Plantamajoside Attenuates Neointima Formation via Upregulation of Tissue Inhibitor of Metalloproteinases in Balloon-Injured Rats.

The abnormal change of vascular smooth muscle cell (VSMC) behavior is an important cellular event leading to neointimal hyperplasia in atherosclerosis and restenosis. Plantamajoside (PMS), a phenylethanoid glycoside compound of the Plantago asiatica, has been reported to have anti-inflammatory, antioxidative, and anticancer activities. In this study, the protective effects of PMS against intimal hyperplasia and the mechanisms underlying the regulation of VSMC behavior were investigated. MTT and BrdU assays were performed to evaluate the cytotoxicity and cell proliferative activity of PMS, respectively. Rat aortic VSMC migrations after treatment with the determined concentration of PMS (50 and 150 µM) were evaluated using wound healing and Boyden chamber assays. The inhibitory effects of PMS on intimal hyperplasia were evaluated in balloon-injured (BI) rat carotid artery. PMS suppressed the proliferation in platelet-derived growth factor-BB-induced VSMC, as confirmed from the decrease in cyclin-dependent kinase (CDK)-2, CDK-4, cyclin D1, and proliferating cell nuclear antigen levels. PMS also inhibited VSMC migration, consistent with the downregulated expression and zymolytic activities of matrix metalloproteinase (MMP)2, MMP9, and MMP13. PMS specifically regulated MMP expression through p38 mitogen-activated protein kinase and focal adhesion kinase pathways. Tissue inhibitor of metalloproteinase (TIMP)1 and TIMP2 levels were upregulated via Smad1. TIMPs inhibited the conversion of pro-MMPs to active MMPs. PMS significantly inhibited neointimal formation in BI rat carotid arteries. In conclusion, PMS inhibits VSMC proliferation and migration by upregulating TIMP1 and TIMP2 expression. Therefore, PMS could be a potential therapeutic agent for vascular atherosclerosis and restenosis treatment.

Pharmacological strategies for protection of extrahepatic islet transplantation.

The safety and effectiveness of islet transplantation has been proven through world-wide trials. However, acute and chronic islet loss has hindered the ultimate objective of becoming a widely used treatment option for type 1 diabetes. A large islet loss is attributed, in part, to the liver being a less-than-optimal site for transplantation. Over half of the transplanted islets are destroyed shortly after transplantation due to direct exposure to blood and non-specific inflammation. Successfully engrafted islets are continuously exposed to the liver micro-environment, a unique immune system, low oxygen tension, toxins and high glucose, which is toxic to islets, leading to premature islet dysfunction/death. Investigations have continued to search for alternate sites to transplant islets that provide a better environment for prolonged function and survival. This article gathers courses and conditions that lead to islet loss, from organ procurement through islet transplantation, with special emphasis on hypoxia, oxidative stress, and antigen non-specific inflammation, and reviews strategies using pharmacological agents that have shown effectiveness in protecting islets, including a new treatment approach utilizing siRNA. Pharmacological agents that support islet survival and promote ß-cell proliferation are also included. Treatment of donor pancreata and/or islets with these agents should increase the effectiveness of islets transplanted into extrahepatic sites. Furthermore, the development of methods designed to release these agents over an extended period, will further increase their efficacy. This requires the combined efforts of both islet transplant biologists and bioengineers.

Pigment epithelium-derived factor as a natural matrix metalloproteinase inhibitor: a comparison with classical matrix metalloproteinase inhibitors used for cancer treatment.

OBJECTIVES: In the 1990s, the discovery of the important role of matrix metalloproteinases (MMPs) in cancer angiogenesis, growth and metastasis galvanised research efforts to search for ways to inhibit these MMPs. To date, this has resulted in the investigation of approximately 50 MMPIs which have undergone various phases of clinical trials. However, despite a large body of research being devoted to discovery and development of MMPIs, results have largely not been supportive of this approach to anticancer treatment. KEY FINDINGS: The reasons for the general failure of these drugs in clinical trials include various unwanted side-effects, the use of healthy volunteers to provide drug dosages which did not correctly reflect dosages for cancer patients, and the exclusion of patients with early stage cancer in clinical trials despite MMPs being determined to be critical for the angiogenic switch, a process associated with early tumour growth. In contrast, a naturally-occurring endogenous protein and a non-functional serine protease inhibitor (serpin), pigment epithelium-derived factor (PEDF), has been proposed for cancer therapy partly due to its ability to regulate specific MMPs central to cancer progression. SUMMARY: PEDF has been found to specifically downregulate membrane-type I matrix metalloproteinase (MT1-MMP) and furthermore, potentially matrix metalloproteinase-2 (MMP-2), two of the most commonly implicated MMPs in neoplasia.

