MOLECULAR NEUROBIOLOGY
·
2024
·
IF 4.6
Xu Yao,Liu Yongsheng,Wu Yan,Sun Jingshan,Lu Xiaocheng,Dai Kun,Zhang Yiting,Luo Chengliang,Zhang Jian
Early brain injury caused by subarachnoid hemorrhage (SAH) is associated with inflammatory response and ferroptosis. Curcumin alleviates neuroinflammation and oxidative stress by as yet unknown neuroprotective mechanisms. The objective of this study was to investigate the impact of curcumin on neuronal ferroptosis and microglia-induced neuroinflammation following SAH. By examining Nrf2/HO-1 expression levels and ferroptosis biomarkers expression both in vitro and in vivo, it was demonstrated that curcumin effectively suppressed ferroptosis in neurons after SAH through modulation of the Nrf2/HO-1 signaling pathway. Furthermore, by analyzing the expression levels of Nrf2, HO-1, p-p65, and inflammation-related genes, it was confirmed that curcumin could prevent the upregulation of pro-inflammatory factors following SAH by regulating the Nrf2/HO-1/NF-κB signaling pathway in microglia. The ability of curcumin to reduce neuronal damage and cerebral edemas after SAH in mice was validated using TUNEL staining, Nissl staining, and measurement of brain tissue water content. Additionally, through implementation of the modified Garcia test, open field test, and Y-maze test, it was established that curcumin ameliorated neurobehavioral impairments in mice post-SAH. Taken together, these data suggest that curcumin may offer a promising therapeutic approach for improving outcomes following SAH by concurrently attenuating neuronal ferroptosis and reducing neuroinflammation. Graphical Abstract
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TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2020
·
IF 3.347
Yang Zhang,Jiabei Zhou,Qin Ye,Kui Zeng,Jie Pan,Lu Chen,Yingying Wang,Bo Yang,Qiaojun He,Jianqing Gao,Su Zeng,Lushan Yu
Thioredoxin 1 (Trx1) and telomerase play key roles in the development and progression process of most tumors, and they both are promising drug therapy targets. We have, for the first time, discovered that Trx1 and telomerase had a dual-target synergistic effect. Based on that results, we designed a series of 6-dithio-2′-deoxyguanosine analogs (named as YLS00X) and verified whether they can inhibit Trx1 and telomerase simultaneously. TrxR1/Trx1 system activity and telomerase expression were significantly inhibited by 6-dithio-2′-deoxyguanosine analogs, especially YLS004. YLS004 can also cause ROS accumulation, and induce tumor cell apoptosis . The vitro antitumor activity of 6-dithio-2′-deoxyguanosine analogs using MTT assay on 11 different human cancer cells and found that human colon cancer cells(HCT116) and melanoma cells (A375) were the most sensitive cells to 6-dithio-2′-deoxyguanosine analogs treatment and vivo xenografts models also confirmed that. The serum biochemical parameters and multiple organs HE staining results of subacute experiments indicated that YLS004 might be mildly toxic to immune organs, including the thymus, spleen, and hematopoietic system . Besides, YLS004 was rapidly metabolized in the rats' blood. Our study revealed that YLS004, a Trx1 and telomerase inhibitor , has strong anti-tumor effects to colon cancer and melanoma cells and is a promising new candidate drug.
