Effect of matrix metalloproteinase inhibitors on bonding durability of universal adhesives.

This study aimed to evaluate the effect of different matrix metalloproteinase inhibitors (MMPIs) on the microtensile bond strength (µTBS) and nanoleakage of universal adhesives. One hundred twenty non-carious human molars were prepared and randomly assigned to two groups: Scotchbond Bond Universal (SBU) and Gluma Bond Universal (GBU). The samples in each group were assigned to five subgroups (n=12) based on one control (water) and four MMPIs (Benzalkonium-chloride (BAC), Batimastat (BB94), Chlorhexidine (CHX), and Epigallocatechin-gallate (EGCG)). Each adhesive was applied in self-etch (SE) mode or etch-and-rinse (ER) mode. Dentin/composite sticks were fabricated and subjected to the µTBS test after 24 h or 6 months. At 6 months, MMPIs did not affect the µTBS of the adhesives, regardless of etching mode. Nanoleakage was more pronounced in ER mode than in SE mode for all subgroups. All MMPIs, with the exception of CHX, decreased the nanoleakage of GBU in ER mode.

Recombinant Human Clusterin Seals Damage to the Ocular Surface Barrier in a Mouse Model of Ophthalmic Preservative-Induced Epitheliopathy.

There is a significant unmet need for therapeutics to treat ocular surface barrier damage, also called epitheliopathy, due to dry eye and related diseases. We recently reported that the natural tear glycoprotein CLU (clusterin), a molecular chaperone and matrix metalloproteinase inhibitor, seals and heals epitheliopathy in mice subjected to desiccating stress in a model of aqueous-deficient/evaporative dry eye. Here we investigated CLU sealing using a second model with features of ophthalmic preservative-induced dry eye. The ocular surface was stressed by topical application of the ophthalmic preservative benzalkonium chloride (BAC). Then eyes were treated with CLU and sealing was evaluated immediately by quantification of clinical dye uptake. A commercial recombinant form of human CLU (rhCLU), as well as an rhCLU form produced in our laboratory, designed to be compatible with U.S. Food and Drug Administration guidelines on current Good Manufacturing Practices (cGMP), were as effective as natural plasma-derived human CLU (pCLU) in sealing the damaged ocular surface barrier. In contrast, two other proteins found in tears: TIMP1 and LCN1 (tear lipocalin), exhibited no sealing activity. The efficacy and selectivity of rhCLU for sealing of the damaged ocular surface epithelial barrier suggests that it could be of therapeutic value in treating BAC-induced epitheliopathy and related diseases.

[Effect of acupuncture combined with moxibustion on serum matrix metalloproteinase-9 and matrix metalloproteinase inhibitor-1 in patients with knee osteoarthritis].

OBJECTIVE: To observe the effect of acupuncture combined with moxibustion on serum bone metabolism indexes in patients with knee osteoarthritis (KOA), so as to evaluate its clinical efficacy on KOA. METHODS: Ninety-six patients with KOA were randomly divided into control and observation groups, with 48 cases in each group. The patients in the control group were treated with acupuncture at Zusanli(ST36), Neixiyan(EX-LE4), Heding(EX-LE2) and Xuanzhong(GB39) etc. on the affected side for 30 min once daily. Patients in the observation group were given moxibustion on the above-mentioned acupoints on the basis of treatment in the control group. The course of treatment for both groups was 4 weeks. The Western Ontario and MacMaster University Osteoarthritis Index (WOMAC) scores were compared before and after treatment and the clinical efficacy of the two groups were calculated according to the WOMAC scores after treatment. Ultrasound examination of the knee joint was used to analyze the thickness of joint effusion and synovial membrane thickness of the patients. Enzyme-linked immunoassay was used to detect the serum type Ⅰ collagen C-terminal foreign body peptide (CTX-Ⅰ), insulin-like growth factor (IGF), bone gla protein (BGP), matrix metalloproteinase-9 (MMP-9), matrix metalloproteinase inhibitor-1 (TIMP-1) levels. RESULTS: Compared with those before treatment, WOMAC score, knee joint synovial thickness and joint effusion thickness, serum CTX-Ⅰ, MMP-9, TIMP-1 levels, and MMP-9/TIMP-1 ratio were all down-regulated (P<0.05), while the levels of serum IGF and BGP up-regulated (P<0.05) in the two groups after treatment. The improvements of the above indexes in the observation group were superior to those in the control group (P<0.05). The total effective rate in the observation group was 95.83% (46/48), which was higher than 81.25% (39/48) in the control group(P<0.05). CONCLUSION: Acupuncture combined with moxibustion can regulate bone metabolism and effectively improve the symptoms of KOA patients, which may be related to its effect in regulating the dynamic balance of MMP-9 and TIMP-1 in serum.