Tratamiento médico de los aneurismas de aorta abdominal / No disponible

No disponible

[Effects of matrix metalloproteinase-9 inhibitor in Lewis rats with experimental autoimmune myocarditis].

OBJECTIVE: To investigate the effects of matrix metalloproteinase-9 (MMP-9) inhibitor minocyclin hydrochloride in Lewis rats with experimental autoimmune myocarditis (EAM). METHODS: EAM was induced by injection of cardiac C protein emulsified in completed Freund adjuvant in double footpad and intraperitoneal injection of pertussis toxin on 6- to 8-week old Lewis rats. Sixty EAM Lewis rats were divided into 3 groups (early, middle and late intervention groups, n = 20 each: 10 minocyclin treated and 10 control rats). In early intervention group, rats in treatment group received intraperitoneal injection of minocyclin hydrochloride from 1(st) to 21(st) day after immunization; in middle intervention group, rats were treated from 8(th) to 28(th) day after immunization and in late intervention group, rats were treated from 15(th) to 35(th) day after immunization (50 mg/kg body weight, once daily). Control rats received intraperitoneal injection of same volumetric physiological saline at corresponding time periods. At the end of intervention, rats were euthanatized and hearts were harvested. Paraffin sections were used for hematoxylin and eosin stain to determine the inflammatory score, for picrosirius stain to determine fibrosis score and collagen content, and for immunohistological stain to determine macrophages and T lymphocytes. Real time PCR was used to detect mRNA expression of myocardial MMP-2 and MMP-9. Cryostat sections were used for in situ zymography to detect protein activity of gelatinase. RESULTS: Inflammatory score in cardiac paraffin slides, number of cardiac macrophages and T lymphocytes, cardiac interstitial fibrosis score and content, expression of MMP-2, 9 mRNA and activity of gelatinase in treatment group were all significantly lower than in control group for early and middle intervention groups (inflammatory score: early control group vs. treatment group: 3.03 ± 1.35 vs.1.51 ± 0.36, P < 0.05, middle control group vs. treatment group: 3.75 ± 0.29 vs. 2.11 ± 0.82, P < 0.01; cardiac interstitial fibrosis score, early control group vs. treatment group: 2.75 ± 0.29 vs.1.51 ± 0.35, P < 0.01, middle control group vs. treatment group: 2.50 ± 0.41 vs. 1.61 ± 0.42, P < 0.05; gelatinase, early control group vs. treatment group: 162 367 ± 5095 vs. 62 366 ± 2131, P < 0.01, middle control group vs. treatment group: 184 256 ± 5427 vs. 113 197 ± 4809, P < 0.01) while these parameters were similar between minocyclin-treated and control rats in late intervention group (all P > 0.05). CONCLUSIONS: MMP-9 plays an important role in the pathogenesis of autoimmune myocarditis. Inhibition of MMP-9 in early and middle stage could significantly attenuate inflammatory responses and myocardial fibrosis in this experimental EAM model.

Targeting matrix metalloproteinases in inflammatory conditions.

The matrix metalloproteinases (MMPs) and their endogenous regulators, the tissue inhibitors of MMPs (TIMPs) are responsible for the physiological remodelling of the extracellular matrix (ECM) in healthy connective tissues. MMPs are also involved in the regulation of cell behaviour via the release of growth factors and cytokines from the substrates they cleave, increasing the magnitude of their effects. Excess MMP activity is associated with ECM destruction in various inflammatory conditions, such as osteoarthritis (OA), while MMP under-activity potentially impairs healing by promoting fibrosis and preventing the effective removal of scar tissue. Both direct (TIMPs, small molecule MMP inhibitor drugs, blocking antibodies and anti-sense technologies) and indirect (glucocorticoids and non-steroidal anti-inflammatory drugs, statins, anti-sense technologies and various phytochemicals) strategies for MMP inhibition have been proposed and investigated. The strategy of MMP inhibition for degenerative and neoplastic diseases has been relatively unsuccessful due to undesired sequelae, often caused by non-selectivity of the MMP inhibition method. Therapeutic strategies for MMP-related conditions ideally should regulate MMP activity in order to maintain the optimum balance between MMPs and TIMPs. By avoiding complete inhibition it may be possible to prevent the complications of MMP over- and under-activity. Furthermore, MMP sub-type specificity is critical for minimising detrimental off-target effects that have been observed with broad-spectrum MMP inhibitors. Any potential MMP inhibitor or modulator must be subjected to rigorous pharmacokinetic, toxicity and safety studies and data obtained using in vitro models must be verified in clinically relevant animal models before therapeutic use is considered.

