ANTI-CANCER DRUGS
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2021
·Vol. 32
·期 7
·727
·
IF 2.248
Zhang Zuo-yan,Dong Shu-min,Liu Ye-han,Zhang Man-man,Zhang Jian-kang,Zhu Hua-jian,Shao Jia-an,Liu Hua-qing,Li Yang-ling,Zhang Chong,Zeng Ling-hui
Vinpocetine is widely used to treat cerebrovascular diseases. However, the effect of vinpocetine to treat hepatocellular carcinoma (HCC) has not been investigated. In this study, we revealed that vinpocetine was associated with antiproliferative activity in HCC cells, but induced cytoprotective autophagy, which restricted its antitumor activity. Autophagy inhibitors improved the antiproliferative activity of vinpocetine in HCC cells. Sorafenib is effective to treat advanced HCC, but the effect of autophagy induced by sorafenib is indistinct. We demonstrated vinpocetine plus sorafenib suppressed the cytoprotective autophagy activated by vinpocetine in HCC cells and significantly induced apoptosis and suppressed cell proliferation in HCC cells. In addition, vinpocetine plus sorafenib activates glycogen synthase kinase 3β (GSK-3β) and subsequently inhibits cytoprotective autophagy induced by vinpocetine in HCC cells. Meanwhile, overexpression of GSK-3β was efficient to increase the apoptosis induced by vinpocetine plus sorafenib in HCC cells. Our study revealed that vinpocetine plus sorafenib could suppress the cytoprotective autophagy induced by vinpocetine and subsequently show synergistically anti-HCC activity via activating GSK-3β and the combination of vinpocetine and sorafenib might reverse sorafenib resistance via the PI3K/protein kinase B/GSK-3β signaling axis. Thus, vinpocetine may be a potential candidate for sorafenib sensitization and HCC treatment, and our results may help to elucidate more effective therapeutic options for HCC patients with sorafenib resistance.
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FOOD AND CHEMICAL TOXICOLOGY
·
2019
·
IF 3.775
Jiankang Wang,Yutong He,Deqing Yu,Liang Jin,Xiaobao Gong,Baoshun Zhang
Perilla oil (PerO), a natural oil with a high unsaturated fatty acid content derived from the mature seeds of Perilla frutescens , is a homology of medicine and food . The type 2 diabetes mellitus (T2DM) model was successfully established using a high-fat and high-sugar diet combined with a single low-dose of streptozocin (STZ). PerO intervention reduced the levels of fasting blood glucose and the level, size and accumulation of lipid droplets , increased the insulin level and diminished the body weight loss. PerO pretreatment markedly promoted the serum levels of alanine transaminase (ALT) and aspartate transaminase alanine (AST) and inhibited the levels of glucose (GLU), glucose-6-phosphate dehydrogenase (G6PD), triglycerides (TGs) and total cholesterol (TC). Moreover, PerO treatment enhanced the expression of phosphoinositide-3 kinase (PI3K)/protein kinase B (AKT) and activated the expression of glucose transporter 4 (Glut4) and phospho-AKT serine/threonine kinase (p-AS160) in the liver. Additionally, PerO treatment distinctly decreased the abundance of Aerococcus and facilitated the richness of Alloprevotella in the intestine, as well as accelerated the restoration of the gut microflora diversity. Thus, PerO regulates intestinal microbiota and alleviates insulin resistance through the PI3K/AKT signaling pathway in type-2 diabetic KKAy mice and may be a potential functional food for diabetic treatment.
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Biomedical Journal
·
2023
·
IF 5.5
Chen Ke,Changhan Chen,Ming Yang,Hao Chen,Youhui Ke,Liqun Li
Background Infantile hemangioma (IH) is a common vascular tumor in female infants, which can lead to aesthetic issues and facial scarring. This study aimed to investigate the inhibitory effects and underlying mechanisms of 755 nm long-pulsed alexandrite laser on IH. Methods Hemangioma endothelial cells (HemECs) were exposed to 755 nm long-pulsed alexandrite laser to evaluate its impact on cell proliferation and apoptosis. A patient-derived xenograft model was established to assess the inhibitory effects of laser treatment on IH in vivo . Results In vitro , 755 nm long-pulsed alexandrite laser effectively suppressed the proliferation of HemECs and induced cell apoptosis. Laser treatment significantly inhibited the volume and weight of tumors, accompanied by significant downregulation of vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor receptor 2 (VEGFR2), phosphatidylinositol 3-kinase (PI3K), and protein kinase B (Akt) expression levels in both hemangioma cells and tumors. Additionally, laser treatment resulted in the conversion of VEGFA 165a to VEGFA 165b . TUNEL staining demonstrated increased apoptosis in tumor cells after laser treatment, along with upregulation of cleaved caspase-3 and Bax, and downregulation of Bcl-2. Conclusion In addition to the principle of selective photothermal decomposition, modulation of the VEGF/PI3K/Akt axis may serve as a potential mechanism for IH treatment using a long pulse-width 755 nm laser. This sheds valuable light on the molecular mechanisms underlying IH pathogenesis and potential therapeutic targets while providing a theoretical basis for the safe and efficient management of proliferative IH using laser therapy.
