RSC Advances
·
2020
·Vol. 10
·期 32
·18927-18935
·
IF 3.119
Xia Jiang,Genyun Tang,Jie Yang,Jiacheng Ding,Hongwei Lin,Xiaoliang Xiang
In the present study, a novel series of acylhydrazone compounds (A0–A10) with the structure of 1,2,4-triazole have been designed and synthesized. In addition, all the synthesized compounds have been evaluated for neuritogenic activity in mouse neuroblastoma (Neuro-2a) cells. Notably, we found that one of these 11 acylhydrazone compounds, compound A5 (2-(4-amino-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N′-(2-hydroxybenzylidene)-acetohydrazide) displays excellent neuritogenic activity. Moreover, our present study revealed that compound A5 had the ability to induce neurite outgrowth through the PI3K/Akt and MEK-ERK signaling pathway in Neuro-2a cells. These findings suggest that compound A5 might exert neuritogenic effects and thus may be useful for the treatment of neural repair and regeneration.
研究领域:
药理学
·
神经生物学
·
有机化学
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高影响因子
CURRENT MEDICINAL CHEMISTRY
·
2024
·
IF 3.5
Liu Wei,Zheng Yi-nan,Jiang Shuang,Ren Shen,Tang Shan,Zhang Jing,Wang Zi,Li Wei
Background: Based on the Maillard reaction principle of red ginseng, this
study innovatively synthesized a new amino acid derivative by combining arginine with
lactose through simulated synthesis and was separated and purified through repeated silica
gel and polyacrylamide gel (Bio-gel P-II) column chromatography.
Purpose: The work was aimed at elucidating the synthesis of a novel amino acid derivative
and investigating the intestinal protective activity of the novel amino acid derivative
and possible molecular mechanism by establishing the intestinal injury model induced
by cisplatin in mice.
Methods: The purity and molecular weight of the amino acid derivatives were determined
to be by electrospray ionization mass spectrometry (ESI-MS). Subsequently, by
establishing cisplatin (20 mg/kg)-induced intestinal injury in vivo for 10 days and IEC-6
cell model. The biochemical indexes and histopathological analysis were used to evaluate
the oxidative stress and inflammatory and pathological changes of intestinal tissue in
mice. The protein expression levels of p-Nuclear transcription factor-κB (p-NF-κB),
cleaved caspase 3/caspase 3, cleaved caspase 9/caspase-9, Bcl-2, Bax, cytochrome C,
phosphatidylinositol 3-kinase (PI3K), Protein Kinase B (Akt), p-PI3K, p-Akt were quantified
through immunofluorescence staining and western blot analysis.
Results: The new amino acid derivatives of chemical structure were identified to be 1-
(arginine-Nαgroup)-1-deoxy-4-O-(β-D-galactopyranosyl)-D-fructose, named Argininylfructosyl-
galactose (AFGA, C18H34N4O12). The results showed that pretreatment with a
single AFGA dose remarkably alleviated cisplatin-evoked intestinal oxidative stress injury,
and the levels of reactive oxygen species (ROS) were lessening in IEC-6 cells
(p<0.05, p<0.01) and could effectively reduce the secretion of TNF-α and IL-1β in
serum and the expression level of NF-κB protein in intestinal tissues (p<0.01). Meantime,
AFGA also significantly suppressed the caspase 3, caspase 9, cytochrome C and
Bax protein expression in intestinal tissue in mice (p<0.01), and regulated the PI3K/Akt
pathway (p<0.05, p<0.01). Importantly, the molecular docking results of AFGA also
suggested a better binding ability with the above-mentioned related target proteins.
Conclusion: The results clearly revealed AFGA as a potential multifunctional therapeutic
agent with a clear protective effect against cisplatin-induced intestinal injury may be
related to the PI3K/Akt signaling pathway.
