Drug Design Development and Therapy
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2022
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IF 4.319
Lei Lei,Jing Zhao,Xue-Qi Liu,Juan Chen,Xiang-Ming Qi,Ling-Ling Xia,Yong-Gui Wu
Introduction Kidney tubular epithelial injury is one of the key factors in the progression of diabetic nephropathy (DN). Wogonin is a kind of flavonoid, which has many pharmacological effects, such as anti-inflammation, anti-oxidation and anti-fibrosis. However, the effect of wogonin in renal tubular epithelial cells during DN is still unknown.Materials and Methods STZ-induced diabetic mice were given doses of wogonin (10, 20, and 40 mg/kg) by intragastric administration for 16 weeks. The metabolic indexes from blood and urine and pathological damage of renal tubules in mice were evaluated. Human tubular epithelial cells (HK-2) were cultured in high glucose (HG) condition containing wogonin (2μM, 4μM, 8μM) for 24 h. Tubular epithelial cell inflammation and autophagic dysfunction both in vivo and in vitro were assessed by Western blot, qRT-PCR, IHC, and IF analyses.Results The treatment of wogonin attenuated urinary albumin and histopathological damage in tubulointerstitium of diabetic mice. We also found that wogonin down-regulated the expression of pro-inflammatory cytokines and autophagic dysfunction in vivo and in vitro. Molecular docking and Cellular Thermal Shift Assay (CETSA) results revealed that mechanistically phosphoinositide 3-kinase (PI3K) was the target of wogonin. We then found that inhibiting PI3K eliminated the protective effect of wogonin. Wogonin regulated autophagy and inflammation via targeting PI3K, the important connection point of PI3K/Akt/NF-κB signaling pathway.Conclusion Our study is the first to demonstrate the novel role of wogonin in mitigating tubulointerstitial fibrosis and renal tubular cell injury via regulating PI3K/Akt/NF-κB signaling pathway-mediated autophagy and inflammation. Wogonin might be a latent remedial drug against tubular epithelial injury in DN by targeting PI3K.
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Chinese Medicine
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2022
·Vol. 17
·期 1
·1-21
·
IF 4.546
Huang Qianqian,Zhang Chen,Dong Shi,Han Junwen,Qu Sihao,Xie Tianshu,Zhao Haibin,Shi Yuanyuan
Background Alzheimer's Disease (AD) is a serious neurodegenerative disease and there is currently no effective treatment for AD progression. The use of TCM as a potential treatment strategy for AD is an evolving field of investigation. Asafoetida (ASF), an oleo-gum-resin isolated from Ferula assa-foetida root, has been proven to possess antioxidative potential and neuroprotective effects, which is closely associated with the neurological disorders. However, the efficacy and further mechanisms of ASF in AD experimental models are still unclear. Methods A cognitive impairment of mouse model induced by scopolamine was established to determine the neuroprotective effects of ASF in vivo , as shown by behavioral tests, biochemical assays, Nissl staining, TUNEL staining, Immunohistochemistry, western blot and qPCR. Furthermore, the PC12 cells stimulated by H 2 O 2 were applied to explore the underlying mechanisms of ASF-mediated efficacy. Then, the UPLCM analysis and integrated network pharmacology approach was utilized to identified the main constitutes of ASF and the potential target of ASF against AD, respectively. And the main identified targets were validated in vitro by western blot, qPCR and immunofluorescence staining. Results In vivo , ASF treatment significantly ameliorated cognitive impairment induced by scopolamine, as evidenced by improving learning and memory abilities, and reducing neuronal injury, cholinergic system impairment, oxidative stress and apoptosis in the hippocampus of mice. In vitro , our results validated that ASF can dose-dependently attenuated H 2 O 2 -induced pathological oxidative stress in PC12 cells by inhibiting ROS and MDA production, as well as promoting the activities of SOD, CAT, GSH. We also found that ASF can significantly suppressed the apoptosis rate of PC12 cells increased by H 2 O 2 exposure, which was confirmed by flow cytometry analysis. Moreover, treatment with ASF obviously attenuated H 2 O 2 -induced increase in caspase-3 and Bax expression levels, as well as decrease in Bcl-2 protein expression. KEGG enrichment analysis indicated that the PI3K/Akt/GSK3β/Nrf2 /HO-1pathway may be involved in the regulation of cognitive impairment by ASF. The results of western blot, qPCR and immunofluorescence staining of vitro assay proved it. Conclusions Collectively, our work first uncovered the significant neuroprotective effect of ASF in treating AD in vivo . Then, we processed a series of vitro experiments to clarify the biological mechanism action. These data demonstrate that ASF can inhibit oxidative stress induced neuronal apoptosis to foster the prevention of AD both in vivo and in vitro , and it may exert the function of inhibiting AD through PI3K/Akt/GSK3β/Nrf2/HO-1pathway.
