Nutrients
·
2025
·Vol. 17
·期 21
·3335
·
IF 5
Cuiping Xu,Hao Cui,Qionglian Fang,Pengfei Tu,Xiuming Cui
Background: Steamed Panax notoginseng saponins (SPNSs) can alleviate cyclophosphamide-induced anemia. However, the hepatointestinal effects of SPNSs and their role in ameliorating cyclophosphamide-induced anemia remain unexplored. Objective: To elucidate the hepatointestinal effects of SPNSs and their role in ameliorating cyclophosphamide-induced anemia. Methods: Blood samples were collected and analyzed on days 7 and 14. Liver tissues and small intestinal villi structures were observed via HE staining. Liver and colon content metabolites were detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Liver proteins were analyzed by using an Orbitrap Astral mass spectrometer. Colon content microbiota composition was assessed via metagenomics. Signaling pathway protein expression was analyzed via Western blotting (WB). Results : SPNSs significantly increased the red blood cell (RBC) count and hemoglobin (HGB) level by day 14 and alleviated hepatointestinal damage. Hepatic metabolomics revealed: the most abundant metabolites were fatty acids and stachyose on day 7 and amino acid and arachidonic acid derivatives on day 14. KEGG analysis implicated cAMP signaling. Proteomics revealed upregulated immune-related proteins and enhanced PI3K pathway activity (WB-validated). Colon content metabolomics showed increased daidzein, 3-(2,5-dimethoxyphenyl) propanoic acid, γ-CEHC, and adenosine in SPNS groups on day 14. Metagenomics indicated differential abundances of Heminiphilus faecis , Phocaeicola sartorii , and s-bacterium_J10.2018 on day 14. Multiomics integration demonstrated significant correlations between hepatic metabolites, hematopoietic proteins, colon content metabolites, and probiotic bacteria. Conclusions: SPNS alleviates cyclophosphamide-induced hepato-intestinal injury in anemic mice by modulating the gut microbiota and enhancing hepato-intestinal immune defense. Additionally, SPNSs ameliorate anemia in cyclophosphamide-treated mice by activating the cAMP/PI3K/AKT pathway, promoting hepatocyte proliferation, and increasing hematopoietic protein expression.
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Human Cell
·
2025
·Vol. 39
·期 1
·1-17
·
IF 3.1
Guo Yan,Liu Ying,Zhou Mingkai,Zhao Yulan
Mitochondrial dysfunction is a key contributor to septic cardiomyopathy, driving myocardial inflammation and apoptosis. This study found that Sushi-repeat containing protein X-linked 2 (Srpx2) is associated with mitochondrial damage and is downregulated in the myocytes of lipopolysaccharide (LPS)-treated rats. Sprague Dawley rats were intraperitoneally injected with LPS (10 mg/kg) to establish a septic cardiomyopathy model. Adeno-associated viruses (8.5 × 10 11 vg/mL) containing Srpx2-overexpressing plasmids were injected into rats through their tail vein. Srpx2 overexpression improved hemodynamics and decreased myocardial damage in LPS-treated rats. H9C2 cells were treated with LPS (10 μg/mL) to establish an in vitro septic model. The cells were then transfected with Srpx2-overexpressing plasmids. Srpx2 overexpression ameliorated mitochondrial damage, which was evidenced by restoring mitochondrial morphology, enhancing the complex activities, and elevating ATP and mitochondrial membrane potential levels in cardiomyocytes. Srpx2 overexpression reduced mitochondrial reactive oxygen species levels and superoxide generation in cardiomyocytes. Srpx2 overexpression decreased cleaved caspase-3 and 9 protein levels. Tumor necrosis factor-α and interleukin-1 beta levels were also reduced in cardiomyocytes with Srpx2 overexpression, suggesting reversal of inflammation. The RNA-sequencing data indicated that Srpx2 might regulate the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway to protect cardiomyocytes. Srpx2 overexpression increased the p-PI3K and p-AKT protein levels. The treatment of H9C2 cells with 10 μM LY294002, a PI3K/AKT pathway inhibitor, reversed the protective effects of Srpx2 against mitochondrial damage and apoptosis. In conclusion, Srpx2 alleviates mitochondrial damage by activating the PI3K/AKT pathway, thereby reducing apoptosis and inflammation in septic cardiomyopathy. Graphical abstract
