Current Molecular Pharmacology
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2024
·Vol. 17
·期 1
·e150923221164
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IF 2.4
Yejiao Ruan,Guangrong Lu,Yaojun Yu,Yue Luo,Hao Wu,Yating Shen,Zejun Gao,Yao Shen,Zhenzhai Cai,Liyi Li
Introduction Colorectal cancer remains a life-threatening malignancy with increasing morbidity and mortality worldwide. Therefore, new and effective anti-colorectal cancer therapeutics are urgently needed. Methods In this study, we have studied the anti-tumor properties and potential mechanisms of PF-04449913. Colorectal cancer cell viability was reduced by PF-04449913 in a dose-dependent manner. The migration and invasion ability of malignant colon cells were attenuated by the drug, as demonstrated by the Transwell test. Moreover, PF-04449913 repressed the phosphorylation levels of ERK and other proteins, and the expression levels of MMP9. The anti-tumor effects of the drug in vivo were demonstrated in BALB/c-nude mice models, and PF-04449913 inhibited the malignant phenotype of colorectal cancer cells, including reduction of tumor size and promotion of apoptosis. At the molecular level, PF-04449913 induced a significant decrease in ERK and p65 protein phosphorylation levels and inhibited MMP9 protein expression. Results Both in vivo and in vitro results showed PF-04449913 to demonstrate antitumor effects, which have been proposed to be mediated through blockade of the ERK/p65 signaling pathway, and subsequent repression of MMP9 expression. Conclusion Our study provides a new perspective on the potential clinical application of PF-04449913 in the treatment of colorectal cancer.
研究领域:
肿瘤学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
MOLECULAR BIOLOGY REPORTS
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2025
·Vol. 52
·期 1
·1-13
·
IF 2.8
Wu Wanqi,Wang Jun,Wang Guanglu,Wang Feibiao,Yang Yue,Liu Zhijun,Song Qimei,Chen Si,Chen Huizhen
Background Sepsis can cause severe cardiac damage, and matrix metalloproteinase 9 (MMP9) is involved in the inflammatory response and tissue injury processes. Monotropein is a monoterpene glycoside with anti-inflammatory and antioxidant effects. This study aims to investigate whether monotropein can alleviate sepsis-induced cardiac injury by affecting the activity of MMP9. Methods and results The correlation between MMP9 and septic cardiac injury was explored using differential expression gene analysis from the GEO database and an in vitro lipopolysaccharide (LPS)-stimulated H9c2 cell model. In a cecal ligation and puncture (CLP)-induced mouse sepsis model, the effects of monotropein on myocardial cell apoptosis, inflammatory factor expression, and antioxidant enzyme levels were validated through drug administration. The results showed that MMP9 was significantly upregulated in sepsis patients. In the H9c2 cell model, LPS-induced MMP9 activity was positively correlated with cell damage. Inhibition of MMP9 alleviates LPS-induced myocardial matrix disruption and apoptosis. Monotropein exerts anti-matrix degradation and anti-apoptotic effects through MMP9 in LPS-induced H9c2 cells. Monotropein also reduced the expression of LPS-induced inflammatory factors (TNF-α, IL-1β, IL-6).In the mouse model, monotropein decreased oxidative stress damage (lower MDA levels, increased GSH, T-AOC, CAT enzyme activity), and improved cardiac injury by inhibiting myocardial cell apoptosis-related proteins (Bax, Bcl-2, and Caspase-3 activation). Conclusion Monotropein exerts a protective effect on septic cardiac injury by inhibiting MMP9 activity, reducing inflammatory response, and enhancing antioxidant capacity, thereby ameliorating myocardial cell damage and apoptosis. Graphical abstract
研究领域:
医学
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药理学
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DOI
PubMed
高影响因子
Chinese Journal of Integrative Medicine
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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
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DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2025
·
IF 5.7
Jinze Wang,Haiqi Zhang,Sentao Hu,Lie Ma
Excessive reactive oxygen species (ROS) leads to persistent inflammation in diabetic wounds inducing excessive inflammatory factors and matrix metalloproteinases (MMPs) and thereby hindering wound healing. However, low concentration ROS also function as a signaling molecule for maintaining cell function and promoting vascularization. Therefore, it is important to regulate ROS levels adaptively to match the healing process. Here, a nanozyme hydrogel was developed to intelligently clear wound ROS in response to dynamic changes of matrix metalloproteinase-9 (MMP9). Specifically, Prussian blue nanoparticles (PBNPs) loaded-gelatin nanospheres (PGs) were encapsulated in polyvinyl alcohol (PVA) hydrogel to obtain the nanozyme hydrogel (PGs@PVA). Hydrogen bonding between PGs and PVA not only improves the mechanical properties of PGs@PVA hydrogel but also ensures the controlled release of PBNPs. With the release of PBNP from PGs@PVA hydrogel in response to the high level of MMP9 in the pro-inflammatory stage, excessive ROS were cleared. The phenotype of macrophages was regulated correspondingly. The in vivo results proved that PGs@PVA hydrogel promoted healing speed, epithelialization, vascularization, and collagen deposition of diabetic wounds by adaptive immunomodulation. The MMP9-responsive nanozyme hydrogel shows great potential in diabetic wound healing by reconstructing the balance of pro-inflammation and anti-inflammation.