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CHEMICO-BIOLOGICAL INTERACTIONS
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2023
·
IF 5.1
Heng-Jun Zhou,Xiao-Yi Wang,Li-Qing Wang,Jie-Sheng Zheng,Ren-Ya Zhan,Jian-Wei Pan
This study aimed to treat diabetic cerebral ischemia-reperfusion injury (CI/RI) by affecting blood brain barrier (BBB) permeability and integrity. The CI/RI model in DM mice and a high glucose (HG) treated oxygen and glucose deprivation/reoxygenation (OGD/R) brain endothelial cell model were established for the study. Evans blue (EB) staining was used to evaluate the permeability of BBB in vivo . TTC staining was used to analyze cerebral infarction . The location and expression of tribbles homolog 3 (TRIB3) in endothelial cells were detected by immunofluorescence. Western blotting was used to detect the protein expressions of TRIB3, tight junction molecules, adhesion molecules , phosphorylated protein kinase B (p-AKT) and AKT. The levels of pro-inflammatory cytokines were detected by qRT-PCR. Trans -epithelial electrical resistance (TEER) and fluorescein isothiocyanate (FITC)-dextran were used to measure vascular permeability in vitro . TRIB3 ubiquitination and acetylation levels were detected. Acetyltransferase bound to TRIB3 were identified by immunoprecipitation . TRIB3 was localized in cerebral endothelial cells and was highly expressed in diabetic CI/R mice. The BBB permeability in diabetic CI/R mice and HG-treated OGD/R cells was increased, while the junction integrity was decreased. Interference with TRIB3 in vitro reduces BBB permeability and increases junction integrity. In vivo interfering with TRIB3 reduced cerebral infarction volume, BBB permeability and inflammation levels, and upregulated p-AKT levels. The phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin reversed the effects of TRIB3-interfering plasmid. In vitro HG treatment induced TRIB3 acetylation through acetyltransferase p300, which in turn reduced ubiquitination and stabilized TRIB3. Interfering TRIB3 protects BBB by activating PI3K/AKT pathway and alleviates brain injury, which provides a new target for diabetic CI/RI.
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Journal of Functional Foods
·
2023
·
IF 5.6
Shuyan Han,Hongmei Hou,Yiren Zhang,Zhongxiang Fang,Yun Li,Le Zhang,Yandan Wang,Shijia Zhang,Hui Zhang,Qingzhe Jin,Gangcheng Wu,Xingguo Wang
Naturally existing polyphenols in virgin olive oil possess significative biological activities and are potential nutraceutical therapeutic for breast cancer. In the present study, we investigated the anti-breast cancer activity of oleuropein and its hydrolysates, and further explored their molecular mechanisms. A similar cellular viability was observed in MCF-7 and MDA-MB-231 cells both treated with oleocanthal (3 μg/mL), hydroxytyrosol (30 μg/mL) and oleuropein (200 μg/mL) showed the same cellular viability, indicating oleocanthal structure may be the main structural component part of the physiological activity of oleuropein. Results showed that olive polyphenols produced reactive oxygen species and suppressed breast cancer cells. For flow cytometry analysis, the three polyphenols impacted the MCF-7 cell and MDA-MB-231 cycle, stagnated in the G1 phase and S phase, respectively, via reducing Cyclin D protein expression and promoting cell apoptosis. The pro-apoptosis, anti-proliferation capacity and delaying cell cycle of the three olive oil polyphenols could be achieved through the PI3K-AKT signaling pathway, mainly inhibited phosphorylation of AKT, PI3K protein.