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JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY
·
2022
·Vol. 36
·期 8
·e23084
·
IF 3.568
Qian Shang,Li Zhu,Weina Shang,Jia Zeng,Yong Qi
Dioscin is a natural product that possesses protective effects on multiple chronic injuries, but its effects on asthma are not fully understood. Herein, we evaluated its effects on asthmatic mice established by ovalbumin (OVA) sensitization and challenges and further explored the mechanism. Inflammatory cells in bronchoalveolar lavage fluids (BALFs) were analyzed using Diff-Quik staining. OVA-specific immunoglobulin E (IgE)/IgG1 in serum and inflammatory cytokines (interleukin 4[IL-4], IL-5, IL-13, and tumor necrosis factor-α) in BALFs and lung tissues were measured using Enzyme-Linked Immunosorbent Assay Kits. Hematoxylin and eosin, periodic acid–Schiff, and immunohistochemistry staining showed histopathological changes in lung tissues. Epithelial–mesenchymal transition (EMT) in human bronchial epithelial (16HBE) cells was assessed by immunofluorescence staining. Hydroxyproline content was used to evaluate collagen deposition. Polymerase chain reaction and Western blot were performed to measure messenger RNA and protein expression. We found that dioscin treatment (particularly at the dose of 80 mg/kg) significantly inhibited pulmonary inflammation in asthmatic mice, as evidenced by the decreased serum OVA-specific IgE/IgG1 and the reduced inflammatory cells and cytokines in BALFs and lung tissues. Moreover, dioscin effectively ameliorated the goblet cell hyperplasia, mucus hypersecretion, collagen deposition, and smooth muscle hyperplasia in the airways of asthmatic mice. Mechanistically, dioscin restrained the activated TGF-β1/Smad2/3 and protein kinase B (AKT) signal pathways in lung tissues and potently reversed the TGF-β1-induced EMT and phosphorylation of Smad2/3 and AKT in 16HBE cells. Collectively, dioscin displayed protective effects on OVA-induced asthmatic mice via adjusting TGF-β1/Smad2/3 and AKT signal pathways, supporting the fact that dioscin could be a candidate for chronic asthma prevention in the future.
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BIOORGANIC CHEMISTRY
·
2021
·
IF 5.275
Yingying Ma,Xiaorong Yang,Hongwei Han,Zhongling Wen,Minkai Yang,Yahan Zhang,Jiangyan Fu,Xuan Wang,Tongming Yin,Guihua Lu,Jinliang Qi,Hongyan Lin,Xiaoming Wang,Yonghua Yang
Triple-negative breast cancer (TNBC) has an unfavorable prognosis attribute to its low differentiation, rapid proliferation and high distant metastasis rate. PI3K/Akt/mTOR as an intracellular signaling pathway plays a key role in the cell proliferation, migration, invasion, metabolism and regeneration. In this work, we designed and synthesized a series of anilide (dicarboxylic acid) shikonin esters targeting PI3K/Akt/mTOR signaling pathway, and assessed their antitumor effects. Through three rounds of screening by computer-aided drug design method (CADD), we preliminarily obtained sixteen novel anilide (dicarboxylic acid) shikonin esters and identified them as excellent compounds. CCK-8 assay results demonstrated that compound M9 exhibited better antiproliferative activities against MDA-MB-231, A549 and HeLa cell lines than shikonin (SK), especially for MDA-MB-231 (M9: IC 50 = 4.52 ± 0.28 μM; SK: IC 50 = 7.62 ± 0.26 μM). Moreover, the antiproliferative activity of M9 was better than that of paclitaxel. Further pharmacological studies showed that M9 could induce apoptosis of MDA-MB-231 cells and arrest the cell cycle in G2/M phase. M9 also inhibited the migration of MDA-MB-231 cells by inhibiting Wnt/β-catenin signaling pathway. In addition, western blot results showed that M9 could inhibit cell proliferation and migration by down-regulating PI3K/Akt/mTOR signaling pathway. Finally, a three-dimensional quantitative structure–activity relationship (3D-QSAR) model was also constructed to provide a basis for further development of shikonin derivatives as potential antitumor drugs through structure–activity relationship analysis. To sum up, M9 could be a potential candidate for TNBC therapy.