Insights into the immunomodulatory regulation of matrix metalloproteinase at the maternal-fetal interface during early pregnancy and pregnancy-related diseases.

Trophoblast immune cell interactions are central events in the immune microenvironment at the maternal-fetal interface. Their abnormalities are potential causes of various pregnancy complications, including pre-eclampsia and recurrent spontaneous abortion. Matrix metalloproteinase (MMP) is highly homologous, zinc(II)-containing metalloproteinase involved in altered uterine hemodynamics, closely associated with uterine vascular remodeling. However, the interactions between MMP and the immune microenvironment remain unclear. Here we discuss the key roles and potential interplay of MMP with the immune microenvironment in the embryo implantation process and pregnancy-related diseases, which may contribute to understanding the establishment and maintenance of normal pregnancy and providing new therapeutic strategies. Recent studies have shown that several tissue inhibitors of metalloproteinases (TIMPs) effectively prevent invasive vascular disease by modulating the activity of MMP. We summarize the main findings of these studies and suggest the possibility of TIMPs as emerging biomarkers and potential therapeutic targets for a range of complications induced by abnormalities in the immune microenvironment at the maternal-fetal interface. MMP and TIMPs are promising targets for developing new immunotherapies to treat pregnancy-related diseases caused by immune imbalance.

A novel model of a biomechanically induced osteoarthritis-like cartilage for pharmacological in vitro studies.

Excessive pressure or overload induces and aggravates osteoarthritic changes in articular cartilage, but the underlying biomechanical forces are largely ignored in existing pharmacological in vitro models that are used to investigate drugs against osteoarthritis (OA). Here, we introduce a novel in vitro model to perform pathophysiological and pharmacological investigations, in which cartilage explants are subjected to intermittent cyclic pressure, and characterize its ability to mimic OA-like tissue reactivity. Mechanical loading time-dependently increased the biosynthesis, content and retention of fibronectin (Fn), whereas collagen metabolism remained unchanged. This protocol upregulated the production and release of proteoglycans (PGs). The release of PGs from explants was significantly inhibited by a matrix metalloproteinase (MMP) inhibitor, suggesting the involvement of such proteinases in the destruction of the model tissue, similar to what is observed in human OA cartilage. In conclusion, the metabolic alterations in our new biomechanical in vitro model are similar to those of early human OA cartilage, and our pharmacological prevalidation with an MMP-inhibitor supports its value for further in vitro drug studies.

Matrixmetalloproteinase Inhibitors: Promising Therapeutic Targets Against Cancer.

