Matrix Metalloproteinase
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2021 ◽  
Vol 4 (1) ◽  
Maren Hülsemann ◽  
Colline Sanchez ◽  
Polina V. Verkhusha ◽  
Vera Des Marais ◽  
Serena P. H. Mao ◽  

AbstractDuring breast cancer metastasis, cancer cell invasion is driven by actin-rich protrusions called invadopodia, which mediate the extracellular matrix degradation required for the success of the invasive cascade. In this study, we demonstrate that TC10, a member of a Cdc42 subfamily of p21 small GTPases, regulates the membrane type 1 matrix metalloproteinase (MT1-MMP)-driven extracellular matrix degradation at invadopodia. We show that TC10 is required for the plasma membrane surface exposure of MT1-MMP at these structures. By utilizing our Förster resonance energy transfer (FRET) biosensor, we demonstrate the p190RhoGAP-dependent regulation of spatiotemporal TC10 activity at invadopodia. We identified a pathway that regulates invadopodia-associated TC10 activity and function through the activation of p190RhoGAP and the downstream interacting effector Exo70. Our findings reveal the role of a previously unknown regulator of vesicular fusion at invadopodia, TC10 GTPase, in breast cancer invasion and metastasis.

2021 ◽  
Vol 14 (12) ◽  
pp. 101221
Minglong Liang ◽  
Jian Wang ◽  
Chuanjian Wu ◽  
Manman Wu ◽  
Jingping Hu ◽  

Marike Leijs ◽  
Katharina Fietkau ◽  
Hans F. Merk ◽  
Thomas Schettgen ◽  
Thomas Kraus ◽  

Polychlorinated biphenyls (PCBs) are well known immunotoxic and carcinogenic compounds. Although cutaneous symptoms are the hallmark of exposure to these compounds, exact pathophysiologic mechanisms are not well understood. We took skin biopsies from moderately high PCB exposed workers (n = 25) after an informed consent and investigated the expression of immunological markers such as CCL-7, CCL-20, CXCL2, IL-1β and IL-6, as well as the matrix metalloproteinase MMP-9, EPGN and NRF2 by RT-qPCR, and compared expression levels with plasma PCB levels. Statistical analyses showed a significant correlation between CCL-20, CXCL2, IL-6, IL-1β, CCL-7 and MMP-9 and PCB serum levels. EPGN and NRF2 were not correlated to PCB levels in the blood. We found a significant correlation of genes involved in autoimmune, auto-inflammatory and carcinogenesis in skin samples of PCB exposed individuals with elevated plasma PCB levels. Confirmation of these findings needs to be performed in bigger study groups and larger gen-sets, including multiple housekeeping genes. Further study needs to be performed to see whether a chronical exposure to these and similar compounds can cause higher incidence of malignancies and inflammatory disease.

2021 ◽  
Vol 22 (18) ◽  
pp. 9976
Jose Maria Zapico ◽  
Lourdes Acosta ◽  
Miryam Pastor ◽  
Loganathan Rangasamy ◽  
Laura Marquez-Cantudo ◽  

Osteoarthritis is a degenerative disease, often resulting in chronic joint pain and commonly affecting elderly people. Current treatments with anti-inflammatory drugs are palliative, making the discovery of new treatments necessary. The inhibition of matrix metalloproteinase MMP-13 is a validated strategy to prevent the progression of this common joint disorder. We recently described polybrominated benzotriazole derivatives with nanomolar inhibitory activity and a promising selectivity profile against this collagenase. In this work, we have extended the study in order to explore the influence of bromine atoms and the nature of the S1′ heterocyclic interacting moiety on the solubility/selectivity balance of this type of compound. Drug target interactions have been assessed through a combination of molecular modeling studies and NMR experiments. Compound 9a has been identified as a water-soluble and highly potent inhibitor with activity in MG-63 human osteosarcoma cells.

2021 ◽  
Li Feng ◽  
Qing Wang ◽  
Yanjiao Li ◽  
Wanwen Cheng ◽  
Jie Liu ◽  

Abstract Objectives Matrix metalloproteinase-9 (MMP9) functions as a collagenase, it promotes the infarct expansion and cardiac rupture after myocardial infarction (MI). This study sought to identify the mechanism mediating MI-induced MMP9 expression, and explore the new therapeutic target improving healing process after MI. Materials and Methods HIMF expression is manipulated by genetic ablation of HIMF in mice (Himf−/−), and adenoviral overexpression of HIMF by recombinant adenovirus encoding a green fluorescent protein (GFP)-tagged mouse HIMF in cultured neonatal rat ventricular myocytes (NRVMs), cardiac fibroblasts (CFs) and the murine macrophage RAW264.7 cells. The mouse model of left descending coronary artery ligation was established to investigate the expression of MMP9 and HIMF. Results MMP9 was predominantly expressed in macrophages of MI hearts, and positively correlated to the expression of HIMF, a marker for anti-inflammatory macrophage polarization. HIMF deficiency (Himf−/−) results in significantly decreased MMP9 expression, increased collagen deposition, reduced infarction size and improved cardiac contraction. Mechanistic analysis reveals that HIMF increases MMP9 expression by activating STAT3 signaling in murine macrophage RAW264.7. This was verified by the inhibited STAT3 phosphorylation in the MI heart of Himf−/− mouse. Conclusions This study identified a novel HIMF-STAT3-MMP9 regulation module in macrophages that influences collagen deposition in infarct heart, providing a new sight for MI treatment.