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JOURNAL OF GENERAL VIROLOGY
·
2021
·Vol. 102
·期 12
·001710
·
IF 3.891
Jian Yang,Jia Wang,Xiaowei Peng,Chengfeng Lei,Xiulian Sun,Jia Hu
Dendrolimus punctatuscauses great damage to pine forests worldwide. Dendrolimus punctatus cypovirus 1 (DpCPV-1) is an important pathogen ofD. punctatus. However, the mechanism of DpCPV-1 cell entry has not been elucidated. In this study, we revealed that both GTase and MTase domains of VP3 (B-spike) and VP4 (A-spike) of DpCPV-1 interacted with the midgut proteins ofBombyx mori. Binding and competition assays revealed that GTase, MTase and VP4 played roles as viral attachment proteins. Far-Western blotting and LC-MS/MS analyses identified that heat shock protein 70 (BmHSP70), glutamate dehydrogenase (BmGDH), and angiotensin-converting enzyme (BmACE) in the midgut proteins as ligand candidates of the viral attachment proteins, and this was further verified by co-immunoprecipitation and fluorescence co-localization assays. Viral binding to the host midgutin vitrowas inhibited by pre-treatingB. morimidgut proteins with anti-BmHSP70, anti-BmGDH, anti-BmACE antibodies singly and in combination. Incubating DpCPV-1 virions with prokaryotically expressed BmHSP70, BmGDH, and BmACE also decreased viral attachment to the host midgut.In vivobioassays revealed that viral infection inHelicoverpa armigerawas partially neutralized by BmHSP70, BmGDH, and BmACE. Taking together, we concluded that HSP70, GDH, and ACE mediate DpCPV attachment and entry via binding to the viral attachment proteins, VP3 and VP4. The findings provide foundation for further understanding the entry mechanisms of cypoviruses.
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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2025
·Vol. 26
·期 23
·11548
·
IF 4.9
Haowen Fang,Xiaodong Sun,Yanting Ding,Siyuan Gu,Bing Niu,Qin Chen
This study aimed to develop a potent, safe, and cost-effective small-molecule hypoglycemic agent derived from Loureirin B, with preliminary evaluation of its efficacy and mechanistic underpinnings. Thirty structural analogs of Loureirin B were synthesized. Molecular docking identified LB-A as the lead compound targeting GLP-1R. Its hypoglycemic activity was initially assessed in a murine model. Molecular dynamics simulations, surface plasmon resonance (SPR), and circular dichroism (CD) were employed to characterize LB-A–GLP-1R interactions. The involvement of the GLP-1R/cAMP/PKA pathway and downstream mediators was examined using cellular assays, gene knockout, and Western blotting, with emphasis on FOXO1. LB-A exhibited the strongest binding affinity for GLP-1R among the analogs and significantly reduced blood glucose levels in mice. It formed hydrogen bonds and hydrophobic interactions with key residues (e.g., LYS197) and induced conformational changes in GLP-1R. LB-A activation of GLP-1R upregulated cAMP, PKA, and pCREB, suppressed PTEN/FOXO1 signaling, and subsequently stimulated insulin secretion. LB-A represents a novel small molecule agonist that ameliorates hyperglycemia in diabetic mice through specific activation of the GLP-1R/cAMP/PKA/pCREB/PTEN/FOXO1 pathway.
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BMC CANCER
·
2021
·Vol. 21
·期 1
·1-12
·
IF 4.43
Hong Xian,Li Zhi-Xuan,Hou Jie,Zhang Hui-Yu,Zhang Chun-Yan,Zhang Jian,Sun He,Pang Li-Hong,Wang Tao,Deng Zhi-Hui
Background Anterior gradient-2 (AGR2) is a proto-oncogene involved in tumorigenesis and cancer progression. AGR2, predominantly localized in the endoplasmic reticulum (ER), is also a secreted protein detected in the extracellular compartment in multiple cancers. However, the biological functions of intracellular and extracellular AGR2 remain to be elucidated. Methods Based on the biochemical structure of AGR2 protein, PANC-1 pancreatic cancer cells stably expressing ER-resident or secreted AGR2 were generated by a lentivirus-mediated stable overexpression system. The capacities of cell proliferation, migration, invasion and survival were assessed in PANC-1 stable cells. Moreover, EGFR expression and activation were determined to explore the possible mechanism of AGR2 roles in pancreatic cancer tumorigenesis. Results It was discovered that secreted AGR2, but not ER-resident AGR2, promotes cell proliferation, migration and invasion of PANC-1 cells. Moreover, the data indicated that both the ER-resident and the secreted AGR2 enhance the survival capacity of PANC-1 cells after tunicamycin-induced ER stress and gemcitabine treatment. However, EGFR expression and activation were not found to be involved in AGR2-dependent oncogenic phenotypes in PANC-1 cells. Conclusions Secreted AGR2 is predominantly involved in cell proliferation, migration and invasion in PANC-1 pancreatic cancer cells. Both secreted and ER-resident AGR2 contribute to the survival of PANC-1 cells under the challenging conditions. These findings provide insight into how different localizations of AGR2 have contributed to pancreatic cancer growth, metastasis, and drug sensitivity.
