查找使用阿拉丁产品的科研文献

Nitidine chloride inhibits proliferation, induces apoptosis via the Akt pathway and exhibits a synergistic effect with doxorubicin in ovarian cancer cells

Feng Ding,Tianfeng Liu,Nina Yu,Shihong Li,Xiaofei Zhang,Guanghong Zheng,Chunming Lv,Kai Mou,Jia Xu,Bo Li,Surong Wang,Haibo Song

Nitidine chloride (NC) exhibits anti-tumor properties in various types of tumor. However, to the best of our knowledge there is no previous evidence of NC involvement in the apoptosis or proliferation of ovarian cancer cells and the underlying molecular mechanisms. The present study aimed to investigate the influence of NC on the viability and apoptosis of ovarian cancer cells and the synergistic effect NC and doxorubicin (DOX) may have on ovarian cancer cells. The viability and proliferation of ovarian cancer cells were examined using a methyl thiazolyl tetrazolium assay and 3H-thymidine incorporation assay. The apoptotic rate of ovarian cancer cells was detected by flow cytometry. The expression of apoptosis‑associated proteins and Akt serine/threonine kinase 1 (Akt) were determined by western blot analysis following NC treatment. The inhibitory effect of NC on the proliferation of ovarian cancer cells was demonstrated in a time and dose‑dependent manner. The pro-apoptotic effect of NC on ovarian cancer cells was also observed. It was determined that NC significantly downregulated the protein expression levels of B‑cell CLL/lymphoma 2 (Bcl-2) and upregulated the expression of Bcl‑2‑associated X protein, p53, caspase‑3 and ‑9. NC suppressed Akt phosphorylation. Additionally, the present study demonstrated that the effect of NC on the proliferation and apoptosis of ovarian cancer cells was Akt‑dependent by using the phosphatidylinositol-4,5-bisphosphate 3-kinase/Akt signaling pathway inhibitor, LY294002. NC exhibited a synergistic inhibitory effect on the viability of ovarian cancer cells when combined with DOX. The current study demonstrated that NC inhibited the proliferation and induced the apoptosis of ovarian cancer cells via the Akt signaling pathway and highlighted its potential clinical application for the treatment of ovarian cancer.

Synergistic Induction of Apoptosis by Apocytochrome C and Sodium Aescinate Is Mediated by Excessive Autophagy via the AKT-mTOR-TFEB Signaling Axis

Jia-Wei Sun,Yin-Kang Chen,Liang Ji,Jian Zhao,Fu-Jun Wang

Cytochrome C (Cyt C) is a central mediator of intrinsic apoptosis, whereas its heme-free precursor, apocytochrome C (APO-Cyt C), competitively inhibits this process. Sodium aescinate (SA), a natural triterpene saponin, is known to facilitate the endosomal escape of protein drugs. We initially aimed to investigate the effects of enhancing endosomal escape efficiency on protein activity through the combination of SA and Cyt C. However, this study investigates an cytotoxicity observed when APO-Cyt C is combined with SA and aims to elucidate the underlying molecular mechanism. Contrary to its established anti-apoptotic function, APO-Cyt C, when co-administered with a non-toxic concentration of SA, induced potent, caspase-dependent mitochondrial apoptosis in cancer cells. This pro-apoptotic switch was not primarily triggered by BCL-2 family protein modulation, ROS generation, or calcium overload. Instead, the primary mechanism is the induction of excessive and lethal autophagy. SA was found to induce lysosomal membrane damage, evidenced by Galectin-9 recruitment, which initiates lysophagy. The addition of APO-Cyt C significantly amplified the autophagic flux, leading to decreased p62 levels and enhanced LC3-II turnover. Mechanistically, this synergy is driven by a dual impact on the AKT-mTOR-TFEB pathway: APO-Cyt C treatment decreased mTOR phosphorylation, while the combination promoted the nuclear translocation of the autophagy regulator, TFEB. Inhibition of autophagic flux using Bafilomycin A1 or Tetrandrine rescued cells from apoptosis, confirming that excessive autophagy is the direct cause of cell death. This study reveals a novel therapeutic strategy wherein an anti-apoptotic protein is converted into a potent pro-apoptotic agent. The combination of APO-Cyt C and SA triggers apoptosis by overwhelming the cell with excessive autophagic flux, driven by synergistic inhibition of the mTOR-TFEB axis. These findings highlight the therapeutic potential of modulating autophagy and suggest that combining mTOR inhibitors with lysosome-targeting agents like SA could be an effective anti-cancer strategy. Summary This study reveals a novel strategy to combat cancer by repurposing an endogenous anti-apoptotic protein into a potent therapeutic agent. We demonstrate that apocytochrome C (APO-Cyt C), when combined with the natural compound sodium aescinate (SA), triggers cancer cell death through excessive autophagy rather than conventional apoptotic pathways. The discovery that this combination induces lethal autophagy by synergistically targeting both mTOR signaling and lysosomal function provides important insights for overcoming drug resistance. These findings highlight the promising therapeutic potential of combining mTOR inhibitors with lysosome-targeting saponins, establishing a new paradigm for cancer treatment through coordinated regulation of autophagic processes.

