Bioactive Materials
·
2021
·
IF 14.593
Can Liu,Lei Fan,Zhenming Tian,Huiquan Wen,Lei Zhou,Pengfei Guan,Yian Luo,Chuncheung Chan,Guoxin Tan,Chengyun Ning,Limin Rong,Bin Liu
Conductive scaffolds have been shown to exert a therapeutic effect on patients suffering from peripheral nerve injuries (PNIs). However, conventional conductive conduits are made of rigid structures and have limited applications for impaired diabetic patients due to their mechanical mismatch with neural tissues and poor plasticity. We propose the development of biocompatible electroconductive hydrogels (ECHs) that are identical to a surgical dressing in this study. Based on excellent adhesive and self-healing properties, the thin film-like dressing can be easily attached to the injured nerve fibers, automatically warps a tubular structure without requiring any invasive techniques. The ECH offers an intimate and stable electrical bridge coupling with the electrogenic nerve tissues. The in vitro experiments indicated that the ECH promoted the migration and adhesion of the Schwann cells. Furthermore, the ECH facilitated axonal regeneration and remyelination in vitro and in vivo through the MEK/ERK pathway, thus preventing muscle denervation atrophy while retaining functional recovery. The results of this study are likely to facilitate the development of non-invasive treatment techniques for PNIs in diabetic patients utilizing electroconductive hydrogels.
研究领域:
生物医学工程
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神经科学
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材料科学
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产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2026
·
IF 5.1
Sheng-Li Wu,Xiao-Feng He,Pianchou Gongpan,Xiao-Yan Huang,Chang-An Geng
DCA stimulated GLP-1 secretion in STC-1 and NCI-H716 cells. • DCA decreased fasting blood glucose levels by promoting GLP-1 secretion in db/db mice. • DCA ameliorated glucose intolerance and insulin resistance and lowered serum TC levels. • DCA promoted GLP-1 secretion through specific activation on TGR5/PKA/MEK/ERK pathway. Type 2 diabetes mellitus (T2DM) is a heterogeneous metabolic disorder characterized by insulin resistance and progressive β cell dysfunction. Deoxycalyxin A (DCA), a unique diarylheptanoid-chalcone hybrid isolated from Alpinia katsumadai , was identified as a novel stimulator of GLP 1 secretion in both STC-1 (EC 50 : 10.7 μM) and NCI-H716 (EC 50 : 13.4 μM) cells. Oral administration of DCA (40 and 80 mg/kg) in db/db mice significantly reduced fasting blood glucose, ameliorated glucose intolerance and insulin resistance by enhancing endogenous GLP-1 secretion, and lowered the total serum cholesterol levels. Mechanistic study demonstrated that DCA identify the TGR5 receptor, which induces a significant increase in intracellular cyclic AMP (cAMP) levels, which activates PKA with subsequent sequential phosphorylation of MEK1/2 and ERK activation, ultimately enhancing GLP-1 secretion. Our findings identify DCA as a novel TGR5 agonist to stimulate GLP-1 secretion via the TGR5/PKA/MEK/ERK pathway, which has the potential to be developed as a promising antidiabetic lead with a distinct mechanism of action. DCA, a unique diarylheptanoid-chalcone from Alpinia katsumadai , is a novel TGR5 agonist to stimulate GLP-1 secretion via PKA/MEK/ERK pathway, which has the potential to be developed as a promising antidiabetic candidate. Download: Download high-res image (123KB) Download: Download full-size image
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DOI
高影响因子
GENE
·
2022
·
IF 3.913
Xiang Li,Nan Wang,Yutong Wu,Yidan Liu,Ruoyu Wang