研究领域:
生物材料学
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医学
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药剂学
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DOI
PubMed
高影响因子
FOOD RESEARCH INTERNATIONAL
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2025
·
IF 8
Ziyi Shen,Simeng Zhou,Yaru Zhang,Yuan Zhang,Hongyan Wang,Daxiang Li,Yijun Wang,Zhongwen Xie,Huifang Ge
Large-leaf yellow tea protein-derived oligopeptides (TPP) contain a substantial number of antioxidant peptides that facilitate skin damage repair and may be employed to mitigate skin photoaging. However, the potential alleviating mechanism by which TPP alleviates skin photoaging damage remains insufficiently understood. This study investigated the in vitro antioxidant capacity and cell migration-promoting ability of TPP. Additionally, it utilized ultraviolet (UV)-exposed and intrinsically aged ICR mice, which exhibit signs of skin aging, to assess the effects of an 8-week oral TPP intervention. The findings indicate that TPP exhibits potent free radical scavenging properties, which mitigate oxidative damage in Raw264.7 cells and promote the migration of NIH/3 T3 cells. TPP intervention significantly ameliorates oxidative stress and skin inflammation symptoms in UV-induced skin photoaging damage by restoring the activity of endogenous antioxidant enzymes and suppressing the mRNA expression of pro-inflammatory cytokines, including IL-1β , IL-6 , and TNF-α ., as well as inhibiting the MAPK/AP-1/MMP9 signaling pathways. This study proposes that TPP is a viable plant protein-derived nutritional supplement for the prevention of UV-induced skin photoaging damage.
研究领域:
营养科学
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皮肤科学
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分子生物学
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食品科学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Small
·
2023
·
IF 13.3
Keke Huang,Xin Liu,Ziru Lv,Di Zhang,Yuling Zhou,Zhiqing Lin,Juan Guo
Age-related macular degeneration (AMD), especially wet AMD with choroidal neovascularization (CNV), commonly causes blindness in older patients and disruption of the choroid followed by second-wave injuries, including chronic inflammation, oxidative stress, and excessive matrix metalloproteinase 9 (MMP9) expression. Increased macrophage infiltrate in parallel with microglial activation and MMP9 overexpression on CNV lesions is shown to contribute to the inflammatory process and then enhance pathological ocular angiogenesis. Graphene oxide quantum dots (GOQDs), as natural antioxidants, exert anti-inflammatory effects and minocycline is a specific macrophage/microglial inhibitor that can suppress both macrophage/microglial activation and MMP9 activity. Herein, an MMP9-responsive GOQD-based minocycline-loaded nano-in-micro drug delivery system (C18PGM) is developed by chemically bonding GOQDs to an octadecyl-modified peptide sequence (C18-GVFHQTVS, C18P) that can be specifically cleaved by MMP9. Using a laser-induced CNV mouse model, the prepared C18PGM shows significant MMP9 inhibitory activity and anti-inflammatory action followed by antiangiogenic effects. Moreover, C18PGM combined with antivascular endothelial growth factor antibody bevacizumab markedly increases the antiangiogenesis effect by interfering with the “inflammation-MMP9-angiogenesis” cascade. The prepared C18PGM shows a good safety profile and no obvious ophthalmic or systemic side effects. The results taken together suggest that C18PGM is an effective and novel strategy for combinatorial therapy of CNV.