研究领域:
药理学
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毒理学
·
分子生物学
·
生物化学
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高影响因子
MOLECULES
·
2024
·Vol. 29
·期 17
·3990
·
IF 4.2
Shuang Tian,Yinxu Zhao,Siqi Deng,Liman Hou,Juan Song,Ming Wang,Ming Bu
In the following study, a series of new lupeol-3-carbamate derivatives were synthesized, and the structures of all the newly derived compounds were characterized. The new compounds were screened to determine their anti-proliferative activity against human lung cancer cell line A549, human liver cancer cell line HepG2, and human breast cancer cell line MCF-7. Most of the compounds were found to show better anti-proliferative activity in vitro than lupeol. Among them, obvious anti-proliferation activity (IC50= 5.39~9.43 μM) was exhibited by compound3iagainst all three tumor cell lines. In addition, a salt reaction was performed on compound3k(IC50= 13.98 μM) and it was observed that the anti-proliferative activity and water solubility of compound3k·CH3I(IC50= 3.13 μM), were significantly enhanced subsequent to the salt formation process. The preliminary mechanistic studies demonstrated that apoptosis in HepG2 cells was induced by compound3k·CH3Ithrough the inhibition of the PI3K/AKT/mTOR pathway. In conclusion, a series of new lupeol-3-carbamate derivatives were synthesized via the structural modification of the C-3 site of lupeol, thus laying a theoretical foundation for the design of this new anticancer drug.
研究领域:
药理学
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肿瘤学
·
药物化学
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CELL BIOLOGY INTERNATIONAL
·
2024
·
IF 3.3
Guang Yang,Xin Shi,Meixia Zhang,Kaiwen Wang,Xin Tian,Xiaofeng Wang
Oral squamous cell carcinoma (OSCC) is the most common oral malignancy. DEAD/H-box helicase 11 (DDX11), a DNA helicase, has been implicated in the progression of several cancers. Yet, the precise function of DDX11 in OSCC is poorly understood. The DDX11 expression in OSCC cells and normal oral keratinocytes was evaluated in the Gene Expression Omnibus database (GSE146483 and GSE31853). SCC-4 and CAL-27 cells expressing doxycycline-inducible DDX11 or DDX11 shRNA were generated by lentiviral infection. The role of DDX11 in OSCC cells was determined by 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay, colony formation assay, flow cytometry assay, TUNEL staining, and western blot. The effects of DDX11 on tumor growth were explored in a xenograft nude mouse model. The relationship between DDX11 and transcription factor Yin Yang-1 (YY1) was researched using the dual luciferase report assay and chromatin immunoprecipitation assay. DDX11 expression was significantly upregulated in OSCC cells. Knockdown of DDX11 inhibited cell proliferation, induced cell cycle arrest, and suppressed PI3K-AKT pathway, while DDX11 overexpression showed opposite effects. The number of apoptotic cells was increased in DDX11 silenced cells. DDX11 upregulation or knockdown accelerated or suppressed tumor growth in vivo, respectively. Moreover, the YY1 bound and activated the DDX11 promoter, resulting in increasing DDX11 expression. Forced expression DDX11 reversed the anticancer effects of YY1 silencing on OSCC cells. DDX11 has tumor-promoting function in OSCC and is transcriptionally regulated by YY1, indicating that DDX11 may serve as a potential target for the OSCC treatment.
研究领域:
肿瘤学
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分子生物学
·
细胞生物学
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转化医学
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2022
·
IF 5.895
Sinan Chen,Fanhua Wu,Chenchen Yang,Cheng Zhao,Ni Cheng,Wei Cao,Haoan Zhao
Insulin resistance (IR) is the central link to metabolic syndrome (MS), and IR prevention has become the key to overcoming this worldwide public health problem. A diet rich in simple sugars is an important pathogenic factor in IR development. To investigate the effect of honey on IR compared to the sugar-water diet, we analyzed phenolics and oligosaccharides in jujube honey and rape honey based on LC-MS and silane derivatization/GC–MS. The effects of different diets on glucose and lipid profile, histopathology and IR-related mechanism pathways were analyzed and compared by equal sugar levels intervention of fructose, fructose + glucose and two kinds of unifloral honey (high-/low-dose) in rats. The results suggested that sugar-equivalent honey, which differs from sugar solution, especially 17.1 g/kg BW jujube honey rich in phenolics (1.971 mg/100 g of isoquercitrin) and oligosaccharides (2.18 g/100 g of turanose), suppressed IR via maintaining glucose (OGTT and ITT) and lipid (TC, TG, LDL-C, HDL-C, and NEFA) homeostasis, improving histological structural abnormalities of the liver, adipose and skeletal muscle, reducing oxidative stress (GSH-Px and MDA) and inflammation (IL-6 and TNF-α), modulating the NF-κB (NF-κB gene expression was down-regulated to 0.94) and IRS/PI3K/AKT signaling pathways (e.g., AKT and GLUT2 expression in liver increased by 4.56 and 13.37 times, respectively) as well as reshaping the gut microbiota. These revealed a potential nutritional contribution of substituting honey for simple sugar in the diet, providing a theoretical basis for controlling IR development via dietary modification and supplementation.
