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IV Activity (iv + activity)
Selected AbstractsMelatonin protects hepatic mitochondrial respiratory chain activity in senescence-accelerated miceJOURNAL OF PINEAL RESEARCH, Issue 3 2002Yuji Okatani Mitochondrial oxidative damage from free radicals may be a factor underlying aging, and melatonin, a powerful free radical scavenger, may participate in mitochondrial metabolism. We measured respiratory chain complex I and IV activities in liver mitochondria from a strain of senescence-accelerated prone mice (SAMP8) and a strain of senescence-accelerated resistant mice (SAMR1) at age 3, 6, and 12 months. No age-associated effects were found in either complex I and IV activities, thiobarbituric acid-reactive substances (TBARS), or glutathione peroxidase (GPx) activity in SAMR1. In contrast, SAMP8 showed significant age-associated decreases in complex I and IV activities. While no age effect was found in TBARS in SAMP8, TBARS levels in SAMP8 were significantly more abundant than in SAMR1. GPx activity in SAMP8 decreased significantly by 12 months. Daily oral melatonin administration (2 ,g/mL of drinking fluid) beginning when the mice were 7 months old significantly increased complex I and IV activity, decreased TBARS, and increased GPx activities in both SAMR1 and SAMP8 at 12 months. The implication of the findings is that melatonin may be beneficial during aging as it reduced the deteriorative oxidative changes in mitochondria and other portions of the cell associated with advanced age. [source] Studies on the aminopeptidase activities of Porphyromonas gingivalisMOLECULAR ORAL MICROBIOLOGY, Issue 4 2001D. Grenier Porphyromonas gingivalis is an asaccharolytic bacterium that requires nitrogen substrates as carbon and energy sources. The aims of this study were to investigate the aminopeptidase activities of P. gingivalis and to evaluate the effect of aminopeptidase inhibitors on bacterial growth. Only arginine aminopeptidase and dipeptidyl aminopeptidase IV activities were detected. Experimental evidence was obtained suggesting that the Arg-gingipains of P. gingivalis can function as both an endopeptidase and an aminopeptidase. Firstly, the arginine aminopeptidase activity was found to be inhibited by leupeptin, a well-known inhibitor of Arg-gingipain activity. Secondly, a preparation of Arg-gingipain activity could hydrolyze the chromogenic substrate for arginine aminopeptidase. Lastly, a mutant of P. gingivalis constructed via gene disruption by use of suicide plasmids and deficient in both Arg-gingipain A and B was also devoid of arginine aminopeptidase activity. To investigate the key role of aminopeptidase activities in growth of P. gingivalis, aminopeptidase inhibitors were incorporated in the culture medium prior to inoculation. Bestatin and actinonin were the only ones to inhibit growth of P. gingivalis. Their mechanism of growth inhibition appears to be different but does not involve inhibition of the two major aminopeptidase activities (arginine aminopeptidase and dipeptidyl aminopeptidase IV). [source] Function of a long-term, GLP-1-treated, insulin-secreting cell line is improved by preventing DPP IV-mediated degradation of GLP-1DIABETES OBESITY & METABOLISM, Issue 5 2005B. D. Green Glucagon-like peptide-1 (GLP-1) is an important insulinotropic hormone with potential in the treatment of type 2 diabetes. However, the short biological half-life of the peptide after cleavage by dipeptidylpeptidase IV (DPP IV) is a major limitation. Inhibition of DPP IV activity and the development of resistant GLP-1 analogues is the subject of ongoing research. In this study, we determined cell growth, insulin content, insulin accumulation and insulin secretory function of a insulin-secreting cell line cultured for 3 days with either GLP-1, GLP-1 plus the DPP IV inhibitor diprotin A (DPA) or stable N -acetyl-GLP-1. Native GLP-1 was rapidly degraded by DPP IV during culture with accumulation of the inactive metabolite GLP-1(9,36)amide. Inclusion of DPA or use of the DPP IV-resistant analogue, N -acetyl-GLP-1, improved cellular function compared to exposure to GLP-1 alone. Most notably, basal and accumulated insulin secretion was enhanced, and glucose responsiveness was improved. However, prolonged GLP-1 treatment resulted in GLP-1 receptor desensitization regardless of DPP IV status. The results indicate that prevention of DPP IV action is necessary for beneficial effects of GLP-1 on pancreatic , cells and that prolonged exposure to GLP-1(9,36)amide may be detrimental to insulin secretory function. These observations also support the ongoing development of DPP-IV-resistant forms of GLP-1, such as N -acetyl-GLP-1. [source] Functional demonstration of surface carbonic anhydrase IV activity on rat astrocytesGLIA, Issue 3 2006Nataliya Svichar Abstract Buffering of the brain extracellular fluid is catalyzed by carbonic anhydrase (CA) activity. Whereas the extracellular isoform CA XIV has been localized exclusively to neurons in the brain, and to glial cells in the retina, there has been uncertainty regarding the form or forms of CA on the surface of brain astrocytes. We addressed this issue using physiological methods on cultured and acutely dissociated rat astrocytes. Prior work showed that the intracellular lactate-induced acidification (LIA) of