Background Aldehyde dehydrogenase 6 family member A1 (ALDH6A1) is associated with multiple diseases, but its pathogenesis in colon cancer (CC) is ambiguous and needs further study so that this research explores the function of ALDH6A1 in CC. Methods The level of ALDH6A1 in colon adenocarcinoma (COAD), CC tissues, and cells was measured by starBase v2.0, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot. Post transfection with overexpressed (oe)-ALDH6A1, cell biological behaviors, as well as apoptosis-, matrix metalloproteinase (MMP)-, and rat sarcoma virus (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway-related markers were measured by cell function experiments, qRT-PCR, and western blot. Next, the effects of small interfering RNA targeting ALDH6A1 (si-ALDH6A1) and RAS/RAF inhibitor (MCP110) on cell biological behaviors, as well as apoptosis-, MMP-, and RAS/RAF/MEK/ERK pathway-related markers were detected again. Results ALDH6A1 was low-expressed in COAD, CC tissues, and cells. Oe-ALDH6A1 weakened cell vitality, migration and invasionbut facilitated apoptosis; while it reduced expression levels of Bcl-2, MMP-2, MMP-9 and the RAS/RAF/MEK/ERK pathway-related markers but promoted Bax level. However, the regulation of si-ALDH6A1 on cell biological behaviors and related genes was opposite to that of oe-ALDH6A1. Moreover, MCP110 rescued the regulation of si-ALDH6A1 on cell biological behaviors, expressions of apoptosis- MMP- as well as RAS/RAF/MEK/ERK pathway-related markers. To sum up, ALDH6A1 attenuated CC progression by down-regulating the expressions of RAS/RAF/MEK/ERK pathway-related markers.
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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DOI
PubMed
高影响因子
Chemical Biology & Drug Design
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2025
·Vol. 105
·期 2
·e70067
·
IF 3.3
Jingting Zeng,Zhenshuo Luo,Tiansheng Zhao,Chunhua Xia,Fanglan Liu,Na Li,Lailiang Qu,Cheng Wang
Aberrant activation of the RAS/RAF/MEK/ERK pathway occurs in more than 30% of human cancers. As part of this pathway, MEK1/2 has crucial roles in tumorigenesis, cell proliferation, and inhibition of apoptosis. At present, a number of MEK1/2 inhibitors are approved for the treatment of melanoma. However, MEK1/2 inhibitors have poor single-drug efficacy in the treatment of solid tumors and are prone to drug resistance. A series of compounds containing a diarylamine skeleton and phenylacrylamide (acrylamide) have been designed and synthesized in this paper. The most promising compound M15 showed good inhibitory activity of MEK1 (IC 50 = 10.29 nM) and good inhibitory effect on three types of solid tumor cells: MDA-MB-231(IC 50 = 2.76 μM), HepG2 (IC 50 = 2.57 μM) and A549 (IC 50 = 5.40 μM). At the same time, M15 was less toxic to human normal cells (MCF-10A IC 50 > 20 μM) and has certain stability of liver microsomes in vitro (human, t 1/2 = 27.9 min; rat, t 1/2 > 60 min). It can induce apoptosis of MDA-MB-231 cells and slow down their migration. Therefore, compound M15 acts as a novel MEK1/2 inhibitor and may be a promising candidate for solid tumor intervention.
研究领域:
肿瘤学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2019
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IF 4.825
Wensong Yao,Zhen Lin,Peiying Shi,Bing Chen,Gang Wang,Jianyong Huang,Yuxia Sui,Qicai Liu,Shaoguang Li,Xinhua Lin,Qicai Liu,Hong Yao
Colorectal cancer (CRC) is one of the most common malignant tumors worldwide and tends to have drug resistance. Delicaflavone (DLF), a novel anticancer agent of biflavonoid from Selaginella doederleinii Hieron , showed strong anti-CRC activities, which has not yet been reported. In this study, we investigated the effects and possible anti-CRC mechanism of DLF in vitro and in vivo . It was shown that DLF significantly inhibited the cells viability and induced G2/M phase arrest, apoptosis , the loss of mitochondrial membrane potential (Δψm), generation of ROS and increase of intracellular Ca 2+ in HT29 and HCT116 cells by MTT assay, TEM, flow cytometry and inverted fluorescence microscope. Western blot and qPCR assays results further confirmed DLF induced caspase-dependent apoptosis and inhibited PI3K/AKT/mTOR and Ras/MEK/Erk signaling pathways in CRC cells. Meanwhile, DLF significantly suppressed the tumor growth via activation of Caspase-9 and Caspase-3 protein and decrease of ki67 and CD34 protein without apparent side effects in vivo . In summary, these results indicated DLF induced ROS-mediated cell cycle arrest and apoptosis through ER stress and mitochondrial pathway accompanying with the inhibition of PI3K/AKT/mTOR and Ras/MEK/Erk signaling cascade. Thus DLF could be a potential therapeutic agent for CRC.