BACKGROUND: Cancer is a wide range cellular level disease that occurs when cells go through uncontrolled division and growth. The mechanisms by which the cells undergo metastasis are complex and involve many interactions between the tumor cells and their cellular environment. Matrix metalloproteinases (MMPs) have been found to over-express at various stages of tumor progression and their inhibition using MMP inhibitors has been a subject of potential therapy against cancer. OBJECTIVE: This review discusses recent research in MMP inhibitors (MMPI) used for preventing tumor progression. METHODS: In this review, we explored the role of MMPs in cancer progression and summarized the current developments in MMPIs, their role in cancer suppression in in vitro and in vivo studies and their evaluation in clinical trials from the current research data. RESULTS: MMPIs have shown to be very successful in in vitro models, cell lines and in some in vivo studies. Unfortunately, their efficacy in clinical trials has been found to be hit and miss. Recent studies have shown that the novel delivery approaches of MMP inhibitors may enhance their therapeutic effects towards the prevention of cancer. CONCLUSION: In this review, we presented different MMP inhibitors, their performance at different stages of models - in vitro, in vivo, small animal models and eventually clinical trials. We provide newer methods of MMPI delivery that may be better targeted to suppress only specific MMPs and avoid toxic side effects in healthy cells.

Inhibitors of gelatinases (MMP-2 and MMP-9) for the management of hematological malignancies.

Matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) are collectively known as gelatinases whereas MMP-2 is gelatinase-A and MMP-9 is termed as gelatinase-B. Gelatinases and other matrix metalloproteinases (MMPs) have long been associated with solid tumor invasion, metastasis and angiogenesis. However, there is paucity of data available regarding the role of gelatinases in hematological malignancies. Recent studies have shown that gelatinases activities or functions are correlated with hematological malignancies. Strategies for designing more specific gelatinase inhibitors like catalytic (CAT) domain inhibitors and hemopexin (PEX) domain inhibitors as well as signaling pathway based or gelatinase expression inhibitors had been reported against hematologic malignant cells. Several substrate based non-selective to non-substrate based relatively selective synthetic matrix metalloproteinase inhibitors (MMPIs) had been developed. Few MMPIs had reached in clinical trials during the period of 1990s-2000s. Unfortunately the anti-tumor and anti-metastatic efficacies of these MMPIs were not justified with patients having several advanced stage solid tumor cancers in any substantial number of clinical trials. Till date not a single MMPI passed phase III clinical trials designed for advanced metastatic cancers due to adverse events as well as lack of ability to show uniformity in disease prolongation. With the best of our knowledge no clinical trial study has been reported with small molecule synthetic inhibitors against hematological malignancies. This review looks at the outcome of clinical trials of MMPIs for advanced stage solid tumors. This can therefore, act as a learning experience for future development of successful gelatinase inhibitors for the management of hematological malignancies.

Effect of Doxycycline Microencapsulation on Buccal Films: Stability, Mucoadhesion and In Vitro Drug Release.

The aim of this work was to stabilize doxycycline in mucoadhesive buccal films at room temperature (25 °C). Since doxycycline is susceptible to degradation such as oxidation and epimerization, tablets are currently the only formulation that can keep the drug fully stable at room temperature, while liquid formulations are limited to refrigerated conditions (4 °C). In this study, the aim was to make formulations containing subclinical (antibiotic) doxycycline concentration that can act as matrix metalloproteinase inhibitors (MMPI) and can be stored at temperatures such as 25 °C. Here, doxycycline was complexed with excipients using three techniques and entrapped into microparticles that were stored at 4 °C, 25 °C and 40 °C. Effect of addition of precomplexed doxycycline microparticles on films: stability mucoadhesion capacity, tensile strength, swelling index and in vitro release was studied. The complexation efficiency between drug-excipients, microparticles and films was studied using Fourier-transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). Two of the films were found to be stable at 4 °C but the film containing microparticle composed of precomplexed doxycycline with ß-cyclodextrin, MgCl2, sodium thiosulfate, HPMC and Eudragit® RS 12.5 was found to be stable at 25 °C until 26 weeks. The addition of microparticles to the films was found to reduce the mucoadhesive capacity, peak detachment force, tensile strength and elasticity, but improved the stability at room temperature.

Matrix Metalloproteinase 13 Inhibitors for Modulation of Osteoclastogenesis: Enhancement of Solubility and Stability.