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BONE
·
2022
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IF 4.626
Abdusami Abdurahman,Xinle Li,Jie Li,Daquan Liu,Lidong Zhai,Xuetong Wang,Yifan Zhang,Yao Meng,Hiroki Yokota,Ping Zhang
Bone vasculature influences osteogenesis and haematopoiesis in the bone microenviroment. Mechanical loading has been shown to stimulate the formation of osteogenesis-related type H vessels in an ovariectomy (OVX)-induced osteoporosis mouse model. To determine the loading-driven mechanism of angiogenesis and the formation of type H vessels in bone, we evaluated the roles of PI3K/Akt signaling and erythropoiesis in the bone marrow . The daily application of mechanical loading (1 N at 5 Hz for 6 min/day) for 2 weeks on OVX mice inhibited osteoclast activity , associated with an increase in the number of osteoblasts and trabecular volume ratio. Mechanical loading enhanced bone vasculature and vessel formation, as well as PI3K/Akt phosphorylation and erythropoiesis in the bone marrow. Notably, LY294002 , an inhibitor of PI3K signaling, blocked the tube formation by endothelial progenitor cells , as well as their migration and wound healing. The conditioned medium, derived from erythroblasts , also promoted the function of HUVECs with elevated levels of VEGF, CD31 , and Emcn. Collectively, this study demonstrates that mechanical loading prevents osteoporotic bone loss by promoting angiogenesis and type H vessel formation. This load-driven preventing effect is in part mediated by PI3K/Akt signaling and erythropoiesis in the bone marrow.
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JOURNAL OF ETHNOPHARMACOLOGY
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2021
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IF 4.36
Li-na Ji,Shan Wu,Dan-qing Fu,Si-jia Fang,Guan-qun Xie,Yong-sheng Fan,Jie Bao
Ethnopharmacological relevance Jieduquyuziyin prescription (JP) is a traditional Chinese medicine (TCM) formula. According to both TCM theory and more than a decade of clinical practice, JP has been testified to be effective for systemic lupus erythematosus (SLE) treatment as an approved hospital prescription in China. Aim of the study To determine the effect of JP on the treatment of SLE by glucocorticoid (GC) and to further examine the molecular mechanisms. Materials and methods We conducted in vivo experiments to estimate the effect of JP on hepatic gluconeogenesis in MRL/lpr mice treated with GC. Additionally, isoproterenol (ISO) induced hepatic gluconeogenesis model and GC-treated MRL/lpr mouse hepatocytes were carried out in vitro experiments to verify the effect of JP on gluconeogenesis. Results The results showed that JP combined with GC could effectively alleviate the lupus symptoms in MRL/lpr mice and improve the pathological changes of the kidney and liver. And the combination of JP reduced the side effects caused by GC, which was related to the inhibition of GC-induced hepatic gluconeogenesis in MRL/lpr mice. Specifically, JP up-regulated the expression of glucocorticoid receptor (GR) α, phosphoinositide-3-kinase (PI3K) and Akt restrained by GC to reduce the production of forkhead box O1 (FoxO1), peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), and the gluconeogenic genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). In viv o, the use of JP either alone or with GC could reduce spleen enlargement , high levels of serum antibodies, aggravated urine protein and renal pathological damage in MRL/lpr mice. Furthermore, the glucose content was reduced in the liver of MRL/lpr mice treated with JP, and the liver damage and steatosis were also alleviated. In vitro , the expressions of PI3K and Akt increased and the expressions of FoxO1, PGC-1α, PEPCK and G6Pase decreased after JP treatment in ISO-treated hepatocytes. Compared with MRL/MP mice, we found that JP could significantly inhibit the expression of gluconeogenesis in the hepatocytes of MRL/lpr mice induced by GC to a greater extent. Conclusions The therapeutic effect of JP on GC-induced is likely related to hepatic gluconeogenesis, which provides a new perspective to reveal the positive role of JP in SLE.
