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Pharmaceuticals (Basel, Switzerland) May 2019Diabetic foot ulcers (DFUs) are significant complications of diabetes and an unmet medical need. Matrix metalloproteinases (MMPs) play important roles in the pathology... (Review)
Review
Diabetic foot ulcers (DFUs) are significant complications of diabetes and an unmet medical need. Matrix metalloproteinases (MMPs) play important roles in the pathology of wounds and in the wound healing process. However, because of the challenge in distinguishing active MMPs from the two catalytically inactive forms of MMPs and the clinical failure of broad-spectrum MMP inhibitors in cancer, MMPs have not been a target for treatment of DFUs until recently. This review covers the discovery of active MMP-9 as the biochemical culprit in the recalcitrance of diabetic wounds to healing and targeting this proteinase as a novel approach for the treatment of DFUs. Active MMP-8 and MMP-9 were observed in mouse and human diabetic wounds using a batimastat affinity resin and proteomics. MMP-9 was shown to play a detrimental role in diabetic wound healing, whereas MMP-8 was beneficial. A new class of selective MMP-9 inhibitors shows clinical promise for the treatment of DFUs.
PubMed: 31121851
DOI: 10.3390/ph12020079 -
Tropical Medicine and Infectious Disease Apr 2018With the inclusion of snakebite envenoming on the World Health Organization's list of Neglected Tropical Diseases, an incentive has been established to promote research... (Review)
Review
With the inclusion of snakebite envenoming on the World Health Organization's list of Neglected Tropical Diseases, an incentive has been established to promote research and development effort in novel snakebite antivenom therapies. Various technological approaches are being pursued by different research groups, including the use of small molecule inhibitors against enzymatic toxins as well as peptide- and oligonucleotide-based aptamers and antibody-based biotherapeutics against both enzymatic and non-enzymatic toxins. In this article, the most recent advances in these fields are presented, and the advantages, disadvantages, and feasibility of using different toxin-neutralizing molecules are reviewed. Particular focus within small molecules is directed towards the inhibitors varespladib, batimastat, and marimastat, while in the field of antibody-based therapies, novel recombinant polyclonal plantivenom technology is discussed.
PubMed: 30274438
DOI: 10.3390/tropicalmed3020042 -
The Journal of Investigative... Dec 2000Vascular tumors occur in approximately 10% of infants, and range from small cherry-red lesions to large, life-threatening tumors. Although the majority of these tumors... (Review)
Review
Vascular tumors occur in approximately 10% of infants, and range from small cherry-red lesions to large, life-threatening tumors. Although the majority of these tumors involute after several years, there are few therapeutic options and their use is limited by the risk of side-effects. The recent increase in understanding of angiogenesis has led to investigations of new antiangiogenic treatment options using models of vascular tumors in mice. These studies have demonstrated the success of a variety of antiangiogenic approaches, including systemic administration of the antiangiogenic proteins AGM-1470 and angiostatin or of the matrix metalloproteinase inhibitor batimastat, and gene gun therapy with interleukin-12. Although these trials provide further evidence of the role of angiogenesis in the enlargement of these vascular tumors, their potential utility and safety await future trials in patients.
Topics: Angiogenesis Inhibitors; Angiostatins; Animals; Cyclohexanes; Disease Models, Animal; Hemangioma; Humans; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Peptide Fragments; Plasminogen; Sesquiterpenes; Skin Neoplasms
PubMed: 11147681
DOI: 10.1046/j.1087-0024.2000.00011.x -
Turkish Neurosurgery 2023To investigate the efficacy of locally applied batimastat after laminectomy in preventing postoperative epidural fibrosis.
AIM
To investigate the efficacy of locally applied batimastat after laminectomy in preventing postoperative epidural fibrosis.
