EXPERIMENTAL CELL RESEARCH
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2023
·
IF 3.7
Hai-Tao Yang,Guan Wang,Peng-Cheng Zhu,Zhao-Yang Xiao
Pulmonary vascular remodeling caused by the excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs) is the hallmark feature of pulmonary arterial hypertension (PAH). Eukaryotic initiation factor 3 subunit A (EIF3A) exhibited proliferative activity in multiple cell types. The present study investigated the role of EIF3A in the progression of PAH. A monocrotaline (MCT)-induced PAH rat model was constructed, and adeno-associated virus type 1 (AAV1) carrying EIF3A shRNA was intratracheally delivered to PAH rats to block EIF3A expression. PASMCs were isolated from rats and treated with PDGF-BB to simulate PASMC proliferation , and shRNA for EIF3 was conducted to investigate the mechanism behind the role of EIF3A in PASMC function in vitro . EIF3A expression was upregulated in pulmonary arteries, and EIF3A inhibition effectively improved pulmonary hypertension and right ventricular hypertrophy and suppressed MCT-induced vascular remodeling in vivo . In addition, we found that genetic knockdown of EIF3A reduced PDGF-triggered proliferation and arrested cell cycle, accompanied by downregulated proliferation-related protein expression in PASMCs. Mechanistically, the histone deacetylase 1 (HDAC1)-mediated PTEN/PI3K/AKT pathway was recognized as a primary mechanism in PAH progression. Silencing EIF3A decreased HDAC1 expression, and further inhibited the excessive proliferation of PASMCs by increasing the phosphatase and tension homolog (PTEN) expression and suppressing the AKT phosphorylation. Notably, HDAC1 expression reversed the effect of silencing EIF3A on PAH and PTEN/PI3K/AKT pathway. Collectively, silencing EIF3A improved PAH by decreasing PASMC proliferation through the HDAC1-mediated PTEN/PI3K/AKT pathway. These findings suggest that targeting EIF3A may represent a potential approach for the treatment of PAH.
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Experimental and Therapeutic Medicine
·
2023
·Vol. 25
·期 4
·1-11
·
IF 2.7
Chun-Lian Liang,Xiu-Li Li,Xiao-Juan Quan,Lin Zhang
Idiopathic pulmonary fibrosis (IPF) is a heterogeneous lung disease associated with high mortality. Disabled‑2 (DAB2), an adapter protein, regulates cell‑fibrinogen adhesion and fibrinogen uptake. DAB2 is differentially expressed in mouse fibrotic lungs induced by bleomycin according to a genome microarray analysis based on Gene Expression Omnibus database. However, the role of DAB2 in IPF has not been revealed. A bleomycin‑induced mouse model of pulmonary fibrosis was constructed in the present study. It found that the expression of DAB2 was upregulated in bleomycin‑induced fibrotic lung tissue with collagen fiber deposition and pulmonary interstitium thickening. Colocalization of DAB2 with α‑smooth muscle actin (SMA) was observed in lung tissue sections. In vitro, human lung fibroblast MRC‑5 cells were treated with TGF‑β1 and the expression of DAB2 was increased. Knockdown of DAB2 suppressed cell proliferation and the expression of α‑SMA, collagen I, collagen IV and fibronectin in TGF‑β1‑treated MRC‑5 cells. The phosphorylation levels of PI3K and AKT were suppressed in DAB2‑knockdown cells. IGF‑1/IGF‑1R has been reported to promote pulmonary fibrosis and activate the PI3K/Akt signaling. In the present study, the activation of IGF‑1/IGF‑1R signaling pathways in bleomycin‑induced fibrotic lung tissues were positively associated with DAB2 expression. The phosphorylation level of IGF‑1R was increased in MRC‑5 cells with TGF‑β1 treatment, and DAB2 expression was decreased by silencing of IGF‑1R. This suggested that DAB2 might be a downstream target of the IGF‑1R pathway and thus induced PI3K/AKT signaling activation and fibrogenesis. The current study demonstrated the importance of DAB2 in pulmonary fibrosis and suggested the potential of IGF‑1R/DAB2/PI3K in the pathogenesis of IPF.