Insights into preventive measures for dental erosion: [review]

Dental erosion is defined as the loss of tooth substance by acid exposure not involving bacteria. The etiology of erosion is related to different behavioral, biological and chemical factors. Based on an overview of the current literature, this paper presents a summary of the preventive strategies relevant for patients suffering from dental erosion. Behavioral factors, such as special drinking habits, unhealthy lifestyle factors or occupational acid exposure, might modify the extent of dental erosion. Thus, preventive strategies have to include measures to reduce the frequency and duration of acid exposure as well as adequate oral hygiene measures, as it is known that eroded surfaces are more susceptible to abrasion. Biological factors, such as saliva or acquired pellicle, act protectively against erosive demineralization. Therefore, the production of saliva should be enhanced, especially in patients with hyposalivation or xerostomia. With regard to chemical factors, the modification of acidic solutions with ions, especially calcium, was shown to reduce the demineralization, but the efficacy depends on the other chemical factors, such as the type of acid. To enhance the remineralization of eroded surfaces and to prevent further progression of dental wear, high-concentrated fluoride applications are recommended. Currently, little information is available about the efficacy of other preventive strategies, such as calcium and laser application, as well as the use of matrix metalloproteinase inhibitors. Further studies considering these factors are required. In conclusion, preventive strategies for patients suffering from erosion are mainly obtained from in vitro and in situ studies and include dietary counseling, stimulation of salivary flow, optimization of fluoride regimens, modification of erosive beverages and adequate oral hygiene measures.

Insights into preventive measures for dental erosion.

Dental erosion is defined as the loss of tooth substance by acid exposure not involving bacteria. The etiology of erosion is related to different behavioral, biological and chemical factors. Based on an overview of the current literature, this paper presents a summary of the preventive strategies relevant for patients suffering from dental erosion. Behavioral factors, such as special drinking habits, unhealthy lifestyle factors or occupational acid exposure, might modify the extent of dental erosion. Thus, preventive strategies have to include measures to reduce the frequency and duration of acid exposure as well as adequate oral hygiene measures, as it is known that eroded surfaces are more susceptible to abrasion. Biological factors, such as saliva or acquired pellicle, act protectively against erosive demineralization. Therefore, the production of saliva should be enhanced, especially in patients with hyposalivation or xerostomia. With regard to chemical factors, the modification of acidic solutions with ions, especially calcium, was shown to reduce the demineralization, but the efficacy depends on the other chemical factors, such as the type of acid. To enhance the remineralization of eroded surfaces and to prevent further progression of dental wear, high-concentrated fluoride applications are recommended. Currently, little information is available about the efficacy of other preventive strategies, such as calcium and laser application, as well as the use of matrix metalloproteinase inhibitors. Further studies considering these factors are required. In conclusion, preventive strategies for patients suffering from erosion are mainly obtained from in vitro and in situ studies and include dietary counseling, stimulation of salivary flow, optimization of fluoride regimens, modification of erosive beverages and adequate oral hygiene measures.

Systemic MMP inhibition for periodontal wound repair: results of a multi-centre randomized-controlled clinical trial.

AIM: This multi-centre, prospective, controlled trial was designed to examine the biological response of the matrix metalloproteinase(MMP) inhibitor subantimicrobial dose doxycycline (SDD) combined with access flap surgery on periodontal wound repair in patients with chronic severe periodontitis. MATERIAL AND METHODS: Seventy subjects were enrolled into a 12-month, randomized, placebo-controlled, double-masked trial to evaluate disease response to 6 months therapy and "wash-out" of either placebo+surgery or SDD (20 mg b.i.d.)+surgery. Primary outcome measure included clinical attachment levels (CAL) and secondary outcomes included probing depth (PD), bleeding on probing (BOP), as well as gingival crevicular fluid bone marker assessment [collagen telopeptides (ICTP)]. These measurements were taken at baseline through 12 months post-surgery and drug administration. RESULTS: Patients treated with SDD and surgery demonstrated stronger reductions in PD in surgically-treated sites of >or=7 mm as well as gains in CAL (p<0.004). Furthermore, SDD+surgery resulted in short-term reductions in ICTP levels compared with placebo. Rebounds in ICTP levels and clinical parameters occurred when SDD was withdrawn. CONCLUSIONS: The results from this multi-centre study suggests that SDD in combination with surgery improves the short-term response of periodontal therapy by reducing PD, increasing CAL gain and inhibiting early stage bone resorption.