MATERIAL AND METHODS
Thirty-two Wistar albino male rats weighing 200?250 g were used. The rats were assigned to four different groups (I-Control group, II-sham group, III-Laminectomy+Batimastat group, and IV-Laminectomy+SpongostanTM group). The rats were euthanized 28 days after surgery before TNF-?, IL6, IL-1?, IL10, TGF-?1, and MMP9 gene expression levels of tissue in the surgical area were determined with qPCR. TNF-?, IL6, and IL10 protein levels were also measured in both tissue and plasma. In addition, the surgical area was evaluated by histopathological and immunohistochemical methods.
RESULTS
TNF-?, IL6, and IL-1? gene expression levels were higher in the batimastat group than in the control group. Whereas IL10 gene expression levels increased about two-fold in the sham and SpongostanTM groups, in the batimastat group, it was similar to that in the control group. TGF-?1 gene expression was three-fold higher in the sham group but was similar to that in the control group in both batimastat and SpongostanTM groups. MMP9 gene expression levels significantly decreased only in the batimastat group. In addition, fibrosis score, fibroblast cell count, inflammatory cell count, and CD105 expression decreased in the batimastat group relative to the control.
CONCLUSION
Molecular and pathological examination results suggested that batimastat is an effective agent in reducing the occurrence of epidural fibrosis after laminectomy.
Topics: Animals; Rats; Epidural Space; Fibrosis; Interleukin-1; Interleukin-10; Interleukin-6; Laminectomy; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Rats, Wistar
PubMed: 36482856
DOI: 10.5137/1019-5149.JTN.41841-22.2 -
RSC Advances Feb 2023Matrix metalloproteinases (MMPs) play roles in remodelling of the extracellular matrix that occurs during morphogenesis, repair, and angiogenesis. Dysregulation of... (Review)
Review
Matrix metalloproteinases (MMPs) play roles in remodelling of the extracellular matrix that occurs during morphogenesis, repair, and angiogenesis. Dysregulation of extracellular matrix remodelling can lead to cell proliferation, invasion, and tissue fibrosis. Identification of a specific MMP(s) in a disease has been challenging due to the presence of 24 closely-related human MMPs, each existing in three forms, of which only one is active and capable of catalysis. This review focuses on methods for MMP profiling, with particular emphasis on the batimastat affinity resin that binds only to the active forms of MMPs and related ADAMs (a disintegrin and metalloproteinases), which are then identified by mass spectrometry. Use of the batimastat affinity resin has identified targets for intervention in several human diseases.
PubMed: 36825288
DOI: 10.1039/d2ra07005g -
International Journal of Molecular... Apr 2024The role of metalloproteinases (MMPs) in hematological malignancies, like acute myeloid leukemia (AML), myelodysplastic neoplasms (MDS), and multiple myeloma (MM), is...
The role of metalloproteinases (MMPs) in hematological malignancies, like acute myeloid leukemia (AML), myelodysplastic neoplasms (MDS), and multiple myeloma (MM), is well-documented, and these pathologies remain with poor outcomes despite treatment advancements. In this study, we investigated the effects of batimastat (BB-94), an MMP inhibitor (MMPi), in single-administration and daily administration schemes in AML, MDS, and MM cell lines. We used four hematologic neoplasia cell lines: the HL-60 and NB-4 cells as AML models, the F36-P cells as an MDS model, and the H929 cells as a model of MM. We also tested batimastat toxicity in a normal human lymphocyte cell line (IMC cells). BB-94 decreases cell viability and density in a dose-, time-, administration-scheme-, and cell-line-dependent manner, with the AML cells displaying higher responses. The efficacy in inducing apoptosis and cell cycle arrests is dependent on the cell line (higher effects in AML cells), especially with lower daily doses, which may mitigate treatment toxicity. Furthermore, BB-94 activated apoptosis via caspases and ERK1/2 pathways. These findings highlight batimastat's therapeutic potential in hematological malignancies, with daily dosing emerging as a strategy to minimize adverse effects.