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Photodiagnosis and Photodynamic Therapy
·
2018
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IF 2.895
Kunpeng Wang,Zijian Zhang,Kai Liu,Xin Yang,Heng Zou,Jiangjiao Zhou,Xiongying Miao,Wei Chen,Li Xiong,Yu Wen
Background Inflammatory bowel disease (IBD) is a group of inflammatory conditions characterized by chronic inflammation of the gastrointestinal (GI) tract. Recent preclinical and clinical studies have shown the therapeutic value of photodynamic therapy with low doses of photosensitizer and/or light in colitis treatment, but the detailed mechanism is unclear. Methods We examined 5-aminolevulinic acid (5-ALA) mediated photodynamic therapy (PDT) in dextran sulfate sodium (DSS)-induced colitis in mice. Endoscopic and macroscopic observations as well as the Disease Activity Index score (DAI) was used to monitor the disease. Cytokine expression was measured by quantitative RT-PCR analysis to evaluate the efficacy of PDT. We applied the Clariom™ D bioinformatics analysis to investigate the differentially expressed genes after PDT. Finally, we used quantitative RT-PCR analysis and Western blotting to validate the targets of differentially expressed genes. Results 5-ALA-PDT improved the DAI score and decreased the expression of various inflammatory cytokines. The Clariom™ D bioinformatics analysis identified 2043 diff ;erentially expressed genes (702 up-regulated and 1341 down-regulated). We confirmed the down-regulation of lncRNA-Neat1, lncRNA-Snhg5 and lncRNA-Gm9926 and the up-regulation of miRNA-204-5p, miRNA-218-5p, miRNA-200a-3p and miRNA-466h-5p. Additionally, the decreased expression level of the AKT3, p-AKT3, PI3K, p-PI3K protein were confirmed. Conclusions This study provides in vivo comprehensive lncRNA and miRNA microarray analysis after 5-ALA-PDT treatment in DSS-induced colitis, and it may help to develop novel lncRNA-miRNA-related therapeutic approaches, such as the Neat1-miRNA204-5p-PI3K-AKT axis, to further increase the efficiency of PDT in IBD.
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FOOD AND CHEMICAL TOXICOLOGY
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2023
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IF 4.3
Eun-Ji Han,Eun-Young Choi,Su-Ji Jeon,Sang-Woo Lee,Jun-Mo Moon,Soo-Hyun Jung,Bumseok Kim,Sung-Dae Cho,Jeong-Seok Nam,Changsun Choi,Jeong-Hwan Che,Ji-Youn Jung
Natural products are continuously being researched to develop safe and effective treatment options for cervical cancer , the fourth most common cancer in women. Piperlongumine (PL), an amide alkaloid mainly present in long pepper , exhibits neuroprotective and anti-cancer properties. However, the specific effect of PL in cervical cancer and the relationship between the anti-cancer pathway and autophagy remain unclear. Therefore, we aimed to investigate PL-induced apoptosis in KB human cervical cancer cells and the relationship between apoptosis and autophagy therein. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and wound-healing assays showed that PL treatment suppressed KB cell viability and proliferation. Apoptosis was identified through 4′,6-diamidino-2-phenylindole and annexin V-propidium iodide staining, increased cleaved-poly (ADP-ribose) polymerase and Bcl-2 associated X levels, and decreased B cell lymphoma 2 levels. Acridine orange staining and increased microtubule-associated protein 1A/1B-light chain 3-II and Beclin-1 levels confirmed autophagy. We determined that KB cell-related autophagy exerted cytoprotective effects using the autophagy inhibitors 3-methyladenine and hydroxychloroquine . PL treatment promoted apoptosis by inhibiting the phosphatidylinositol-3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin pathway in KB cells; inhibiting the pathway using PI3K inhibitors increased autophagy. We suggest that PL is a potential natural anticancer agent for cervical cancer treatment.
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RSC Advances
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2018
·Vol. 8
·期 43
·24470-24476
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IF 2.936
Xiaofang Chen,Jianyang Tan,Lu Zhang,Yonggang Liu,Yahong Cheng,Qianying Zhang,Hong Ding
The abuse of fructose in daily diet may cause cardiovascular diseases that seriously threaten human health, and both safe and efficient solutions need to be developed. We investigated whether apigenin can prevent the harmful impact of excessive fructose on cardiovascular events. Based on the reduction of percentage of body fat and systolic pressure as well as the improvements in insulin resistance, lipid metabolism, and pathological injury to the thoracic aorta, we suggested that high levels of fructose cause vascular injury and metabolic disorders, which can be improved to some extent by using apigenin. Fundamentally, apigenin down-regulates levels of phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and glucose transporter 1 (GLUT1), which increase with high concentrations of fructose. Moreover, the inflammation and asymmetric dimethylarginine (ADMA) levels increased in fructose group, but they decreased when the rats were fed with apigenin. The results suggest that PI3K/AKT/GLUT1 may have potential for alleviating cardiovascular injury, and apigenin can be an excellent candidate for supplements to ameliorate cardiovascular diseases related to high fructose consumption.