研究领域:
营养学
·
代谢学
·
内分泌学
·
分子生物学
·
药理学
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动物生理学
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2026
·
IF 6.1
Shaoying Gong,Tianju Yang,Ruoyu Wu,Qinghai Sheng,Tangwei Zhang,Ming Xiao,Miao Wang,Yongxin She,Jing Wang,A.M. Abd El-Aty
Nonylphenol (NP) is known to damage the intestinal epithelial barrier (IEB), although its mechanisms remain unclear. Arabinogalactan (AG) is a natural polysaccharide with intestinal protective properties. This study explored the mechanisms of NP-induced IEB damage and evaluated the protective potential of AG in a Caco-2 cell monolayer model. The results revealed that NP induces inflammation and oxidative stress through the PI3K/AKT/mTOR signaling pathway, thereby inhibiting tight junction (TJ) gene and protein expression and ultimately leading to IEB damage. Conversely, AG enhanced TJ expression and suppressed inflammation and oxidative stress by activating the PI3K/AKT/mTOR signaling pathway, thus alleviating NP-induced IEB damage. This research provides new insights into the molecular mechanisms of NP-induced IEB damage and highlights the potential of AG as a functional food ingredient for promoting intestinal health. Moreover, our study provides a theoretical basis for supporting policies aimed at restricting NP residues in food and offers a potential dietary reference for high-risk populations exposed to NP-contaminated environments.
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Chinese Journal of Integrative Medicine
·
2022
·Vol. 29
·期 3
·244-252
·
IF 2.626
Wang Yuan-chun,Hui Jian-rong,Xiao Gang,Ma Qiao-lin
Objective To investigate the mechanism of the effect of Astragalus membranaceus ( A. membranaceus ) on lung adenocarcinoma at the molecular level to elucidate the specific targets according to the network pharmacology approach. Methods The active components of A. membranaceus and their potential targets were collected from the Traditional Chinese Medicine Systems Pharmacology Database. Lung adenocarcinoma-associated genes were acquired based on GeneCards, Online Mendelian Inheritance in Man (OMIM), PharmGKB, and Therapeutic Targets databases. The PI3K/AKT signaling pathway-related genes were obtained using Reactome portal. Networks of “ingredient-target” and “ingredient-target-pathway-disease” were constructed using the Cytoscape3.6.0 software. The relationships among targets were analyzed according protein-protein interaction (PPI) network. Finally, molecular docking was applied to construct the binding conformation between active ingredients and core targets. Cell counting kit 8 (CCK8) and Western blot assays were performed to determine the mechanism of the key ingredient of A. membranaceus . Results A total of 20 active components and their 329 targets, and 7,501 lung adenocarcinoma-related genes and 130 PI3K/AKT signaling pathway-related genes were obtained. According to Venn diagram and PPI network analysis, 2 mainly active ingredients, including kaempferol and quercetin, and 6 core targets, including TP53, MAPK1, EGF, AKT1, ERBB2, and EGFR, were identified. The two important active ingredients of A. membranaceus , kaempferol and quercetin, exert the therapeutic effect in lung adenocarcinoma partly by acting on the 6 core targets (TP53, MAPK1, EGF, AKT1, ERBB2, and EGFR) of PI3K/AKT signaling pathway. Expressions of potential targets in lung adenocarcinoma and normal samples were analyzed by using UALCAN portal and found that ERBB2 was overexpressed in lung adenocarcinoma tissues and upregulation of it correlated with clinicopathological characteristics. Finally, quercetin repressed viabilities of lung adenocarcinoma cells by targeting ERBB2 on PI3K/AKT signaling confirmed by CCK8 and Western blot. Conclusion Our finding unraveled that an active ingredient of A. membranaceus , quercetin, significantly inhibited the lung adenocarcinoma cells proliferation by repressing ERBB2 level and inactivating the PI3K/AKT signaling pathway.
