NEUROPHARMACOLOGY
·
2025
·
IF 4.6
Wen-Hui Ni,Ke Wang,Yun Wang,Jia Lu,Chun-Ting Lu,Wen Rong,Yi-Feng Gu,Wen-Juan Qian,Hai-Long Zhang
Chronic inflammatory pain is a top priority for arthritis patients seeking medical care. Despite the availability of NSAIDs and glucocorticoids, pain management becomes increasingly challenging due to central and peripheral sensitization. Previous studies have shown that Matrix metalloproteinase 2 (MMP2) promotes neuroinflammation by cleaving extracellular matrix proteins and activating pro-inflammatory cytokines. Folic acid acts as a promising candidate for the treatment of neuroinflammatory diseases due to its neuroprotective effects. However, the role of folic acid in inflammatory pain remains unclear. This study investigated the analgesic mechanisms of folic acid in inflammatory pain. Adult rats underwent inflammatory pain by injecting complete freund's adjuvant (CFA) into the right hindpaw. Behavioral tests were used to assess the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). The results demonstrated that CFA injection induced abnormal mechanical and thermal pain and increased MMP2 expression in L3-L5 DRG and SDH of CFA rats. MMP2 was mainly expressed in neurons rather than glial cells in L3-L5 DRG of CFA rats. We further discovered that MMP2 inhibitor auraptene or knockdown alleviated inflammatory pain in CFA rats. Interestingly, we observed that long-term folic acid treatment reversed MMP2 overexpression, resulting in sustained relief of chronic inflammatory pain. Consistently, long-term folic acid treatment also relieved pain-induced anxiety. These results indicated that folic acid had a protective role in chronic inflammatory pain and pain-induced anxiety by repressing MMP2 expression. Folic acid or auraptene might be promising therapeutic options for the treatment of chronic inflammatory pain.
研究领域:
药理学
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神经科学
·
炎症研究
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产品关联
DOI
PubMed
高影响因子
Frontiers in Oncology
·
2021
·
IF 6.244
Qin Hongkun,Gui Yanping,Ma Rong,Zhang Heng,Guo Yabing,Ye Yuting,Li Jia,Zhao Li,Wang Yajing
MicroRNAs are a group of endogenous small non-coding RNAs commonly dysregulated in tumorigenesis, including glioblastoma (GBM), the most malignant brain tumor with rapid proliferation, diffuse invasion, and therapeutic resistance. Accumulating evidence has manifested that miR-1258 exerts an inhibitory role in many human cancers. However, the expression pattern of miR-1258 and its potential function in GBM tumorigenesis remain unclear. In this study, we reported that miR-1258 expression decreased with the ascending pathological grade of glioma, which indicated an unfavorable prognosis of patients. Functional assays revealed an inhibitory effect of miR-1258 on malignant proliferation, therapeutic resistance, migration, and invasion of GBM in vitro. Moreover, xenograft models also suggested a repression effect of miR-1258 on gliomagenesis. Mechanistically, miR-1258 directly targeted E2F1 in 3’-untranslated regions and attenuated E2F1-mediated downstream gene PCNA and MMP2 transcriptions. Furthermore, restoration of E2F1 expression in GBM cells effectively rescued the tumor-suppressive effect of miR-1258. Our studies illustrated that miR-1258 functioned as a tumor suppressor in GBM by directly targeting E2F1, subsequently inhibiting PCNA and MMP2 transcriptions, which contributed to new potential targets for GBM therapy and other E2F1-driven cancers.