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ENVIRONMENTAL TOXICOLOGY
·
2022
·Vol. 37
·期 8
·1840-1852
·
IF 4.109
Huijie Chen,Yue Zhang,Mengmeng Zou,Xiaowei Sun,Xiaodan Huang,Shiwen Xu
Dibutyl phthalate (DBP) is a phthalic acid ester (PAE) that has posed a health hazard to the organisms. Naringenin (NRG) is a flavanone compound that has shown protection against several environmental chemicals through suppression of oxidative stress and activation of phosphatidylinositol 3-kinase/threonine kinase (PI3K/AKT) signaling pathway. Herein, swine testis (ST) cells were treated with 1.8 μM of DBP or/and 25.39 nM of NRG for 24 h, we described the discovery path of NRG inhibition on apoptosis in DBP-exposed ST cells through targeting phosphatase and tensin homologue deleted on chromosome 10 (PTEN). We first found that the anti-apoptosis effect of NRG is dependent on mitochondrial pathway through flow cytometry and related gene/protein expression, and then we detected PI3K/AKT pathway-related gene/protein expression, and established a computational docking assay between NRG and PTEN. We found that NRG specifically binds to three basic residues (His93, Lys125, Lys128) of P loop in PTEN, as well as phosphatase domains (Asp92, His93, Cys124, Lys125, Ala126, Lys128, and Arg130) in active dephosphorylation pockets, thereby reducing PTEN level and activating PI3K/AKT signaling pathway, and further inhibiting oxidative stress and mitochondrial pathway apoptosis. Taken together, our results push forward that NRG deserves further attention as a potential antagonistic therapy against DBP through targeting PTEN to inhibit oxidative stress and activate PI3K/AKT signaling pathway.
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FOOD RESEARCH INTERNATIONAL
·
2025
·
IF 8
Mingxiu Long,Hui Wang,Fang Zhang,Yaoqi Ran,Yongfu Li,Jingwen Luo,Zhaojun Chen,Zhuxi Tian,Shuming Tan,Xiong Liu
Rosa roxburghii Tratt fruit polyphenols (RP) possess antioxidant, anti-inflammatory, and immunomodulatory properties, showing potential for ulcerative colitis (UC) treatment. However, their efficacy is limited by bioavailability and targeting efficiency. To address this, RP were encapsulated into acylated chitosan-crosslinked carboxymethyl konjac glucomannan (ACs-CKGM) nanogel (RPNG). Experimental results demonstrated that RPNG significantly enhanced intestinal barrier function by upregulating tight junction proteins (ZO-1, Occludin and Claudin-3) and mucus secretion (MUC2). It effectively mitigated oxidative stress by restoring antioxidant enzymes (SOD, GSH-Px and CAT) while reducing MPO, COX-2 and iNOS activation. Through integrated ELISA, western blot, and transcriptomic analyses, we emonstrated that RPNG specifically inhibited PI3K/Akt/mTOR and NF-κB signaling pathways, decreasing inflammatory cytokines (e.g., TNF-α, IL-6) while increasing anti-inflammatory mediators (e.g., IL-10). Gut microbiome analysis showed RPNG reversed DSS-induced dysbiosis by enriching beneficial bacteria (e.g., Muribaculum sp.) and suppressing pathogens (e.g., Escherichia coli ). These findings highlight RPNG as a novel targeted strategy for UC management, supported by multi-omics mechanistic insights.