Matrix metalloproteinase 13 (MMP-13) activity has been correlated to breast cancer bone metastasis. It has been proposed that MMP-13 contributes to bone metastasis through the promotion of osteoclastogenesis. To explore the mechanisms of MMP-13 action, we previously described a highly efficacious and selective MMP-13 inhibitor, RF036. Unfortunately, further pursuit of RF036 as a probe of MMP-13 in vitro and in vivo activities was not practical due to the limited solubility and stability of the inhibitor. Our new study has explored replacing the RF036 backbone sulfur atom and terminal methyl group to create inhibitors with more favorable pharmacokinetic properties. One compound, designated inhibitor 3, in which the backbone sulfur and terminal methyl group of RF036 were replaced by nitrogen and oxetane, respectively, had comparable activity, selectivity, and membrane permeability to RF036, while exhibiting greatly enhanced solubility and stability. Inhibitor 3 effectively inhibited MMP-13-mediated osteoclastogenesis but spared collagenolysis, and thus represents a next-generation MMP-13 probe applicable for in vivo studies of breast cancer metastasis.

Phyto-derived Products as Matrix Metalloproteinases Inhibitors in Cardiovascular Diseases.

Matrix metalloproteinases (MMPs) are enzymes that present a metallic element in their structure. These enzymes are ubiquitously distributed and function as extracellular matrix (ECM) remodelers. MMPs play a broad role in cardiovascular biology regulating processes such as cell adhesion and function, cellular communication and differentiation, integration of mechanical force and force transmission, tissue remodeling, modulation of damaged-tissue structural integrity, cellular survival or apoptosis and regulation of inflammation-related cytokines and growth factors. MMPs inhibition and downregulation are correlated with minimization of cardiac damage, i.e., Chinese herbal medicine has shown to stabilize abdominal aorta aneurysm due to its antiinflammatory, antioxidant and MMP-2 and 9 inhibitory properties. Thus phyto-derived products rise as promising sources for novel therapies focusing on MMPs inhibition and downregulation to treat or prevent cardiovascular disorders.

[Surgical treatment of internal carotid artery kinking following fibromuscular dysplasia]. / Rezul'taty khirurgicheskogo lecheniya patologicheskoi izvitosti vnutrennei sonnoi arterii na fone fibrozno-myshechnoi displazii.

OBJECTIVE: To evaluate the results of surgical treatment of internal carotid artery kinking following fibromuscular dysplasia. MATERIAL AND METHODS: There were 32 patients who underwent surgical treatment of internal carotid artery kinking following fibromuscular dysplasia. Structural changes of carotid artery wall were analyzed using immunohistochemical survey. Considering destructive changes revealed, we divided all patients into 2 groups in order to assess long-term postoperative outcomes: 1 - ICA resection followed by anastomosis in end-to-end fashion; 2 - ICA replacement. Postoperative analysis included incidence of stroke, thrombosis and deformities of anastomosis zone, regression of cerebrovascular insufficiency. RESULTS: The main «phenotype¼ of arterial wall in patients with ICA kinking following fibromuscular dysplasia is a large number of smooth muscle cells releasing matrix matelloproteinases-2 and -9 and low level of their tissue inhibitor type 1. Postoperative deformities are more common within a year after surgery. Maximum incidence is observed after 12 months. Both ICA resection and replacement are followed by similar incidence of deformity later. No severe deformities were diagnosed. Resection of ICA kinking on the background of fibromuscular dysplasia is followed by comparable results with ICA replacement regarding the incidence stroke, thrombosis and regression of cerebrovascular insufficiency. CONCLUSION: Despite degradation of extracellular matrix, destruction of elastic fibers and their fragmentation, no significant deformities are observed in long-term postoperative period in patients with ICA kinking and fibromuscular dysplasia.

[Effects of smoking on the wound healing of stage 4 pressure ulcers in rats].

