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- The Haptoglobin-CD163-Heme Oxygenase-1 Pathway for Hemoglobin Scavenging. [Journal Article]
- Oxid Med Cell Longev 2013.:523652.
The haptoglobin- (Hp-) CD163-heme oxygenase-1 (HO-1) pathway is an efficient captor-receptor-enzyme system to circumvent the hemoglobin (Hb)/heme-induced toxicity during physiological and pathological hemolyses. In this pathway, Hb tightly binds to Hp leading to CD163-mediated uptake of the complex in macrophages followed by lysosomal Hp-Hb breakdown and HO-1-catalyzed conversion of heme into the metabolites carbon monoxide (CO), biliverdin, and iron. The plasma concentration of Hp is a limiting factor as evident during accelerated hemolysis, where the Hp depletion may cause serious Hb-induced toxicity and put pressure on backup protecting systems such as the hemopexin-CD91-HO pathway. The Hp-CD163-HO-1 pathway proteins are regulated by the acute phase mediator interleukin-6 (IL-6), but other regulatory factors indicate that this upregulation is a counteracting anti-inflammatory response during inflammation. The heme metabolites including bilirubin converted from biliverdin have overall an anti-inflammatory effect and thus reinforce the anti-inflammatory efficacy of the Hp-CD163-HO-1 pathway. Future studies of animal models of inflammation should further define the importance of the pathway in the anti-inflammatory response.
- The study of complications of vivax malaria in comparison with falciparum malaria in Mumbai. [Journal Article]
- J Assoc Physicians India 2012 Oct.:15-8.
Severe malaria due to P. vivax infection is increasingly observed now a days. Organ failure in vivax malaria is caused by mechanisms of inflammation as well as sequestration. In this study we have compared the complications in vivax malaria with those in falciparum or mixed malaria.1) To study various complications in adult inpatients of vivax malaria. 2) To compare the incidence of complications in vivax, falciparum and mixed malaria.This was a retrospective observational study done at a tertiary care hospital in Mumbai over 3 months period. All adult indoor patients positive for malarial infection based on peripheral smear or malarial antigen (LDH) spot test were included in the study. Their demographic profile, complications, course in ward till discharge or death was noted. Data was analysed using appropriate statistical tests.680 cases of malaria were included in the study. 338 were infected with P. vivax, 206 with P. falciparum, 136 with mixed infection. Severe disease was present in 162 (23.82%) cases of malaria of which 50 (31%) had vivax infection, 64 (39%) had falciparum infection and 48 (30%) had mixed infection. The complications seen in vivax malaria were: thrombocytopenia (68%), leukopenia (19%), ARDS (3%), high bilirubin (5%), acute renal failure (3.5%), anemia (3%), mucosal bleeding (8%), cerebral malaria (3.5%), hypotension (5%), metabolic acidosis (4%) and death (1.77%).31% cases of severe malaria had vivax monoinfection. Thrombocytopenia, leukopenia, acute respiratory distress syndrome, hypotension, mucosal bleeding were seen as frequently as in falciparum and mixed malaria. Acute renal failure, cerebral malaria, high bilirubin, anaemia, metabolic acidosis and death were also found in vivax malaria but less frequently than in falciparum and mixed malaria.
- Sixth hour transcutaneous bilirubin predicting significant hyperbilirubinemia in ABO incompatible neonates. [JOURNAL ARTICLE]
- World J Pediatr 2013 Jun 17.
BACKGROUND:Neonates with ABO hemolytic disease are at greater risk for developing significant hyperbilirubinemia. We aimed to determine whether sixth hour transcutaneous bilirubin (TcB) could predict such a risk.
METHODS:TcB measurements were obtained at the 6th hour of life in blood group A or B neonates born to blood group O, rhesus factor compatible mothers. Subsequent hyperbilirubinemia was monitored and considered significant if a neonate required phototherapy/exchange transfusion. The predictive role of sixth hour TcB was estimated.
RESULTS:Of 144 ABO incompatible neonates, 41(OA, 24; O-B, 17) had significant hyperbilirubinemia. Mean sixth hour TcB was significantly higher among neonates who developed significant hyperbilirubinemia than those who did not (5.83±1.35 mg/dL vs. 3.65±0.96 mg/dL, P<0.001). Sixth hour TcB value >4 mg/dL had the highest sensitivity of 93.5% and >6 mg/dL had the highest specificity of 99%. Area under receiver operating characteristic curve was 0.898.
