JOURNAL OF TRACE ELEMENTS IN MEDICINE AND BIOLOGY
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2019
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IF 2.895
Yiming Li,Guanhui Chen,Yi He,Xiliu Zhang,Binghui Zeng,Chao Wang,Chen Yi,Dongsheng Yu
Background Patients with metabolic bone diseases often have high risk of titanium implant failure due to compromised bone regeneration ability. Clinical evidence indicates that the poor osteogenic ability is partly because of excessive oxidative stress. To date, specific treatments for these patients are urgently needed. Ebselen, a non-toxic organoselenium compound, is reported to be a potent antioxidant agent. In this study, we hypothesized that ebselen exerted protective effects on osteogenic differentiation of bone-marrow-derived mesenchymal stem cells (BMSCs) under oxidative stress. Methods BMSCs were isolated from SD rats, and their morphology and multiple differentiation abilities were characterized. Proliferation rates of BMSCs treated with different concentrations of ebselen were analyzed. Then BMSCs were pretreated by hydrogen peroxide (H 2 O 2 ), after which ebselen at different concentrations (0, 1, 5, 10 μM) was added, alkaline phosphatase (ALP) activity, mineralization and osteogenic-related protein levels were evaluated and an optimum concentration of ebselen was selected. Subsequently, intracellular reactive oxygen species (ROS) generation and the role of the PI3K/AKT pathway were also investigated. Results Ebselen within a proper range could promote the proliferation of BMSCs. H 2 O 2 -induced oxidative stress suppressed osteogenic differentiation of BMSCs, which was verified by the decrease in ALP activity, calcium deposition, Runx2 and β-catenin expression. However, ebselen could alleviate osteogenic dysfunction of BMSCs. We also observed that ebselen reduced ROS accumulation in H 2 O 2 -pretreated BMSCs. Moreover, the pro-osteogenic effects afforded by ebselen were almost abolished by the Akt inhibitor. Conclusion We concluded that ebselen could attenuate osteogenic dysfunction of BMSCs induced by H 2 O 2 through an antioxidant effect and the activation of the PI3K/Akt pathway, suggesting that ebselen has a potential therapeutic effect for patients with metabolic bone diseases.
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Biomed Research International
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2019
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IF 2.197
Hao Lu,Hui Yao,Rong Zou,Xiwen Chen,Hanlin Xu
Renal inflammation can result in renal injury. Uric acid (UA) is the final product of purine metabolism in humans and because of the lack of urate oxidase, UA may accumulate in tissues, including kidney, causing inflammation. Galangin was isolated from a traditional Chinese medicine plant and possesses several beneficial effects, working as an anti-oxidant, anti-mutagenic, anti-tumor, anti-inflammatory, anti-microbial, and anti-viral agent. Therefore, this study aimed at investigating the molecular mechanism of galangin in the attenuation of UA induced renal inflammation in normal rat kidney epithelial cells NRK-52E. Our findings suggested that galangin treatment efficiently protected NRK-52E cells against UA induced renal inflammation by decreasing tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-18, prostaglandin E2 (PGE2), and nitric oxide (NO) release, and it inhibited nitric oxide synthase (iNOS), prostaglandin endoperoxide synthase 2 (PTGS2), TNF-α, IL-1β, and IL-18 mRNA expression. In addition, galangin was not exerting any cytotoxicity at the concentrations that were effective against inflammation as assessed by CCK8 assay. Moreover, western blotting showed that galangin treatment effectively inhibited nuclear factor-kappa B (NF-κB), phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) and nucleotide-binding domain- (NOD-) like receptor protein 3 (NLRP3) signaling pathway activation. Taken together, these findings suggested that galangin plays a pivotal role in renal inflammation by suppressing inflammatory responses, which might be closely associated with the inhibition of NLRP3 inflammasome, NF-κB and PI3K/AKT signaling pathway activation.