研究领域:
眼科学
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纳米技术
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药学
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
ANALYTICAL CHEMISTRY
·
2025
·
IF 6.7
Wendi Wang,Qing Han,Tianwei Wang,Jian Liu,Qingbin Ni,Jingyi Sun,Ying Wang,Baoliang Sun
Ischemic stroke (IS) has a high mortality rate. Multiplexed detection of IS core biomarkers is of great significance to early diagnosis and personalized treatment of IS patients. Whether pericytes, a key component of the neurovascular unit and blood-brain barrier located on the capillary wall, could serve as a promising biomarker for IS is to be explored. Herein, we observed a significant upregulation of inflammatory and apoptotic factors, such as MMP9, in pericytes subjected to in vitro ischemia. By transfecting pericytes with ASK1-shRNA to inhibit ASK1 expression, we noted reduced levels of inflammatory and apoptotic markers, including MMP9, as well as enhanced pericyte contraction and migration, thereby preserving the integrity of the blood-brain barrier. Additionally, ELISA assays conducted using plasma samples from patients with varying NIHSS scores revealed statistically significant concentrations of PDGFRβ and MMP9. Furthermore, we developed a highly sensitive and specific quantitative detection method for PDGFRβ and MMP9 based on fluorescence sensor technology. This novel detector exhibits high sensitivity, repeatability, and stability, enabling precise dual detection. Thus, the results suggest the great potential of the detection of PDGFRβ and MMP9 for early diagnosis of IS and prognosis prediction of the disease.
研究领域:
神经科学
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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
Materials Today Bio
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2025
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IF 10.2
Qingyu Zhao,Yong Li,Qian Sun,Ronggui Wang,Haoran Lu,Xinyi Zhang,Lun Gao,Qiang Cai,Baohui Liu,Gang Deng
Glioblastoma (GBM) is the most prevalent and aggressive primary malignant brain tumor in adults, known for its poor prognosis and resistance to conventional treatments. The blood-brain barrier (BBB) presents a significant challenge in delivering effective treatments. In this study, we developed a carrier-free, self-assembled nanosystem using genistein (GE), a naturally occurring isoflavone, to enhance therapeutic delivery across the BBB. GE nanoparticles (GE NPs) were synthesized via solvent emulsification evaporation, in uniform spherical particles (∼180 nm), stabilized by hydrogen bonding and π-π interactions. The GE NPs demonstrated optimal physicochemical properties, including stability, high BBB permeability, prolonged circulation time. In vitro studies revealed that GE NPs inhibited GBM cell proliferation, induced apoptosis and suppressed epithelial-mesenchymal transition (EMT) by promoting the degradation of MMP9. In vivo, GE NPs significantly reduced tumor growth and extended survival in an orthotopic GBM mouse model, outperforming temozolomide treatment. Mechanistic analysis indicated that GE NPs inhibited the degradation of the extracellular matrix by targeting the catalytic domain of MMP9, thereby effectively suppressing the EMT of GBM. This research highlights the potential of GE NPs as a novel therapeutic approach for GBM, addressing drug delivery challenges while improving anti-tumor efficacy. Further optimization for enhanced tumor retention and exploration of combination therapies may improve clinical outcomes (Graphical ).
研究领域:
肿瘤学
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纳米医学
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神经科学
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药理学
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产品关联
DOI
PubMed
高影响因子
TROPICAL JOURNAL OF PHARMACEUTICAL RESEARCH
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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
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分子生物学
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药理学
✓ 已验证
DOI
高影响因子
MICROCHEMICAL JOURNAL
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2025
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IF 5.1
Xinyue Lin,Luxi Zhou,Lingfang Chen,Qiyue Chen,Zhuming Jin,Peixi Zhu,Ni Yang
Houttuynia cordata Thunb. is a perennial herb with a distinct “fishy” flavour, commonly used in Asian cuisine and traditional medicine. To overcome the compound identification challenges in the composite formula of its mixture, a comprehensive two-dimensional ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (2D UHPLC-QTOF-MS) method was developed and identified 293 chemical compounds. Given the herb’s strong anti-inflammatory properties, network pharmacology was employed to predict potential targets, revealing TNF, AKT1, MMP9, and PTGS2 as key theoretical targets for its anti-inflammatory effects. Molecular docking showed strong binding energies between these targets and the top 10 compounds (8,13-dihydroxy-9,11-octadecadienoic acid, neobaicalein, chrysin, apigenin, genistein, chrysoeriol, norwogonin, cirsiliol, luteolin and deoxyandrographolide), with genistein exhibiting the highest affinity for AKT1 (−10.4 kcal/mol). This innovative approach, combining advanced 2D UHPLC-QTOF-MS with network pharmacology, offers great potential for screening active components in herbs and their complex mixtures.
