PHYTOMEDICINE
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2019
·
IF 4.18
Jun-Shan Liu,Chu-Ying Huo,Hui-Hui Cao,Chun-Lin Fan,Jian-Yang Hu,Li-Juan Deng,Zi-Bin Lu,Hua-Yi Yang,Lin-Zhong Yu,Zhi-Xian Mo,Zhi-Ling Yu
Background Hepatocellular carcinoma (HCC) ranks third among the most common causes of cancer-related deaths worldwide. The chemotherapy for HCC is still insufficient, so far. In searching for effective anti-HCC agents from traditional Chinese medicine , we discovered that aloperine (ALO), a quinolizidine alkaloid from Sophora alopecuroides L., exerts anti-HCC activities. However, the effects of ALO on HCC have been rarely studied, and its underlying mechanisms remain unknown. Purpose This study aims to evaluate the anti-HCC activities of ALO and explore its underlying mechanisms. Methods MTT assay and colony formation assay were used to investigate the anti-proliferative effects of ALO on human HCC Hep3B and Huh7 cells. Hoechst 33258 staining was used to observe the morphological changes of cells after ALO treatment . Flow cytometry was used to analyze apoptosis induction, the collapse of the mitochondrial membrane potential and cell cycle distribution. Western blotting was used to examine the expression levels of proteins associated with apoptosis and cell cycle arrest , and key proteins in the PI3K/Akt signaling pathway . Small interfering RNA (siRNA) transfection was used to investigate the role of Akt in ALO-induced apoptosis and cell cycle arrest. Zebrafish tumor model was used to evaluate the anti-HCC effects of ALO in vivo. Results ALO inhibited the proliferation of Hep3B and Huh7 cells. ALO induced apoptosis in HCC cells, which was accompanied by the loss of mitochondrial potential, the release of cytochrome c into cytosol, as well as the increased cleavages of caspase-9, caspase-3 and PARP . Moreover, ALO induced G2/M cell cycle arrest by downregulating the expression levels of cdc25C, cdc2 and cyclin B1 . In addition, ALO inhibited activation of the PI3K/Akt signaling pathway by decreasing the expression levels of p110α , p85, Akt and p-Akt (Ser473) . Further study showed that inhibition of Akt by siRNA augmented ALO-mediated apoptosis and G2/M cell cycle arrest in HCC cells. Critically, ALO inhibited the growth of Huh7 cells in vivo. Conclusion We first demonstrated that ALO induced apoptosis and G2/M cell cycle arrest in HCC cells through inhibition of the PI3K/Akt signaling pathway. This study provides a rationale for ALO as a potential chemotherapeutic agent for HCC.
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CELL CYCLE
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2018
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IF 3.304
Xiaoyu Chen,Danrui Cui,Yanli Bi,Jianfeng Shu,Xiufang Xiong,Yongchao Zhao
Breast cancer is a common type of cancer among female cancer patients and the main cause of cancer-related deaths. During the last decades, targeted therapies for breast cancer have been rapidly developing. Among them, MLN4924, a first-in-class NEDD8-activating enzyme (NAE) inhibitor, has performed antitumor activity by inactivating the cullin-RING ligases and causing the accumulation of their substrates to induce apoptosis in a number of studies. In this study, we found that MLN4924 activates the AKT pathway in both HER2-positive and triple-negative breast cancer (TNBC) cell lines. Given that AKT signaling is responsible for tumor progression and drug resistance in some types of cancers, we hypothesized that the AKT inhibitor may synergistically enhance the tumor suppression capability in breast cancer by MLN4924. To demonstrate the sensitizing effect, MK-2206 was chosen as the adjuvant treatment, and cell growth, migration and apoptosis were detected. The results showed that MLN4924 treatment inhibited cell growth and migration and induced apoptosis in both SK-BR3 and MDA-MB231 breast cancer cell lines. More importantly, the combined treatment of MLN4924 and MK-2206 indeed caused stronger cytotoxicity and inhibition of migration and a much higher induction of apoptosis compared with MLN4924 treatment alone. Our study provides the proof-of-concept evidence for strategic drug combination of MLN4924 with an AKT inhibitor for maximal killing of breast cancer cells via the enhancement of apoptosis.