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MOLECULAR IMMUNOLOGY
·
2021
·
IF 4.407
Limei Ao,Han Gao,Lifen Jia,Shimin Liu,Jie Guo,Bingzhen Liu,Qiumei Dong
Matrine (Mat) is an alkaloid of tetracycline quinazine, and previous studies have demonstrated its specific effect on relieving rheumatoid arthritis (RA). However, the effect of Mat on joint synovial angiogenesis in the pathogenesis of RA has not been elucidated. In this study, body weight, joint swelling, arthritis index (AI) score, histopathological changes, immunohistochemical, and western blot- were used in collagen-induced arthritis (CIA) rats to detect pro-inflammatory factors and, - expression levels of key cytokines and proteins along the hypoxia-inducible factor (HIF)-endothelial growth factor (VEGF)-angiopoietin (Ang) axis and VEGF-phosphoinositide 3-kinase (PI3K) / protein kinase B (Akt) pathway. In vitro experiments were conducted to observe the effect of Mat on the proliferation, migration and lumen formation of RA-fibroblast-like synovial cells (FLS) and human umbilical vein endothelial cells (HUVECs). Results showed that Mat reduced the degree of paw swelling and AI score in CIA rats, joint synovial tissue proliferation, inflammatory cell infiltration, and neovascularization; moreover, it down-regulated the expression levels of inflammatory factors interleukin-1β, interferon-γ, and pro-angiogenic factors VEGF, placental growth factor, HIF-α, Ang-1, Ang-2, Tie-2, and phosphorylation-Akt in the ankle joint of CIA rats. In addition, the in vitro experiments showed that Mat inhibited the proliferation and migration of RA-FLS and inhibited the proliferation and lumen formation of HUVECs. Therefore, Mat exerts an anti-angiogenesis effect by regulating the HIF-VEGF-Ang axis and inhibiting the PI3K/Akt signaling pathway. This inhibits the pathogenesis and improve the symptoms of RA, and may be offered as a candidate drug for the treatment of RA.
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Aging-US
·
2020
·
IF 4.831
Yan Sun,Shiting Dai,Jin Tao,Yunlong Li,Ziqi He,Quan Liu,Jiawen Zhao,Yaoliang Deng,Juening Kang,Xuepei Zhang,Sixing Yang,Yunlong Liu
Oxidative stress and autophagy are the key promoters of calcium oxalate (CaOx) nephrolithiasis. Taurine is an antioxidant that plays a protective role in the pathogenesis of kidney disease. Previous studies found that taurine suppressed cellular oxidative stress, and inhibited autophagy activation. However, the effect of taurine on CaOx kidney stone formation remains unknown. In the present work, we explored the regulatory effects of taurine on CaOx crystals-induced HK-2 cell injury. Results showed that pretreatment with taurine significantly enhanced the viability of HK-2 cells and ameliorated kidney tissue injury induced by CaOx crystals. Taurine also markedly reduced the levels of inflammatory cytokines, apoptosis, and CaOx crystals deposition. Furthermore, we observed that taurine supplementation alleviated CaOx crystals-induced autophagy. Mechanism studies showed that taurine reduced oxidative stress via increasing SOD activity, reducing MDA concentration, alleviating mitochondrial oxidative injury, and decreasing the production of intracellular ROS. Taurine treatment also effectively activated Akt/mTOR signaling pathway in CaOx crystals-induced HK-2 cells both in vitro and in vivo . In summary, the current study shows that taurine inhibits ROS-dependent autophagy via activating Akt/mTOR signaling pathway in CaOx crystals-induced HK-2 cell and kidney injury, suggesting that taurine may serve as an effective therapeutic agent for the treatment of CaOx nephrolithiasis.
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EXPERIMENTAL CELL RESEARCH
·
2021
·
IF 3.905
Yiming Li,Yi He,Guanhui Chen,Ziqing Huang,Chen Yi,Xiliu Zhang,Feilong Deng,Dongsheng Yu
abstract Dental implant surgery is currently a routine therapy for the repair of missing dentition or dentition defects. Both clinical and basic research have elucidated that oxidative stress caused by the accumulation of reactive oxygen species (ROS) for various reasons impairs the process of osteointegration after dental implantation. Therefore, the osteogenic micro-environment must be ameliorated to decrease the damage caused by oxidative stress. Selenomethionine (SEMET) has been reported to play an important role in alleviating oxidative stress and accelerating cell viability and growth. However, it remains unclear whether it exerts protective effects on bone-marrow-derived mesenchymal stem cells (BMSCs) under oxidative stress. In this study, we explored the influence of selenomethionine on the viability and osteogenic differentiation of BMSCs under oxidative stress and the underlying mechanisms. Results showed that 1 μM selenomethionine was the optimum concentration for BMSCs under H 2 O 2 stimulation. H 2 O 2 -induced oxidative stress suppressed the viability and osteogenic differentiation of BMSCs, manifested by the increases in ROS production and cell apoptosis rates , and by the decrease of osteogenic differentiation-related markers. Notably, the aforementioned oxidative damage and osteogenic dysfunction induced by H 2 O 2 were rescued by selenomethionine. Furthermore, we found that the PTEN expression level was suppressed and its downstream PI3K/AKT pathway was activated by selenomethionine. However, when PTEN was stimulated, the PI3K/AKT pathway was down-regulated, and the protective effects of selenomethionine on BMSC osteogenic differentiation diminished, while the inhibition of PTEN up-regulated the protective effects of selenomethionine. Together, these results revealed that selenomethionine could attenuate H 2 O 2 -induced BMSC dysfunction through an antioxidant effect, modulated via the PTEN/PI3K/AKT pathway, suggesting that selenomethionine is a promising antioxidant candidate for reducing oxidative stress during the process of dental implant osteointegration.