Topics: Humans; Apoptosis; Hematologic Neoplasms; Cell Line, Tumor; Cell Survival; Antineoplastic Agents; Cytostatic Agents; Cell Proliferation; Hydroxamic Acids; HL-60 Cells; Matrix Metalloproteinase Inhibitors; Cell Cycle Checkpoints; MAP Kinase Signaling System; Leukemia, Myeloid, Acute; Phenylalanine; Thiophenes
PubMed: 38674139
DOI: 10.3390/ijms25084554 -
Current Drug Targets Mar 2013Varicose veins (VVs) are a common venous disease of the lower extremity characterized by incompetent valves, venous reflux, and dilated and tortuous veins. If untreated,... (Review)
Review
Varicose veins (VVs) are a common venous disease of the lower extremity characterized by incompetent valves, venous reflux, and dilated and tortuous veins. If untreated, VVs could lead to venous thrombosis, thrombophlebitis and chronic venous leg ulcers. Various genetic, hormonal and environmental factors may lead to structural changes in the vein valves and make them incompetent, leading to venous reflux, increased venous pressure and vein wall dilation. Prolonged increases in venous pressure and vein wall tension are thought to increase the expression/activity of matrix metalloproteinases (MMPs). Members of the MMPs family include collagenases, gelatinases, stromelysins, matrilysins, membrane- type MMPs and others. MMPs are known to degrade various components of the extracellular matrix (ECM). MMPs may also affect the endothelium and vascular smooth muscle, causing changes in the vein relaxation and contraction mechanisms. Endothelial cell injury also triggers leukocyte infiltration, activation and inflammation, which lead to further vein wall damage. The vein wall dilation and valve dysfunction, and the MMP activation and superimposed inflammation and fibrosis would lead to progressive venous dilation and VVs formation. Surgical ablation is an effective treatment for VVs, but may be associated with high recurrence rate, and other less invasive approaches that target the cause of the disease are needed. MMP inhibitors including endogenous tissue inhibitors (TIMPs) and pharmacological inhibitors such as zinc chelators, doxycycline, batimastat and marimastat, have been used as diagnostic and therapeutic tools in cancer, autoimmune and cardiovascular disease. However, MMP inhibitors may have side effects especially on the musculoskeletal system. With the advent of new genetic and pharmacological tools, specific MMP inhibitors with fewer undesirable effects could be useful to retard the progression and prevent the recurrence of VVs.
Topics: Cell Movement; Dermatitis; Dilatation, Pathologic; Female; Humans; Hydrostatic Pressure; Male; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Scleroderma, Localized; Thrombophlebitis; Varicose Veins; Vasoconstriction; Wound Healing
PubMed: 23316963
DOI: No ID Found -
Toxins May 2020Snakebite envenomation causes over 140,000 deaths every year, predominantly in developing countries. As a result, it is one of the most lethal neglected tropical...
Snakebite envenomation causes over 140,000 deaths every year, predominantly in developing countries. As a result, it is one of the most lethal neglected tropical diseases. It is associated with incredibly complex pathophysiology due to the vast number of unique toxins/proteins present in the venoms of diverse snake species found worldwide. Here, we report the purification and functional characteristics of a Group I (PI) metalloprotease (CAMP-2) from the venom of the western diamondback rattlesnake, . Its sensitivity to matrix metalloprotease inhibitors (batimastat and marimastat) was established using specific in vitro experiments and in silico molecular docking analysis. CAMP-2 shows high sequence homology to atroxase from the venom of and exhibits collagenolytic, fibrinogenolytic and mild haemolytic activities. It exerts a mild inhibitory effect on agonist-induced platelet aggregation in the absence of plasma proteins. Its collagenolytic activity is completely inhibited by batimastat and marimastat. Zinc chloride also inhibits the collagenolytic activity of CAMP-2 by around 75% at 50 μM, while it is partially potentiated by calcium chloride. Molecular docking studies have demonstrated that batimastat and marimastat are able to bind strongly to the active site residues of CAMP-2. This study demonstrates the impact of matrix metalloprotease inhibitors in the modulation of a purified, Group I metalloprotease activities in comparison to the whole venom. By improving our understanding of snake venom metalloproteases and their sensitivity to small molecule inhibitors, we can begin to develop novel and improved treatment strategies for snakebites.