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Evidence-based Complementary and Alternative Medicine
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2016
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IF 1.931
Ke Fang,Hui Dong,Shujun Jiang,Fen Li,Dingkun Wang,Desen Yang,Jing Gong,Wenya Huang,Fuer Lu
To determine the effects and the underlying mechanism of diosgenin (DSG) and 5-methoxypsoralen (5-MOP), two main active components in the classical Chinese prescription Hu-Lu-Ba-Wan (HLBW), on insulin resistance, HepG2 cells were incubated in medium containing insulin. Treatments with DSG, 5-MOP, and their combination were performed, respectively. The result showed that the incubation of HepG2 cells with high concentration insulin markedly decreased glucose consumption and glycogen synthesis. However, treatment with DSG, 5-MOP, or their combination significantly reversed the condition and increased the phosphorylated expression of estrogen receptor-α (ERα), sarcoma (Src), Akt/protein kinase B, glycogen synthase kinase-3β (GSK-3β), and the p85 regulatory subunit of phosphatidylinositol 3-kinase p85 (PI3Kp85). At the transcriptional level, expression of the genes mentioned above also increased except for the negative regulation of GSK-3β mRNA. The increased expression of glucose transport-4 (GLUT-4) was meanwhile observed through immunofluorescence. Nevertheless, the synergistic effect of DSG and 5-MOP on improving glycometabolism was not obvious in the present study. These results suggested that DSG and 5-MOP may improve insulin resistance through an ER-mediated PI3K/Akt activation pathway which may be a new strategy for type 2 diabetes mellitus, especially for women in an estrogen-deficient condition.
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MOLECULAR PHARMACEUTICS
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2017
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IF 4.44
Yiyue Wang,Jing Li,Jing Jing Chen,Xuan Gao,Zun Huang,Qi Shen
The polylactic-co-glycolic acid polyethylene glycol conjugated with cell penetrating peptide R7 (PLGA–PEG-R7)/polysulfadimethoxine-folate nanoparticles loaded with docetaxel (DTX) and GDC0941 (R7/PSD-Fol NPs) were prepared to overcome multidrug resistance (MDR) and enhance the antitumor activity. First, polysulfadimethoxine-folate was synthesized to construct the R7/PSD-Fol NPs. The R7/PSD-Fol NPs were prepared with the abilities of effective entrapment and drug loading. Due to the pH-sensitive effect of PSD-folate, the releasing of DTX and GDC0941 from the R7/PSD-Fol NPs was lower in pH 7.4 buffer solution than that in pH 5.0 buffer solution. The half maximal inhibitory concentration (IC50) of MCF-7 and resistant to doxorubicin (MCF-7/Adr) cells illustrated the cytotoxicity of R7/PSD-Fol nanoparticles by using the MTT method. The uptake of R7/PSD-Fol NPs was visualized by using the fluorescence of Rh-123 to detect the targeting effect of folate on the surface of R7/PSD-Fol NPs. The results of the cell apoptosis and the depolarization of mitochondrial membrane potential (MMP) were adopted to show the cytotoxicity of the R7/PSD-Fol NPs on MCF-7/Adr cells. The Western blot revealed the inhibition of PI3K/Akt pathway in MCF-7/Adr cells induced by R7/PSD-Fol NPs. Finally, both in vivo distribution and in vivo antitumor showed the R7/PSD-Fol NPs displayed the better distribution at tumor site and the stronger suppression of tumor growth in the tumor bearing nude mice compared with control group. It was concluded that R7/PSD-Fol NPs loaded with DTX and GDC0941 could overcome MDR and enhance the antitumor effect further.