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FOOD AND CHEMICAL TOXICOLOGY
·
2023
·
IF 4.3
Xin Xie,Yan Zhu,Huimin Cheng,Haili Li,Yadi Zhang,Rong Wang,Wenyong Li,Fengrui Wu
Long-term exposure to bisphenol A (BPA) in humans may promote ovarian cancer development. In present study, the mechanisms by which BPA mediates the aggression metastatic behavior of ovarian cancer were investigated in vitro/in vivo . The results showed that BPA (10 μM) significantly promoted the proliferation, migration and invasion of human ovarian cancer cells (ES-2 and OVCAR-3 cells); moreover, it promoted ES-2 and OVCAR-3 cell glucose uptake, lactic acid release and intracellular ATP synthesis. After administration of 5 μg/kg/day BPA, tumor volume was increased compared with that in control group. KEGG and GO enrichment analyses showed that the genes from ES-2 cell in 10 μM BPA-treated group were enriched mainly in central carbon metabolism and PI3K-AKT signaling pathway. Then, qRT‒PCR and western blotting results showed that BPA (10 μM) increased the mRNA and protein expression levels of glycolysis-related genes and mTOR, p-AKT HIF-1α and ERα in vitro/vivo ; whereas this effect was reduced after treatment with the ERα inhibitor methyl-piperidino-pyrazole. Furthermore, coimmunoprecipitation and mass spectrometry showed that BPA promoted the direct interaction of ERα with lactate dehydrogenase A. These results show that BPA directly promoted the proliferation, migration and invasion of ovarian cancer cells through the ERα/AKT/mTOR/HIF-1α signaling axis to enhance glycolysis.
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2019
·
IF 3.571
Feier Cheng,Lin Han,Yao Xiao,Chuanying Pan,Yunlong Li,Xinhui Ge,Yao Zhang,Shaoqing Yan,Min Wang
d-chiro-Inositol (DCI) is a biologically active component found in tartary buckwheat, which can reduce hyperglycemia and ameliorate insulin resistance. However, the mechanism underlying the antidiabetic effects of DCI remains largely unclear. This study investigated the effects and underlying molecular mechanisms of DCI on hepatic gluconeogenesis in mice fed a high fat diet and saturated palmitic acid-treated hepatocytes. DCI attenuated free fatty acid uptake by the liver via lipid trafficking inhibition, reduced diacylglycerol deposition, and hepatic PKCε translocation. Thus, DCI could improve insulin sensitivity by suppressing hepatic gluconeogenesis. Subsequent analyses revealed that DCI decreased hepatic glucose output and the expression levels of PEPCK and G6 Pase in insulin resistant mice through PKCε-IRS/PI3K/AKT signaling pathway. Likewise, such effects of DCI were confirmed in HepG2 cells with palmitate-induced insulin resistance. These findings indicate a novel pathway by which DCI prevents hepatic gluconeogenesis, reduces lipid deposition, and ameliorates insulin resistance via regulation of PKCε-PI3K/AKT axis.
