FOOD RESEARCH INTERNATIONAL
·
2021
·
IF 6.475
Ting Xia,Chang-Shun Liu,Yan-Nan Hu,Zhen-Ye Luo,Fei-Long Chen,Li-Xia Yuan,Xiao-Mei Tan
Type 2 diabetes mellitus (T2DM) has become a worldwide concern in recent years. Coix seed (CS) as a homologous substance of traditional Chinese medicine and food, its polysaccharides can improve the symptoms of patients with metabolic disorders. Since most plant polysaccharides are difficult to digest and absorb, we hypothesized that Coix seed polysaccharides (CSP) exert hypoglycemic effects through the gut. In this study, the underlying mechanisms regulating hypoglycemic effects of CSP on a T2DM mouse model were investigated. After treatment with CSP, serum insulin and high-density lipoprotein cholesterol levels were increased, while total cholesterol, triglycerides and low-density lipoprotein cholesterol levels were decreased in T2DM mice. In addition, CSP treatment helped repair the intestinal barrier and modulated the gut microbial composition in T2DM mice, mainly facilitating the growth of short-chain fatty acid (SCFA)-producing bacteria, Spearman’s analysis revealed these bacteria were positively related with the hypoglycemic efficacy of CSP. Colonic transcriptome analysis indicated the hypoglycemic effect of CSP was associated with the activation of the IGF1/PI3K/AKT signaling pathway. Correlative analysis revealed that this activation may result from the increase of SCFAs-producing bacteria by CSP. GC–MS detection verified that CSP treatment increased fecal SCFAs levels. Molecular docking revealed that SCFAs could bind with IGF1, PI3K, and AKT. Our findings demonstrated that CSP treatment modulates gut microbial composition, especially of the SCFAs-producing bacteria, activates the IGF1/PI3K/AKT signaling pathways, and exhibits hypoglycemic efficacy.
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JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2021
·Vol. 25
·期 8
·4073-4087
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IF 5.31
Farooq Riaz,Qian Chen,Kaikai Lu,Ezra Kombo Osoro,Litao Wu,Lina Feng,Rong Zhao,Luyun Yang,Yimeng Zhou,Yingli He,Li Zhu,Xiaojuan Du,Muhammad Sadiq,Xudong Yang,Dongmin Li
Persistent hepatic damage and chronic inflammation in liver activate the quiescent hepatic stellate cells (HSCs) and cause hepatic fibrosis (HF). Several microRNAs regulate the activation and proliferation of HSCs, thereby playing a critical role in HF progression. Previous studies have reported that miR-188-5p is dysregulated during the process of HF. However, the role of miR-188-5p in HF remains unclear. This study investigated the potential role of miR-188-5p in HSCs and HF. Firstly, we validated the miR-188-5p expression in primary cells isolated from liver of carbon tetrachloride (CCl 4 )-induced mice, TGF-β1-induced LX-2 cells, livers from 6-month high-fat diet (HFD)-induced rat and 4-month HFD-induced mice NASH models, and human non-alcoholic fatty liver disease (NAFLD) patients. Furthermore, we used miR-188-5p inhibitors to investigate the therapeutic effects of miR-188-5p inhibition in the HFD + CCl 4 induced in vivo model and the potential role of miR-188-5p in the activation and proliferation of HSCs. This present study reported that miR-188-5p expression is significantly increased in the human NAFLD, HSCs isolated from liver of CCl 4 induced mice, and in vitro and in vivo models of HF. Mimicking the miR-188-5p resulted in the up-regulation of HSC activation and proliferation by directly targeting the phosphatase and tensin homolog (PTEN). Moreover, inhibition of miR-188-5p reduced the activation and proliferation markers of HSCs through PTEN/AKT pathway. Additionally, in vivo inhibition of miR-188-5p suppressed the HF parameters, pro-fibrotic and pro-inflammatory genes, and fibrosis. Collectively, our results uncover the pro-fibrotic role of miR-188-5p. Furthermore, we demonstrated that miR-188-5p inhibition decreases the severity of HF by reducing the activation and proliferation of HSCs through PTEN/AKT pathway.
