查找使用阿拉丁产品的科研文献

The Toxic Effects and Mechanism of Acetamiprid Exposure on Testicular Tissue: ALKBH5 Regulates m6A Modification to Affect PI3K-AKT-Mediated Apoptosis

Xiaoyan Hua,Yubin Li,Lixiang Pang,Huiyuan Zhang,Yuwen Wang,Bing Wu,Haoxuan Gao,Yanan Song,Yucheng Yan,Ji Zhao

(1) Background: Acetamiprid, a widely used neonicotinoid insecticide, has increasingly drawn people’s attention to its potential reproductive toxicity risks. Although existing studies have shown that exposure to acetamiprid can cause testicular damage, its underlying molecular mechanism has not been fully elucidated. (2) Methods: This study established a mouse model of acetamiprid exposure via free drinking water and combined it with in vitro culture of TM3 cells, aiming to explore the toxic effects of acetamiprid on testicular tissue and its potential mechanism. (3) Results: Acetamiprid exposure induced significant pathological damage to the testicular tissue of mice and significantly reduced sperm quality. Further mechanism studies have shown that acetamiprid down-regulates the expression of RNA demethylase ALKBH5, leading to an overall increase in m6A modification levels, thereby inhibiting the activity of the PI3K/AKT signaling pathway and ultimately inducing apoptosis of TM3 cells. (4) Conclusions: In conclusion, this study, by integrating both internal and external models, has revealed a molecular mechanism by which acetamiprid is involved in testicular injury through epigenetic pathways, providing scientific basis and mechanism clues for assessing reproductive hazards caused by exposure to environmental toxins.

Colorectal cancer cell-derived arginine drives SMS-mediated spermine synthesis and PI3K-AKT-mTOR-dependent M2 polarization of tumor-associated macrophages

Wang Qi,Bi Pengfei,Wang Chunlin,Li Wenyang,Chi Bowen,Li Haitong,Tang Xin,Ma Tianyi

Colorectal cancer (CRC) often exhibits severe tolerance to immunotherapy due to the highly immunosuppressive nature of the tumor microenvironment (TME), with the polarization of tumor-associated macrophages (TAMs) toward the pro-tumor M2 phenotype playing a key role. Arginine (Arg), as a core precursor for the synthesis of the immune-microenvironment-reshaping metabolite spermine (Spm), is a crucial factor influencing the fate of TAMs. Unlike some tumors with Arg auxotrophy, CRC cells exhibited elevated argininosuccinate synthetase 1 (ASS1) expression, which was associated with increased extracellular Arg availability in our co-culture system. This study aimed to investigate the specific regulatory mechanisms of CRC cell metabolic reprogramming on immune function in the TME. Single-cell and clinical tissue analyses revealed elevated ASS1 expression in CRC epithelial cells and enrichment of SMS in M2-like TAMs, while higher spermine synthase (SMS) expression was associated with poorer survival in the analyzed PD-1-treated CRC cohort. The Transwell co-culture model demonstrated that CRC cells specifically upregulated ASS1 and released large amounts of Arg into the TME. Macrophages took up Arg and utilized their significantly enriched SMS to convert it into Spm. The intracellular accumulation of Spm further activated the PI3K-AKT-mTOR signaling pathway, driving macrophage polarization toward the M2 phenotype and upregulating immunosuppressive factors such as IL-10 and TGF-β, which in turn induced the exhaustion of local CD8 + T cells. Based on these findings, combined treatment with AMXT 1501 and Nivolumab attenuated M2-like polarization and the CD8⁺ T-cell exhaustion-associated phenotype, reduced CRC-cell proliferation, and increased apoptosis in vitro, with the major findings further validated in the MSS CRC cell line SW480. In conclusion, this study clarified the importance of the ASS1/Arg/SMS/Spm cross-cellular metabolic axis in CRC immune escape and demonstrated that targeting polyamine metabolism in combination with immune checkpoint blockade represents a promising strategy for overcoming immune tolerance across molecularly distinct CRC models.

Argininyl-Fructosyl-Galactose: A Novel Amino Acid Derivative improves Cisplatin-induced Intestinal Toxicity via Reactive Oxygen Species- mediated Apoptosis Pathway