CONCLUSION:Sixth hour TcB predicts subsequent significant hyperbilirubinemia in ABO incompatible neonates.
- Structural Elucidation of Transmembrane Transporter Protein Bilitranslocase: Conformational analysis of the second transmembrane region TM2 by molecular dynamics and NMR spectroscopy. [JOURNAL ARTICLE]
- Biochim Biophys Acta 2013 Jun 14.
Membrane proteins represent about a third of the gene products in most organisms, as revealed by the genome sequencing projects. They account for up to two thirds of known drugable targets, which emphasizes their critical pharmaceutical importance. Here we present a study on bilitranslocase (BTL) (TCDB 2.A.65), a membrane protein primarily involved in the transport of bilirubin from blood to liver cells. Bilitranslocase has also been identified as a potential membrane transporter for cellular uptake of several drugs and due to its implication in drug uptake, it is extremely important to advance the knowledge about its 3D structure. However, at present, only a limited knowledge is available beyond the primary structure of BTL. It has been recently confirmed experimentally that one of the four computationally predicted transmembrane segments of bilitranslocase, TM3, has a helical structure with hydrophilic amino acid residues oriented towards one side, which is typical for transmembrane domains of membrane proteins. In this study we confirmed by the use of multidimensional NMR spectroscopy that the second transmembrane segment, TM2, also appears in a form of α-helix. The stability of this polypeptide chain was verified by molecular dynamics (MD) simulation in dipalmitoyl phosphatidyl choline (DPPC) and in sodium dodecyl sulfate (SDS) micelles. The two α-helices, TM2 corroborated in this study, and TM3 confirmed in our previous investigation, provide reasonable building blocks of a potential transmembrane channel for transport of bilirubin and small hydrophilic molecules, including pharmaceutically active compounds.
- An Optimized Fluorogenic ADAMTS13 Assay with Increased Sensitivity for the Investigation of Patients with Thrombotic Thrombocytopenic Purpura. [JOURNAL ARTICLE]
- J Thromb Haemost 2013 Jun 14.
BACKGROUND:Most ADAMTS13 assays use non-physiological conditions (low ionic strength, low pH, barium chloride), are subject to interference from plasma proteins, hemoglobin and bilirubin, and have limited sensitivity, especially for inhibitors.
OBJECTIVES:We addressed these constraints by designing a substrate that can be used in undiluted plasma.
METHODS:A polypeptide was expressed in E. coli that corresponds to von Willebrand factor Gln(1599) -Arg(1668) , with mutations N1610C and K1617R and an N-terminal Gly. Substrate FRETS-rVWF71 was prepared by modifying Cys(1610) with DyLight 633 (abs 638 nm, em 658 nm) and the N-terminus with IRDye QC-1 (abs 500-800 nm). Assays were performed at pH 7.4 in 150 mM NaCl, 10 mM CaCl2 .
RESULTS:Serum and plasma anticoagulated with citrate or heparin had equivalent ADAMTS13 activity with FRETS-rVWF71. Neither bilirubin (≤20 mg/dL) nor hemoglobin (≤20 g/L) interfered with product detection. Assays with FRETS-rVWF71 and FRETS-VWF73 gave similar results (R(2) = 0.95) for plasma from 80 subjects with thrombotic microangiopathy, 22 subjects with other causes of thrombocytopenia, and 20 healthy controls. The limit of detection with FRETS-rVWF71 for ADAMTS13 activity was ≤0.3%. Inhibitor assays with FRETS-rVWF71 gave titers ~2.5-fold higher than with FRETS-VWF73 and clearly distinguished patients with and without inhibitors.
CONCLUSIONS:FRETS-rVWF71 is suitable for ADAMTS13 assays in minimally diluted plasma or serum without interference from proteins, bilirubin or free hemoglobin in plasma. Optimized detection of ADAMTS13 inhibitors will facilitate the monitoring of antibody responses during the treatment of thrombotic thrombocytopenic purpura. This article is protected by copyright. All rights reserved.