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BIOMEDICINE & PHARMACOTHERAPY
·
2020
·
IF 4.545
Ye Zhou,Meng Zhang,Zhilei Zhang,Yuming Jia,Chong Zhang,Li Peng
Hydrazinocurcumin (HZC), a curcumin analogue, serves as a tumor suppressor in breast cancer and lung cancer. In this study, we investigate the role and mechanism of HZC in regulating HepG2 cell apoptosis and tumorigenicity, and its synergistic effects with 5-fluorouracil (5-Fu). HepG2 cells were treated with HZC and/or 5-Fu to analyze the possible synergistic effects on cell proliferation, apoptosis and cell cycle distribution in vitro using EdU staining, Hoechst staining and flow cytometry, respectively. For mechanistic investigation we used pic, a phosphatase and tensin homolog (PTEN) inhibitor, and in other studies assessed the expression pattern of PTEN and PI3K/Akt signaling pathway-related genes. Additionally, we tested in vivo effects of HZC and 5-Fu treatment on growth of HepG2 cell tumors in nude mice. We found that HZC or 5-Fu induced apoptosis and repressed proliferation of HepG2 cells by upregulating the expression of PTEN and disrupting the PI3K/Akt signaling pathway activation. Moreover, HZC had a higher pro-apoptotic effect than 5-Fu. HZC and 5-Fu induced HepG2 cell apoptosis and inhibited their tumorigenicity in vivo . Inhibition of PTEN expression activated the PI3K/Akt signaling pathway and reversed the protective effects of HZC or 5-Fu. Thus, HZC and 5-Fu increase PTEN, which blocks the PI3K/Akt signaling pathway, ultimately inducing HepG2 cell apoptosis. Importantly, the synergistic combination of HZC and 5-Fu may present promising strategy for the treatment of HCC.
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Molecular Medicine Reports
·
2016
·Vol. 14
·期 3
·2853-2859
·
IF 1.559
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.
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JOURNAL OF BIOCHEMISTRY
·
2024
·
IF 2.1
Wang Rui,Liao Zhaoping,Liu Chunhua,Yu Shifang,Xiang Kaihua,Wu Ting,Feng Jie,Ding Senjuan,Yu Tingao,Cheng Gang,Li Sanlian
Prostate cancer (PCa) has become a worldwide health burden among men. Previous studies have suggested that Cellular Retinoic Acid Binding Protein 2 (CRABP2) significantly affects the regulation of cell proliferation, motility, and apoptosis in multiple cancers, yet the effect of CRABP2 on PCa is poorly reported. The CRABP2 expression in different PCa cell lines and its effect on different cellular functions were various. While CRABP2 promotes cell migration and invasion, it appears to inhibit cell proliferation specifically in PC-3 cells. However, the proliferation of DU145 and 22RV1 cells did not appear to be significantly affected by CRABP2. Besides, CRABP2 had no influence on the cell cycle distribution of PCa cells. RNA-seq assay showed that overexpressing CRABP2 up-regulated Laminin subunit beta-3 (LAMB3) mRNA expression, and the enrichment analyses revealed that the differentially expressed genes were enriched in PI3K/AKT and MAPK signaling pathway. The following WB experiments also confirmed the up-regulated LAMB3 protein level and the activation of PI3K/AKT and MAPK signaling pathways. Moreover, overexpressing CRABP2 inhibited tumor growth significantly in vivo. In conclusion, CRABP2 facilitates cell migration and invasion by activating PI3K/AKT and MAPK signaling pathways through upregulating LAMB3 in PCa.
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