kappa-B (NF-κB), were determined by Western blotting. There were 46 components determined in PLEO with many terpenoids compounds. PLEO decreased TC and TG contents in the FFA-treated HepG2 cells. Furthermore, PLEO inhibited TNF-α, IL-6 and IL-1β excretion, decreased NF-κB, FAS, ACC and SCD-1 while increased phosphorylation of NF-κB, PI3K, Akt, and CPT-1 expression. It is the first time to reveal that PLEO alleviates FFA-induced steatosis in HepG2 cells by regulating lipid metabolism, inhibiting inflammatory response, and improving insulin sensitivity.
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2022
·
IF 7.129
Tianmeng Zhang,Zhuhua Dong,Feixue Liu,Enzhuang Pan,Nana He,Fenfen Ma,Guanglu Wang,Yan Wang,Jingquan Dong
Avermectin, a "low toxicity insecticide", has been widely used in recent years, but its non-target toxicity, especially to aquatic organisms, has been neglected. In this study, we evaluated the neurotoxic effects of avermectin on carp by establishing a 96 h avermectin acute toxicity test, and its possible mechanism was discussed. The 96 h LC 50 of avermectin in carp was found to be 24.04 μg/L. Therefore, 3.005 μg/L and 12.02 μg/L were used as the low-dose and high-dose groups, respectively, to investigate the neurotoxic effects of avermectin on carp. The results of high-performance liquid chromatography (HPLC) analysis showed that avermectin accumulated in the carp brain. Histopathological observation and immunohistochemical analysis (IHC) of TNF-α and Bax showed that avermectin exposure led to inflammatory cell infiltration and neuronal necrosis. The mRNA levels of tight junction genes and the IHC results of ZO-1 and Occludin showed that the structure of the blood-brain barrier (BBB) was destroyed. Biochemical analysis showed that avermectin induced the accumulation of MDA in the brain and decreased the activity of antioxidant enzymes CAT and SOD, leading to oxidative stress. In addition, avermectin induces brain inflammation by activating NF-κB pathway and releasing inflammatory factors IL-1β, IL-6, TNF-α and iNOS. TEM and TUNEL assays showed that exposure to avermectin induced apoptosis in brain. what is more, the expression of apoptosis-related genes and proteins suggested that avermectin-induced apoptosis may be associated with inhibition of the PI3K/Akt signaling pathway. This study also showed that avermectin-induced NF-κB signaling activation was partially dependent on its upstream PI3K/Akt signaling pathway. Therefore, this study concludes that avermectin can induce neurotoxicity in carp by disrupting the blood-brain barrier structure and generating oxidative stress, inflammation, and apoptosis and that NF-κB and PI3K/Akt signaling pathways are involved in this process.
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