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EUROPEAN JOURNAL OF PHARMACOLOGY
·
2023
·
IF 5
Tao Mi,Zhaoxia Zhang,Chenghao Zhanghuang,Liming Jin,Xiaojun Tan,Jiayan Liu,Xin Wu,Mujie Li,Jinkui Wang,Zhang Wang,Peng Guo,Dawei He
Objective To identify therapeutic targets for malignant rhabdoid tumors of kidney (MRTK) and to investigate the effects and underlying mechanism of doxycycline hydrochloride on these tumors. Methods Gene expression and clinical data of MRTK were retrieved from the TARGET database. Differentially expressed genes (DEGs) and prognostic-related genes (PRGs) were selected through a combination of statistical analyses. The functional roles of MMP17 and MMP1 were elucidated through RNA overexpression and intervention experiments. Furthermore, in vitro and in vivo studies provided evidence for the inhibitory effect of doxycycline hydrochloride on MRTK. Additionally, transcriptome sequencing was employed to investigate the underlying molecular mechanisms. Results 3507 DEGs and 690 PRGs in MRTK were identified. Among these, we focused on 41 highly expressed genes associated with poor prognosis and revealed their involvement in extracellular matrix regulatory pathways. Notably, MMP17 and MMP1 stood out as particularly influential genes. When these genes were knocked out, a significant inhibition of proliferation, invasion and migration was observed in G401 cells. Furthermore, our study explored the impact of the matrix metalloproteinase inhibitor , doxycycline hydrochloride, on the malignant progression of G401 both in vitro and in vivo . Combined with sequencing data, the results indicated that doxycycline hydrochloride effectively inhibited MRTK progression, due to its ability to suppress the expression of MMP17 and MMP1 through the PI3K-Akt signaling pathway. Conclusion Doxycycline hydrochloride inhibits the expression of MMP17 and MMP1 through the PI3K-Akt signaling pathway, thereby inhibiting the malignant progression of MRTK i n vivo and in vitro .
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COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY C-TOXICOLOGY & PHARMACOLOGY
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2023
·
IF 3.9
Guangxing Li,Yang Chen,Menglin Wu,Kaiting Chen,Di Zhang,Ruili Zhang,Guijun Yang,Xiaodan Huang
Di (2-ethyl) hexyl phthalate (DEHP) is a common environmental endocrine disruptor that induces oxidative stress, posing a significant threat to human and animal health. Oxidative stress can activate the PTEN/PI3K/AKT pathway, which is closely related to cell apoptosis. However, it is unclear whether DEHP induces apoptosis of chicken liver cells by regulating the PTEN/PI3K/AKT pathway through oxidative stress. In this experiment, male laying hens were continuously exposed to 400 mg/kg, 800 mg/kg, and 1600 mg/kg DEHP for 14 d, 28 d, and 42 d. The results showed that liver injury was aggravated with the dose of DEHP gavage, and the ROS/MDA levels in L, M, and H DEHP exposure groups were significantly increased, while the T-AOC/T-SOD/GSH-PX levels were decreased. Meanwhile, DEHP exposure up-regulated the mRNA and protein expression levels of PTEN/Bax/Caspase-9/Caspase-3 and down-regulated the mRNA and protein expression levels of PI3K/AKT/BCL-2, indicating that DEHP may lead to hepatocyte apoptosis through ROS regulation of PTEN/PI3K/AKT axis. In order to further clarify the relationship between oxidative stress and liver injury, we treated chicken hepatocellular carcinoma cell line (LMH) with 2.5 mM N -acetylcysteine (NAC). NAC attenuated these phenomena. In summary, our study suggests that DEHP can induce apoptosis of chicken liver through ROS activation of the PTEN/PI3K/AKT axis.