Salvianolic Acid B Enhances Motor Function Recovery after Spinal Cord Injury in Association with AKT/mTOR/HIF-1α Pathway Activation and Angiogenesis

Jiange Yao,Yingfeng Chen,Fengjun Pan,Susu Zhang

Folium Isatidis suppresses PCV2 replication and alleviates PCV2-induced lung injury by modulating the PI3K/AKT signaling pathway and TNF-α activity

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.

Salidroside alleviates senile osteoporosis in SAMP8 mice by inhibiting the ferroptosis of bone marrow stromal cells via PI3K/AKT/mTOR signaling pathway

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.

Microbiome Modulation with Lactobacillus rhamnosus GG Potentiates Curcumin's Efficacy in Reversing Gemcitabine Resistance of Gallbladder Cancer through Gut Microbiota-PI3K/AKT Axis

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.

Targeting SLC7A11 to Suppress PI3K/AKT Signaling: Dapagliflozin ameliorates MASH and associated renal injury via ferroptosis inhibition and Liver-Kidney axis regulation

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.

Platycodon grandiflorus root extract activates hepatic PI3K/PIP3/Akt insulin signaling by enriching gut Akkermansia muciniphila in high fat diet fed mice

Zichen Luo,Weichen Xu,Tianjie Yuan,Chen Shi,Tianzi Jin,Ying Chong,Jianjian Ji,Lili Lin,Jianya Xu,Ying Zhang,An Kang,Wei Zhou,Tong Xie,Liuqing Di,Jinjun Shan

Background Increasing hepatic insulin signaling is found to be an important mechanism of Platycodon grandiflorus root to alleviate metabolic syndrome (MetS) symptoms such as insulin resistance, obesity, hyperlipidemia and hepatic steatosis , but the details are not yet clear. Since the main constituents of Platycodon grandiflorus root were hard to be absorbed by gastrointestinal tract , getting opportunity to interact with gut microbiota , we speculate the gut microorganisms may mediate its effect. Purpose Our work aimed to confirm the critical role of gut microbes in the intervention of Platycodon grandiflorus root extract (PRE) on MetS, and investigate the mechanism. Methods Biochemical analyses, glucose tolerance test and hepatic lipidomics analysis were used to evaluate the anti-MetS effect of PRE on high fat diet (HFD) fed mice. Perform 16S rDNA analysis, qPCR analysis and in vitro co-incubation experiment to study its effect on gut microbes, followed by fecal microbiota transplantation (FMT) experiment and antibiotics intervention experiment. Also, the effect of Akkermansia muciniphila treatment on HFD mice was investigated. Results PRE alleviated lipid accumulation and insulin resistance in HFD mice and remodeled the fecal microbiome . It also increased the gene expression of colonic tight junction proteins , alleviated metabolic endotoxemia and inflammation, so that reduced TNF-α induced hepatic JNK-dependent IRS-1 serine phosphorylation and the impairment of PI3K/PIP3/Akt insulin signaling pathway. A. muciniphila was one of the most significantly enriched microbes by PRE treatment, and its administration to HFD mice showed similar effects to PRE, repairing the gut barrier and activating hepatic PI3K/PIP3/Akt pathway. Finally, anti-MetS effect of PRE could be delivered to FMT recipients, and PRE could not further attenuate MetS in gut microbiota depleted mice. Conclusion We demonstrated for the first time that PRE alleviated MetS in a gut microbiota dependent manner, and found activation of hepatic insulin signaling mediated by gut A. muciniphila was a potential mechanism of it.