研究领域:
中药学
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分析化学
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药理学
✓ 已验证
产品关联
DOI
高影响因子
MOLECULAR NEUROBIOLOGY
·
2024
·
IF 4.6
Wang Zhenhua,Li Yuan,Wang Zhixu,Liao Yuhui,Ye Qingqing,Tang Shilong,Wei Ting,Xiao Pengyu,Huang Juan,Lu Weitian
Oxidative stress (OS) is the main cause of secondary damage following intracerebral hemorrhage (ICH). The polarity expression of aquaporin-4 (AQP4) has been shown to be important in maintaining the homeostasis of water transport and preventing post-injury brain edema in various neurological disorders. This study primarily aimed to investigate the effect of the oxygen free radical scavenger, edaravone, on AQP4 polarity expression in an ICH mouse model and determine whether it involves in AQP4 polarity expression via the OS/MMP9/β-dystroglycan (β-DG) pathway. The ICH mouse model was established by autologous blood injection into the basal nucleus. Edaravone or the specific inhibitor of matrix metalloproteinase 9 (MMP9), MMP9-IN-1, called MMP9-inh was administered 10 min after ICH via intraperitoneal injection. ELISA detection, neurobehavioral tests, dihydroethidium staining (DHE staining), intracisternal tracer infusion, hematoxylin and eosin (HE) staining, immunofluorescence staining, western blotting, Evans blue (EB) permeability assay, and brain water content test were performed. The results showed that OS was exacerbated, AQP4 polarity was lost, drainage function of brain fluids was damaged, brain injury was aggravated, expression of AQP4, MMP9, and GFAP increased, while the expression of β-DG decreased after ICH. Edaravone reduced OS, restored brain drainage function, reduced brain injury, and downregulated the expression of AQP4, MMP9. Both edaravone and MMP9-inh alleviated brain edema, maintained blood–brain barrier (BBB) integrity, mitigated the loss of AQP4 polarity, downregulated GFAP expression, and upregulated β-DG expression. The current study suggests that edaravone can maintain AQP4 polarity expression by inhibiting the OS /MMP9/β-DG pathway after ICH.
研究领域:
神经科学
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药理学
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病理生理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Small
·
2026
·
IF 11.8
Jitong Zhou,Boyu Su,Ching Kang,Yujun Pei,Keke Zhang,Wenwen He,Jiao Qi,Tao Sun,Jiaqi Meng,Xiangjia Zhu
High myopia (HM), a major cause of global blindness, also significantly elevates anxiety risk via a newly discovered eye-brain inflammatory axis. We identified C-C motif chemokine ligand 2 (CCL2) as the key driver: HM visual stimuli trigger retinal CCL2 upsurge, promoting monocyte/macrophage infiltration into eyes and brain, disrupting blood-brain (BBB) and blood-ocular (BOB) barriers, and inducing anxiety. To shatter this vicious cycle, unmet by traditional CCL2 blockers (poor targeting, non-selectivity, no barrier repair), we engineered a revolutionary ROS-responsive nanocomplex, TK-F-PEI/siR@A. This system synergistically integrates: (1) Surface CCL2 aptamers for targeted lesion homing and CCL2 neutralization; (2) A fluorinated, thioketal-crosslinked low-MW PEI core enabling inflammation-triggered release; (3) Encapsulated MMP9 siRNA to restore barrier integrity. TK-F-PEI/siR@A demonstrated excellent ROS responsiveness, low cytotoxicity, and effective MMP9 silencing, enhancing tight junctions. Guided by aptamers, it achieved superior accumulation in inflamed ocular/brain regions of HM mice, with high biosafety. Critically, it delivered a dual-action strike: significantly reducing CCL2 levels, suppressing systemic/local monocyte/macrophage infiltration, and robustly repairing BBB/BOB integrity. This synergistic blockade of inflammation and barrier restoration reversed anxiety-like behaviors. We pioneer the first nanocomplex specifically co-targeting the eye-brain axis, establishing a potent dual-pronged strategy against HM-related anxiety and offering a new paradigm for inter-organ crosstalk disorders.
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产品关联
DOI
PubMed
高影响因子
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