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CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY
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2018
·Vol. 46
·期 4
·389-397
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IF 2.092
Hao Yuan,Hongyan Zhao,Jiafeng Wang,Hong Zhang,Lihua Hong,He Li,Hongze Che,Zhimin Zhang
Summary Pulpitis suppressed the level of let-7c-5p that promotes osteogenesis and bone formation by repressing HMGA2. In the current study, the function of let-7c-5p in the inflammation and osteogenesis in dental pulp stem cells (DPSCs) was explored. The level of let-7c-5p in DPSCs was up-regulated, and the cells were subjected to lipopolysaccharide (LPS) to induce inflammation. The effect of let-7c-5p on cell proliferation potential, osteogenic differentiation potential, and activity of HMGA2/PI3K/Akt pathway was detected. The administration of LPS suppressed the cell proliferation of DPSCs and suppressed calcium deposition, activity of alkaline phosphatase (ALP), and levels of OCN, OPN, OSX, MSX2, and RUNX2 in inflamed DPSCs. The impaired osteogenic differentiation of inflamed DPSCs was associated with the increased levels of HMGA2, p-PI3K, and p-Akt. In let-7c-5p-overexpressed inflamed DPSCs, the proliferation and osteogenic differentiation potential of DPSCs were restored, and the activation of HMGA2/PI3K/Akt signalling was inhibited. In rat pulpitis models, the injection of let-7c-5p agomir restored the osteogenic differentiation potential of dental pulp cells and inhibited HMGA2/PI3K/Akt signalling. The findings demonstrated the anti-inflammation and pro-osteogenesis effect of let-7c-5p during the attack of pulpitis, which depended on the inhibition of HMGA2/PI3K/Akt signalling.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2018
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IF 3.909
Wan Li,Zheng-Nan Cai,Shomaila Mehmood,Ya Wang,Wen-Juan Pan,Wen-Na Zhang,Yong-Ming Lu,Yan Chen
Oxidative stress is considered to involve cell death in severe pulmonary diseases like idiopathic pulmonary fibrosis (IPF). Polysaccharide FMP-1 from Morchella esculenta can exert significant antioxidant activity. However, its effects on alveolar epithelial cells remain unperceived. Herein, the effects of FMP-1 against H 2 O 2 -induced oxidative damage in human alveolar epithelial A549 cells were investigated. FMP-1 could inhibit H 2 O 2 -induced cytochrome C and Caspase-3 release to prevent cell apoptosis via attenuation of MDA and ROS levels, and enhancement the enzymatic activities of SOD and T-AOC. Furthermore, the underlying molecular mechanisms were clarified. The phosphorylation of AKT and the nuclear translocation of Nrf2 were observed to be promoted by FMP-1 as well as the level of HO-1. These findings suggested that FMP-1 attenuate cellular oxidative stress through PI3K/AKT pathway, and FMP-1 could be explored as natural potential antioxidants to lower oxidative stress relevant to the progression of IPF.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2018
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IF 3.118
Yan-dan Zhou,Jin-gang Hou,Wei Liu,Shen Ren,Ying-ping Wang,Rui Zhang,Chen Chen,Zi Wang,Wei Li
Although ginsenoside Rg3 was isolated as a major component of Korea red ginseng and confirmed to exert potential hepatoprotective effect on acetaminophen (APAP)-induced liver injury via induction of glutathione S-transferase (GST) in vitro, the in vivo hepatoprotective effect of Rg3 and the underlying molecular mechanism of action remain unclear. The current study was aimed to explore whether 20( R )-Ginsenoside Rg3 (20( R )-Rg3) could alleviate acetaminophen-induced liver injury in mice and to determine the involvement of PI3K/AKT signaling pathway . Our findings demonstrated that a single injection of APAP (250 mg/kg) increased the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β); such increases were attenuated by pretreatment of mice with 20( R )-Rg3 for seven days. The depletion of glutathione (GSH), generation of malondialdehyde (MDA) and the over expression of cytochrome P450 E1 (CYP2E1) and 4-hydroxynonenal (4-HNE) caused by APAP exposure were also inhibited by 20( R )-Rg3 pretreatment. Moreover, 20( R )-Rg3 pretreatment significantly alleviated APAP-induced apoptosis , necrosis, and inflammatory infiltration in liver tissues. Importantly, 20( R )-Rg3 effectively attenuated APAP-induced liver injury in part via activating PI3K/AKT signaling pathway. In summary, 20( R )-Rg3 exerted liver protection against APAP-caused hepatotoxicity evidenced by inhibition of oxidative stress and inflammatory response, alleviation of hepatocellular necrosis and apoptosis via activation of PI3K/AKT signaling pathway, showing potential as a novel therapeutic agent to prevent liver damage.