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BIOMEDICINE & PHARMACOTHERAPY
·
2018
·
IF 3.457
Min Chen,Xiaodong Wang,Bo Hu,Jian Zhou,Xin Wang,Wei Wei,Hua Zhou
Echinacoside is a natural ingredient with various pharmacological activities . In this study, we investigated the protective effects of echinacoside on cardiomyocytes (rat H9c2 cells) in an anoxia/reperfusion (A/R) model. Further, the regulatory function of sodium-calcium exchanger protein 3 (SLC8A3/NCX3) as well as the protein kinase B (AKT) signaling were studied. The present results indicated that echinacoside protected against A/R-induced apoptosis in a dose manner, which was characterized by a decrease in the apoptosis and caspase 3 protein levels in H9c2 cells. Further, Ca 2+ uptake were dose-dependently reduced in H9c2 cells by echinacoside under A/R conditions. Whereas, relative mRNA expression of SLC8A3 and protein levels of SLC8A3 and p-AKT showed opposite tendency. On the one hand, the A/R-induced abnormalities in H9c2 cells were remarkably ameliorated by activated p-AKT and over-expression of SLC8A3 but aggravated by inhibited p-AKT, and the aggravated effection were ameliorated by echinacoside. Moreover, protein levels of SLC8A3 were positively regulated by p-AKT signaling. On the other hand, apoptosis and Ca 2+ uptake as well as protein levels of caspase 3 were significantly increased by SLC8A3 silencing in H9c2 cells under normoxic conditions, and this symptom was remarkably reversed by echinacoside or Nimodipine (an antagonis of Ca 2+ ) treatment . Collectively, echinacoside has showed a cardioprotective effect against A/R treatment in a dose dependent manner in vitro, and this cardioprotective effect was potentially achieved via up-regulating p-AKT and SLC8A3.
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BIOMEDICINE & PHARMACOTHERAPY
·
2018
·
IF 3.457
YingHui Zhang,Bing Wang,Feng Guo,ZhiZhen Li,GuiJun Qin
Diabetic nephropathy is one of the manifestations of systemic microangiopathy in diabetes. Hesperetin , a natural flavanone glycoside compound in citrus fruits, has been demonstrated to exert hypoglycemic effects and protect kidney in experimental diabetic animals. The current study was aimed to investigate the mechanisms underlying the hypoglycemic effects of hesperetin in high-fat/streptozocin (STZ)–induced diabetic nephropathy. The results showed that mice in whom hesperetin was administered for 4 weeks attenuated the increased fasting blood glucose and impaired glucose tolerance ability that was observed in high-fat/STZ mice. In addition, we found that hesperetin ameliorated the abnormalities of biochemical parameters in serum, liver, and kidney of mice with diabetic nephropathy. Hesperetin also rescued the irregular distortions in glomerular basement membrane and expanded mesangial regions. Moreover, hesperetin repaired the function of podocyte by increasing renal nephrin expression and decreasing renal alpha-smooth muscle actin expression. Furthermore, hesperetin inhibited the expression of transforming growth factor-β1 (TGF-β1) and its downstream effectors integrin-linked kinase (ILK) and Akt. In conclusion, our study implies that hesperetin produced protective effects in diabetic nephropathy possibly by suppressing TGF-β1-ILK-Akt signaling.
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PHYTOMEDICINE
·
2024
·
IF 6.7
Yinhuang Gao,Peng Zhao,Chunyan Wang,Keren Fang,Yueqing Pan,Yan Zhang,Zhishuo Miao,Meirong Wang,Minlong Wei,Wei Zou,Menghua Liu,Kang Peng
Background Chronic cerebral hypoperfusion (CCH) has been confirmed as one of the pathogenesis underlying vascular cognitive impairment. A series of pathological changes, including inflammation, oxidative stress, and apoptosis, are involved in this pathophysiology and contribute to cognitive impairment and neuropathological alterations. The traditional Chinese medicine (TCM) of Buqi Huoxue Tongnao (BQHXTN) prescription possesses a remarkable clinical efficacy for treating patients with CCH, but still lacks a scientific foundation for its pharmacological mechanisms. Purpose To investigate the role and underlying mechanism of the effects of BQHXTN on CCH both in vitro and in vivo . Methods In this study, we established a two-vessel occlusion (2-VO) induced CCH model in Sprague-Dawley rats, an oxygen-glucose deprivation model in BV2 cells, and a steatosis cell model in L02 cells to reveal the underlying mechanisms of BQHXTN by behavioral test, histopathological analysis and the detection of pro-inflammatory cytokine, apoptotic factors and reactive oxide species. Donepezil hydrochloride and Buyang Huanwu decoction were used as positive drugs. Results Compared with the 2-VO group, BQHXTN treatment at three doses significantly enhanced the memory and learning abilities in the Y-maze and novel object recognition tests. The hematoxylin-eosin staining indicated that BQHXTN protected against hippocampal injury induced by CCH. Of note, in both in vivo and in vitro experiments, BQHXTN prominently inhibited the production of IL-1β, TNF-α, cleaved-caspase 3, and iNOS by regulating the PI3K/AKT pathway, consequently exerting anti-inflammatory, anti-apoptotic, and antioxidant effects. Moreover, it provided the first initial evidence that BQHXTN treatment mitigated dyslipidemia by increasing the LXRα/CYP7A1 expression, thereby delaying the neuropathological process. Conclusion In summary, these findings firstly revealed the pharmacodynamics and mechanism of BQHXTN, that is, BQHXTN could alleviate cognitive impairment, neuropathological alterations and dyslipidemia in CCH rats by activating PI3K/AKT and LXRα/CYP7A1 signaling pathways, as well as providing a TCM treatment strategy for CCH.