研究领域:
肿瘤学
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分子生物学
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神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2021
·
IF 5.875
Chaoqun Li,Ke Zhang,Aidi Liu,Tianxiang Yue,Yinghui Wei,Hangsheng Zheng,Ji-Gang Piao,Fanzhu Li
Arsenic trioxide (ATO) is the active ingredient in traditional Chinese medicine, i.e., Arsenic, which has shown excellent therapeutic effects on hepatocellular carcinoma. However, due to its poor tumor distribution and high toxicity, the mass adoption of ATO in clinical applications has been severely impeded. In this study, matrix metalloproteinase 2 (MMP2)-responsive cleaved cell-penetrating peptide (PF) and folate (FA) co-modified liposome coated calcium arsenate nanoparticles (FA/PF-LP-CaAs) were fabricated based on these two considerations: (1) The tumor microenvironment characterized by overexpressed MMP2 in extracellular matrix and folate receptor on the cell membrane can enhance drug accumulation and accelerate endocytosis; (2) leveraging different toxicity of arsenic in different valence states, i.e., AsV can be reduced to more toxic AsIII by glutathione in tumor cells. Furthermore, FA/PF-LP-CaAs could be responsively degraded by the mild acidic tumor environment, and the degraded product could escape from lysosomes after endocytosis. More importantly, in light of the in vivo biodistribution and pharmacodynamic studies, the vehicle was able to accumulate in the tumor efficiently. Also, it was able to exhibit excellent anti-tumor efficacy with minimized side effects when compared to single-modified counterparts. Thus, the novel strategy based on the tumor microenvironment proposed in this work can enhance the tumor-targeting efficiency and intratumor toxicity.
研究领域:
药理学
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肿瘤学
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纳米医学
·
癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Chinese Journal of Integrative Medicine
·
2024
·
IF 2.2
Liu Xiao-rong,Li Shuo-fu,Mei Wen-ya,Liu Xiang-dan,Zhou Ri-bao
Objective To investigate the effect of isorhamnetin on the pathology of rheumatoid arthritis (RA). Methods Tumor necrosis factor (TNF)- α -induced fibroblast-like synoviocytes (FLS) was exposed to additional isorhamnetin (10, 20 and 40 µ mol/L). Overexpression vectors for matrix metalloproteinase-2 (MMP2) or MMP9 or SRC were transfected to explore their roles in isorhamnetin-mediated RA-FLS function. RA-FLS viability, migration, and invasion were evaluated. Moreover, a collagen-induced arthritis (CIA) rat model was established. Rats were randomly divided to sham, CIA, low-, medium-, and high-dosage groups using a random number table ( n =5 in each group) and administed with normal saline or additional isorhamnetin [2, 10, and 20 mg/(kg·day)] for 4 weeks, respectively. Arthritis index was calculated and synovial tissue inflammation was determined in CIA rats. The levels of MMP2, MMP9, TNF-α, interleukin-6 (IL-6), and IL-1 β, as well as the phosphorylation levels of SRC, extracellular regulated kinase (ERK), and cyclic adenosine monophosphate response element-binding (CREB), were detected in RA-FLS and synovial tissue. Molecular docking was also used to analyze the binding of isorhamnetin to SRC. Results In in vitro studies, isorhamnetin inhibited RA-FLS viability, migration and invasion ( P <0.05). Isorhamnetin downregulated the levels of MMP2, MMP9, TNF-α, IL-6, and IL-1 β in RA-FLS ( P <0.05). The overexpression of either MMP2 or MMP9 reversed isorhamnetin-inhibited RA-FLS migration and invasion, as well as the levels of TNF-α, IL-6, and IL-1 β ( P <0.05). Furthermore, isorhamnetin bound to SRC and reduced the phosphorylation of SRC, ERK, and CREB ( P <0.05). SRC overexpression reversed the inhibitory effect of isorhamnetin on RA-FLS viability, migration and invasion, as well as the negative regulation of MMP2 and MMP9 ( P <0.05). In in vivo studies, isorhamnetin decreased arthritis index scores ( P <0.05) and alleviated synovial inflammation. Isorhamnetin reduced the levels of MMP2, MMP9, TNF-α, IL-6, and IL-1 β, as well as the phosphorylation of SRC, ERK, and CREB in synovial tissue ( P <0.05). Notably, the inhibitory effect of isorhamnetin was more pronounced at higher concentrations ( P <0.05). Conclusion Isorhamnetin exhibited anti-RA effects through modulating SRC/ERK/CREB and MMP2/MMP9 signaling pathways, suggesting that isorhamnetin may be a potential therapeutic agent for RA.