- Neurobehavior of term neonates with neonatal hyperbilirubinemia. [Journal Article]
- J Pediatr Neurosci 2013 Jan; 8(1):11-4.
To find the effect of neonatal hyperbilirubinemia on neurobehavior of term infants.This study was undertaken in the neonatal unit of our tertiary care hospital. Term neonates who developed jaundice with serum bilirubin value of above 15 mg/dl within 1(st) week of life were enrolled in the study. Peak total serum bilirubin (PSB) levels of cases were recorded. Age and sex matched normal controls were assigned to every case. Both the groups were assessed by Brazelton's neurobehavioral assessment scale (NBAS) and the scores of the individual clusters were compared.Habituation, range of state, autonomic regulation and regulation of state clusters were significantly altered in the case group, while motor organization cluster was mainly affected in neonates with severe jaundice (PSB > 25 mg/dl). No differences were noted in the reflex and orientation NBAS clusters.Neonatal hyperbilirubinemia causes definite alteration in the neonatal neurobehavior.
- Glycyrrhizin represses total parenteral nutrition-associated acute liver injury in rats by suppressing endoplasmic reticulum stress. [Journal Article]
- Int J Mol Sci 2013; 14(6):12563-80.
Total parenteral nutrition (TPN) is an artificial way to support daily nutritional requirements by bypassing the digestive system, but long-term TPN administration may cause severe liver dysfunction. Glycyrrhizin is an active component of licorice root that has been widely used to treat chronic hepatitis. The aim of this study is to investigate the hepatoprotective effect of glycyrrhizin on TPN-associated acute liver injury in vivo. Liver dysfunction was induced by intravenous infusion of TPN at a flow rate of 20 mL/kg/h for three h in Sprague Dawley rats. The rats were pretreated with Glycyrrhizin (1, 3 and 10 mg/kg intravenously). After receiving TPN or saline (control group) for three h, the rats were sacrificed, blood samples were collected for biochemical analyses and liver tissue was removed for histopathological and immunohistochemical examination. We found that aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TB) and triglyceride (TG) levels were significantly increased in the TPN group without glycyrrhizin pretreatment and decreased in the glycyrrhizin-pretreated TPN group in a dose-dependent manner. The stained liver sections showed that glycyrrhizin relieved acute liver injury. The upregulation of serum protein biomarkers of reactive nitrogen species, including nitrotyrosine and inducible NO synthase (iNOS), were attenuated by glycyrrhizin pretreatment. Levels of endoplasmic reticulum (ER) stress factors, such as phosphorylation of JNK1/2, p38 MAPK and CHOP, were decreased by glycyrrhizin pretreatment. In summary, our results suggest that glycyrrhizin decreases TPN-associated acute liver injury factors by suppressing endoplasmic reticulum stress and reactive nitrogen stress.
- Hepatoprotective and antioxidant capacity of Melochia corchorifolia extracts. [Journal Article]
- Asian Pac J Trop Med 2013 Jul; 6(7):537-43.
To evaluate hepato protective and antioxidant capacity of Melochia corchorifolia (M. corchorifolia) aerial part extracts.Antioxidant activity was evaluated by using three free radicals (Superoxide, Hydroxyl and DPPH) and hepatoprotective activity was assessed against CCl4 induced liver intoxication in rats.The extracts produced concentration dependent percentage protection in decrease of serum enzymes and percentage inhibition on free radicals. Among all extracts methanol extract showed better activity with percentage protection of SGOT (78.98%), SGPT (79.65%), ALP (82.48%) and total bilirubin (80.0%) levels against CCl4 liver intoxication and also methanolic extract showed better activity with IC50 values on superoxide, hydroxyl and DPPH radicals were 127 μ g, 240 μ g and 179 μ g.From the results obtained during the study it could be concluded that M. corchorifolia aerial part extracts have antioxidant and hepatoprotective components. Further study is necessary for isolation and characterization of bioactive molecules which are responsible for hepatoprotective and antioxidant activity.
- Endoscopic ultrasound-guided hepaticogastrostomy for advanced cholangiocarcinoma after failed stenting by endoscopic retrograde cholangiopancreatography. [JOURNAL ARTICLE]
- Asian J Surg 2013 Jun 12.