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BRAZILIAN JOURNAL OF MEDICAL AND BIOLOGICAL RESEARCH
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2024
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IF 1.9
Zheng Delu,Cui Chenli,Ye Chengsong,Shao Chen,Zha Xiujing,Xu Ying,Liu Xu,Wang Can
Coenzyme Q10 (CoQ10) is a potent antioxidant that is implicated in the inhibition of osteoclastogenesis, but the underlying mechanism has not been determined. We explored the underlying molecular mechanisms involved in this process. RAW264.7 cells received receptor activator of NF-κB ligand (RANKL) and CoQ10, after which the differentiation and viability of osteoclasts were assessed. After the cells were treated with CoQ10 and/or H2O2 and RANKL, the levels of reactive oxygen species (ROS) and proteins involved in the PI3K/AKT/mTOR and MAPK pathways and autophagy were tested. Moreover, after the cells were pretreated with or without inhibitors of the two pathways or with the mitophagy agonist, the levels of autophagy-related proteins and osteoclast markers were measured. CoQ10 significantly decreased the number of TRAP-positive cells and the level of ROS but had no significant impact on cell viability. The relative phosphorylation levels of PI3K, AKT, mTOR, ERK, and p38 were significantly reduced, but the levels of FOXO3/LC3/Beclin1 were significantly augmented. Moreover, the levels of FOXO3/LC3/Beclin1 were significantly increased by the inhibitors and mitophagy agonist, while the levels of osteoclast markers showed the opposite results. Our data showed that CoQ10 prevented RANKL-induced osteoclastogenesis by promoting autophagy via inactivation of the PI3K/AKT/mTOR and MAPK pathways in RAW264.7 cells.
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PLoS One
·
2016
·Vol. 11
·期 4
·e0152371
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IF 3.057
Wei Jiang,Tao Luo,Sheng Li,Yue Zhou,Xiu-Yin Shen,Feng He,Jie Xu,Hua-Qiao Wang
Increasing evidence shows that oxidative stress and the hyperphosphorylation of tau protein play essential roles in the progression of Alzheimer’s disease (AD). Quercetin is a major flavonoid that has anti-oxidant, anti-cancer and anti-inflammatory properties. We investigated the neuroprotective effects of quercetin to HT22 cells (a cell line from mouse hippocampal neurons). We found that Okadaic acid (OA) induced the hyperphosphorylation of tau protein at Ser199, Ser396, Thr205, and Thr231 and produced oxidative stress to the HT22 cells. The oxidative stress suppressed the cell viability and decreased the levels of lactate dehydrogenase (LDH), superoxide dismutase (SOD), mitochondria membrane potential (MMP) and Glutathione peroxidase (GSH-Px). It up-regulated malondialdehyde (MDA) production and intracellular reactive oxygen species (ROS). In addition, phosphoinositide 3 kinase/protein kinase B/Glycogen synthase kinase3β (PI3K/Akt/GSK3β) and mitogen activated protein kinase (MAPK) were also involved in this process. We found that pre-treatment with quercetin can inhibited OA-induced the hyperphosphorylation of tau protein and oxidative stress. Moreover, pre-treatment with quercetin not only inhibited OA-induced apoptosis via the reduction of Bax, and up-regulation of cleaved caspase 3, but also via the inhibition of PI3K/Akt/GSK3β, MAPKs and activation of NF-κB p65. Our findings suggest the therapeutic potential of quercetin to treat AD.