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高影响因子
JOURNAL OF CELLULAR PHYSIOLOGY
·
2020
·Vol. 236
·期 5
·3660-3674
·
IF 5.546
Xinxuan Cheng,Danxue He,Chunyan Liao,Sijie Lin,Liying Tang,Yuan-Liang Wang,Jiaoyue Hu,Wei Li,Zuguo Liu,Yalin Wu,Yi Liao
The underlying mechanisms of complement activation in Stargardt disease type 1 (STGD1) and age-related macular degeneration (AMD) are not fully understood. Overaccumulation of all- trans -retinal (atRAL) has been proposed as the pathogenic factor in both diseases. By incubating retinal pigment epithelium (RPE) cells with atRAL, we showed that C5b-9 membrane attack complexes (MACs) were generated mainly through complement alternative pathway. An increase in complement factor B (CFB) expression as well as downregulation of complement regulatory proteins CD46, CD55, CD59, and CFH were observed in RPE cells after atRAL treatment. Furthermore, interleukin-1β production was provoked in both atRAL-treated RPE cells and microglia/macrophages. Coincubation of RPE cells with interleukin-1 receptor antagonist (IL1Ra) and atRAL ameliorated complement activation and downregulated CFB expression by attenuating both p38 and c-Jun N-terminal kinase (JNK) signaling pathways. Our findings demonstrate that atRAL induces an autocrine/paracrine IL-1/IL-1R signaling to promote complement alternative pathway activation in RPE cells and provide a novel perspective on the pathomechanism of macular degeneration.
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Drug Metabolism and Pharmacokinetics
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2013
·
IF 2.071
Qiuxia Chen,Yicong Bian,Su Zeng
Caco-2 is a widely used cell model in drug absorption and P-glycoprotein (P-gp,MDR1) substrate identification. Long term vinblastine treatment of Caco-2 cells could increase the expression of P-gp, thus, the vinblastine resistant Caco-2 (Caco-2 vbl) cells can be used as a rapid and sensitive alternative model in identifying P-gp substrates. The mechanism of P-gp induction in this model is not clear, this study was therefore intended to clarify the possible factors involved in P-gp up- regulation in Caco-2 vbl cells. Since vinblastine is the inducer of both activator protein-1 (AP-1) and nuclear factor kappa B(NF-κB), we investigated the role of AP-1 and NF-κB in regulation of MDR1 gene expression. Our results indicated that the AP-1 and NF-κB luciferase activity was higher in Caco-2 vbl cells than that in Caco-2 cells by reporter gene assay. The mRNA expression of AP-1 subunit c-Jun and NF-κB was increased in Caco-2 vbl cells. The c-Jun inhibitor SP600125 and NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) suppressed the expression of MDR1 mRNA in Caco-2 vbl cells. In conclusion, this study provides the evidence that AP-1 and NF-κB are involved in the P-gp induction in Caco-2 vbl cells.