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BIOCHEMICAL PHARMACOLOGY
·
2024
·
IF 5.3
Huan Liu,Longsheng Wang,Xiaokai Shi,Lei Yin,Wei Zhai,Shenglin Gao,Yonghui Chen,Tao Zhang
Current therapeutic options for renal cell carcinoma (RCC) are very limited, which is largely due to inadequate comprehension of molecular pathological mechanisms as well as RCC's resistance to chemotherapy. Dual-specificity phosphatase 6 (DUSP6) has been associated with numerous human diseases. However, its role in RCC is not well understood. Here, we show that diminished DUSP6 expression is linked to RCC progression and unfavorable prognosis. Mechanistically, DUSP6 serves as a tumor suppressor in RCC by intervening the TAF10 and BSCL2 via the ERK-AKT pathway. Further, DUSP6 is also transcriptionally regulated by HNF-4a. Moreover, docking experiments have indicated that DUSP6 expression is enhanced when bound by Calcium saccharate, which also inhibits RCC cell proliferation, metabolic rewiring, and sunitinib resistance. In conclusion, our study identifies Calcium saccharate as a prospective pharmacological therapeutic approach for RCC.
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Food & Function
·
2024
·
IF 5.1
Like Lin,Cong Li,Yujiao Zhang,Li Zhang,Lu Gao,Lihua Jin,Yu Shu,Yehua Shen
Akt acts as a central protein influencing multiple pathologies in neurodegenerative diseases including AD and PD, and Akt activators are promising management strategies. The current study characterized the effects of an Akt-activating peptide (Glu-Pro-Glu-Val-Leu-Pro, EPEVLR) obtained from walnut protein degradation on D-gal-induced memory impairment in mice. The EPEVLR was obtained by hydrolysis of walnut proteins, identification of peptide sequences, and screening for molecular docking sequentially. The MWM test in mice indicated that the oral administration of EPEVLR (80, 200 and 400 mg/kg·d) significantly (p < 0.05) reversed D-gal-induced memory impairment. WB tests of the mice hippocampus confirmed that EPEVLR could activate Akt by promoting its phosphorylation. In addition, further characterizations (including TEM, ELISA, and immunohistochemistry) related to Akt phosphorylation observed lower Aβ and p-Tau levels, as well as more autophagosomes than in the model group. Moreover, the EPEVLR treatment significantly increased Lactobacillus and reduced Helicobacter abundance of the gut microbiome, and caused up-regulation of SCFAs and down-regulation of LPS of serum metabolite. Therefore, EPEVLR ingestion reversed cognitive impairment symptoms possibly related to the activation of Akt and regulation of the intestinal flora pathway. Consumption of the EPEVLR diet is beneficial for cognitive dysfunction.