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Experimental and Therapeutic Medicine
·
2021
·Vol. 21
·期 3
·1-1
·
IF 2.447
Qing Lin,Weili Wang,Liping Yang,Xiaohua Duan
Damage to the blood‑brain barrier (BBB) during the process of cerebral ischemic injury is a key factor that affects the treatment of this condition. The present study aimed to assess the potential effects of 4‑methoxybenzyl alcohol (4‑MA) on brain microvascular endothelial cells (bEnd.3) against oxygen‑glucose deprivation/reperfusion (OGD/Rep) using an in vitro model that mimics in vivo ischemia/reperfusion injury. In addition, the present study aimed to explore whether this underlying mechanism was associated with the inhibition of pro‑inflammatory factors and the activation status of the PI3K/Akt signaling pathway. bEnd.3 cells were subjected to OGD/Rep‑induced injury before being treated with 4‑MA, following which cell viability, lactate dehydrogenase (LDH) release and levels of nitric oxidase (NO) were detected by colorimetry, pro‑inflammatory factors including tumor necrosis factor‑α (TNF‑α), interleukin (IL)‑1β and IL‑6, were detected by ELISA. The expression levels of occluding and claudin‑5were evaluated by immunofluorescence staining. The expression levels of AKT, phosphorylated (p)‑Akt, endothelial nitric oxide synthase (eNOS) and p‑eNOS were also measured by western blot analysis. After bEnd.3 cells were subjected to OGD/Rep‑induced injury, cell viability and NO levels were significantly decreased, whilst LDH leakage and inflammatory factor (TNF‑α, IL‑1β and IL‑6) levels were significantly increased. Treatment with 4‑MA significantly ameliorated cell viability, LDH release and the levels of NO and pro‑inflammatory factors TNF‑α, IL‑1β and IL‑6 as a result of OGD/Rep. Furthermore, treatment with 4‑MA upregulated the expression of occludin, claudin‑5, Akt and eNOS, in addition to increasing eNOS and AKT phosphorylation in bEnd.3 cells. These results suggest that 4‑MA can alleviate OGD/Rep‑induced injury in bEnd.3 cells by inhibiting inflammation and by activating the PI3K/AKT signaling pathway as a possible mechanism. Therefore, 4‑MA can serve as a potential candidate for treating OGD/Rep‑induced injury.
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Journal of Functional Foods
·
2020
·
IF 3.701
Fenfen Li,Danfei Huang,Weiyu Yang,Xiaozhen Liu,Shaoping Nie,Mingyong Xie
The preventive role of polysaccharide from the seeds of Plantago asiatica L. (PLCP) against reproductive system injury induced by nonylphenol (NP) was investigated. Male Sprague-Dawley rats were exposed orally to NP 1 h after PLCP intragastric administration continuously for 45 days. The results showed that NP induced significant decrease in relative weight of testes and epididymis, changed testicular histomorphology, and disrupted hormone secretions. Moreover, oxidative stress occurred after NP exposure by overproduction of Malondialdehyde, lipid peroxidation, inducible nitric oxide synthase, and low activities of superoxide dismutase and catalase. Furthermore, the induction of apoptosis and disturbance of PI3K/Akt/mTOR pathway by NP were also proved. Interestingly, PLCP alleviated NP toxicity by improving antioxidant enzymes, recovering hormone secretions, inhibiting apoptosis and autophagy, which involves PI3K/Akt/mTOR pathway. These findings provide a good direction that PLCP may be a good candidate to help body defend against toxic substance, particularly endocrine disrupting chemicals induced reproductive toxicity.