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CURRENT ISSUES IN MOLECULAR BIOLOGY
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2024
·Vol. 46
·期 10
·11359-11374
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IF 2.8
Xin Li,Kai Zheng,Hao Chen,Wei Li
While Ginsenoside Re has been shown to protect the central nervous system, reports of its effects on memory in the model of scopolamine-induced memory impairment are rare. The aim of this study was to investigate the effects of Ginsenoside Re on scopolamine (SCOP)-induced memory damage and the mechanism of action. Male ICR mice were treated with SCOP (3 mg/kg) for 7 days and with or without Ginsenoside Re for 14 days. As evidenced by behavioral studies (escape latency and cross platform position), brain tissue morphology, and oxidative stress indicators after Ginsenoside Re treatment, the memory damage caused by SCOP was significantly ameliorated. Further mechanism research indicated that Ginsenoside Re inhibited cell apoptosis by regulating the PI3K/Akt/Nrf2 pathway, thereby exerting a cognitive impairment improvement effect. This research suggests that Ginsenoside Re could protect against SCOP-induced memory defects possibly through inhibiting oxidative stress and cell apoptosis.
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ACS Omega
·
2024
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IF 3.7
Hong Duan,Han Li,Tianyi Liu,Yuan Chen,Mengmeng Luo,Ying Shi,Jing Zhou,Marwan M. A. Rashed,Kefeng Zhai,Lili Li,Zhaojun Wei
Atherosclerosis (AS) is a common cardiovascular disease that poses a major threat to health. Schisandra chinensis is a medicinal and edible plant that is commonly used to treat cardiovascular diseases. In this paper, HPLC was used to detect and analyze 5 different components in Schisandra chinensis. Network pharmacological predictions highlight the PI3K/AKT/mTOR pathway as an important pharmacological pathway. The effective ingredient Schisandrin C was screened by the molecular docking technique. ox-LDL-induced HUVECs were used to construct the atherosclerosis model for further experimental verification. The results showed that Schisandrin C interfered with the PI3K/AKT/mTOR autophagy pathway. This study lays a foundation for the further application of Schisandrin C in the prevention and treatment of atherosclerosis in the future.
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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2024
·Vol. 25
·期 23
·12844
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IF 4.9
Zhining Gao,Haoyang Dai,Qinqin Zhang,Fan Yang,Chenxi Bu,Suiqing Chen
Acute liver injury (ALI) is an injury to liver tissue caused by viruses, drugs, alcohol, and oxygen deprivation, and is one of the most common and serious clinical disorders. Hydroxytyrosol (HT) is a naturally occurring polyphenolic compound isolated from forsythia and has excellent anti-inflammatory properties. However, the effect and mechanisms of HT in ALI remain unclear. We used the LPS/D-GalN induced experimental ALI mouse model and AML12 cells to reveal the efficacy and potential mechanisms of HT in ALI, and HE staining was used for the evaluation of pathologies. A biochemical assay was used to detect changes in liver function, RNA-seq was conducted to reveal the underlying mechanisms of HT for ALI, and WB, RT-qPCR, and IF were used to assess the effects of HT action. Furthermore, an in vitro ALI model against HT in AML12 cells induced by LPS/D-GalN was used to assess the HT protection mechanism. HT significant alleviated LPS/D-GalN-induced ALI in the mice by suppressing inflammatory. In terms of RNA-seq, HT improved the TNF, ECM-receptor interaction, and PI3K/AKT signaling pathway, and it downregulated the mRNA levels of VCAM-1, CXCL5, TNF-α and IL-6 in the liver. Mechanically, HT alleviated LPS/D-GalN in the mice by targeting TNF-α, thereby inhibiting the TNF-α/PI3K/AKT signaling pathway.