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JOURNAL OF BIOMEDICAL SCIENCE
·
2023
·Vol. 30
·期 1
·1-19
·
IF 11
Li Peisi,Zhou Dawang,Chen Dongwen,Cheng Yikan,Chen Yuan,Lin Zhensen,Zhang Xi,Huang Zhihong,Cai Jiawei,Huang Wenfeng,Lin Yanyun,Ke Haoxian,Long Jiahui,Zou Yifeng,Ye Shubiao,Lan Ping
Background A large proportion of the patients with cancer do not respond to immunotherapies. Recent studies suggested an important role for tumor-infiltrating cytotoxic T lymphocytes (CTL) in enhancing response to immunotherapy. Here, we aim to identify gene that induce proliferative and cytotoxic states of CD8 + T cells, and to investigate its effect on CAR-T cells against colorectal cancer. Methods Correlation between the expression of IFI35 with the activation and cytotoxicity of CD8 + T cells was assessed with TCGA and proteomic databases. Then we constructed murine colon cancer cells over-expressing IFI35 and tested their effect on anti-tumor immunity in both immunodeficient and immunocompetent mouse models. Flow cytometry and immunohistochemistry were performed to assess the immune microenvironment. Western blot analysis was used to identify the potential down-stream signaling pathway regulated by IFI35. We further investigated the efficacy of the rhIFI35 protein in combination with immunotherapeutic treatment. Results The transcriptional and proteomic analysis of the activation and cytotoxicity of CD8 + T cells in human cancer samples demonstrated that IFI35 expression is correlated with increased CD8 + T cell infiltration and predicted a better outcome in colorectal cancer. The number and cytotoxicity of CD8 + T cells were significantly increased in IFI35-overexpressing tumors. Mechanistically, we identified that the IFNγ-STAT1-IRF7 axis stimulated IFI35 expression, and that IFI35-mediated regulation of CD8 + T cell proliferation and cytotoxicity was dependent on PI3K/AKT/mTOR signaling pathway in vitro. Furthermore, IFI35 protein enhanced the efficacy of CAR-T cells against colorectal cancer cells. Conclusion Our findings identify IFI35 as a new biomarker that can enhance the proliferation and function of CD8 + T cells, as well as increase the efficacy of CAR-T cells against colorectal cancer cells. Graphical Abstract
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JOURNAL OF CELLULAR PHYSIOLOGY
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2023
·Vol. 238
·期 6
·1256-1274
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IF 5.6
Zhe Li,Tong Xu,Xue Fan,Kai Chen,Chunyan Wan,Xiang Li,Hang Yin,Shu Li
Both bisphenol A (BPA) and selenium (Se) deficiency can affect the expression of microRNAs (miRNAs), which can specifically regulate its target mRNA and induce apoptosis, and play a significant role in cardiovascular injury diseases. To explore the mechanism of apoptosis induced by BPA and Se deficiency in chicken arterial endothelial tissue and the role of miRNAs in this process, the model of BPA exposure/Se deficiency in chicken and PAEC cells have been employed. The targeting relationship between miR-215-3p and iodothyronine deiodinase 1 (Dio1) in PAEC was verified by double luciferase gene report. The level of miR-215-3p was detected by qRT-PCR. The oxidative stress level of arterial endothelial cells was detected by oxidative stress kit and DCFH-DA probe method. The PI3K/AKT pathway, mitochondrial dynamics, and apoptosis-related genes were detected by qRT-PCR and western blot. The mitochondrial ATP level and nitric oxide synthases (NOSs) level were detected with the kit. TUNEL, acridine orange/ethidium bromide, and flow cytometry were used to detect the level of apoptosis. The results showed that BPA exposure and Se deficiency led to overexpression of miR-215-3p, aggravated oxidative stress, inhibited activation of PI3K/AKT pathway, promoted mitochondrial division, increased expression of apoptosis related genes, and finally led to apoptosis of chicken arterial endothelial cells. We also established knockdown/overexpression models of miR-215-3p and Dio1 in vitro, and found that overexpression of miR-215-3p and knockout of Dio1 can induce apoptosis. Interestingly, miR-215-3p-Inhibitor and N-acetyl- l -cysteine (NAC) partially prevented apoptosis caused by BPA exposure and Se deficiency, and LY294002 aggravated apoptosis. These results suggest that BPA exposure aggravates the apoptosis of Se deficient arterial endothelial cells in chickens by regulating the ROS/PI3K/AKT pathway activated by miR-215-3p/Dio1. The miR-215-3p/Dio1 axis provides a new way to understand the toxic mechanism of BPA exposure and Se deficiency, and reveals a new regulatory model of apoptosis damage in vascular diseases.
