Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Preclinical safety and efficacy evaluation of a novel bioartificial liver support system (BLSS) was conducted using a D-galactosamine canine liver failure model. The BLSS houses a suspension of porcine hepatocytes in a hollow fiber cartridge with the hepatocytes on one side of the membrane and whole blood flowing on the other. Porcine hepatocytes harvested by a collagenase digestion technique were infused into the hollow fiber cartridge and incubated for 16 to 24 hours prior to use. Fifteen purpose-bred male hounds, 1-3 years old, 25-30 kg, were administered a lethal dose, 1.5 g/kg, of D-galactosamine. The animals were divided into three treatment groups: (1b) no BLSS treatment (n = 6); (2b) BLSS treatment starting at 24-26 h post D-galactosamine (n = 5); and (2c) BLSS treatment starting at 16-18 h post D-galactosamine (n = 4). While maintained under isoflurane anesthesia, canine supportive care was guided by electrolyte and invasive physiologic monitoring consisting of arterial pressure, central venous pressure, extradural intracranial pressure (ICP), pulmonary artery pressure, urinary catheter, and end-tidal CO2. All animals were treated until death or death-equivalent (inability to sustain systolic blood pressure > 80 mmHg for 20 minutes despite massive fluid resuscitation and/or dopamine administration), or euthanized at 60 hours. All animals developed evidence of liver failure at 12-24 hours as evidenced by blood pressure lability, elevated ICP, marked hepatocellular enzyme elevation with microscopic massive hepatocyte necrosis and cerebral edema, elevated prothrombin time, and metabolic acidosis. Groups 2b and 2c marginally prolong survival compared with Group 1b (pairwise log rank censored survival time analysis, p = 0.096 and p = 0.064, respectively). Since survival times for Groups 2b and 2c are not significantly different (p = 0.694), the groups were combined for further statistical analysis. Survival times for the combined active treatment Groups 2b and 2c are significantly prolonged versus Group 1b (p = 0.047). These results suggest the novel BLSS reported here can have a significant impact on the course of liver failure in the D-galactosamine canine liver failure model. The BLSS is ready for Phase I safety evaluation in a clinical setting.
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PMID:Novel bioartificial liver support system: preclinical evaluation. 1041 80

The function of the adrenal cortex of the marmoset monkey Callithrix jacchus has been investigated. In common with other New World primates, these animals seem to be glucocorticoid resistant. Blood and adrenal glands were obtained from male and female animals under terminal pentobarbitone anesthesia. Dispersed adrenal cell preparations were obtained by treatment with collagenase and incubated with ACTH(1-24), (0.1-1000 nM) angiotensin II (0.1-1000 nM), dibutyryl cyclic AMP (dbcAMP; 30-1000 microM), and forskolin (FSK; 1-30 microM). Plasma cortisol levels (2113 +/- 449 ng/ml male; 3858 +/- 429 ng/ml female) were found to be 10- to 20-fold higher than those quoted for Old World primates and man. The cell preparations showed no significant response to any dose of ACTH tested (0.1-1000 nM), although addition of exogenous precursor (22R-hydroxycholesterol, 2.5 microM) resulted in an increased yield of cortisol and aldosterone. Cyclic AMP production was increased in response to forskolin (1-30 microM) but not ACTH(1-24) (1-1000 nM). In addition, dose-related responses to angiotensin II (maximal stimulation of 316 +/- 49% basal aldosterone at 100 nM angiotensin II), dbcAMP (maximal stimulation of 449 +/- 24% basal cortisol at 300 microM dbcAMP), and forskolin (maximal stimulation of 394 +/- 31% basal cortisol at 10 microM FSK) were obtained. The lack of a response in vitro to ACTH in C. jacchus cannot, therefore, be attributed either to general failure of the cells or to defects in postreceptor signaling mechanisms. The results suggest that there is a reduction in adrenal ACTH receptor number or affinity, with a high basal production rate in vivo maintaining the elevated plasma cortisol levels.
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PMID:Adrenocortical function in a new world primate, the marmoset monkey, Callithrix jacchus. 1104 5