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Bioengineered
·
2022
·
IF 6.832
Kenan Zheng,Baojiang Lv,Lulu Wu,Chen Wang,Haoyou Xu,Xiaojun Li,Zhibing Wu,Yuanqi Zhao,Zequan Zheng
Experimental autoimmune encephalomyelitis (EAE) is characterized by demyelination of the central nervous system. Emodin is an anthraquinone derivative with comprehensive anti-inflammatory, anti-cancer, and immunomodulatory effects and is widely used in the treatment of inflammatory, tumor, and immune system diseases. However, none of the clinical or experimental studies have explored the therapeutic efficacy of emodin in EAE/multiple sclerosis (MS). Thus, we evaluated the protective effect of emodin on EAE mediated via inhibition of microglia activation and inflammation. Wild-type mice were randomly divided into the normal control, EAE, low-dose emodin, and high-dose emodin groups. Clinical scores and pathological changes were assessed 21 days after immunization. The network pharmacology approach was used to elucidate the underlying mechanisms by using an online database. Molecular docking, polymerase-chain reaction tests, western blotting, and immunofluorescence were performed to verify the network pharmacology results. An in vivo experiment showed that high-dose emodin ameliorated clinical symptoms, inflammatory cell infiltration, and myelination. Pharmacological network analysis showed AKT1 was the main target and that emodin played a key role in MS treatment mainly via the PI3K–Akt pathway. Molecular docking showed that emodin bound well with PI3K, AKT1, and NFKB1. Emodin decreased the expression of phosphorylated(p)-PI3K, p-Akt, NF-κB, and myeloid differentiation factor 88 and the levels of markers (CD86 and CD206) in M1- and M2-phenotype microglia in EAE. Thus, the emodin inhibited microglial activation and exhibited anti-inflammatory and neuroprotective effects against EAE via the Myd88/PI3K/Akt/NF-κB signalling pathway. In conclusion, emodin has a promising role in EAE/MS treatment, warranting further detailed studies.
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BIOCHEMICAL PHARMACOLOGY
·
2022
·
IF 6.1
Yanbei Tu,Lihua Tan,Tao Lu,Kai Wang,Haiyong Wang,Bing Han,Yuxin Zhao,Hanbin Chen,Yanfang Li,Haixia Chen,Meiwan Chen,Chengwei He
The roots of Glycine tabacina are used to treat rheumatoid arthritis (RA) and joint infection in folk medicine. Glytabastan B (GlyB), a newly reported coumestan isolated from this species, was found to significantly attenuate IL-1β-induced inflammation in SW982 human synovial cells at 3 and 6 μM, as evidenced by the decreased levels of pro-inflammatory mediators and matrix metalloproteinases (MMPs). GlyB also suppressed RANKL-induced osteoclastogenesis, decreased the expression of osteoclastogenic markers (NFATc1, CTSK , MMP-9) and osteoclast-mediated bone resorption. Further, GlyB administration (12.5 and 25 mg/kg) significantly inhibited inflammation, osteoclast formation and disease progression in collagen-induced arthritis (CIA) mice. Integration of network pharmacology , quantitative phosphoproteomic and experimental pharmacology results revealed that these beneficial actions were closely associated with the blockade of GlyB on the activation of MAPK , PI3K/AKT and their downstream signals including NF-κB and GSK3β/NFATc1. Drug affinity responsive target stability (DARTS) assay, cellular thermal shift (CETSA) assay and molecular docking analysis confirmed that there were direct interactions between GlyB and its target proteins ERK2 , JNK1 and class Ⅰ PI3K catalytic subunit p110 (α, β, δ and γ), which significantly contributed to the inhibition of activation of MAPK and PI3K/AKT pathways. In conclusion, these results strongly suggest GlyB is a promising multiple-target candidate for the development of agents for the prevention and treatment of RA.