2021 ◽  
Vol 11 (1) ◽  
Jixuan Liu ◽  
Hongyan Ban ◽  
Yafang Liu ◽  
Jinsong Ni

AbstractAldosterone reductase family 1 member B10 (AKR1B10) is a nicotinamide adenine dinucleotide phosphate (reduced coenzyme II)-dependent oxidoreductase, and its biological functions include carbonyl detoxification, hormone metabolism, osmotic adjustment, and lipid synthesis. Studies suggested that AKR1B10 is a new biomarker for cancer based on its overexpression in epithelial tumors, such as breast cancer, cervical cancer, and lung cancer. At present, studies on the expression of AKR1B10 in laryngeal cancer have not been reported. However, we found that AKR1B10 is upregulated in laryngeal carcinoma, and its expression was negatively correlated with the degree of differentiation. In addition, AKR1B10 expression was positively correlated with tumor size; lymph node metastasis; alcohol use; and Ki-67, mutant p53, and matrix metalloproteinase 2 expression. AKR1B10 was overexpressed in Hep-2 laryngeal carcinoma cells. Oleanolic acid inhibited AKR1B10 activity and expression in Hep-2 cells and suppressed Hep-2 cell proliferation, migration, and invasion. Therefore, AKR1B10 may be related to the development of laryngeal carcinoma, suggesting its use as a prognostic indicator for laryngeal cancer.

Plants ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1893
Kunle Okaiyeto ◽  
Ayodeji Osmund Falade ◽  
Oluwafemi Omoniyi Oguntibeju

Clerodendrum volubile is an underutilized leafy vegetable consumed in some parts of Nigeria. The interest in C. volubile has continued to increase due to its multipurpose values, including traditional uses, nutritional properties, and some therapeutic potentials; however, the pharmacological prospects of the plant are yet to be fully explored. Therefore, in the present review, different databases such as PubMed, Scopus, Web of Science, Google Scholar, etc. were explored to retrieve publications used to write this review. The pharmacological potentials of C. volubile, such as anticancer, antioxidant, antiviral, antimicrobial, anti-inflammatory, hepatoprotective, antidiabetic, and anti-hypertensive properties, were highlighted. The toxicological potential of the plant is also discussed. Proposed mechanisms that underline its biological activities include modulation of redox homeostasis, leading to decreased oxidative stress; down-regulation of matrix metalloproteinase-9 (MMP-9) expression; inhibition of key enzymes implicated in diabetes mellitus, hypertension, and neurological diseases; and inhibition of oxidative burst and inflammatory cytokines. Furthermore, the prospect of endophytes from C. volubile as a bioresource to produce novel therapeutic agents, as well as the development of nanotherapeutics from the plant extracts and its phytoconstituents, are discussed. In conclusion, C. volubile possesses an enormous number of possible pharmacological properties and therapeutic potentials waiting to be explored.

2021 ◽  
Vol 12 ◽  
Tenghua Wang ◽  
Wenxiu Ye ◽  
Yin Wang ◽  
Maoxing Zhang ◽  
Yusuke Aihara ◽  

Stomata in the epidermis of plants play essential roles in the regulation of photosynthesis and transpiration. Stomata open in response to blue light (BL) by phosphorylation-dependent activation of the plasma membrane (PM) H+-ATPase in guard cells. Under water stress, the plant hormone abscisic acid (ABA) promotes stomatal closure via the ABA-signaling pathway to reduce water loss. We established a chemical screening method to identify compounds that affect stomatal movements in Commelina benghalensis. We performed chemical screening using a protease inhibitor (PI) library of 130 inhibitors to identify inhibitors of stomatal movement. We discovered 17 PIs that inhibited light-induced stomatal opening by more than 50%. Further analysis of the top three inhibitors (PI1, PI2, and PI3; inhibitors of ubiquitin-specific protease 1, membrane type-1 matrix metalloproteinase, and matrix metalloproteinase-2, respectively) revealed that these inhibitors suppressed BL-induced phosphorylation of the PM H+-ATPase but had no effect on the activity of phototropins or ABA-dependent responses. The results suggest that these PIs suppress BL-induced stomatal opening at least in part by inhibiting PM H+-ATPase activity but not the ABA-signaling pathway. The targets of PI1, PI2, and PI3 were predicted by bioinformatics analyses, which provided insight into factors involved in BL-induced stomatal opening.

Jingwen Chen ◽  
Eun Na ◽  
Sun Young Lim

Aim and Objective: We investigated the inhibitory effects of fractions from Lycopus lucidus Turcz. leaves on genomic DNA oxidation, nitric oxide (NO) production and matrix metalloproteinase (MMP) activity. Material and Methods: Oxidative damage of genomic DNA was detected after Fenton reaction with H2O2 using DNA electrophoresis. Western blotting was performed to compare the expression levels of MMP-2 in phorbol 12-myristate 13-acetate (PMA)-induced HT-1080 cells. Lipopolysacchride (LPS)-induced NO production in RAW 264.7 cells was measured using Griess reagent. Results: ll fractions (n-Hexane, 85% aq. MeOH, n-BuOH, and water fractions) from the leaves of L. lucidus Turcz. significantly inhibited intracellular production of reactive oxygen species (ROS) (p<0.05). Particularly, 85% aq. MeOH and n-BuOH fractions showed higher ROS inhibitory activity than the other fractions. n-Hexane, 85% aq. MeOH, n-BuOH and water (0.05 mg/mL) fractions significantly inhibited oxidative DNA damage by 57.97%, 68.48%, 58.97%, and 68.39%, respectively (p <0.05). Treatment of RAW 264.7 cells with each fraction reduced LPS-induced NO production in a dose-dependent manner (p<0.05). n-Hexane and 85% aq. MeOH fractions notably reduced MMP-2 secretion levels of in the culture supernatants from HT-1080 cells. Conclusion: Overall, these results indicated that L. lucidus Turcz. leaves can be exploited as plant based sources of antioxidants in the pharmaceutical, cosmetic, nutraceutical and food industries.

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