The increasing availability of mice with gene supplementation (transgenic), site-specific inactivation mutations (gene "knock-outs"), or site-specific genetic modification mutations (gene "knock-ins") has spurred interest in the development of murine trauma models. In this study, C57 BL/6 mice (28 g) were given a cutaneous burn over 40% total body surface area by applying brass probes (1 x 2 x 0.003 cm) heated to 100 degrees C in boiling water to the animals side and back for 5 s. Shams received anesthesia alone and not burn. Mice were killed 24 h post-burn to determine presence of partial-thickness or full-thickness burn injury, cardiac contractile function (Langendorff perfusion, n = 7 or 8 mice/group) or to examine cardiac myocyte cytokine secretion in isolated cardiomyocytes (collagenase perfusion, n = 4 or 5 mice/group). All mice were killed 24 h post-burn for subsequent cardiac or cardiomyocyte studies. Our studies confirm that this murine model of burn trauma produced mixed partial- or full-thickness burn injury, whereas there was no necrosis or inflammation in sham burn mice. Baseline hematocrits were similar in all mice (44+/-1) but decreased after burn trauma (37+/-1), likely because of the volume of fluid resuscitation and hemodilution. Burn trauma impaired cardiac contraction and relaxation as indicated by the lower left ventricular pressure (LVP) measured in burn (56+/-4) compared to that measured in shams (84+/-1 mmHg, P < 0.001), a lower rate of LVP rise (+dP/dt max, 1393+/-10 vs. 2000+/-41 mmHg/s, P < 0.002), and reduced LVP fall (-dP/dt max, 1023 - 40 vs. 1550+/-50, P < 0.001). These differences occurred despite similar coronary perfusion pressures and heart rates in both sham and burn mice. Ventricular function curves were shifted downward in the burn mice in the direction of contractile failure; in addition, hearts from burn mice had reduced LVP and +dP/dt responses to increases in coronary flow rate, increases in perfusate Ca2+, and to isoproterenol challenge (P < 0.05). Burn trauma promoted cardiac myocyte secretion of tumor necrosis factor (TNFalpha) (175+/-6 pg/mL) compared to that measured in shams (72+/-9 pg/mL, P < 0.05); burn trauma also increased cardiac myocyte secretion of interleukin 1beta (IL-1beta) (sham: 2+/-0.5; burn: 22+/-1 pg/mL, P < 0.05) and IL-6 (sham: 70+/-6; burn: 148+/-16 pg/mL, P < 0.05). Anti-TNFalpha strategies prevented burn-mediated cardiac contractile deficits. Burn trauma altered Ca2+ homeostasis in murine cardiomyocytes (Fura-2 AM loading). [Ca2+]i in myocytes from burns (185+/-4 nM) was higher than values measured in myocytes from shams (86+/-nM, P < 0.05). These data confirm that the murine burn model provides a reasonable approach to study the molecular and cell biology of inflammation in organ dysfunction after burn trauma.
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PMID:Development of an acute burn model in adult mice for studies of cardiac function and cardiomyocyte cellular function. 1150 64

The aim of this study was to investigate the biodegradation of carbonate apatite (CO(3)Ap)/collagen composite membrane as a new guided tissue regeneration membrane in vivo and to estimate its controlled release of CO(3)Ap in vitro. To control the biodegradation of the guided tissue regeneration membrane and to promote hard tissue regeneration in the periodontal region, we added CO(3)Ap into the collagen membrane. To investigate the biodegradation of CO(3)Ap/collagen composite membranes, the prepared membranes (CO(3)Ap:0, 10 wt %) were cut into 5 x 5 x 0.1 mm and subcutaneously implanted into the backside of male rats under general anesthesia. The explanted membranes were investigated histologically. To estimate their controlled release of CO(3)Ap in vitro, the membranes (CO(3)Ap 0-10 wt %, 5 x 5 x 0.1 mm) were immersed into collagenase solution and compulsorily dissolved for 48 h. Histological results suggested that the membrane had a good biocompatibility and the biodegradable period was shortened with the presence of CO(3)Ap. In the solubility experiments of the membrane, eluted Ca concentrations gradually increased with total dependence on the dissolution of the collagen membrane. Our study demonstrated that the biodegradation time can be controlled by CO(3)Ap contents in the membrane and CO(3)Ap could be released from the membrane with the biodegradation period.
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PMID:Biodegradation of carbonate apatite/collagen composite membrane and its controlled release of carbonate apatite. 1194 24