Objective: To explore the effect of smoking on the wound healing of stage 4 pressure ulcers in rats. Methods: Fifty male Sprague-Dawley rats aged 6-8 weeks were divided into simple pressure ulcer group and smoking+ pressure ulcer group according to the random number table, with 25 rats in each group. After the rats in the smoking+ pressure ulcer group received passive smoking intervention for 12 weeks, an iron plate was placed in the back muscle of each rat in 2 groups, and a magnet was placed outside the skin at the corresponding position of the iron plate for 2 h at each time, with 5 times a day and continuously for 6 days to reproduce stage 4 pressure ulcer model. Immediately after establishing the model, 3 rats in each group were sacrificed and wound tissue was collected, and hematoxylin-eosin staining was applied to observe the pathological changes of the wounds. On 1, 3, 7, and 14 day (s) after establishing the model, 3 rats in each group were collected to measure the pressure ulcer wound area by the paper jam method. After measurement of the wound area, the rats were sacrificed and the wound tissue was collected, and the protein expression levels of matrix metalloproteinases 9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1) in wound tissue were detected by immunohistochemical method, and the ratio of MMP-9/TIMP-1 was calculated.The wound healing time of the remaining 10 rats in each group was recorded. Data were statistically analyzed with analysis of variance for factorial design, two independent sample t test, and Bonferroni correction. Results: (1) Immediately after establishing the model, muscle fiber necrosis and dissolution with large areas were seen on the wound, the myofibrils arranged loosely, and more lymphocytes and monocytes infiltration were seen around the wound of rats in simple pressure ulcer group. A large number of necrotic myofibers were dissolved and gradually disappeared, the myofibrils arranged loosely, and the number of diffuse lymphocytes and monocyte infiltration in wound of rats in smoking+ pressure ulcer group were significantly higher than those in simple pressure ulcer group. (2) The wound areas of rats in smoking+ pressure ulcer group were significantly larger than those in simple pressure ulcer group on 1, 3, 7, and 14 day (s) after establishing the model (t=3.019, 2.549, 2.181, 3.674, P<0.05 or P<0.01). (3) On 1 to 14 days after establishing the model, the protein expression levels of MMP-9 and TIMP-1 in the wound tissue and the ratio of MMP-9/TIMP-1 of rats in the two groups increased first and then decreased. On 1, 3, 7, and 14 day (s) after establishing the model, the protein expression levels of MMP-9 in the wound tissue and the ratio of MMP-9/TIMP-1 of rats in smoking+ pressure ulcer group were significantly higher than those in simple pressure ulcer group (t=4.783, 4.508, 6.325, 7.204, 3.078, 2.989, 4.081, 4.696, P<0.05 or P<0.01), and the protein expression levels of TIMP-1 in wound tissue of rats in the two groups were similar. (4) The wound healing time of rats in smoking+ pressure ulcer group was (48.9±2.6) d, which was significantly longer than (35.2±2.3) d of simple pressure ulcer group (t=12.477, P<0.05). Conclusions: Smoking can up-regulate the expression of MMP-9 in pressure ulcer wound and result in an imbalance of MMP-9/TIMP-1, thereby affecting the wound healing of stage 4 pressure ulcers in rats.

[Application value of urinary IGFBP7 and TIMP-2 in acute kidney injury with decompensated hepatitis B virus-related liver cirrhosis].