研究领域:
药理学
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免疫学
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风湿病学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
DIGESTIVE DISEASES AND SCIENCES
·
2022
·Vol. 67
·期 10
·4780-4796
·
IF 3.487
Duan Houyu,Ding Xiang,Luo Hesheng
Background and Aims KISS-1 is an established tumor suppressor that inhibits metastases in various malignancies. However, little is known regarding its role in esophageal squamous cell carcinoma (ESCC). The aim of the present study was to identify the possible mechanisms of KISS-1 in ESCC metastasis. Methods The expression levels of KISS-1 mRNA and protein in ESCC samples and cell lines were analyzed by qRT-PCR, IHC, and western blotting. Bisulfite sequencing PCR (BSP) and methylation-specific PCR (MSP) were used to analyze the methylation pattern of KISS-1 promoter in ESCC cells with or without 5-Aza-dC treatment. The role of KISS-1 in the progression and metastasis of ESCC was analyzed through in vitro functional assays. Results KISS-1 mRNA and protein were markedly downregulated in ESCC tissues and cell lines compared to the respective controls. Hypermethylation of KISS-1 promoter correlated to its lower expression levels in ESCC, and KISS-1 demethylation inhibited tumor progression. Ectopic KISS-1 overexpression inhibited tumor cell metastasis in vitro. In addition, KISS-1 overexpression downregulated the matrix metalloproteinase 2 and 9 (MMP2 and 9) and inhibited epithelial–mesenchymal transition (EMT). Finally, KISS-1 downregulated phosphorylated extracellular regulated protein kinase 1/2 (ERK1/2) and phosphorylated p38 mitogen-activated protein kinase (MAPK) without affecting their total expression levels in the ESCC cells. MAPK/ERK and p38 MAPK agonists reversed the suppressive effects of KISS-1. Conclusions The hypermethylation of KISS-1 promoter partly contributed to its downregulation in ESCC. KISS-1 inhibits the metastasis of ESCC cells by targeting the MMP2/9/ERK/p38 MAPK axis.
研究领域:
肿瘤学
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分子生物学
·
癌症遗传学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2016
·
IF 7.145
Wenxiu Hou,Fangfang Xia,Carla S. Alves,Xiaoqing Qian,Yuming Yang,Daxiang Cui
A unique matrix metalloproteinase 2-targeted photosensitizer delivery platform was developed in this study for tumor-targeting imaging and photodynamic therapy. The model photosensitizer therapeutic agent chlorin e6 (Ce6) was first covalently conjugated with matrix metalloproteinase 2-cleavable polypeptide and then modified with polyethylene glycol via a redox-responsive cleavable disulfide linker. The resultant matrix metalloproteinase 2-cleavable polypeptide modified PEGylated Ce6 (PEG-SS-Ce6-MMP2) nanoparticles, which formed via self-assembly, were observed to be monodisperse and significantly stable in aqueous solution. In addition, owing to their cellular redox-responsiveness at the cleavable disulfide linker, the PEG-SS-Ce6-MMP2 nanoparticles were able to release Ce6 rapidly. Despite displaying enhanced intracellular internalization, the synthesized PEG-SS-Ce6-MMP2 nanoparticles did not compromise their phototoxic effects toward A549 cancer cells when compared with free Ce6 and PEGylated Ce6 nanoparticles. In vivo experiments further revealed that, in contrast with the free Ce6 or with the PEGylated Ce6 nanoparticles, the PEG-SS-Ce6-MMP2 nanoparticles showed a remarkable increase in tumor-targeting ability and a significantly improved photodynamic therapeutic efficiency in A549 tumor-bearing mice. These results suggest that the PEG-SS-Ce6-MMP2 nanoparticles hold great potential for tumor-targeting imaging and photodynamic therapy.