An inflammatory response occurs during cardiac surgery involving cardiopulmonary bypass. Matrix metalloproteinase-9 is an enzyme involved in cytokine processing and leucocyte extravasation. It is secreted as a pro-enzyme in response to several inflammatory mediators and is inhibited by endogenous tissue inhibitor of metalloproteinase-1. The interaction between matrix metalloproteinase-9 and its inhibitor during cardiopulmonary bypass is not known. We measured tumour necrosis factor alpha, and matrix metalloproteinase-9 and its inhibitor using enzyme immunoassay at three time points in 20 patients undergoing elective coronary artery bypass grafting with cardiopulmonary bypass. Tumour necrosis factor and matrix metalloproteinase concentrations increased in all patients during bypass (both p < 0.0001), whereas the inhibitor in contrast, decreased (p < 0.0001). We conclude that matrix metalloproteinase-9 is released as part of the inflammatory response during cardiac surgery. Levels of the endogenous inhibitor of metalloproteinase, however, show a different pattern of release, suggesting independent regulation.
Anaesthesia 2002 Jul
PMID:Matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1 and tumour necrosis factor alpha release during cardiopulmonary bypass. 1205 24

Although numerous studies have provided evidence that the inflammatory cytokines TNF-alpha and IL-1beta have significant negative inotropic effects, the role of the interleukins in burn-mediated cardiac dysfunction has not been defined. Furthermore, most studies examining the cardiotoxic effects of inflammatory cytokines have ignored the complex inflammatory milieu that occurs in the intact subject with trauma, sepsis, or ischemic heart disease. Therefore, this study examined the time course of IL-1beta and IL-6 secretion by cardiomyocytes after burn trauma, and additional studies examined the effects of these cytokines alone or in combination with TNF-alpha on cardiac contractile performance (Langendorff). Sprague-Dawley rats were given a full thickness burn injury over 40% of the total body surface area; fluid resuscitation was lactated Ringers solution, 4 mL/kg per burn percentage of burn area. Sham burn animals received identical anesthesia and handling, but no burn injury. Rats were sacrificed at several different times postburn, and isolated hearts (n = 4-5 rats/group/time period) were perfused with collagenase-containing buffer to prepare cardiomyocytes or were perfused in vitro to examine cardiac contractile function (n = 5-6 rats/group/time period). Additional naive control rats (n = 10) were included to prepare cardiomyocytes that, in turn, were challenged with different concentrations of either IL-1beta, IL-6, or TNF-alpha alone or in combination for several time periods (CO2 incubator at 37 degrees C for 1-3 h). Finally, inflammatory cytokines alone or in combination were added to the perfusate of hearts isolated from additional control rats (n = 6-7/group) to assess the cardiac contraction and relaxation effects of cytokine challenge. Despite aggressive fluid resuscitation, burn trauma produced a time-related increase in cardiomyocyte secretion of IL-1beta, IL-6, and TNF-alpha. Exposure of naive cardiomyocytes prepared from control rats to each cytokine alone or combined cytokine challenge produced a time-dependent and concentration-dependent decrease in cell viability and an increase in supernatant creatine kinase levels. Either IL-1beta or TNF-alpha produced greater cardiac defects than IL-6 when added separately to Langendorff-perfused hearts; dysfunction was maximal with combined cytokine challenge (IL-1beta plus TNF-alpha plus IL-6). The data confirm that burn trauma upregulates inflammatory cytokine secretion by cardiomyocytes and suggest that these inflammatory cytokines act in concert to produce burn-mediated cardiac contractile dysfunction.
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PMID:IL-1beta and IL-6 act synergistically with TNF-alpha to alter cardiac contractile function after burn trauma. 1239 81

Irsogladine is a commonly used anti-gastric ulcer agent in Japan, and recent in vivo studies have shown it to have anti-angiogenic properties. The exact role of irsogladine as an inhibitor of angiogenesis remains uncertain. In this study, we show that irsogladine inhibited breast cancer regrowth and pulmonary metastasis but had no anti-angiogenic function against HUVEC cells. Irsogladine failed to inhibit proliferation, tubular formation, and the uPA/MMP-1 mRNA expression of HUVEC cells. We also examined the effect of irsogladine in an orthotopic transplant model of human breast cancer metastasis in athymic mice. Human MDA-MB-435 cells were injected into the mammary fat pads. After 9 weeks, the tumors were resected under general anesthesia. Irsogladine or vehicle was given p.o. daily thereafter. Daily administration of irsogladine at 120 mg/kg per day over a 5-week period had no effect on the body weight of the mice. Tumor regrowth, average volume of pulmonary metastases, and the number of metastases were inhibited by 40, 48 and 64%, respectively. These results suggest that irsogladine may be useful in the breast cancer adjuvant setting.
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PMID:Inhibition of breast cancer regrowth and pulmonary metastasis in nude mice by anti-gastric ulcer agent, irsogladine. 1475 89