Objective: To investigate the application value of new urinary biomarkers insulin-like growth factor binding protein 7 (IGFBP7) and tissue matrix metalloproteinase inhibitor-2 (TIMP-2) in acute kidney injury with decompensated hepatitis B virus-related liver cirrhosis. Methods: 45 newly hospitalized cases with decompensated hepatitis B virus-related liver cirrhosis were selected. Among them, 19 cases were combined with AKI on admission (cirrhosis-AKI group), 26 cases without AKI (cirrhosis-non-AKI group), and 12 healthy cases (normal control group). First-morning urine samples were collected and IGFBP7 and TIMP-2 were detected by enzyme-linked immunosorbent assay (ELISA). Urinary IGFBP7 and serum creatinine (SCr) were dynamically monitored after hospitalization in cirrhosis-non-AKI group. Normally distributed measurement data were compared by t-test, and non-normally distributed measurement data were compared by rank sum test. The receiver operating characteristic (ROC) curve and area under the curve (AUC) were used to evaluate the diagnostic accuracy of the indicators. Results: Urinary IGFBP7, IGFBP7 with TIMP-2 (IGFBP7×TIMP-2) in cirrhosis-AKI group (n = 19) were equally higher than that of the cirrhosis-non-AKI group (P < 0.05). Urinary IGFBP7, TIMP-2 and IGFBP7×TIMP-2 in cirrhosis-AKI group or cirrhosis-non-AKI group were significantly higher than those of the normal control group (P < 0.01). The AUC of urinary IGFBP7 and urinary IGFBP7×TIMP-2 for diagnosis of AKI were 0.703 (95% CI 0.547-0.860) and 0.700 (95% CI 0.541-0.859), respectively. In the liver cirrhosis-non-AKI group (n = 26), 5 cases of AKI were newly diagnosed according to the changes in SCr during hospitalization (progressive group). Urinary IGFBP7 was significantly increased 2 days before the diagnosis of AKI. The concentration of urinary IGFBP7 at admission in the progressive group (n = 5) was higher than that of the non-progressive group (n = 21) (P < 0.05). Conclusion: Urinary IGFBP7 and TIMP-2 concentrations were significantly increased in patients with decompensated hepatitis B virus-related liver cirrhosis. When AKI occurred, urinary IGFBP7 and IGFBP7×TIMP-2 was further increased. Urinary IGFBP7 is valuable for early AKI diagnosis, and may play a role in predicting AKI occurrence.

Cardioprotective Effect of Novel Matrix Metalloproteinase Inhibitors.

BACKGROUND: We recently developed novel matrix metalloproteinase-2 (MMP-2) inhibitor small molecules for cardioprotection against ischemia/reperfusion injury and validated their efficacy in ischemia/reperfusion injury in cardiac myocytes. The aim of the present study was to test our lead compounds for cardioprotection in vivo in a rat model of acute myocardial infarction (AMI) in the presence or absence of hypercholesterolemia, one of the major comorbidities affecting cardioprotection. METHODS: Normocholesterolemic adult male Wistar rats were subjected to 30 min of coronary occlusion followed by 120 min of reperfusion to induce AMI. MMP inhibitors (MMPI)-1154 and -1260 at 0.3, 1, and 3 µmol/kg, MMPI-1248 at 1, 3, and 10 µmol/kg were administered at the 25th min of ischemia intravenously. In separate groups, hypercholesterolemia was induced by a 12-week diet (2% cholesterol, 0.25% cholic acid), then the rats were subjected to the same AMI protocol and single doses of the MMPIs that showed the most efficacy in normocholesterolemic animals were tested in the hypercholesterolemic animals. Infarct size/area at risk was assessed at the end of reperfusion in all groups by standard Evans blue and 2,3,5-triphenyltetrazolium chloride (TTC) staining, and myocardial microvascular obstruction (MVO) was determined by thioflavine-S staining. RESULTS: MMPI-1154 at 1 µmol/kg, MMPI-1260 at 3 µmol/kg and ischemic preconditioning (IPC) as the positive control reduced infarct size significantly; however, this effect was not seen in hypercholesterolemic animals. MVO in hypercholesterolemic animals decreased by IPC only. CONCLUSIONS: This is the first demonstration that MMPI-1154 and MMPI-1260 showed a dose-dependent infarct size reduction in an in vivo rat AMI model; however, single doses that showed the most efficacy in normocholesterolemic animals were abolished by hypercholesterolemia. The further development of these promising cardioprotective MMPIs should be continued with different dose ranges in the study of hypercholesterolemia and other comorbidities.