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高影响因子
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
·
2020
·Vol. 393
·期 9
·1739-1752
·
IF 2.05
Song Lin,Yao Lifen,Zhang Limei,Piao Zhongyuan,Lu Yichan
Autophagy, a lysosomal degradative pathway, is crucial for the pathogenesis of Alzheimer’s disease (AD). Schizandrol A (SchA) shows multiple pharmacological effects. However, the potential effects and mechanisms of SchA on amyloid-β (Aβ)-induced autophagy remain unclear. In this study, differentiated SH-SY5Y cells or primary hippocampal neurons were pretreated with SchA (2 μg/ml) for 1 h before subjected to Aβ 1–42 (10 μM) for 24 h to test its effects on cell viability, apoptosis, oxidative stress, and autophagy. Then an mTOR inhibitor (rapamycin) and a PI3K inhibitor (LY294002) were employed to explore the role of PI3K/AKT/mTOR pathway. The results showed that SchA significantly inhibited Aβ 1–42 -triggered reduction of viable cells, increases of apoptotic cell number and pro-apoptotic protein expressions, as well as alterations of oxidative stress markers. In addition, the increases of LC3-II/LC3-I and Beclin-1 and decrease of p62 were suppressed by SchA. At the molecular level, we found that the inactivation of PI3K/AKT/mTOR pathway was ameliorated by SchA. Inhibition of PI3K/AKT/mTOR pathway deteriorated the protective effects of SchA against Aβ 1–42 -induced autophagy activation, cell death, and apoptosis. In conclusion, we demonstrate that SchA attenuates Aβ 1–42 -induced autophagy through activating PI3K/AKT/mTOR signaling pathway. SchA may be a novel drug for the prevention and treatment of AD.
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MOLECULAR NEUROBIOLOGY
·
2023
·
IF 5.1
Guo Xiying,Lei Min,Ma Guandi,Ouyang Changhan,Yang Xiaosong,Liu Chao,Chen Qingjie,Liu Xiufen
Clinical and epidemiological research shows that people with diabetes mellitus frequently experience diabetic cognitive impairment. Schisandrin A (SchA), one of the lignans found in the dried fruit of Schisandra chinensis, has a variety of pharmacological effects on immune system control, apoptosis suppression, anti-oxidation and anti-inflammation. The goal of the current investigation was to clarify the probable neuro-protective effects of SchA against streptozotocin-induced diabetes deficiencies of the spatial learning and memory in rats. The outcomes show that SchA therapy effectively improved impaired glucose tolerance, fasting blood glucose level and serum insulin level in diabetic rats. Additionally, in the Morris water maze test, diabetic rats showed deficits in spatial learning and memory that were ameliorated by SchA treatment. Moreover, giving diabetic rats SchA reduced damage to the hippocampus structure and increased the production of synaptic proteins. Further research revealed that SchA therapy reduced diabetic-induced hippocampus neuron damage and the generation of Aβ, as demonstrated by the upregulated phosphorylation levels of insulin signaling pathway connected proteins and by the decreased expression levels of inflammatory-related factors. Collectively, these results suggested that SchA could improve diabetes-related impairments in spatial learning and memory, presumably by reducing inflammatory responses and regulating the insulin signaling system.
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Food & Function
·
2020
·Vol. 11
·期 11
·9535-9546
·
IF 4.171
Na Deng,Ruixue Guo,Bisheng Zheng,Tong Li,Rui Hai Liu
The effects of whole grain highland barley (WGH) with rich phenolics on glucose metabolism, the insulin pathway, and microRNA (miRNA) expression in db/db mice were explored in the present study. Supplementation with WGH decreased the levels of blood glucose, glycosylated serum protein (GSP), insulin, and inflammatory cytokines in db/db mice. Furthermore, WGH administration triggered a remarkable amelioration of glucose intolerance and insulin resistance. The hepatic glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxylase (PEPCK) activities and the G6PC, PEPCK, and forkhead transcription factor 1 (FOXO1) mRNA levels in the WGH-treated group were also reduced. Moreover, WGH promoted the glycogen storage in the liver via up-regulating the activities of hexokinase (HK) and glycogen synthase (GS) and the phosphorylation of glycogen synthase kinase 3β (GSK3β) protein, while down-regulating the GSK3β mRNA level. The protein expression of phosphatidylinositol 3-kinase (PI3K), the phosphorylation of protein kinase B (Akt), and the mRNA levels of insulin receptor substrate-1 (IRS-1), PI3K and Akt were also up-regulated by WGH treatment. Moreover, WGH significantly augmented the expression of miRNA-26a and miRNA-451, but reduced those of miRNA-126a and miRNA-29a. These results demonstrated that WGH exhibits a hypoglycemic effect through regulating the IRS-1/PI3K/Akt pathway and related miRNAs, further modulating the expression of G6PC, PEPCK, and FOXO1 mRNAs and p-GSK3β protein, thus inhibiting hepatic gluconeogenesis, improving glycogen synthesis and alleviating insulin resistance. Therefore, this study suggested WGH as an effective candidate to ameliorate the hyperglycemia of type 2 diabetes mellitus.
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