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Evidence-based Complementary and Alternative Medicine
·
2022
·
IF 2.65
Ying-Ying Wu,Yi-Lin Huang,Bin Dai,Jian-Wei Liu,Xu Han
Background/Aim. Abnormal proliferation and migration of vascular smooth muscle cells is one of the main causes of atherosclerosis (AS). Therefore, the suppression of abnormal proliferation and migration of smooth muscle cells are the important means for the prevention and inhibition of AS. The clinical effects of Guanxinping (GXP) tablets and preliminary clinical research on the topic have proved that GXP can effectively treat coronary heart disease, but its underlying mechanism remains unclear. This study aimed to confirm the inhibitory effect of GXP on the abnormal proliferation of mouse aortic vascular smooth muscle (MOVAS) cells and to explore the underlying mechanism. Methods. MOVAS cells were divided into two major groups: physiological and pathological groups. In the physiological group, MOVAS cells were directly stimulated with GXP, whereas in the pathological group, the cells were stimulated by endothelin-1 (ET-1) before intervention by GXP. At the same time, atorvastatin calcium, which effectively inhibits the abnormal proliferation of MOVAS cells, was used in the negative control group. CCK8 assay, scratch test, ELISA, Western blotting, and immunofluorescence staining were performed to observe the proliferation and migration of MOVAS cells and the expression levels of related factors after drug intervention in each group. Results. In the physiological group, GXP had no significant effect on the proliferation and migration of MOVAS cells and the related factors. In the pathological group, a high dose of GXP reduced the abnormal proliferation and migration of MOVAS cells. Further, it reduced the expression levels of PI3K; inhibited the phosphorylation of Akt (protein kinase B); upregulated IκB-α levels; prevented nuclear factor kappa B (NF-κB) from entering the nucleus; downregulated the expression of interleukin 6 (IL6), IL-1β, and iNOS; and upregulated the ratio of apoptosis-related factor Bax/Bcl-2. There was no significant difference between the high-dose GXP group and the atorvastatin calcium group (negative control group). Conclusion. Our findings revealed that GXP was able to inhibit the proliferation and migration of MOVAS cells by regulating the PI3K/Akt/NF-κB pathway.
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Science of Advanced Materials
·
2022
·Vol. 14
·期 7
·1175-1184
·
IF 1.067
Mei Qing,Shou Diwen,Quan Ying,Cheng Jiemin,Pan Pan,Chen Huiting,Huang Hongli,Li Yongqiang,Xia Yu,Zhou Yongjian
Lipid deposition is a key predisposing factor of nonalcoholic fatty liver disease (NAFLD). FOXO1 is obviously expressed in polarized M1 macrophages and may cause liver cell steatosis. Thus, silencing FOXO1 during M1 macrophage polarization using small interfering RNA (siRNA) technology
may alleviate lipid deposition in liver cells. However, a lack of effective and biocompatible carriers is challenging for such siRNA-delivery to macrophages. To improve this, RGDfC peptide-modified selenium nanoparticles (RGDfC-Se NPs) were fabricated as a siFOXO1 delivery carrier system.
We showed that RGDfC-Se NPs effectively increased siFOXO1 cellular uptake and silenced FOXO1 expression in human peripheral blood monocyte-like macrophages (THP-1 cells). Additionally, RGDfC-Se@siFOXO1 blocked M1 polarization in these cells. Also, FOXO-1-suppressed cell supernatants extenuated
lipid deposition in LO2 liver cells probably by down-regulating the expression of lipid deposition-related fat metabolic enzymes acetyl-CoA carboxylase 1 and fatty acid synthase. Furthermore, our in vivo analyses showed that RGDfC-Se@siFOXO1 attenuated hepatic steatosis by inhibiting
M1 macrophage polarization in mouse liver tissue. Our studies represent a new strategy and clinic treatment target for NAFLD.
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BIOMATERIALS
·
2017
·
IF 8.402
Si-An Xie,Tao Zhang,Jin Wang,Feng Zhao,Yun-Peng Zhang,Wei-Juan Yao,Sung Sik Hur,Yi-Ting Yeh,Wei Pang,Li-Sha Zheng,Yu-Bo Fan,Wei Kong,Xian Wang,Jeng-Jiann Chiu,Jing Zhou
Cells perceive the physical cues such as perturbations of extracellular matrix (ECM) stiffness, and translate these stimuli into biochemical signals controlling various aspects of cell behavior, which contribute to the physiological and pathological processes of multiple organs. In this study, we tested the hypothesis that during arterial stiffening , vascular smooth muscle cells (SMCs) sense the increase of ECM stiffness, which modulates the cellular phenotype through the regulation in DNA methyltransferases 1 (DNMT1) expression. Moreover, we hypothesized that the mechanisms involve intrinsic stiffening and deficiency in contractility of vascular SMCs. Substrate stiffening was mimicked in vitro with polyacrylamide gels. A contractile-to-synthetic phenotypic transition was induced by substrate stiffening in vascular SMCs through the down-regulation of DNMT1 expression. DNMT1 repression was also observed in the tunica media of mice aortas in an acute aortic injury model and a chronic kidney failure model, as well as in the tunica intima of human carotid arteries with calcified atherosclerotic lesions. DNMT1 inhibition facilitates arterial stiffening in vivo and promotes osteogenic transdifferentiation , calcification and cellular stiffening of vascular SMCs in vitro . These effects may be attributable, at least in part, to the role of DNMT1 in regulating the promoter activities of Transgelin (SM22α) and α-smooth muscle actin (SMA) and the functional contractility of SMCs. We conclude that DNMT1 is a critical regulator that negatively regulates arterial stiffening via maintaining the contractile phenotype of vascular SMCs. This research may facilitate elucidation of the complex crosstalk between vascular SMCs and their surrounding matrix in healthy and in pathological conditions and provide new insights into the implications for potential targeting of the phenotypic regulatory mechanisms in material-related therapeutic applications.