Finding the culprit: a review of the influences of proteases on the chronic wound environment.

Chronic leg ulcers are a complex medical condition with varied underlying causes and requiring diverse treatment strategies. It is generally accepted that chronic ulcers occur when the normal wound healing process is interrupted. These wounds are characterized by excessive protease activity, abundant granulation tissue, and decreased levels of growth factors, resulting in an overall poor prognosis for the patient. Many studies have focused on identifying the key proteases, specifically matrix metalloproteinases (MMPs), responsible for an ulcer's chronicity. Of note, the results of these studies are often conflicting. This report therefore focuses on a review of this literature to identify which MMPs are important in terms of ulcer prognosis and healing outcome. This has revealed that MMPs are clearly important in many biological processes in wound healing, hence are critical to consider when developing improved therapies to enhance both ulcer healing times and ulcer healing outcomes.

Host-response therapeutics for periodontal diseases.

Periodontal diseases are initiated by Gram-negative tooth-associated microbial biofilms that elicit a host response, with resultant osseous and soft tissue destruction. In response to endotoxins derived from periodontal pathogens, several osteoclast-related mediators target the destruction of alveolar bone and supporting connective tissues. Major drivers of this aggressive tissue destruction are matrix metalloproteinases (MMPs), cathepsins, and other osteoclast-derived enzymes. This article focuses on the downstream factors of the osteoclast responsible for the degradation of bone and soft tissues around teeth and oral implants. Furthermore, therapeutic approaches that target MMP-2, -8, and -9 inhibition, such as MMP inhibitors, chemically modified tetracyclines, and subantimicrobial formulations of tetracycline analogues, are discussed. The use of rapid, chair-side tests of MMP activity, in particular for MMP-8 and bone collagen fragments, show strong potential as non-invasive measures of tissue health or disease. In addition, studies using other agents for the preservation of bone mass, such as bisphosphonates that inhibit osteoclast recruitment, are highlighted. The application of these bone-preservation strategies to periodontal management and treatment are discussed in the context of high-risk patients susceptible to disease reactivation or disease complications.

[Prophylactic effect of matrix metalloproteinase inhibitor on acute graft-versus-host disease in a murine model].

OBJECTIVE: To explore the prophylactic effect of tissue inhibitor of matrix metalloproteinase (TIMP) on acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in a murine model. METHODS: The murine model of aGVHD after allo-HSCT was established by using female C57BL/b (H-2b) mouse as the donor, and male BALB/c (H-2b) as the recipient. After allo-HSCT, recipient mice were divided into 3 groups. For aGVHD prophylaxis group A was given TIMP (2 mg/d) , group B CsA (5 mg x kg(-1) x d (-1)) was given, and group C nothing. Physical signs, mean survival time (MST), peripheral blood counts and aGVHD histopathology were observed. RESULTS: Mice in group C developed typical aGVHD and 100% of mortality, with a MST of 8 days, and those in group A and B had longer survival, the MST being (4.8 +/- 1.4) d and (4.3 +/- 0.9) d respectively, with no statistical difference in peripheral blood count between these two groups. Mice in group A showed less severe signs. CONCLUSIONS: TIMP markedly prolongs MST of allo-HSCT recipients, delays the onset of aGVHD signs, and has no adverse effect on hematopoiesis reconstitution.

The role of matrix metalloproteinase inhibitors in ischemia-reperfusion injury in the liver.

Liver ischemia-reperfusion injury is characterized by cell necrosis and apoptosis and by profound modifications in the extracellular matrix (ECM). During the complex series of events that take place both during ischemia and when normal blood flow is restored (reperfusion), a concerted regulation of release and activation of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) mainly by stellate cells, Kupffer cells and inflammatory cells leads first to endothelial cell injury and subsequent infiltration of neutrophils into the wounded area. Later, MMP activation causes degradation of extracellular matrix components of the liver, mainly collagen and fibronectin, altering tissue architecture. The fibrosis that can result after liver injury is also dependent on the imbalance between MMPs and TIMPs and to new collagen deposition. Several experimental models of liver ischemia-reperfusion injury have demonstrated protective effects of MMP inhibitors in terms of cell necrosis, apoptosis and rearrangement of the extracellular matrix. This review summarizes current knowledge of MMP biology, with particular attention to the most recent evidence of novel, non-extracellular matrix MMP substrates involved in inflammation and cell cycle regulation. An overview of MMP and TIMP expression and activation in hepatic ischemia-reperfusion injury is provided. The analysis of such provides a rational basis for MMP inhibition as a viable strategy to prevent liver injury.