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Molecular Medicine Reports
·
2020
·Vol. 22
·期 4
·3151-3160
·
IF 2.1
Bing‑Feng Guan,Xiao‑Feng Dai,Qi‑Bin Huang,Di Zhao,Jin‑Long Shi,Cheng Chen,Yan Zhu,Fen Ai
Icariside II (ICAII) is a bioflavonoid compound which has demonstrated anti‑oxidative, anti‑inflammatory and anti‑apoptotic biological activities. However, to the best of our knowledge, whether ICAII can alleviate myocardial ischemia and reperfusion injury (MIRI) remains unknown. The aim of the present study was to determine whether ICAII exerted a protective effect on MIRI and to investigate the potential underlying mechanism of action. A rat MIRI model was established by ligation of the left anterior descending coronary artery for 30 min, followed by a 24 h reperfusion. Pretreatment with ICAII with or without a PI3K/AKT inhibitor was administered at the beginning of reperfusion. Morphological and histological analyses were detected using hematoxylin and eosin staining; the infarct size was measured using Evans blue and 2,3,5‑triphenyltetrazolium chloride staining; and plasma levels of lactate dehydrogenase (LDH) and creatine kinase‑myocardial band (CK‑MB) were analyzed using commercialized assay kits. In addition, the cardiac function was evaluated by echocardiography and the levels of cardiomyocyte apoptosis were determined using a TUNEL staining. The protein expression levels of Bax, Bcl‑2, cleaved caspase‑3, interleukin‑6, tumor necrosis factor‑α, PI3K, phosphorylated (p)‑PI3K, AKT and p‑AKT were analyzed using western blotting analysis. ICAII significantly reduced the infarct size, decreased the release of LDH and CK‑MB and improved the cardiac function induced by IR injury. Moreover, ICAII pretreatment significantly inhibited myocardial apoptosis and the inflammatory response. ICAII also upregulated the expression levels of p‑PI3K and p‑AKT. However, the protective effects of ICAII were abolished by an inhibitor (LY294002) of the PI3K/AKT signaling pathway. In conclusion, the findings of the present study suggested that ICAII may mitigate MIRI by activating the PI3K/AKT signaling pathway.
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2019
·
IF 3.571
Yue Gao,Mingwei Zhang,Ruifen Zhang,Lijun You,Tong Li,Rui Hai Liu
The therapeutic benefits of whole grains on diabetes mellitus have been continuously confirmed by in-depth research. To date, limited studies have investigated the effect of extruded products of whole grains on the insulin signaling pathway in vivo. This study investigated the effects of oral consumption of whole grain extrudate, including 97% brown rice and 3% defatted rice bran (w/w, BRD), on glucose metabolism and the hepatic insulin signaling pathway in C57BL/KsJ-db/db mice. BRD treatment induced a remarkable reduction in blood glucose. Moreover, glucose intolerance and insulin resistance were ameliorated in the BRD-treated group compared with those in the db/db control group. BRD also increased the hepatic glycogen content by reducing the expression and increasing the phosphorylation of glycogen synthase kinase 3β (GSK3β). The activities of glucose-6-phosphatase and phosphoenolpyruvate carboxylase and their respective mRNA expression levels in the liver were simultaneously decreased in the BRD-treated group. BRD also significantly upregulated the expression of phosphatidylinositol 3-kinase (PI3K) and increased the phosphorylation of insulin receptor substrate 1 (IRS1) and protein kinase B (AKT). These results indicate that BRD exhibits antidiabetic potential by activating the IRS1/PI3K/AKT signaling pathway, further regulating the expression of the FOXO1 gene and p-GSK3β protein, thus inhibiting hepatic gluconeogenesis, increasing hepatic glycogen storage, and improving insulin resistance. Therefore, BRD could be used as a functional ingredient to alleviate the symptoms of hyperglycemia.
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Food Science and Human Wellness
·
2023
·
IF 7
Qihong Jiang,Lin Chen,Rui Wang,Yin Chen,Shanggui Deng,Guoxin Shen,Shulai Liu,Xingwei Xiang
Type 2 diabetes mellitus (T2DM) is a complex metabolic disease threatening human health. We investigated the effects of Tegillarca granosa polysaccharide (TGP) and determined its potential mechanisms in a mouse model of T2DM established through a high-fat diet and streptozotocin. TGP (5.1 × 10 3 Da) was composed of mannose, glucosamine, rhamnose, glucuronic acid, galactosamine, glucose, galactose, xylose, and fucose. It could significantly alleviate weight loss, reduce fasting blood glucose levels, reverse dyslipidemia, reduce liver damage from oxidative stress, and improve insulin sensitivity. RT-PCR and Western blotting indicated that TGP could activate the phosphatidylinositol-3-kinase/protein kinase B signaling pathway to regulate disorders in glucolipid metabolism and improve insulin resistance. TGP increased the abundance of Allobaculum , Akkermansia , and Bifidobacterium , restored the microbiota abundance in the intestinal tracts of mice with T2DM, and promoted short-chain fatty acid production. This study provides new insights into the antidiabetic effects of TGP and highlights its potential as a natural hypoglycemic nutraceutical.