astrocytes is diminished by benzolamide, a poorly permeant, nonspecific CA inhibitor. We demonstrate that pretreatment of astrocytes with phosphatidylinositol-specific phospholipase C (PI-PLC) results in a similar inhibition of the mean LIA (by 66 ± 3%), suggesting that the glycosylphosphatidylinositol-anchored CA IV was responsible. Pretreatment of astrocytes with CA IV inhibitory antisera also markedly reduced the mean LIA in both cultured cortical (by 46 ± 4%) and acutely dissociated hippocampal astrocytes (by 54 ± 8%). Pre-immune sera had no effect. The inhibition produced by PIPLC or CA IV antisera was not significantly less than that by benzolamide, suggesting that the majority of detectable surface CA activity was attributable to CA IV. Thus, our data collectively document the presence of CAIV on the surface of brain astrocytes, and suggest that this is the predominant CA isoform on these cells. © 2005 Wiley-Liss, Inc. [source] Liver damage underlying unexplained transaminase elevation in human immunodeficiency virus-1 mono-infected patients on antiretroviral therapy,HEPATOLOGY, Issue 2 2009Patrick Ingiliz Liver damage associated with chronic unexplained high serum transaminases in human immunodeficiency virus (HIV)-infected patients under combined antiretroviral therapy is unknown. Liver histology was prospectively investigated in patients presenting serum transaminase elevation for more than 6 months, after exclusion of alcohol abuse, hepatitis C virus (HCV) or hepatitis B virus (HBV) infection, autoimmune, and genetic liver diseases. In a subgroup of patients, liver mitochondrial activities were measured by spectrophotometry and mitochondrial DNA (mtDNA) by real-time polymerase chain reaction (PCR). Thirty patients were included with median values of alanine aminotransferase (ALT) levels: 80 U/L, age: 46 years, body mass index: 23 kg/m2, HIV RNA: 200 copies/mL, CD4 count: 365/mm3, duration of HIV infection: 13 years, and duration of treatment exposure: 118, 41, and 53 months for nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors, respectively. Histological anomalies were found in 22 of 30 patients. Steatosis was present in 18 patients, severe in nine patients, and associated with inflammation in 16 patients with a diagnosis of non-alcoholic steatohepatitis (NASH). Fibrosis was found in 18 patients, severe in six patients and associated with steatosis in 13 patients. Significant liver respiratory complex I defect, contrasting with high complex IV activity and normal mitochondrial DNA content, was observed in the group of patients compared with controls. The presence of NASH was correlated with high fasting glycemia and insulin levels, not with liver mitochondrial function or mitochondrial DNA content. Conclusions: HIV-infected patients on combined antiretroviral therapy with chronic transaminase elevation of unknown origin have a high rate of liver lesions, mostly consistent with NASH related to insulin resistance. (HEPATOLOGY 2008.) [source] Melatonin protects hepatic mitochondrial respiratory chain activity in senescence-accelerated miceJOURNAL OF PINEAL RESEARCH, Issue 3 2002Yuji Okatani Mitochondrial oxidative damage from free radicals may be a factor underlying aging, and melatonin, a powerful free radical scavenger, may participate in mitochondrial metabolism. We measured respiratory chain complex I and IV activities in liver mitochondria from a strain of senescence-accelerated prone mice (SAMP8) and a strain of senescence-accelerated resistant mice (SAMR1) at age 3, 6, and 12 months. No age-associated effects were found in either complex I and IV activities, thiobarbituric acid-reactive substances (TBARS), or glutathione peroxidase (GPx) activity in SAMR1. In contrast, SAMP8 showed significant age-associated decreases in complex I and IV activities. While no age effect was found in TBARS in SAMP8, TBARS levels in SAMP8 were significantly more abundant than in SAMR1. GPx activity in SAMP8 decreased significantly by 12 months. Daily oral melatonin administration (2 ,g/mL of drinking fluid) beginning when the mice were 7 months old significantly increased complex I and IV activity, decreased TBARS, and increased GPx activities in both SAMR1 and SAMP8 at 12 months. The implication of the findings is that melatonin may be beneficial during aging as it reduced the deteriorative oxidative changes in mitochondria and other portions of the cell associated with advanced age. [source] Defective mitochondrial translation caused by a ribosomal protein (MRPS16) mutationANNALS OF NEUROLOGY, Issue 5 2004Chaya Miller PhD The mitochondrial respiratory chain comprises 85 subunits, 13 of which are mitochondrial encoded. The synthesis of these 13 proteins requires many nuclear-encoded proteins that participate in mitochondrial DNA replication, transcript production, and a distinctive mitochondrial translation apparatus. We report a patient with agenesis of corpus callosum, dysmorphism, and fatal neonatal lactic acidosis with markedly decreased complex I and IV activity in muscle and liver and a generalized mitochondrial translation defect identified in pulse-label experiments. The defect was associated with marked reduction of the 12S rRNA transcript level likely attributed to a nonsense mutation in the MRPS16 gene. A new group of mitochondrial respiratory chain disorders