Pink Lotus Essential Oil and Alleviates on Free Fatty Acid Induced Steatosis in HepG2 Cells via PI3K/Akt and NF-κB Pathways

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.

Avermectin induces carp neurotoxicity by mediating blood-brain barrier dysfunction, oxidative stress, inflammation, and apoptosis through PI3K/Akt and NF-κB pathways

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.

Coix seed polysaccharides alleviate type 2 diabetes mellitus via gut microbiota-derived short-chain fatty acids activation of IGF1/PI3K/AKT signaling

Ting Xia,Chang-Shun Liu,Yan-Nan Hu,Zhen-Ye Luo,Fei-Long Chen,Li-Xia Yuan,Xiao-Mei Tan

Type 2 diabetes mellitus (T2DM) has become a worldwide concern in recent years. Coix seed (CS) as a homologous substance of traditional Chinese medicine and food, its polysaccharides can improve the symptoms of patients with metabolic disorders. Since most plant polysaccharides are difficult to digest and absorb, we hypothesized that Coix seed polysaccharides (CSP) exert hypoglycemic effects through the gut. In this study, the underlying mechanisms regulating hypoglycemic effects of CSP on a T2DM mouse model were investigated. After treatment with CSP, serum insulin and high-density lipoprotein cholesterol levels were increased, while total cholesterol, triglycerides and low-density lipoprotein cholesterol levels were decreased in T2DM mice. In addition, CSP treatment helped repair the intestinal barrier and modulated the gut microbial composition in T2DM mice, mainly facilitating the growth of short-chain fatty acid (SCFA)-producing bacteria, Spearman’s analysis revealed these bacteria were positively related with the hypoglycemic efficacy of CSP. Colonic transcriptome analysis indicated the hypoglycemic effect of CSP was associated with the activation of the IGF1/PI3K/AKT signaling pathway. Correlative analysis revealed that this activation may result from the increase of SCFAs-producing bacteria by CSP. GC–MS detection verified that CSP treatment increased fecal SCFAs levels. Molecular docking revealed that SCFAs could bind with IGF1, PI3K, and AKT. Our findings demonstrated that CSP treatment modulates gut microbial composition, especially of the SCFAs-producing bacteria, activates the IGF1/PI3K/AKT signaling pathways, and exhibits hypoglycemic efficacy.

Cyclometalated Ru(II)-isoquinoline complexes overcome cisplatin resistance of A549/DDP cells by downregulation of Nrf2 via Akt/GSK-3β/Fyn pathway

Lanmei Chen,Jie Wang,Xianhong Cai,Suxiang Chen,Jingjing Zhang,Baojun Li,Weigang Chen,Xinhua Guo,Hui Luo,Jincan Chen

Both ruthenium (Ru) and isoquinoline (IQ) compounds are regarded as potential anticancer drug candidates. Here, we report the synthesis and characterization of three novel cyclometalated Ru(II)-isoquinoline complexes: RuIQ-3 , RuIQ-4 , and RuIQ-5, and evaluation of their in vitro cytotoxicities against a panel of cell lines including A549/DDP, a cisplatin-resistant human lung cancer cell line. A549/DDP 3D multicellular tumor spheroids (MCTSs) were also used to detect the drug resistance reversal effect of Ru(II)-IQ complexes. Our results indicated that the cytotoxic activities against cancer cells of Ru(II)-IQ complexes, especially RuIQ-5 , were superior compared with cisplatin. In addition, RuIQ-5 exhibited low toxicity towards both normal HBE cells in vitro and zebrafish embryos in vivo . Further investigation on cellular mechanism of action indicated that after absorption by A549/DDP cells, RuIQ-5 was mainly distributed in the nucleus, which is different from cisplatin. Besides, RuIQ-5 could induce apoptosis through mitochondrial dysfunction, reactive oxygen species (ROS) accumulation, ROS-mediated DNA damage, and cycle arrest at both S and G2/M phases. Moreover, RuIQ-5 could inhibit the overexpression of Nrf2 through regulation of Akt/GSK-3β/Fyn signaling pathway and hindering the nuclear translocation of Nrf2. Based on these findings, we firmly believe that the studied Ru(II)-IQ complexes hold great promise as anticancer therapeutics with high effectiveness and low toxicity.