Matrix metalloproteinase inhibitor and sunscreen effective compounds from Rumex crispus L.: isolation, identification, bioactivity and molecular docking study.

INTRODUCTION: Rumex (Polygonaceae) species are widely grown worldwide and their main compounds are anthranoids, tannins, naphthalenes and flavonoids. Matrix metalloproteinase (MMP) enzymes that cause the breakdown of the extracellular matrix and harmful ultraviolet (UV) rays are two important causes of skin ageing. Although there have been many studies on anthraquinones, there are not many studies on their anti-ageing effects. OBJECTIVE: The aim of this study was to determine the anti-ageing effects of pure compounds isolated from Rumex crispus L. by measuring their MMP inhibitory and sunscreen activities. METHODOLOGY: Molecular docking studies on anthranoid, flavonoid, tannin and naphthalene skeletons with MMP enzymes were applied for the first time. Various chromatographic methods were used for isolation studies. The structure elucidation was performed by spectroscopic [UV, infrared (IR), electrospray ionisation mass spectrometry (ESI-MS), nuclear magnetic resonance (NMR)] methods. To determine the anti-ageing capacity of compounds, MMP-1, MMP-8, MMP-13 enzyme inhibitory effects and sun protection factors (SPFs) were investigated for the first time. RESULTS: Molecular docking results showed that skeletons had low binding energy to the target and were likely to inhibit MMP enzymes. Then, eight anthraquinones and a naphthalene glycoside were isolated from the underground parts of Rumex crispus L. According to the results, MMP inhibitory effects of compounds were found to be high. In vitro and molecular docking study results confirmed each other. All anthraquinones showed high sun protection and emodin showed highest UV capability with SPF of 30.59. CONCLUSION: This study shows that anthraquinones may be evaluated as new potential MMP inhibitors, sun protective and anti-ageing agents.

A type IV collagenase inhibitor, N-hydroxy-3-phenyl-2-(4-phenylbenzenesulfonamido) propanamide (BiPS), suppresses skin injury induced by sulfur mustard.

Sulfur mustard (SM) is a highly toxic blistering agent thought to mediate its action, in part, by activating matrix metalloproteinases (MMPs) in the skin and disrupting components of the basement membrane zone (BMZ). Type IV collagenases (MMP-9) degrade type IV collagen in the skin, a major component of the BMZ at the dermal-epidermal junction. In the present studies, a type IV collagenase inhibitor, N-hydroxy-3-phenyl-2-(4-phenylbenzenesulfonamido) propanamide (BiPS), was tested for its ability to protect the skin against injury induced by SM in the mouse ear vesicant model. SM induced inflammation, epidermal hyperplasia and microblistering at the dermal/epidermal junction of mouse ears 24-168 h post-exposure. This was associated with upregulation of MMP-9 mRNA and protein in the skin. Dual immunofluorescence labeling showed increases in MMP-9 in the epidermis and in the adjacent dermal matrix of the SM injured skin, as well as breakdown of type IV collagen in the basement membrane. Pretreatment of the skin with BiPS reduced signs of SM-induced cutaneous toxicity; expression of MMP-9 mRNA and protein was also downregulated in the skin by BiPS. Following BiPS pretreatment, type IV collagen appeared intact and was similar to control skin. These results demonstrate that inhibiting type IV collagenases in the skin improves basement membrane integrity after exposure to SM. BiPS may hold promise as a potential protective agent to mitigate SM induced skin injury.