研究领域:
纳米医学
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癌症研究
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诊疗学
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2024
·
IF 12.2
Di Lei,Tingting Chen,Cuifang Fan,Qingzhen Xie
Benz[a]anthracene (BaA), a hazardous polycyclic aromatic hydrocarbon classified by the EPA, is a probable reproductive toxicant. Epidemiological studies suggest that BaA exposure may be a risk factor for recurrent miscarriage (RM). However, the underlying mechanisms are not well understood. This study identified DEC1 as a key gene through RNA-seq and single-cell RNA sequencing analysis. DEC1 expression was found to be downregulated in villous tissues from women with RM and in primary extravillous trophoblasts (EVTs) exposed to BaA. BaA suppressed DEC1 expression by promoting abnormal methylation patterns. Further analysis revealed that ARHGAP5 is a direct target of DEC1 in EVTs, where DEC1 inhibits trophoblast invasion by directly regulating ARHGAP5 transcription. Additionally, BaA destabilized matrix metalloproteinase 2 (MMP2) by activating the aryl hydrocarbon receptor (AhR) and promoting E3 ubiquitin ligase MID1-mediated degradation. In a mouse model, BaA induced miscarriage by modulating the DEC1/ARHGAP5 and MID1/MMP2 axes. Notably, BaA-induced miscarriage in mice was prevented by DEC1 overexpression or MID1 knockdown. These findings indicate that BaA exposure leads to miscarriage by suppressing the DEC1/ARHGAP5 pathway and enhancing the MID1/MMP2 pathway in human EVTs.
研究领域:
生殖毒理学
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分子生物学
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细胞生物学
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表观遗传学
·
动物模型
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2024
·
IF 6.9
Han Yan-lu,Yan Teng-teng,Li Hua-xin,Chen Sha-sha,Zhang Zhen-zhen,Wang Meng-yao,Chen Mei-jie,Chen Yuan-li,Yang Xiao-xiao,Wei Ling-ling,Duan Ya-jun,Zhang Shuang
Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome with cardiac dysfunction, fluid retention and reduced exercise tolerance as the main manifestations. Current treatment of HFpEF is using combined medications of related comorbidities, there is an urgent need for a modest drug to treat HFpEF. Geniposide (GE), an iridoid glycoside extracted from Gardenia Jasminoides, has shown significant efficacy in the treatment of cardiovascular, digestive and central nervous system disorders. In this study we investigated the therapeutic effects of GE on HFpEF experimental models in vivo and in vitro. HFpEF was induced in mice by feeding with HFD and L -NAME (0.5 g/L) in drinking water for 8 weeks, meanwhile the mice were treated with GE (25, 50 mg/kg) every other day. Cardiac echocardiography and exhaustive exercise were performed, blood pressure was measured at the end of treatment, and heart tissue specimens were collected after the mice were euthanized. We showed that GE administration significantly ameliorated cardiac oxidative stress, inflammation, apoptosis, fibrosis and metabolic disturbances in the hearts of HFpEF mice. We demonstrated that GE promoted the transcriptional activation of Nrf2 by targeting MMP2 to affect upstream SIRT1 and downstream GSK3β, which in turn alleviated the oxidative stress in the hearts of HFpEF mice. In H9c2 cells and HL-1 cells, we showed that treatment with GE (1 μM) significantly alleviated H 2 O 2 -induced oxidative stress through the MMP2/SIRT1/GSK3β pathway. In summary, GE regulates cardiac oxidative stress via MMP2/SIRT1/GSK3β pathway and reduces cardiac inflammation, apoptosis, fibrosis and metabolic disorders as well as cardiac dysfunction in HFpEF. GE exerts anti-oxidative stress properties by binding to MMP2, inhibiting ROS generation in HFpEF through the SIRT1/Nrf2 signaling pathway. In addition, GE can also affect the inhibition of the downstream MMP2 target GSK3β, thereby suppressing the inflammatory and apoptotic responses in HFpEF. Taken together, GE alleviates oxidative stress/apoptosis/fibrosis and metabolic disorders as well as HFpEF through the MMP2/SIRT1/GSK3β signaling pathway.