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EUROPEAN JOURNAL OF PHARMACOLOGY
·
2019
·
IF 3.17
Dong-Shuai Shen,Ya-Jun Yang,Xiao-Jun Kong,Ning Ma,Xi-Wang Liu,Shi-Hong Li,Zeng-Hua Jiao,Zhe Qin,Mei-Zhou Huang,Jian-Yong Li
Aspirin eugenol ester (AEE) was a promising drug candidate for treating inflammation, pain and fever and preventing cardiovascular diseases with fewer side effects than its precursors. Previous researches indicated that AEE could markedly inhibit agonist-induced platelet aggregation in vitro and ex vivo , however, the anti-platelet aggregation mechanisms of AEE remain to be defined. Here, AEE in vitro effects on agonist-induced granule-secretion, intercellular Ca 2+ mobilization and thromboxane A 2 (TXA 2 ) generation were examined. Vasodilator-stimulated phosphoprotein (VASP), mitogen-activated protein kinase (MAPK), Akt, Sirt 1 and CD40L expressions were also studied. In agonist-activated platelets in vitro , AEE markedly attenuated granule secretion markers (P-selectin expression and ATP release), intercellular Ca 2+ mobilization and thromboxane B 2 (TXB 2 ) formation. AEE also attenuated CD40L activation, suppressed extracellular-signal-regulated protein kinase 2 (ERK2), c-Jun N-terminal kinase 1 (JNK1) and Akt phosphorylation, and recovered Sirt1 expression, but the activation of p38, VASP Ser157 and VASP Ser239 , and the levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) were not affected by AEE. Overall, this study demonstrates that AEE inhibits agonist-induced platelet aggregation in vitro by regulating PI3K/Akt, MAPK and Sirt 1/CD40L pathways.
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Frontiers in Microbiology
·
2022
·
IF 6.064
Hexue Jia,Xiaoting Feng,Jiamin Huang,Yingjie Guo,Daolei Zhang,Xuezhi Li,Jian Zhao
Fungal cellulases usually contain a family 1 carbohydrate-binding module (CBM1), and its role was considered to recognize the substrate specifically. This study testified that the CBM1s derived from cellobiohydrolase I of Trichoderma reesei, Penicillium oxalicum , and Penicillium funiculosum could be used as an effective accessory protein in cellulase cocktails to enhance the saccharification of lignocellulose, and its enhancement effect was significantly superior to some reported accessory proteins, such as bovine serum albumin (BSA). The promoting effects of the CBM1s were related to not only the CBM1 sources and protein dosages, but also the substrate characteristics and solid consistency during enzymatic hydrolysis. The adsorption capacity of the CBM1s, the adsorption kinetic of TrCBM from T. reesei and cellobiohydrolase, endoglucanase, and β-glucosidase from P. oxalicum , and the effect of adding TrCBM on enzyme activities of free cellulases in the hydrolysis system were investigated, and the binding conformations and affinities of CBM1s to cellulose and lignin were predicted by molecular docking. It was speculated that the higher affinity of the CBM1s to lignin than cellulases could potentially enable the CBM1s to displace cellulase adsorbed on lignin or to preferentially adsorb onto lignin to avoid ineffective adsorption of cellulase onto lignin, which enhanced cellulase system efficiency during enzymatic hydrolysis of lignocellulose.
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