研究领域:
肿瘤学
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药理学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF MEDICAL VIROLOGY
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2025
·Vol. 97
·期 3
·e70267
·
IF 4.6
Wenting Mao,Yi Wan,Yang Liu,Minmin Zhou,Xiaoying Jia,Yuxia Hou,Wei Wang
The lymphocytic choriomeningitis virus (LCMV) is a widespread pathogen that causes mild-to-severe infections to severe outcomes. In this study, we explored the potential of trametinib, a mitogen-activated protein kinase (MAPK) inhibitor, as an antiviral agent against LCMV. Trametinib demonstrated significant antiviral activity against two distinct LCMV strains, Armstrong and Cl13, with promising half-maximal inhibitory concentrations (IC 50 ) and selectivity indices (SI) indicating its potency and safety profile. Mechanistic investigations revealed that trametinib interfered with multiple stages of the LCMV life cycle, including membrane fusion and genomic replication, leading to the robust inhibition of viral proliferation. Furthermore, trametinib disrupted the MEK/ERK signaling pathway, which is crucial for LCMV infection. In both in vitro and in vivo experiments, trametinib effectively reduced viral loads and mitigated pathological damage to the spleen and liver tissues. Overall, our findings suggest that trametinib is a promising novel therapeutic option for combating LCMV infection by targeting key stages of the viral life cycle and disrupting host cellular signaling pathways. Further exploration of the antiviral properties of trametinib is likely to pave the way for its clinical development as a treatment for LCMV infections.
研究领域:
病毒学
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药物研发
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医学
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产品关联
DOI
PubMed
高影响因子
Clinics and Research in Hepatology and Gastroenterology
·
2021
·
IF 2.947
Huanqiu Liu,Ji Li,Chengwei Jiang,Tong Yuan,Haichun Ma
Objective Hepatic ischemia/reperfusion injury (IRI) is an unsettled and intractable conundrum in clinical treatment after liver transplantation and resection. Cellular communication network factor 1 (CCN1) is upregulated in liver IRI and may play a key role in this process. The objective of this study is to investigate the regulatory mechanism of CCN1 in liver IRI, which may provide new insight into liver IRI clinical treatment. Methods The hepatic ischemia/reperfusion model was established in male C57BL/6 mice by occlusion of vessels in the liver followed by reperfusion. The mice were transfected with two small interfering RNAs (siRNAs) against CCN1 for CCN1 knockdown. The hypoxia/reoxygenation (HR) model was established in vitro using mouse hepatic cells followed by transfection with a siRNA and treatment with an ERK activator TPA to confirm the effects of CCN1 on the MEK/ERK pathway in liver IRI. Results In hepatic IRI, CCN1 was upregulated and its knockdown reduced alanine aminotransferase and aspartate transaminase levels, myeloperoxidase activity, and the levels of IL-6 and TNF-α. CCN1 downregulation alleviated inflammatory cell infiltration and apoptosis in the liver. The expressions of cleaved caspase-9, cleaved caspase-3, Bax, and CHOP were decreased with an increased Bcl-2 level after CCN1 knockdown. The phosphorylation and activation of proteins in ER stress and MEK/ERK pathway were inhibited by CCN1 knockdown. In vitro , the levels of proinflammatory cytokines, apoptosis-inducing proteins, and proteins in ER stress and MEK/ERK pathway, which were decreased by CCN1 knockdown in HR, were restored by TPA, confirming that the activation of ERK aggravated cell apoptosis after reoxygenation. Conclusion Overall, CCN1 knockdown may suppress the inflammation, apoptosis during hepatic IRI by reducing the MEK/ERK pathway activation, which may be a breakthrough point in clinical alleviation of hepatic IRI caused by liver transplantation and resection.