研究领域:
心脏病学
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药理学
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分子生物学
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病理生理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BMC Cardiovascular Disorders
·
2024
·Vol. 24
·期 1
·1-13
·
IF 2
Liu Hai-Hua,Wei Wei,Wu Fei-Fei,Cao Lu,Yang Bing-Jie,Fu Jia-Ning,Li Jing-Xia,Liang Xin-Yue,Dong Hao-Yu,Heng Yan-Yan,Zhang Peng-Fei
Background Hyperlipidemia damages vascular wall and serves as a foundation for diseases such as atherosclerosis, hypertension and stiffness. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is implicated in vascular dysfunction associated with hyperlipidemia-induced vascular injury. Sodium tanshinone IIA sulfonate (STS), a well-established cardiovascular protective drug with recognized anti-inflammatory, antioxidant, and vasodilatory properties, is yet to be thoroughly investigated for its impact on vascular relaxant imbalance induced by hyperlipidemia. Methods In this study, we treated ApoE-knockout (ApoE-/-) mouse with STS and assessed the activation of the NLRP3 inflammasome, expression of MMP2/9, integrity of elastic fibers, and vascular constriction and relaxation. Results Our findings reveal that STS intervention effectively preserves elastic fibers, significantly restores aortic relaxation function in ApoE-/- mice, and reduces their excessive constriction. Furthermore, STS inhibits the phosphorylation of spleen tyrosine kinase (SYK), suppresses NLRP3 inflammasome activation, and reduces MMP2/9 expression. Conclusions These results demonstrate that STS protects vascular relaxation against hyperlipidemia-induced damage through modulation of the SYK-NLRP3 inflammasome-MMP2/9 pathway. This research provides novel insights into the mechanisms underlying vascular relaxation impairment in a hyperlipidemic environment and uncovers a unique mechanism by which STS preserves vascular relaxation, offering valuable foundational research evidence for its clinical application in promoting vascular health.
研究领域:
心血管药理学
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炎症
·
血管生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ANALYTICA CHIMICA ACTA
·
2023
·
IF 6.2
Jihua Wei,Zichun Song,Jiuying Cui,Yuanxun Gong,Qianli Tang,Kai Zhang,Xinlei Song,Xianjiu Liao
In the current study, a novel electrochemiluminescence biosensor based on the entropy-driven DNA tetrahedron for the detection of matrix metalloproteinase 2 (MMP2), an enzyme that regulates extracellular matrix remodeling and affects aging was reported. The biosensor utilizes an inverted DNA tetrahedron structure, which exposes three vertices to the solution, as molecular recognition units for capturing specific biomolecules. The biosensor also employs a ratiometric method and an entropy-driven reaction, which enhance the response rate and sensitivity of the detection. The biosensor can detect MMP2 with a detection limit of 55.2 fM, which is lower than that of conventional sensors. The biosensor also exhibits excellent stability and reproducibility, and can accurately measure MMP2 levels in complex samples, such as human serum. The paper demonstrates the feasibility and effectiveness of using the “inverted” DNA tetrahedron structure and the entropy-driven process to construct interfacial biosensors. The paper also discusses the potential applications of the biosensor in clinical diagnosis and anti-aging research, where MMP2 plays a crucial role in tissue damage and repair. The paper provides a valuable contribution to the field of biosensor development, and opens up new possibilities for using DNA nanotechnology for sensitive and reliable detection of various biomolecules.