This study was undertaken to evaluate the changes in cytokine levels in response to orofacial deep tissue inflammation. Inflammation was induced by injecting complete Freund's adjuvant (CFA, 0.05 ml 1:1 oil/saline suspension) into the masseter of the male Sprague-Dawley rat under brief halothane anesthesia. At 30 min, 5 h and 24 h after CFA injection (n = 3-4/time point), tissues were dissected from masseter and total proteins isolated. Rat Cytokine Antibody Array 1.1 (RayBiotech) coated with 19 specific cytokine antibodies were probed with protein samples and the relative cytokine levels were compared. Compared to saline-injected rats, there were significant increases (p < 0.05-0.01) in the levels of seven cytokines in the masseter tissue after CFA, including interleukin (IL)-1beta (5 h), IL-6 (5 h), tumor necrosis factor-alpha (5 h), monocyte chemoattractant protein-1 (5 h, 24 h), cytokine-induced neutrophil chemoattractant-2 and -3 (5 h, 24 h), and tissue inhibitor of metalloproteinase-1 (5 h, 24 h). All 19 cytokines were detected in the blood samples, but they did not show significant changes after inflammation. Masseter hyperalgesia and allodynia occurred at 30 min and persisted at 5-24 h after inflammation, as assessed by probing the skin above the masseter with von Frey filaments. The present results indicate selective localized cytokine responses to masseter inflammation. Although different cytokines exist in the blood, their levels did not mirror, nor did not appear to depend on, the local cytokine levels. The findings provide specific targets for further studying the involvement of cytokines in orofacial inflammation and hyperalgesia.
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PMID:Antibody array analysis of peripheral and blood cytokine levels in rats after masseter inflammation. 1591 Nov 35

Slow-healing wounds contain insufficient amounts of intrinsic collagenases to provide sufficient wound debridement, so that the use of products containing synergistic collagenases and proteases may be helpful. We report the successful use of collagenase clostridipeptidase A in two newborns, a premature infant with 3rd degree burns, and a term neonate with an extravasation necrosis caused by calcium gluconate. Surgical excision of necrotic tissue is a serious intervention and prolongs the duration of hospitalization. Enzymatic eschar removal may have an advantage over surgery especially in newborns with a high risk for surgery, with its possible complications, need for anesthesia, and perhaps for blood transfusion.
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PMID:Debridement via collagenase application in two neonates. 1746 24

Islet cell transplantation is an attractive alternative therapy to conventional insulin treatment or vascularized whole pancreas transplantation for type 1 diabetic patients. It represents a successful example of somatic cell therapy in humans based on complex procedures for islet isolation from whole pancreas. The islets, that are only 1% of the total pancreas tissue, are isolated by two steps method starting with collagenase digestion that operates a rapid dissociation of the stromal component of the gland, while preserving islet anatomical integrity. After digestion, islets are then separated from exocrine tissue by centrifugation in density gradients. Transplantation consists of a simple injection of few milliliter-purified tissue in the portal vein through a percutaneous trans-hepatic approach performed in local anesthesia. Several studies have now demonstrated that islet transplant can replace pancreatic endocrine function without major side effects and with liver viability preservation in selected patients affected by long-term type 1 diabetes. It can restore endogenous insulin secretion, achieve insulin independence in more than 80% of patients, and recover the metabolism of glucose, protein and lipids. Improved control of glycated HbA1c, reduced risk of recurrent hypoglycemia and of diabetic complications are also seen as important benefits of islet cell transplantation, irrespective of the status of insulin independence. Many protocols are now on going for reduction of immunosuppression therapy in recipients, induction of tolerance, and prolongation of graft function.
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PMID:Islet cell transplantation. 1690 Jun 60


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