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Nanoscale
·
2024
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IF 5.8
Chenlin Zeng,Zhiyou Peng,Sida Huang,Zhijue Xu,Zhaoxi Peng,Zhaoyu Wu,Jiahao Lei,Xing Zhang,Jinbao Qin,Kaichuang Ye,Bo Li,Zhen Zhao,Ying Pan,Minyi Yin,Xinwu Lu
Atherosclerosis is the main pathogenic factor of various cardiovascular diseases. During the pathogenesis of atherosclerosis, macrophages play a major role, mainly by secreting pro-inflammatory cytokines and taking in lipids to form foam cells. Thiamine pyrophosphate (TPP) is an antagonist of the P2Y6 receptor, which is overexpressed on macrophages during atherosclerosis and facilitates the lipid phagocytosis of macrophages. However, the excessive accumulation of TPP may interfere with some vital metabolic processes like the tricarboxylic acid cycle, oxidative phosphorylation and the pentose phosphate pathway. Herein, we designed and constructed a nanoparticle ZIF-8@TPP for the treatment of atherosclerosis. The as-established ZIF-8@TPP nanoplatform exhibited specific cytotoxicity towards macrophages in vitro. Meanwhile, histological analysis confirmed the excellent therapeutic efficacy of ZIF-8@TPP in vivo. Mechanistic studies indicated that ZIF-8@TPP potentially lowered lipid phagocytosis and lipid metabolism of macrophages via the PI3K/AKT/MSR1 pathway. This study also demonstrated that the anti-atherosclerotic effect of TPP was enhanced after combination with a prototypical metal–organic framework (MOF), ZIF-8. This synergistic controlled-release drug delivery system may provide a novel idea for anti-atherosclerosis therapy by combining reagents that can inhibit lipid phagocytosis of macrophages with MOFs.
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Journal of Cardiovascular Translational Research
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2024
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IF 2.4
Hu Guangquan,Chen Jin,Chen Min,Yang Kai,Wang Yuchen,Ma Ziyang,Bao Huangxin,Ding Xiaojie
Cardiac fibrosis following myocardial infarction (MI) seriously affects the prognosis and survival rate of patients. This study aimed to determine the effect and regulation mechanism of the dedicator of cytokinesis 2 (DOCK2) during this process. Experiments were carried out in mice in vivo, and in Ang II treated cardiac fibroblasts (CFs) in vitro. DOCK2 was increased in mouse myocardial tissues after MI and Ang II-treated CFs. In MI mice, DOCK2 silencing improved cardiac function, and ameliorated cardiac fibrosis. DOCK2 knockdown suppressed the activation of CFs and decreased the expression of α-SMA, collagen I, and collagen III. Suppression of DOCK2 mitigated Ang II induced migration of CFs. DOCK2 inhibition reduced the activity of the PI3K/Akt and Wnt/β-catenin pathways, while this change could be reversed by the pathway activators, SC79 and SKL2001. In summary, DOCK2 suppression improves cardiac dysfunction and attenuates cardiac fibrosis after MI via attenuating PI3K/Akt and Wnt/β-catenin pathways.
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BIOMATERIALS
·
2024
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IF 12.8
Haixia Wang,Zheng Liu,Youqiang Fang,Xing Luo,Chunxiong Zheng,Yanteng Xu,Xiangfu Zhou,Qing Yuan,Shixian Lv,Limin Ma,Yeh-Hsing Lao,Yu Tao,Mingqiang Li
Immunotherapy through the activation of the stimulator of interferon genes (STING) signaling pathway is increasingly recognized for its robust anti-tumor efficacy. However, the effectiveness of STING activation is often compromised by inadequate anti-tumor immunity and a scarcity of primed immune cells in the tumor microenvironment. Herein, we design and fabricate a co-axial 3D-printed scaffold integrating a non-nucleotide STING agonist, SR-717, and an AKT inhibitor, MK-2206, in its respective shell and core layers, to synergistically enhance STING activation, thereby suppressing tumor recurrence and growth. SR-717 initiates the STING activation to enhance the phosphorylation of the factors along the STING pathway, while MK-2206 concurrently inhibits the AKT phosphorylation to facilitate the TBK1 phosphorylation of the STING pathway. The sequential and sustained release of SR-717 and MK-2206 from the scaffold results in a synergistic STING activation, demonstrating substantial anti-tumor efficacy across multiple tumor models. Furthermore, the scaffold promotes the recruitment and enrichment of activated dendritic cells and M1 macrophages, subsequently stimulating anti-tumor T cell activity, thereby amplifying the immunotherapeutic effect. This precise and synergistic activation of STING by the scaffold offers promising potential in tumor immunotherapy.