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MOLECULAR NEUROBIOLOGY
·
2023
·
IF 5.1
Wu Yuhan,Zhu Zhanpeng,Lan Tian,Li Shuhan,Li Ye,Wang Changmin,Feng Yabo,Mao Xueqin,Yu Shuyan
Depression is a common psychological disease with high morbidity and mortality. Recently, the involvement of synaptic plasticity in the pathogenesis of depression has shed light on the direction of developing novel antidepressants. Levomilnacipran is a newly approved medication for the treatment of adult major depressive disorder. However, the detailed mechanisms underlying its antidepressant-like effects have yet to be illuminated. In this study, we aimed to investigate the role of levomilnacipran in regulating synaptic plasticity and explore the possible molecular mechanisms of its antidepressant effects using a rat model of depression induced by lipopolysaccharide (LPS). The results demonstrated that levomilnacipran (30 mg/kg, i.p.) significantly ameliorated depression-like behaviors in rats, alleviated the dysregulation of synaptic plasticity, and suppressed neuroinflammation within hippocampus induced by LPS-treatment. Levomilnacipran increased the expression of postsynaptic dense 95 (PSD-95) and synaptophysin (Syn) and reversed the imbalance between pro- and anti-inflammatory cytokines within hippocampus of depressed rats. Additionally, levomilnacipran elevated expression level of brain-derived neurotrophic factor (BDNF), accompanied by increased tyrosine kinase B (TrkB), phosphorylated phosphatidylinositol 3-kinase (PI3K), phosphorylated protein kinase B (p-Akt), and phosphorylated mammalian target of rapamycin (p-mTOR). Taken together, these results suggest that levomilnacipran may exert antidepressant effects via upregulating BDNF/TrkB mediated PI3K/Akt/mTOR signaling pathway to improve synaptic plasticity. These findings reveal potential mechanisms for the antidepressant effects of levomilnacipran and offer new insights into the treatments for depression. Graphical Abstract
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Biomaterials Science
·
2019
·Vol. 7
·期 12
·5054-5067
·
IF 5.251
Tiantian Zuo,Jing Li,Jun Zhang,Liang Sun,Xiao Liang,Jie Yang,Qi Shen
As the principal reason for the inducement of high mortality, tumor metastasis is regulated by different pathways owing to its complexity and multistep process. In order to inhibit the proliferation and metastasis of human breast cancer simultaneously, controlling the codelivery of chemotherapeutics and pathway inhibitors precisely has been considered as a high-potential strategy to accurately eliminate tumor metastasis. In this study, polymer PLGA-p-PEI-DA was synthesised and automatically assembled into a cascade “trinity” response drug delivery system, i.e., PPP-DA/NPs (PLGA: poly(lactin-co-glycolic acid), PEI: polyethyleneimine, DA: 2,3-dimethylmaleic anhydride). In the tumor microenvironment, PPP-DA/NPs could remove the outer DA molecules via the pH-sensitive hydrolysis of β-carboxylic amide bonded with DA and PEI. Then, PPP-DA/NPs were broken up owing to the enzymatically cleavable GFLGF (Gly-Phe-Leu-Gly-Phe) linker. The structure of the polymer and the properties of PPP-DA/NPs were evaluated in detail. Moreover, studies on the antitumor metastasis efficiency and antitumor mechanism of PPP-DA/NPs were carried out in detail. As demonstrated in this study, PPP-DA/NPs could reverse the potential in pH 6.8 PBS and showed elevated cellular uptake efficiency. Moreover, PPP-DA/NPs exhibited strong antitumor metastasis ability in vitro and in vivo. The tumor inhibiting rate (TIR) of PPP-DA/NPs (68.4%) was significantly higher than that of docetaxel (DTX) (5.9%). The antitumor mechanistic studies confirmed that PPP-DA/NPs could down-regulate the expressions of Akt, MMP-9 and pro-caspase-3/9 protein, as indicated by western blot analysis. This multifunctional drug delivery system (DDS) is highly selective and effective in inhibiting tumor metastasis, which shows a great potential in inventing smart nanocarriers for targeted tumor-metastasis therapy.