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CHEMISTRY & BIODIVERSITY
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2025
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IF 2.5
Shao-Jun Zheng,Xiao-Han Diao,Xiao-Yan Gao,Nai-Dong Chen
Dendrobium officinale polysaccharides (DOP) exhibit anticancer potential against colorectal cancer (CRC), yet their mechanisms remain unclear. This study investigated DOP's effects on HCT-116 cells. DOP dose- and time-dependently inhibited proliferation and induced apoptosis, evidenced by elevated cleaved caspase-3/-9, poly ADP-ribose polymerase (PARP), Bax, and reduced Bcl-2. Concurrently, DOP activated autophagy (increased LC3-II/I, Beclin-1; decreased p62) via phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) suppression. Combining DOP with the autophagy inhibitor chloroquine enhanced apoptosis (higher cleaved PARP, Bax; lower Bcl-2) and reactivated PI3K/Akt/mTOR signaling. These findings demonstrate DOP inhibits CRC by dual induction of apoptosis and autophagy blockade through PI3K/Akt/mTOR inhibition, with autophagy suppression synergistically augmenting apoptosis. The study highlights DOP's translational potential as a functional food or adjuvant therapy, proposing a novel combinatorial strategy for CRC treatment. Graphical Dendrobium officinale polysaccharides (DOP) inhibit HCT-116 colorectal cancer cell proliferation and induce apoptosis by upregulating cleaved caspase-3/-9, PARP, and Bax while downregulating Bcl-2. DOP activates autophagy via PI3K/Akt/mTOR inhibition. Combining DOP with chloroquine enhances apoptosis, revealing autophagy blockade as a synergistic anticancer mechanism.
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Discover Oncology
·
2024
·Vol. 15
·期 1
·1-13
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IF 2.8
Lei Ruiwen,Yao Chaoling,Huang Renfeng,Wu Wanming,Ou Linyang,Yang Chuansheng
To investigate the effects of higher cellular stanniocalcin 2 (STC2) on suppressing the migration and invasion but promoting the apoptosis of triple-negative breast cancer (TNBC). STC2 in TNBC and the para-carcinoma tissues were analyzed by immunohistochemistry (IHC), while the mRNA level was measured by qPCR. Over-expressing or silencing STC2 was established in MDA-MB-231 cells. Epithelial mesenchymal transition (EMT) related proteins, cell migration, invasion, proliferation and apoptosis were detected. MDA-MB-231 with over-expressing or silencing STC2 were injected into nude mice to formatting tumors, and then EMT related proteins were measured by IHC. Lower STC2 expressed in TNBC tissues than in the para-carcinoma tissues. Silencing STC2 promoted EMT of TNBC cell MDA-MB-231, as well as cell migration, invasion and proliferation, but suppressed MDA-MB-231 apoptosis, while over-expressing STC2 had the opposite results, which might be related to PKC/PI3K/AKT/mTOR pathway. STC2 was the protective gene in TNBC, by suppressing migration and invasion to inhibit MDA-MB-231 cell EMT but promote cell apoptosis, in order to suppress TNBC progression.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
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2024
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IF 4.2
Chaojin Si,Hongjun Yang,Xiaoyan Wang,Qiaoxin Wang,Min Feng,Huayue Li,Yuqi Feng,Jiayuan Zhao,Ying Liao
Beta-cypermethrin (β-CYP) consists of four chiral isomers, acting as an environmental estrogen and causing reproductive toxicity, neurotoxicity, and dysfunctions in multiple organ systems. This study investigated the toxic effects of β-CYP, its isomers, metabolite 3-phenoxybenzoic acid (3-PBA), and 17β-estradiol (E2) on HTR-8/SVneo cells. We focused on the toxic mechanisms of β-CYP and its specific isomers. Our results showed that β-CYP and its isomers inhibit HTR-8/SVneo cell proliferation similarly to E2, with 100 μM 1S-trans-αR displaying significant toxicity after 48 h. Notably, 1S-trans-αR, 1R-trans-αS, and β-CYP were more potent in inducing apoptosis and cell cycle arrest than 1R-cis-αS and 1S-cis-αR at 48 h. AO/EB staining and flow cytometry indicated dose-dependent apoptosis in HTR-8/SVneo cells, particularly at 100 μM 1R-trans-αS. Scratch assays revealed that β-CYP and its isomers variably reduced cell migration. Receptor inhibition assays demonstrated that post-ICI 182780 treatment, which inhibits estrogen receptor α (ERα) or estrogen receptor β (ERβ), β-CYP, its isomers, and E2 reduced HTR-8/SVneo cell viability, whereas milrinone, a phosphodiesterase 3 A (PDE3A) inhibitor, increased viability. Molecular docking studies indicated a higher affinity of β-CYP, its isomers, and E2 for PDE3A than for ERα or ERβ. Consequently, β-CYP, its isomers, and E2 consistently led to decreased cell viability. Transcriptomics and RT-qPCR analyses showed differential expression in treated cells: up-regulation of Il24 and Ptgs2 , and down-regulation of Myo7a and Pdgfrb , suggesting the PI3K-AKT signaling pathway as a potential route for toxicity. This study aims to provide a comprehensive evaluation of the cytotoxicity of chiral pesticides and their mechanisms.
研究领域:
毒理学
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生殖生物学
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分子生物学
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