研究领域:
生物传感器开发
·
DNA纳米技术
·
衰老研究
·
临床诊断
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CURRENT MEDICINAL CHEMISTRY
·
2023
·
IF 4.1
Xu Cong,Zhang Cheng,Ganesan Kumar,Qui Chen,Tang Hailin,Gao Fei,Liu Qingqing,Wu Jianming,Sui Yue,Li Peng,Zhang Jinming,Chen Jianping
Introduction: Triple-negative breast cancer (TNBC), an aggressive type of
breast cancer, remains difficult to treat. Isoliquiritigenin (ISL) is a bioactive compound
that is insoluble in water and exhibits significant anti-TNBC activity. Method: We previously
prepared oral aqueous ISL@ZLH NPs; however, they were less stable in a freezing
environment. Hence, the present study aimed to improve the stability of ISL@ZLH
NPs using cryoprotectants that can withstand long storage times and are effective in TNBC
treatment by creating an efficient oral drug delivery system. Freeze-dried ISL@ZLH
NP powder was prepared by solvent evaporation, followed by the addition of trehalose
and sucrose. The freeze-dried ISL@ZLH NP pow was optimized and characterized. The
anti-TNBC efficacy and pharmacokinetics of the ISL@ZLH NP-pow were examined in
plasma and organs, compared with those of aqueous ISL@ZLH NPs. Result: The ideal
particle size of the ISL@ZLH NP pow was 118 nm, which was not filtered out by the
glomerulus and allowed the drug to be delivered to the lesions more effectively. Cellular
uptake and biodistribution of the ISL@ZLH NP-pow in vivo and in vitro showed prolonged
storage in the organs. In addition, cryopreserved ISL@ZLH NP-treated tumors
showed significant anti-proliferative and anti-migratory effects through the downregulation
of the PI3K-Akt-mToR and MMP2/9 signaling pathways. Conclusion: These results
suggest that oral ingestion of cryopreserved ISL@ZLH NP has the potential for longterm
storage and can be employed as a clinical therapeutic approach to treat TNBC.
研究领域:
肿瘤学
·
药剂学
·
纳米技术
·
药物递送系统
·
癌症生物学
✓ 已验证
DOI
PubMed
高影响因子
TROPICAL JOURNAL OF PHARMACEUTICAL RESEARCH
·
2021
·Vol. 18
·期 12
·2531-2538
·
IF 0.533
Jun Tang,Jingfang Yang
Purpose: To investigate the potential role of curcumin in osteosarcoma (OS) cell migration and invasion, and also to explore the underlying mechanism of action.
Methods: OS cell lines, Saos-2 and U2OS, were treated with various concentrations of curcumin (0, 10, 20, 50 μM) for 48 h. Transwell assay was used to determine the migratory and invasive activities of human OS cells while miR-33b-5p expression levels were measured using quantitative real time polymerase chain reaction (qRT-PCR). Expressions of metastasis-related genes, such as matrix metalloproteinases (MMPs), were quantified by qRT-PCR or western blot. The interaction between miR33b-5p and Sirtuin 6 (SIRT6) was evaluated by luciferase assay.
Results: Curcumin inhibited the migratory and invasive activities of huamn OS cells, and downregulated MMP2 and MMP9 (p < 0.05). Moreover, in curcumin-treated OS cells, miR-33b-5p expression was upregulated while SIRT6 expression was significantly downregulated (p < 0.05). Overexpression of miR-33b-5p downregulated SIRT6 mRNA and protein expression, whereas transfection with miR-33b-5p inhibitor upregulated SIRT6 expression in OS cells (p < 0.05). Furthermore, curcumin suppressed SIRT6 expression by upregulating miR-33b-5p expression in OS cells. Finally, overexpression of SIRT6 or miR-33b-5p inhibitor reversed the suppression of OS cell metastasis induced by curcumin (p < 0.05).
Conclusion: Curcumin inhibits SIRT6 expression via upregulating miR-33b-5p expression, which leads to the inhibition of OS cell migration and invasion. Thus, curcumin is a potential therapeutic agent for the management of OS.
研究领域:
肿瘤学
·
分子生物学
·
药理学
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）