Matrix metalloproteinase: An upcoming therapeutic approach for idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a debilitating condition where excess collagen deposition occurs in the extracellular matrix. At first sight, it is expected that the level of different kinds of matrix metalloproteinases might be downregulated in IPF as it is a matrix degrading collagenase. However, the role of some matrix metalloproteinases (MMPs) is profibrotic where others have anti-fibrotic functions. These profibrotic MMPs effectively promote fibrosis development by stimulating the process of epithelial to mesenchymal transition. These profibrotic groups also induce macrophage polarization and fibrocyte migration. All of these events ultimately disrupt the balance between profibrotic and antifibrotic mediators, resulting aberrant repair process. Therefore, inhibition of these matrix metalloproteinases functions in IPF is a potential therapeutic approach. In addition to the use of synthetic inhibitor, various natural compounds, gene silencing act as potential natural MMP inhibitor to recover IPF.

FK506 combined with GM6001 prevents tracheal obliteration in a mouse model of heterotopic tracheal transplantation.

BACKGROUND: Obliterative bronchiolitis (OB) is the major complication limiting the long-term survival of allografts after lung transplantation. In this study, we investigated the effect of tacrolimus (FK506) combined with GM6001，a matrix metalloproteinase (MMP) inhibitor， on the formation of OB using a mouse heterotopic tracheal transplantation model. METHODS: Syngeneic tracheal grafts were transplanted heterotopically from BALB/c mice to BALB/c mice. Allografts from C57BL/6 mice were transplanted to BALB/c mice. Isograft group, allograft group, allograft+FK506 group, allograft +GM6001 group and allograft+FK506 + GM6001 group was given respectively intraperitoneal injection of saline, saline, FK506, GM6001 and FK506 + GM6001 once a day. At 28 day after transplantation, OB incidence was determined by hematoxylin-eosin staining and the expressions of MMPs and cytokines were assessed using enzyme linked immunosorbent assay, immunohistochemical assays and western blot assay. RESULTS: The tracheal occlusion rates of isograft group, allograft group, allograft+FK506 group, allograft+GM6001 group and allograft+FK506 + GM6001 group were 0, 74.1 ±â€¯9.79%, 34.4 ±â€¯6.04%, 40.3 ±â€¯8.77% and 26.5 ±â€¯5.73% respectively. There were significant differences between the latter two groups (P < .001). The serum MMP-8 and MMP-9 levels of allograft group were significantly higher than those of isograft group (P < .05) and had no significant decrease when treated by FK506. The serum MMP-8 and MMP-9 levels of allograft+FK506 + GM6001 group were significantly lower than those of allograft+FK506 group (P < .05). MMP-8 and MMP-9 protein expression in the grafts of allograft+FK506 + GM6001 group were lower than those of allograft+FK506 group verified by immunohistochemical staining and western blotting. CONCLUSION: FK506 combined with GM6001 could alleviate tracheal obliteration in mouse heterotopic tracheal transplantation model, due to its inhibitory effect on MMPs.

"Locked" cancer cells are more sensitive to chemotherapy.

The treatment of metastatic cancer is a great challenging issue throughout the world. Conventional chemotherapy can kill the cancer cells and, whereas, would exacerbate the metastasis and induce drug resistance. Here, a new combinatorial treatment strategy of metastatic cancer was probed via subsequentially dosing dual nanomedicines, marimastat-loaded thermosensitive liposomes (MATT-LTSLs) and paclitaxel nanocrystals (PTX-Ns), via intravenous and intratumoral injection. First, the metastasis was blocked and cancer cells were locked in the tumor microenvironment (TME) by delivering the matrix metalloproteinase (MMP) inhibitor, MATT, to the tumor with LTSLs, downregulating the MMPs by threefold and reducing the degradation of the extracellular matrix. And then, the "locked" cancer cells were efficiently killed via intratumoral injection of the other cytotoxic nanomedicine, PTX-Ns, along with no metastasis and 100% inhibition of tumor growth. This work highlights the importance of the TME's integrity in the chemotherapy duration. We believe this is a generalized strategy for cancer treatment and has potential guidance for the clinical administration.