研究领域:
肝病学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
MEDICAL SCIENCE MONITOR
·
2019
·
IF 1.98
Zhongfei Shen,Yun Xu,Xiaohong Jiang,Zhijian Wang,Yanjun Guo,Weiwei Pan,Jie Hou
Background Avicularin (AL, quercetin-3-α-l-arabinofuranoside), a glycoside of quercetin, has been reported to display diverse pharmacological properties. The present study aimed to investigate whether AL has an anti-depressant-like effect on a mouse model of depression induced by chronic unpredictable mild stress (CUMS). Material/Methods A mouse model of depression was established and treated with different concentrations of AL (1.25, 2.5 or 5.0 mg/kg/d) and fluoxetine (20 mg/kg/d). Then, behavioral tests – sucrose preference test (SPT), forced swimming test (FST), and the tail suspension test (TST) – were performed. The levels proinflammatory cytokines – interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) – in the hippocampi of mice were detected by enzyme-linked immunosorbent assay (ELISA). Apoptosis of hippocampal neuronal cells was determined using flow cytometry. Expression levels of phosphorylated (p)-MEK1/2, p-ERK1/2, p-NF-κB (p-p65), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), Caspase3, and B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax) were measured by Western blot assay or/and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. Results The results showed that AL significantly relieved CUMSinduced depressive-like behaviors. Compared with the model mice, AL treatment significantly increased the sucrose preference of the mice, and the immobility time in the FST and the TST were shortened. We also found that AL decreased CUMS-induced increases in the levels of IL-1β, IL-6, and TNF-α in the hippocampi of mice. AL significantly decreased the apoptosis rate of hippocampal neuronal cells in mice, which was increased by CUMS. Furthermore, activation of the MEK/ERK/NF-κB pathway induced by CUMS was inhibited by AL treatment. Conclusions Our results show the anti-depressant-like effects of AL on CUMS-induced depression in a mouse model.
研究领域:
药理学
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神经科学
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行为科学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
RSC Advances
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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
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神经生物学
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有机化学
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DOI
PubMed
高影响因子
Theranostics
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2024
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IF 12.4
Maojiao Li,Qi Tang,Chengcheng Liao,Zhuo Wang,Siyuan Zhang,Qingqing Liang,Cheng Liang,Xiaodong Liu,Jingyi Zhang,Weidong Tian,Li Liao
Rationale: Mesenchymal stromal cells (MSCs) are considered a promising resource for cell therapy, exhibiting efficacy in ameliorating diverse bone diseases. However, most MSCs undergo apoptosis shortly after transplantation and produce apoptotic extracellular vesicles (ApoEVs). This study aims to clarify the potential role of ApoEVs from apoptotic MSCs in ameliorating osteoporosis and molecular mechanism. Methods: In this study, Dio-labeled bone marrow mesenchymal stem cells (BMSCs) were injected into mice to track BMSCs apoptosis and ApoEVs production. ApoEVs were isolated from BMSCs after inducing apoptosis, the morphology, size distribution, marker proteins expression of ApoEVs were characterized. Protein mass spectrometry analysis revealed functional differences in proteins between ApoEVs and BMSCs. BMSCs were adopted to test the cellular response to ApoEVs. Ovariectomy mice were used to further compare the ability of ApoEVs in promoting bone formation. SiRNA and lentivirus were used for gain and loss-of-function assay. Results: The results showed that BMSCs underwent apoptosis within 2 days after being injected into mice and produce a substantial quantity of ApoEVs. Proteomic analysis revealed that ApoEVs carried a diverse functional array of proteins, and easily traversed the circulation to reach the bone. After being phagocytized by endogenous BMSCs, ApoEVs efficiently promoted the proliferation, migration, and osteogenic differentiation of BMSCs. In an osteoporosis mouse model, treatment of ApoEVs alleviated bone loss and promoted bone formation. Mechanistically, ApoEVs carried Ras protein and activated the Ras/Raf1/Mek/Erk pathway to promote osteogenesis and bone formation in vitro and in vivo . Conclusion: Given that BMSC-derived ApoEVs are high-yield and easily obtained, our data underscore the substantive role of ApoEVs from dying BMSCs to treat bone loss, presenting broad implications for cell-free therapeutic modalities.