Topics: Animals; Antineoplastic Agents; Antivenins; Binding Sites; Blood Platelets; Catalytic Domain; Collagen; Crotalid Venoms; Crotalus; Drug Repositioning; Erythrocytes; Fibrin; Fibrinolysis; Hemolysis; Humans; Hydroxamic Acids; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Molecular Docking Simulation; Phenylalanine; Protein Binding; Protein Conformation; Structure-Activity Relationship; Substrate Specificity; Thiophenes
PubMed: 32397419
DOI: 10.3390/toxins12050309 -
Biochemical Pharmacology Jan 2008Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade various components of the extracellular matrix (ECM). Members of the MMP family include... (Review)
Review
Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade various components of the extracellular matrix (ECM). Members of the MMP family include collagenases, gelatinases, stromelysins, matrilysins and membrane-type MMPs. ProMMPs are cleaved into active forms that promote degradation of ECM proteins. Also, recent evidence suggests direct or indirect effects of MMPs on ion channels in the endothelium and vascular smooth muscle, and on other mechanisms of vascular relaxation/contraction. Endogenous tissue inhibitors of metalloproteinases (TIMPs) reduce excessive proteolytic ECM degradation by MMPs. The balance between MMPs and TIMPs plays a major role in vascular remodeling, angiogenesis, and the uterine and systemic vasodilation during normal pregnancy. An imbalance in the MMPs/TIMPs activity ratio may underlie the pathogenesis of vascular diseases such as abdominal aortic aneurysm, varicose veins, hypertension and preeclampsia. Downregulation of MMPs using genetic manipulations of endogenous TIMPs, or synthetic pharmacological inhibitors such as BB-94 (Batimastat) and doxycycline, and Ro-28-2653, a more specific inhibitor of gelatinases and membrane type 1-MMP, could be beneficial in reducing the MMP-mediated vascular dysfunction and the progressive vessel wall damage associated with vascular disease.
Topics: Animals; Aortic Aneurysm, Abdominal; Atherosclerosis; Blood Vessels; Coronary Restenosis; Female; Humans; Hypertension; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Neovascularization, Physiologic; Pre-Eclampsia; Pregnancy; Tissue Inhibitor of Metalloproteinases; Varicose Veins; Vascular Diseases
PubMed: 17678629
DOI: 10.1016/j.bcp.2007.07.004 -
Toxins Jun 2019Snakebite envenoming (SBE) is a priority neglected tropical disease, which kills in excess of 100,000 people per year. Additionally, many millions of survivors also... (Review)
Review
Snakebite envenoming (SBE) is a priority neglected tropical disease, which kills in excess of 100,000 people per year. Additionally, many millions of survivors also suffer through disabilities and long-term health consequences. The only treatment for SBE, antivenom, has a number of major associated problems, not least, adverse reactions and limited availability. This emphasises the necessity for urgent improvements to the management of this disease. Administration of antivenom is too frequently based on symptomatology, which results in wasting crucial time. The majority of SBE-affected regions rely on broad-spectrum polyvalent antivenoms that have a low content of case-specific efficacious immunoglobulins. Research into small molecular therapeutics such as varespladib/methyl-varespladib (PLA inhibitors) and batimastat/marimastat (metalloprotease inhibitors) suggest that such adjunctive treatments could be hugely beneficial to victims. Progress into toxin-specific monoclonal antibodies as well as alternative binding scaffolds such as aptamers hold much promise for future treatment strategies. SBE is not implicit during snakebite, due to venom metering. Thus, the delay between bite and symptom presentation is critical and when symptoms appear it may often already be too late to effectively treat SBE. The development of reliable diagnostical tools could therefore initiate a paradigm shift in the treatment of SBE. While the complete eradication of SBE is an impossibility, mitigation is in the pipeline, with new treatments and diagnostics rapidly emerging. Here we critically review the urgent necessity for the development of diagnostic tools and improved therapeutics to mitigate the deaths and disabilities caused by SBE.
Topics: Animals; Antivenins; Humans; Reptilian Proteins; Snake Bites; Snake Venoms
PubMed: 31226842
DOI: 10.3390/toxins11060363