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JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2018
·
IF 2.297
Yunzhi Yin,Yiyue Wang,Jun Zhang,Jing Li,Jingjing Chen,Qi Shen
Docetaxel (DTX) is one kind of well-known anticancer drugs against tumors. GDC0941 was used to inhibit PI3K/Akt signal pathway and improve anti-tumor activity. PLGA-PEG-R7 (poly lactic-co-glycolic acid polyethylene glycol bending with cell penetrating peptide R7)/poly sulfadimethoxine-Folate nanoparticles (R7/PSD-Fol NPs) were made to load DTX and GDC0941 simultaneously. In vitro, the release capacity of DTX and GDC0941 inside nanoparticles was determined and both drugs could release from nanoparticles to 70% within 48h. The result of flow cytometry showed that GDC0941 had no interference on cell uptake and R7/PSD-Fol NPs could enhance MCF-7 cells uptake the most significantly. In cell colony study, GDC0941 could further improve the anti-tumor effect of DTX and inhibit the formation of cell clones on the basis of enhancing the uptake of R7/PSD-Fol NPs. The capability of cell colony formation was as follows: DTX > DTX + GDC0941 > R7 NPs > R7/PSD-Fol NPs. The expression of cell apoptosis proteins treated with R7/PSD-Fol NPs was the lowest. The addition of GDC0941 could decrease the full-length content of apoptotic proteins caspase-3 and caspase-9. In vivo, pharmacokinetic parameters results showed us that GDC0941 had no interference on pharmacokinetic study. Main pharmacokinetic parameters of DTX suspension and R7/PSD-Folate NPs suspension showed significant differences.
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NEUROSCIENCE LETTERS
·
2017
·
IF 2.18
Bing Chun Yan,Hui Shen,Yuanyuan Zhang,Xiaolu Zhu,Jie Wang,Pei Xu,Dan Jiang,Xing Yu
Levetiracetam (LEV), a second-generation antiepileptic drug, is commonly prescribed to treat certain types of seizures. Few studies have investigated the effects of LEV on hippocampal neurogenesis and its related mechanisms. In the present study, we investigated the effects of LEV on cell proliferation and neuronal differentiation in the mouse hippocampal dentate gyrus (DG). We here demonstrate a dose-dependent increase in Ki-67-immunoreactive cells in the subgranular zone of the DG in LEV-treated mice, and doublecortin-immunoreactive cells were also significantly increased in the hippocampal DG of mice treated with LEV. The above results indicate that LEV could improve cell proliferation and neuroblast differentiation in the hippocampus. In addition, we also found that LEV treatment improved superoxide dismutase (SOD)2, catalase and Gpx-1 levels and increased phosphatidylinositol 3-kinase (PI3K) and phosphorylated Akt protein levels in the hippocampus. Further investigation of the molecular mechanisms underlying these effects revealed that PC12 cell was blocked by a pharmacological inhibitor of PI3K (LY294002), and that LEV treatment rapidly activated PI3K/Akt and SOD2, catalase and Gpx-1. In brief, our results indicate that LEV enhanced cell proliferation and neuroblast differentiation by increasing the expression of antioxidants and PI3K and the level of phosphorylated Akt in the mouse hippocampus.
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Communications Biology
·
2024
·Vol. 7
·期 1
·1-15
·
IF 5.2
Zhang Wen,Cai Shuhui,Qin Lihong,Feng Yaru,Ding Menglei,Luo Zichen,Shan Jinjun,Di Liuqing
Aconiti Lateralis Radix Praeparata ( Fuzi in Chinese) is widely used in the clinical treatment of tumors. This study aims to explore the active fractions and underlying mechanisms of Fuzi in the treatment of non-small cell lung cancer (NSCLC). Fuzi alkaloids (FZA) is prepared and found to inhibit the growth of NSCLC both in vitro and in vivo significantly. A total of 53 alkaloids are identified in FZA by UPLC-Q-TOF-MS. Proteomics experiment show that 238 differentially expressed proteins regulated by FZA are involved in amino acid anabolism, pyrimidine metabolism and PI3K/Akt-mTOR signaling pathway. Metabolomics analyses identify 32 significant differential metabolites which are mainly involved in amino acid metabolism, TCA cycle and other pathways. Multi-omics research combined with molecular biological assays suggest that FZA might regulate glycolysis through PI3K/Akt-mTOR pathway to treat NSCLC. The study lays a foundation for the anti-cancer investigation of Fuzi and provides a possible scientific basis for its clinical application.
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