研究领域:
干细胞生物学
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骨生物学
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再生医学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2024
·
IF 9.4
Jiashang Liu,Ruijia Yan,Bixue Wang,Shu Chen,Hua Hong,Changsheng Liu,Xi Chen
Motor functional improvement represents a paramount treatment objective in the post-spinal cord injury (SCI) recovery process. However, neuronal cell death and axonal degeneration following SCI disrupt neural signaling, impeding the motor functional recovery. In this study, we developed a multifunctional decellularized spinal cord-derived extracellular matrix (dSECM), crosslinked with glial cell-derived neurotrophic factor (GDNF), to promote differentiation of stem cells into neural-like cells and facilitate axonogenesis and remyelination. After decellularization, the immunogenic cellular components were effectively removed in dSECM, while the crucial protein components were retained which supports stem cells proliferation and differentiation. Furthermore, sustained release of GDNF from the dSECM facilitated axonogenesis and remyelination by activating the PI3K/Akt and MEK/Erk pathways. Our findings demonstrate that the dSECM-GDNF platform promotes neurogenesis, axonogenesis, and remyelination to enhance neural signaling, thereby yielding promising therapeutic effects for motor functional improvement after SCI. Statement of significance The dSECM promotes the proliferation and differentiation of MSCs or NSCs by retaining proteins associated with positive regulation of neurogenesis and neuronal differentiation, while eliminating proteins related to negative regulation of neurogenesis. After crosslinking, GDNF can be gradually released from the platform, thereby promoting neural differentiation, axonogenesis, and remyelination to enhance neural signaling through activation of the PI3K/Akt and MEK/Erk pathways. In vivo experiments demonstrated that dSECM-GDNF/MSC@GelMA hydrogel exhibited the ability to facilitate neuronal regeneration at 4 weeks post-surgery, while promoting axonogenesis and remyelination at 8 weeks post-surgery, ultimately leading to enhanced motor functional recovery. This study elucidates the ability of neural regeneration strategy to promote motor functional recovery and provides a promising approach for designing multifunctional tissue for SCI treatment.
研究领域:
神经科学
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组织工程
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再生医学
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干细胞生物学
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产品关联
DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2023
·
IF 5.8
Xingming Wang,Xiupeng Zhu,Danni Wang,Xiaoxu Li,Juan Wang,Guangfu Yin,Zhongbing Huang,Ximing Pu
Inefficient use and loss of exogenously implanted mesenchymal stem cells (MSCs) are major concerns in MSCs-based bone tissue engineering. It is a promising approach to overcome the above issues by recruiting and regulation of endogenous MSCs. However, there are few substances that can recruit MSCs effectively and specifically to the site of bone injury. In this study, we identified a phage clone (termed P11) with specific affinity for MSCs through phage display biopanning, and further investigated the effects of P11 on the cytological behavior of MSCs and macrophages. The results showed that P11 could bind MSCs specifically and promote the proliferation and migration of MSCs. Meanwhile, P11 could polarize macrophages to the M1 phenotype and significantly changed their morphology, which further enhanced the chemotaxis of MSCs. Additionally, RNA-seq results revealed that P11 could promote the secretion of osteogenesis-related markers in MSCs through the TPL2-MEK-ERK signaling pathway. Altogether, P11 has great potential to be used as growth factor alternatives in bone tissue engineering, with the advantages of cheaper and stable activity. Our study also advances the understanding of the effects of phages on macrophages and MSCs, and provides a new idea for the development in the field of phage-based tissue engineering.
研究领域:
组织工程
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干细胞生物学
·
骨再生
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噬菌体疗法
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）