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Neuropsychiatric Disease and Treatment
·
2025
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IF 2.9
Yueyi Zhang,Qianqian Cai,Lingshan Wang,Bei Zhang
Background & Aims Esketamine, a promising treatment for treatment-resistant depression, has shown potential advantages over traditional antidepressants. However, its mechanisms remain unclear. This study explores how esketamine alleviates depressive behaviors through activation of the BDNF/TrkB/PI3K/AKT signaling pathway.Methods Using a Chronic Unpredictable Mild Stress (CUMS) rat model, behavioral assays (Sucrose Preference Test, Morris Water Maze Test) and histological analyses (HE and Nissl’s staining) were performed. Esketamine (5 mg/kg) treatment was administered to evaluate its antidepressant effects, and the PI3K inhibitor, PI3K-IN-6, was used to investigate the role of the PI3K/AKT pathway in the underlying mechanism.Results Esketamine treatment improved depressive behaviors, enhanced neuronal structure, and reduced apoptosis and oxidative stress. These effects were linked to the activation of the BDNF/TrkB/PI3K/AKT pathway. PI3K-IN-6 reversed the effects, confirming the pathway’s involvement.Conclusion Esketamine alleviates depressive behaviors by activating the BDNF/TrkB/PI3K/AKT signaling pathway, reducing oxidative stress and inhibiting neuronal apoptosis. These findings highlight the therapeutic potential of esketamine in treating depression, particularly in cases where traditional treatments fail.
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Drug Delivery and Translational Research
·
2025
·
IF 5.5
Xie Ruiye,Liu Zhen,Zheng Jingjing,Tan Qiwen,Wu Haitao,Liang Yong
Alzheimer’s disease (AD) is a neurodegenerative disorder strongly associated with aging, and Dauricine (DAU) has demonstrated significant neuropharmacological properties for AD treatment. However, its bioavailability is significantly limited when administered orally, leaving the mechanisms underlying its effects on AD largely unexplored. In this study, a DAU-loaded thermosensitive gel was formulated for delivery via the nasal-nerve route, and its potential to enhance the bioavailability of DAU in rat plasma and cerebrospinal fluid (CSF) was assessed through a pharmacokinetic study. The anti-Alzheimer’s disease (AD) mechanism of DAU was investigated using network pharmacology approaches, molecular docking, and dynamics simulations, complemented by in vivo experimental validation. DAU can be effectively incorporated into a thermosensitive gel and administered to the brain within 30 min via intranasal delivery. Following nasal administration, the pharmacokinetic parameters of DAU in cerebrospinal fluid and plasma were significantly elevated compared to oral administration ( ** P < 0.01), indicating a substantial improvement in bioavailability at equivalent doses. Behavioral studies demonstrated that DAU (dose of 1 mg/kg and 2 mg/kg in gel) enhanced cognitive function in intracerebroventricular-streptozotocin (ICV-STZ) rats and decelerated aging processes by reversing oxidative stress and mitigating neuronal apoptosis. Additionally, DAU contributed to lowering blood glucose levels, increasing insulin-like growth factor 1 (IGF-1) content, and reducing insulin resistance. Network pharmacological analysis, molecular docking, molecular dynamics simulations, and in vivo experiments collectively suggested that DAU exerted significant therapeutic effects on Alzheimer’s disease by inhibiting the PI3K/AKT/mTOR pathway. Our study demonstrates a significant enhancement in the bioavailability of DAU in the brain via nasal-nerve delivery route and also this research is the first to report that DAU ameliorates cognitive impairment in ICV-STZ rats through the PI3K/AKT/mTOR pathway. Our findings contribute to the scientific understanding of DAU’s potential in Alzheimer’s disease treatment and offer a novel experimental foundation for the development of anti-Alzheimer’s drugs. Graphic abstract
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