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APOPTOSIS
·
2017
·Vol. 22
·期 5
·672-680
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IF 3.833
Liu Shumin,Sun Zhengwu,Chu Peng,Li Hailong,Ahsan Anil,Zhou Ziru,Zhang Zonghui,Sun Bin,Wu Jingjun,Xi Yalin,Han Guozhu,Lin Yuan,Peng Jinyong,Tang Zeyao
Homocysteine (Hcy) induced vascular endothelial injury leads to the progression of endothelial dysfunction in atherosclerosis. Epigallocatechin gallate (EGCG), a natural dietary antioxidant, has been applied to protect against atherosclerosis. However, the underlying protective mechanism of EGCG has not been clarified. The present study investigated the mechanism of EGCG protected against Hcy-induced human umbilical vein endothelial cells (HUVECs) apoptosis. Methyl thiazolyl tetrazolium assay (MTT), transmission electron microscope, fluorescent staining, flow cytometry, western blot were used in this study. The study has demonstrated that EGCG suppressed Hcy-induced endothelial cell morphological changes and reactive oxygen species (ROS) generation. Moreover, EGCG dose-dependently prevented Hcy-induced HUVECs cytotoxicity and apoptotic biochemical changes such as reducing mitochondrial membrane potential (MMP), decreasing Bcl-2/Bax protein ratio and activating caspase-9 and 3. In addition, EGCG enhanced the protein ratio of p-Akt/Akt, endothelial nitric oxide synthase (eNOS) activation and nitric oxide (NO) formation in injured cells. In conclusion, the present study shows that EGCG prevents Hcy-induced HUVECs apoptosis via modulating mitochondrial apoptotic and PI3K/Akt/eNOS signaling pathways. Furthermore, the results indicate that EGCG is likely to represent a potential therapeutic strategy for atherosclerosis associated with Hyperhomocysteinemia (HHcy).
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Molecular Medicine Reports
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2016
·Vol. 14
·期 1
·904-910
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IF 1.559
Liandi Xie,Yang Wu,Zongjing Fan,Yang Liu,Jixiang Zeng
In the present study, the mechanisms associated with the Astragalus polysaccharide (APS)-mediated protection of human cardiac microvascular endothelial cells (HCMEC) against hypoxia/reoxygenation (HR) injury were investigated. Pretreatment of HCMECs with APS at various concentrations was performed prior to Na2S2O4-induced HR injury. Subsequently, cell viability and apoptosis were measured by MTT and Hoechst assays, respectively. The viability of HCMECs was reduced by Na2S2O4 and apoptosis was enhanced; however, cell viability was observed to be increased by APS via inhibition of apoptosis. Additionally, intracellular reactive oxygen species (ROS), Ca2+, nitric oxide (NO), malondialdehyde (MDA), superoxide dismutase (SOD), phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT), B‑cell lymphoma‑2 (Bcl‑2), Bcl‑2 associated X protein (Bax) and caspase‑3 were measured using detection kits or western blot analysis. In HCMECs with HR injury, the levels of ROS and Ca2+, MDA and Bax expression levels, and the activity of caspase‑3 were elevated. By contrast, the level of NO, the protein expression levels of SOD, Bcl‑2 and PI3K, and the phosphorylation of AKT were decreased. However, compared with the HR group, the effects of HR injury were significantly reduced by APS, with APS providing a protective effect on HCMECs, particularly at higher doses. The current study concluded that APS protects HCMECs from Na2S2O4‑induced HR injury by reducing the levels of ROS, Ca2+, MDA and Bax, inhibiting the activity of caspase‑3, and enhancing the levels of NO, SOD, Bcl‑2, PI3K and phosphorylated AKT. These results may provide an insight into the clinical application of APS and novel therapeutic strategies for HR injury.