is proposed, resulting from mutations in nuclear encoded components of the mitochondrial translation apparatus. Ann Neurol 2004;56:734,738 [source] Effect of Filtration Leukocytapheresis Therapy: Modulation of White Blood Cell Enzyme Activities in Patients with Rheumatoid ArthritisARTIFICIAL ORGANS, Issue 4 2002Satoshi Yamasaki Abstract: We treated 12 patients with rheumatoid arthritis by filtration leukocytapheresis (FLCP) and evaluated its effect on leukocyte enzyme activities. We calculated the number of leukocytes removed and assessed the clinical response. We also evaluated the cellular enzyme activities of elastase and dipeptidylpeptidase IV (DPP IV). Out of 12 patients, 7 patients achieved 20% improvement for 4 weeks following FLCP. The FLCP treatment resulted in removal of 96% of granulocytes, 98% of monocytes, and 61% of lymphocytes. Granulocytes and monocytes with high elastase activity were effectively removed by FLCP. The elastase activity of granulocytes was increased 4 weeks after the last FLCP only in responders. On the other hand, the DPP IV activity of lymphocytes was low at 4 weeks after the last FLCP in responders. Modulation of leukocyte enzyme activities is one of the main effects of FLCP therapy and alteration of granulocytes, monocytes, and lymphocytes. [source] Pharmacokinetics and pharmacodynamics of LC15-0444, a novel dipeptidyl peptidase IV inhibitor, after multiple dosing in healthy volunteersBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2009Kyoung Soo Lim WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , The importance of efficient drug development using biomarkers has been increasingly emphasized, from preclinical studies to clinical trials. , However, as yet few ,validated' or ,qualified' biomarkers are used in early-stage drug development in terms of clinical pharmacology and disease pathophysiology. WHAT THIS STUDY ADDS , This first-time-in-human study provides evidence of the pharmacological activity of LC15-0444 in humans, by using dipeptidyl peptidase IV activity and active glucagon-like peptide-1 concentrations. , LC15-0444 possesses pharmacokinetic and pharmacodynamic characteristics that support a once-daily dosing regimen. AIMS LC15-0444 is a selective and competitive inhibitor of dipeptidyl peptidase (DPP) IV with potential for the treatment of Type 2 diabetes. The aim was to investigate the pharmacokinetic (PK) and pharmacodynamic (PD) profiles after multiple oral ascending doses of LC15-0444 in healthy male subjects. METHODS A dose block-randomized, double-blind, placebo-controlled, parallel group study was performed in three groups with 10 subjects (eight for active drug; two for placebo) per group; each group received 200, 400 or 600 mg of LC15-0444 once daily for 10 days. Blood and urine samples were collected up to 24 h after the first dosing and up to 72 h after the last dosing. RESULTS The LC15-0444 concentration,time profiles exhibited characteristics of multicompartment disposition. No dose- or time-dependent change in PK parameters was observed. Mean elimination half-life was in a range 16.6,20.1 h in the dose groups. Mean renal clearance and fraction of unchanged drug excreted in urine was 18.6,21.9 and 0.40,0.48 l h,1, respectively. In the steady state, mean accumulation ratios by dose groups were between 1.22 and 1.31. More than 80% inhibition of DPP IV activity from baseline was sustained for >24 h in all dose groups. CONCLUSIONS This study provides evidence of the pharmacological activity of LC15-0444 in humans. LC15-0444 possesses PK and PD characteristics that support a once-daily dosing regimen. [source] Inhibitor of DASH proteases affects expression of adhesion molecules in osteoclasts and reduces myeloma growth and bone diseaseBRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2009Angela Pennisi Summary Dipeptidyl peptidase (DPP) IV activity and/or structure homologues (DASH) are serine proteases implicated in tumourigenesis. We previously found that a DASH protease, fibroblast activation protein (FAP), was involved in osteoclast-induced myeloma growth. Here we further demonstrated expression of various adhesion molecules in osteoclasts cultured alone or cocultured with myeloma cells, and tested the effects of DASH inhibitor, PT-100, on myeloma cell growth, bone disease, osteoclast differentiation and activity, and expression of adhesion molecules in osteoclasts. PT-100 had no direct effects on viability of myeloma cells or mature osteoclasts, but significantly reduced survival of myeloma cells cocultured with osteoclasts. Real-time PCR array for 85 adhesion molecules revealed upregulation of 17 genes in osteoclasts after coculture with myeloma cells. Treatment of myeloma/osteoclast cocultures with PT-100 significantly downregulated 18 of 85 tested genes in osteoclasts, some of which are known to play roles in tumourigenesis and osteoclastogenesis. PT-100 also inhibited osteoclast differentiation and subsequent pit formation. Resorption activity of mature osteoclasts and differentiation of osteoblasts were not affected by PT-100. In primary myelomatous severe combined immunodeficient (SCID)-hu mice PT-100 reduced osteoclast activity, bone resorption and tumour burden. These data demonstrated that DASH proteases are involved in myeloma bone disease and tumour growth. [source] | |||||||||||||