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JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
·
2018
·Vol. 78
·期 2
·157-171
·
IF 3.49
Yan Bing Chun,Wang Jie,Rui Yanggang,Cao Jianwen,Xu Pei,Jiang Dan,Zhu Xiaolu,Won Moo-Ho,Bo Ping,Su Peiqing
Gabapentin (GBP), an analgesic, adjunct antiepileptic, and migraine prophylactic drug, reduces neuronal injury induced by cerebral ischemia reperfusion (IR). However, the underlying biological molecular mechanism of GBP neuroprotection is not clear. In this study, we confirmed that dose-dependent (75 and 150 mg/kg) GBP treatment could significantly reduce IR-induced neuronal death. IR-induced neuronal death was inhibited by pretreatment with 150 mg/kg GBP in a middle cerebral artery occlusion rat model. In addition, 150 mg/kg GBP treatment remarkably promoted the levels of antioxidants and reduced the autophagy of neurons in the infarct penumbra. Moreover, the phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway was activated by pretreatment with 150 mg/kg GBP, as detected by Western blot analyses. In vitro, pretreatment of PC12 cells with 450 µM GBP significantly reduced cell death induced by oxygen-glucose deprivation, increased antioxidant function, and reduced the levels of autophagy and reactive oxygen species via activation of the PI3K/Akt/mTOR pathway. This neuroprotection by GBP was inhibited significantly by 10 µM LY294002. In summary, dose-dependent pretreatment with GBP protected against cerebral IR injury via activation of the PI3K/Akt/mTOR pathway, which provided a neuroprotective function to inhibit oxidative stress-related neuronal autophagy.
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Advanced Therapeutics
·
2019
·Vol. 2
·期 5
·1800136
·
IF 0
Yalu Zou,Yuanyuan Wang,Shengsheng Zhang,Yuntang Wu,Xiaofei Liu
Islet β cell failure is a critical metabolic disorder in the development of type 2 diabetes (T2DM), and the decreased viability and dysfunction of β cells accelerate diabetic pathogenesis in association with higher mortality. In this study, the therapeutic effects of chitooligosaccharide biguanide (COSG), which is similar in structure to metformin and has negligible side effects, on islet β-cell dysfunction and the possible mechanism are explored. Streptozocin-induced diabetic rats are administered COSG via daily intragastric gavage for 8 weeks. COSG significantly controlled body weight loss, attenuated glucose levels in blood and urine, and increased serum insulin. Histological examination of the pancreas reveals that COSG also alleviated pancreatic atrophy in T2DM rats. Furthermore, COSG stimulated insulin receptor substrate-2 (IRS-2) signaling in rat islet β cells, thereby mediating the activation of the phosphatidylinositol 3 kinase/protein kinase (PI3K/Akt) signaling pathway. In addition, COSG promoted downstream forkhead transcription factor O1 (FoxO1) nuclear output to potentially activate pancreas duodenum homeobox-1 (PDX-1)/glucose transporter type-2 (GLUT-2)/glucose kinase (GCK) pathway-regulated insulin secretion. COSG also inhibited the glycogen synthase kinase-3β (GSK-3β)/caspase-3 pathway to prevent cell apoptosis. The intrinsic protective effects of COSG on the impaired insulin signaling system to delay β-cell apoptosis, increase β-cell growth and proliferation, improve β-cell function and promote insulin secretion highlight the possibilities of COSG as a novel strategy for the prevention of T2DM.
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Food & Function
·
2016
·Vol. 7
·期 5
·2398-2408
·
IF 2.686
Xiaofei Li,Jian Li,Zhike Li,Ying Sang,Yunhui Niu,Qianying Zhang,Hong Ding,Shanye Yin
Despite major scientific advances in its prevention, treatment and care, hypertension remains a serious condition that might lead to long-term complications such as heart disease and stroke. The great majority of forms of hypertension eventually result from an increased vasomotor tone activity that is regulated by endothelial NOS (eNOS) in vascular endothelium. Here, we examined the effect of fucoidan on eNOS activation in human umbilical vein endothelial cells (HUVECs). We also examined the effects of functional components of Undaria pinnatifida fucoidan on blood pressure and vascular function in eNOS inhibition-induced hypertensive rats in vivo. Our results suggest that fucoidan increased nitric oxide production by activating eNOS and Akt phosphorylation, which could be impaired by Akt or eNOS inhibitors. In the hypertensive rat model, treatment of fucoidan resulted in potent and persistent reduction of high blood pressure (BP) even after drug withdrawal. Our results showed that the mechanisms might involve protection against vascular structure damage, enhanced endothelium-independent vascular function and inhibition of abnormal proliferation of smooth muscle cells, which are mediated by the Akt–eNOS signaling pathway. Moreover, fucoidan treatment reduced the vascular inflammation and oxidative stress control caused by iNOS expression. Together, these results support a putative role of fucoidan in hypertension prevention and treatment.
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