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CELLULAR SIGNALLING
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2024
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IF 4.4
Xin Chen,Liming Yu,Shan Meng,Jikai Zhao,Xinyi Huang,Zhishang Wang,Zijun Zhou,Yuting Huang,Tao Hong,Jinfeng Duan,Tong Su,Zijun Cao,Yanbang Chi,Tao Huang,Huishan Wang
Inflammation and infiltration of immune cells are intricately linked to the pathogenesis of atrial fibrillation (AF). Triggering receptor expressed on myeloid cells-1 (TREM-1), an enhancer of inflammation, is implicated in various cardiovascular disorders. However, the precise role and potential mechanisms of TREM-1 in the development of AF remain ambiguous. Atrial samples from patients with AF were used to assess the expression levels of TREM-1. An angiotensin II (Ang II)-induced AF mouse model was established to assess the functionality of TREM-1. Cardiac function and AF inducibility were assessed through echocardiography, programmed transvenous cardiac pacing, and atrial electrophysiological mapping. Peripheral blood and atrial inflammatory cells were assessed using flow cytometry. Using histology, bulk RNA sequencing, biochemical analyses, and cell cultures, the mechanistic role of TREM-1 in AF was elucidated. TREM-1 expression was upregulated and co-localized with macrophages in the atria of patients with AF. Pharmacological inhibition of TREM-1 decreased Ang II-induced atrial enlargement and electrical remodeling. TREM-1 inhibition also ameliorated Ang II-induced NLRP3 inflammasome activation, inflammatory factor release, atrial fibrosis, and macrophage infiltration. Transcriptomic analysis revealed that TREM-1 modulates Ang II-induced inflammation through the PI3K/AKT/FoxO3a signaling pathway. In vitro studies further supported these findings, demonstrating that TREM-1 activation exacerbates Ang II-induced inflammation, while overexpression of FoxO3a counteracts this effect. This study discovered the critical role of TREM-1 in the pathogenesis of AF and its underlying molecular mechanisms. Inhibition of TREM-1 provides a new therapeutic strategy for the treatment of AF.
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FEBS Open Bio
·
2024
·
IF 2.8
Linqian Chen,Meifeng Chen,Yan Xie,Yuyan Zhang,Shutian Mo,Yongfei He,Tianyi Liang,Yuan Liao,Renbin Huang,Guodong Huang,Chuangye Han,Thi Thai Hoa Pham
Several studies have suggested a potential antitumor effect of 2-dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (DMDD). To further understand the mechanism of action of this compound, we investigated its effect on the phosphatidylinositol-3-kinase (PI3K)/serine–threonine kinase (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. We show that DMDD application significantly inhibited the proliferation of breast cancer cell lines MDA-MB-231 and ER-α positive MCF-7. Furthermore, DMDD application resulted in increased intracellular reactive oxygen species (ROS) levels, apoptosis and autophagy, whereas it downregulated the expression of PI3K, Akt and mTOR mRNA and proteins, and increased the expression of LC3II/I and p62 proteins. In a mouse breast cancer xenograft model, DMDD inhibited tumor growth. Expression analyses suggest that ROS levels were higher in DMDD treated tumor tissues, whereas immunohistochemical analyses suggest that apoptotic cells were more prevalent in the DMDD treated group compared to the control group. Taken together, our results suggest that the molecular mechanism of action of DMDD may involve the enhancement of breast cancer autophagy through the PI3K/Akt/mTOR signaling pathway by mediating ROS expression.