Liu Wei,Zheng Yi-nan,Jiang Shuang,Ren Shen,Tang Shan,Zhang Jing,Wang Zi,Li Wei

Background: Based on the Maillard reaction principle of red ginseng, this study innovatively synthesized a new amino acid derivative by combining arginine with lactose through simulated synthesis and was separated and purified through repeated silica gel and polyacrylamide gel (Bio-gel P-II) column chromatography. Purpose: The work was aimed at elucidating the synthesis of a novel amino acid derivative and investigating the intestinal protective activity of the novel amino acid derivative and possible molecular mechanism by establishing the intestinal injury model induced by cisplatin in mice. Methods: The purity and molecular weight of the amino acid derivatives were determined to be by electrospray ionization mass spectrometry (ESI-MS). Subsequently, by establishing cisplatin (20 mg/kg)-induced intestinal injury in vivo for 10 days and IEC-6 cell model. The biochemical indexes and histopathological analysis were used to evaluate the oxidative stress and inflammatory and pathological changes of intestinal tissue in mice. The protein expression levels of p-Nuclear transcription factor-κB (p-NF-κB), cleaved caspase 3/caspase 3, cleaved caspase 9/caspase-9, Bcl-2, Bax, cytochrome C, phosphatidylinositol 3-kinase (PI3K), Protein Kinase B (Akt), p-PI3K, p-Akt were quantified through immunofluorescence staining and western blot analysis. Results: The new amino acid derivatives of chemical structure were identified to be 1- (arginine-Nαgroup)-1-deoxy-4-O-(β-D-galactopyranosyl)-D-fructose, named Argininylfructosyl- galactose (AFGA, C18H34N4O12). The results showed that pretreatment with a single AFGA dose remarkably alleviated cisplatin-evoked intestinal oxidative stress injury, and the levels of reactive oxygen species (ROS) were lessening in IEC-6 cells (p<0.05, p<0.01) and could effectively reduce the secretion of TNF-α and IL-1β in serum and the expression level of NF-κB protein in intestinal tissues (p<0.01). Meantime, AFGA also significantly suppressed the caspase 3, caspase 9, cytochrome C and Bax protein expression in intestinal tissue in mice (p<0.01), and regulated the PI3K/Akt pathway (p<0.05, p<0.01). Importantly, the molecular docking results of AFGA also suggested a better binding ability with the above-mentioned related target proteins. Conclusion: The results clearly revealed AFGA as a potential multifunctional therapeutic agent with a clear protective effect against cisplatin-induced intestinal injury may be related to the PI3K/Akt signaling pathway.

Lupeol-3-carbamate Derivatives: Synthesis and Biological Evaluation as Potential Antitumor Agents

Shuang Tian,Yinxu Zhao,Siqi Deng,Liman Hou,Juan Song,Ming Wang,Ming Bu

In the following study, a series of new lupeol-3-carbamate derivatives were synthesized, and the structures of all the newly derived compounds were characterized. The new compounds were screened to determine their anti-proliferative activity against human lung cancer cell line A549, human liver cancer cell line HepG2, and human breast cancer cell line MCF-7. Most of the compounds were found to show better anti-proliferative activity in vitro than lupeol. Among them, obvious anti-proliferation activity (IC50= 5.39~9.43 μM) was exhibited by compound3iagainst all three tumor cell lines. In addition, a salt reaction was performed on compound3k(IC50= 13.98 μM) and it was observed that the anti-proliferative activity and water solubility of compound3k·CH3I(IC50= 3.13 μM), were significantly enhanced subsequent to the salt formation process. The preliminary mechanistic studies demonstrated that apoptosis in HepG2 cells was induced by compound3k·CH3Ithrough the inhibition of the PI3K/AKT/mTOR pathway. In conclusion, a series of new lupeol-3-carbamate derivatives were synthesized via the structural modification of the C-3 site of lupeol, thus laying a theoretical foundation for the design of this new anticancer drug.

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.

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.

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.

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.

Growth differentiation factor 15 protects the airway by inhibiting cell pyroptosis in obese asthmatic mice through the phosphoinositide 3-kinase/AKT pathway

Na Li,Fanghan He,Yunxiao Shang

Obese asthma is a form of refractory asthma with inflammation as the underlying mechanism. The specific mechanism of action of anti-inflammatory growth differentiation factor 15 (GDF15) in obese asthma is unclear. The purpose of this study was to explore the effect of GDF15 on cell pyroptosis in obese asthma and to determine its mechanism of airway protection. Male C57BL6/J mice were fed with a high-fat diet, sensitized, and challenged with ovalbumin. Recombinant human (rh)GDF15 was administered 1 h before the challenge. GDF15 treatment significantly reduced airway inflammatory cell infiltration, mucus hypersecretion and airway resistant, and decreased cell counts and inflammatory factors in bronchoalveolar lavage fluid. Serum inflammatory factors decreased, and the increased levels of NLR family pyrin domain containing 3 (NLRP3), caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and gasdermin-D (GSDMD-N) in obese asthmatic mice were inhibited. Furthermore, the suppressed phosphoinositide 3-kinase (PI3K)/AKT signal pathway was activated after rhGDF15 treatment. The same result was obtained by overexpression of GDF15 in human bronchial epithelial cells induced by lipopolysaccharide (LPS) in vitro, and the effect of GDF15 was reversed after the application of a PI3K pathway inhibitor. Thus, GDF15 could protect the airway by inhibiting cell pyroptosis in obese asthmatic mice through the PI3K/AKT signaling pathway.

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.