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Foods
·
2025
·Vol. 14
·期 7
·1110
·
IF 5.1
Yuxin Zhang,Zeyuan Deng,Hongyan Li,Zeyin Jiang
Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by recurrent episodes and an inability to achieve a complete cure. The spermidine derivative (di- p -coumaroyl-caffeoyl spermidine, SPDD), as a key alkaloid, exhibits unique health benefits. However, it has not yet been reported whether SPDD can improve dextran sulfate sodium (DSS)-induced colitis in mice. Herein, we investigated the effects and mechanisms of SPDD on DSS-induced colitis in mice. SPDD was successfully purified from rose bee pollen and was found to have a protective effect on colitis, evidenced by reduced disease activity index (DAI) scores and colonic inflammation, increased colonic length and upregulated the expression of tight junction proteins (TJs) in the model ( p < 0.05). Importantly, the IL-17 signaling pathway showed significant enrichment by RNA sequencing (RNA-seq) technology with SPDD treatment, which resulted in the downregulation of MAPK4 expression ( p < 0.05). Furthermore, SPDD weakened the interaction between MAPK4 and AKT, resulting in a decrease in the phosphorylation level of AKT, thereby reducing the expression of IL-6, IL-1β, iNOS, and COX-2, and alleviating colitis ( p < 0.05). In addition, SPDD treatment also ameliorated TNF-α-induced inflammation in Caco-2 cells. Overall, our study demonstrated that SPDD reversed colonic inflammation in colitis mice through the MAPK4/AKT pathway and might be a promising candidate for UC intervention.
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Toxicology Research
·
2024
·Vol. 13
·期 1
·
IF 2.2
Zhang Chu,Liao Yupei,Li Tangjia,Zhong Haijing,Shan Luchen,Yu Pei,Xia Chenglai,Xu Lipeng
The 2022 US Cancer Statistics show that breast cancer is one of the most common cancers in women. Epidemiology has shown that adding flavonoids to the diet inhibits cancers that arise in particular women, such as cervical cancer, ovarian cancer, and breast cancer. Although there have been research reports on apigenin (API) and breast cancer, its anti-tumor effect and potential mechanism on breast cancer have not yet been clarified. Therefore, in this study, we used 4T1 cells and a 4T1 xenograft tumor mouse model to investigate the antitumor effect of API on breast cancer and its underlying mechanism. In vitro, we used MTT, transwell, staining, and western blotting to investigate the inhibitory effect of apigenin on 4T1 and the underlying molecular mechanism. In vivo by establishing a xenograft tumor model, using immunohistochemistry, and flow cytometry to study the inhibitory effect of apigenin on solid breast tumors and its effect on the tumor immune microenvironment. The results showed that API can induce breast cancer cell apoptosis through the PI3K/AKT/Nrf2 pathway and can improve the tumor immune microenvironment in mice with breast tumors, thereby inhibiting the growth of breast cancer. Thus, API may be a promising agent for breast cancer treatment.
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ACS Biomaterials Science & Engineering
·
2025
·
IF 5.5
Yang Zhang,Han Wang,Ke Liu,Ruimeng Sun,Yurou Wang,Jiayu Guo,Wenxiang Zhou,Haoran Zheng,Yanfei Qi
Acute renal injury (AKI) has a high incidence rate and mortality, but current treatment methods are limited. As a kind of nanomaterial with enzyme-like activity, nanozyme has shown outstanding advantages in treating AKI according to recent reports. Herein, we assess the potential of manganese-based nanozymes (MnO2–BSA NPs) with excellent biosafety in effectively alleviating AKI. Our findings in vitro and in vivo reveal that MnO2–BSA NPs exert regulatory effects on oxidative stress, inflammation, and apoptosis. These effects are mediated through activation of the Nrf2/HO-1 and PI3K/Akt/NF-κB pathways. Notably, it was observed that the cytoprotective effect of MnO2–BSA NPs is abrogated upon inhibition of Nrf2 expression, highlighting the important role of this transcription factor in cellular protection. In summary, the study demonstrates the protective effect of MnO2–BSA NPs in AKI and provides the molecular mechanisms involved, which can contribute to the advancement of potential therapeutic interventions for nanozyme-based treatments.
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