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Journal of Inflammation Research
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2025
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IF 4.1
Haiou Wang,Wenkang Huang,Xiaoya Pan,Meizi Tian,Jiahui Chen,Xiaotong Liu,Qin Li,Jianhua Qi,Yiping Ye,Lijuan Gao
Purpose To explore the protective effect and underlying mechanism of Quzhou Aurantii Fructus flavonoids (QAFF) on Ulcerative colitis (UC).Methods The constituents of QAFF were accurately determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The therapeutic impacts of QAFF were assessed in dextran sulfate sodium (DSS)-induced UC mice, focusing on the changes in body weight, disease activity index (DAI), colon length, histological assessment of colonic tissues, levels of pro-inflammatory cytokines, and expression of tight junction proteins. Western blotting confirmed key regulatory proteins within the differential signaling pathways, guided by transcriptome analysis. Additionally, the influence of QAFF on the gut microbiome was explored through 16S ribosomal RNA (rRNA) sequencing. The alterations in endogenous metabolites were detected by untargeted metabolomics, and their potential correlation with intestinal flora was then examined utilizing Spearman correlation analysis. Subsequently, the regulation of gut microbiome by QAFF was validated by fecal microbiota transplantation (FMT).Results Eleven flavonoids, including Naringin and hesperidin, were initially identified from QAFF. In vivo experiments demonstrated that QAFF effectively ameliorated colitis symptoms, reduced IL-6, IL-1β, and TNF-α levels, enhanced intestinal barrier integrity, and downregulated PI3K/AKT pathway activation. Furthermore, QAFF elevated the levels of beneficial bacteria like Lachnospiraceae_NK4A136_group and Alloprevotella and concurrently reduced the pathogenic bacteria such as Escherichia-Shigella, [Eubacterium]_siraeum_group, and Parabacteroides. Metabolomics analysis revealed that 34 endogenous metabolites exhibited significant alterations, predominantly associated with Glycerophospholipid metabolism. These metabolites were significantly correlated with those differential bacteria modulated by QAFF. Lastly, the administration of QAFF via FMT ameliorated the colitis symptoms.Conclusion QAFF could ameliorate inflammatory responses and intestinal barrier dysfunction in DSS-induced UC mice probably by modulating the PI3K/AKT signaling pathway and gut microbiome, offering promising evidence for the therapeutic potential of QAFF in UC treatment.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Ye Wang,Shao-jie Chen,Ting Ma,Qiu Long,Lan Chen,Ke-xin Xu,Yu Cao
Melanoma is a skin cancer originating from melanocytes. The global incidence rate of melanoma is rapidly increasing, posing significant public health challenges. Identifying effective therapeutic agents is crucial in addressing this growing problem. Natural products have demonstrated promising anti-tumor activity. In this study, a plant flavonoid, taxifolin, was screened using Weighted Correlation Network Analysis (WGCNA) in combination with the Connectivity Map (CMAP) platform. Taxifolin was confirmed to inhibit the proliferation, migration, and invasion ability of melanoma A375 and MV-3 cells by promoting apoptosis. Additionally, it suppressed the Epithelial-Mesenchymal Transition (EMT) process of melanoma cells. Cyber pharmacological analysis revealed that taxifolin exerts its inhibitory effect on melanoma through the PI3K/AKT signaling pathway, specifically by downregulating the protein expression of p-PI3K and p-AKT. Notably, the addition of SC-79, an activator of the PI3K/AKT signaling pathway, reversed the effects of taxifolin on cell migration and apoptosis. Furthermore, in vivo experiments demonstrated that taxifolin treatment slowed tumor growth in mice without significant toxic effects. Based on these findings, taxifolin holds promise as a potential drug for melanoma treatment.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
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IF 4.7
Wenyang Zhou,Zhenhao Liu,Xichuan Qiu,Minghao Tian,Baoqiang He,Chao Tang,Qiang Tang,Rupei Ye,Dejun Zhong,Yehui Liao
Following spinal cord injury (SCI), pyroptosis plays a significant role in regulating neuroinflammation during the secondary phase of injury. Although 1,8-cineole possesses anti-inflammatory effects, its role in SCI and underlying molecular mechanisms remains unclear. This study revealed that 1,8-cineole promoted motor function recovery in spinal cord-injured rats, reduced NLRP3 inflammasome-mediated microglial pyroptosis and activation, enhanced neuronal regeneration, and suppressed neuronal apoptosis and glial scar formation. Network pharmacology analysis showed that 1,8-cineole targets the PI3K/AKT and P38 MAPK pathways to inhibit microglial activation and pyroptosis. Finally, using a conditional co-culture system, we demonstrated that 1,8-cineole-treated microglia facilitated neuronal regeneration while inhibiting apoptosis. These findings indicate that 1,8-cineole promotes functional recovery post-SCI by protecting neurons by suppressing microglial pyroptosis and activation through the PI3K/AKT and P38 MAPK axes.
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