Role of matrix metalloproteinases in delayed cortical responses after stroke.

Matrix metalloproteinases (MMPs) are zinc-endopeptidases with multifactorial actions in central nervous system (CNS) physiology and pathology. Accumulating data suggest that MMPs have a deleterious role in stroke. By degrading neurovascular matrix, MMPs promote injury of the blood-brain barrier, edema and hemorrhage. By disrupting cell-matrix signaling and homeostasis, MMPs trigger brain cell death. Hence, there is a movement toward the development of MMP inhibitors for acute stroke therapy. But MMPs may have a different role during delayed phases after stroke. Because MMPs modulate brain matrix, they may mediate beneficial plasticity and remodeling during stroke recovery. Here, we show that MMPs participate in delayed cortical responses after focal cerebral ischemia in rats. MMP-9 is upregulated in peri-infarct cortex at 7-14 days after stroke and is colocalized with markers of neurovascular remodeling. Treatment with MMP inhibitors at 7 days after stroke suppresses neurovascular remodeling, increases ischemic brain injury and impairs functional recovery at 14 days. MMP processing of bioavailable VEGF may be involved because inhibition of MMPs reduces endogenous VEGF signals, whereas additional treatment with exogenous VEGF prevents MMP inhibitor-induced worsening of infarction. These data suggest that, contrary to MMP inhibitor therapies for acute stroke, strategies that modulate MMPs may be needed for promoting stroke recovery.

Nuevas dianas terapéuticas en artritis reumatoide / No disponible

No disponible

Selective targeting of matrix metalloproteinase inhibition in post-infarction myocardial remodeling.

BACKGROUND: A cause-effect relationship has been established between MMP activation and left ventricular (LV) remodeling following myocardial infarction. The goal of the present study was to examine a selective MMP inhibitor (sMMPi) strategy that effectively spared MMP-1, -3, and -7 with effect to regional and global left ventricular remodeling in a pig model of myocardial infarction. METHODS AND RESULTS: Pigs instrumented with coronary snares and radiopaque markers within the area at risk were randomized to myocardial infarction-only (n = 10) or sMMPi (PGE-530742, 1 mg/kg TID) begun 3 days prior to myocardial infarction. Ten weight-matched noninstrumented pigs served as reference controls. Left ventricular end-diastolic volume in the myocardial infarction-only group was increased from baseline (81 +/- 3 mL versus 55 +/- 4 mL, respectively, P < 0.05) but was attenuated with sMMPi (67 +/- 3 mL, P < 0.05). Fractional area of shortening of marker area was decreased in the myocardial infarction-only group (change from baseline -63 +/- 10%, P < 0.05) but this effect was attenuated with sMMPi (-28 +/- 14%, P < 0.05), indicative of less dyskinesis of the infarct region with sMMPi. Wall stress was reduced within both the septal and posterior wall regions with sMMPi. Myocardial MMP-2 activity was decreased in both remote and border areas of sMMPi-treated samples compared with myocardial infarction-only values, consistent with pharmacologic MMP inhibition. CONCLUSIONS: Selective MMP inhibition favorably affected regional myocardial geometry and decreased left ventricular dilation post-myocardial infarction. This study suggests that a strategy of selective MMP inhibition of a limited array of MMPs may be an achievable goal in preventing pathologic left ventricular remodeling post-myocardial infarction.

Tumour microenvironment - opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy.

The matrix metalloproteinases (MMPs) mediate homeostasis of the extracellular environment. They have multiple signalling activities that are commonly altered during tumorigenesis and that might serve as intervention points for anticancer drugs. However, there are many criteria to consider in validating MMPs as drug targets and for the development of MMP inhibitors. The inhibition of some MMPs could have pro-tumorigenic effects (making them anti-targets), counterbalancing the benefits of target inhibition. These effects might partially account for the failure of MMP inhibitors in clinical trials. What are the major challenges in MMP target validation and MMP-inhibitor-drug development?