- Witenwisenstrasse 4, 8180 Buelach, Switzerland
- Glutamine, Glutamine Synthetase, Glutamine, Hepatic Encephalopathy, Skeletal muscle biology, Muscle Physiology, Muscle Derived Stem Cells, and 21 moreWnt Signaling, Muscular Dystrophy, Adipose-derived stem cells, Hepatology, Gut Microbiota, Glutaminase, Ammonium, Bicarbonate, Enzme Regulation, Mitochondria, Education, Medicine, Artificial Intelligence, Research Methodology, E-learning, Computer Science, Biology, Clinical Microbiology, Music Perception, Research Journal of Medical Sciences, and Muscle strengthedit
- I'm described as a person with a "bright" personality, not referred to as outstanding smart as a would like but as a ... moreI'm described as a person with a "bright" personality, not referred to as outstanding smart as a would like but as a nice person who you work with. I'm a team worker colleague who loves to help people. I'm a researcher collaborating with Advazent, a Company that is helping Startups to find their way into Intellectual Property. I'm a scientist, my background is in biomedical liver research with experience of more than 10 years in the field. I have dedicated my last eight years to personal development and growth (and growing my family as well) and I´m very interested in translational research, innovation, and digital health.edit
Acute-on-chronic liver failure (ACLF) is a newly defined clinical entity with significant morbidity and mortality (~40–90 % at 1 year dependent on need for organ support at presentation). It defines a presentation with acute severe liver... more
Acute-on-chronic liver failure (ACLF) is a newly defined clinical entity with significant morbidity and mortality (~40–90 % at 1 year dependent on need for organ support at presentation). It defines a presentation with acute severe liver injury, often with multiorgan dysfunction, on a background of previously known or unknown cirrhosis. In its severest form, it is almost indistinguishable from acute liver failure, as similarly in around 5%may rapidly progress to intracranial hypertension and cerebral oedema culminating in coma and/or death. Our under-standing of such cerebral sequelae is currently limited to clinical observation, though our knowledge base is rapidly expanding since recent consensus clinical definition and guidance. More-over, there are now animal models of ACLF and imaging modalities to better characterize events in the brain that occur with ACLF. However, as yet there has been little in the way of interventional study of this condition which are much needed. In thi...
Use-N N-phenyl compound - (3-methyl-2-butenyl) thiourea to prepare medicaments for the treatment of hepatic encephalopathy # The present invention relates to N-phenyl pharmaceutical composition comprising the compound. -N -... more
Use-N N-phenyl compound - (3-methyl-2-butenyl) thiourea to prepare medicaments for the treatment of hepatic encephalopathy # The present invention relates to N-phenyl pharmaceutical composition comprising the compound. -N - (3-methyl-2-butenyl) thiourea and the use of N-phenyl-N compound - (3-methyl-2-butenyl) thiourea and said pharmaceutical composition in the manufacture of medicaments for the treatment of diseases with hyperammonemia, such as, but not limited thereto, hepatic encephalopathy in general or hepatic encephalopathy caused by cirrhosis in particular. This compound is capable of partially inhibiting the enzymatic activity of intestinal glutaminase activated phosphate (GAP), causing a reduction in ammonia production.
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Use of the compound N-phenyl-N '' - (3-methyl-2-butenyl) thiourea for the manufacture of medicaments for the treatment of hepatic encephalopathy. The present invention relates to a pharmaceutical composition comprising the... more
Use of the compound N-phenyl-N '' - (3-methyl-2-butenyl) thiourea for the manufacture of medicaments for the treatment of hepatic encephalopathy. The present invention relates to a pharmaceutical composition comprising the compound N-phenyl -N '' - (3-methyl-2-butenyl) thiourea and the use of the compound N-phenyl-N '' - (3-methyl-2-butenyl) thiourea and of said pharmaceutical composition in the manufacture of medicines intended for treatment of diseases that occur with hyperaemia, such as, but not limited to, hepatic encephalopathy in general or hepatic encephalopathy caused by cirrhosis in particular. This compound is capable of partially inhibiting the enzymatic activity of phosphate activated intestinal glutaminase (GAP), causing a reduction in the production of ammonia.
Poster abstrac
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Over the past 100 years a central role of ammonia in the pathogenesis of hepatic encephalopathy (HE) has been hypothesized. Treatment of hyperammonemia and HE are unmet clinical needs. Ornithine phenylacetate (OP) is a novel drug that is... more
Over the past 100 years a central role of ammonia in the pathogenesis of hepatic encephalopathy (HE) has been hypothesized. Treatment of hyperammonemia and HE are unmet clinical needs. Ornithine phenylacetate (OP) is a novel drug that is targeted at reducing ammonia concentration in patients with liver disease and therefore a potential treatment for HE. Ammonia-mediated mechanisms include changes in neurotransmitter synthesis and release, neuronal oxidative stress, impaired mitochondrial function, and osmotic disturbances resulting from astrocytic metabolism of ammonia to glutamine. Systemic hyperammonemia has been largely found in patients with HE with underlying cirrhosis and acute liver failure (ALF). The mechanism by which OP directly reduces ammonia levels in cirrhosis is by increasing muscle glutamine synthesis activity, subsequently trapping and increasing ammonia excretion as phenylacetylglutamine, with the concomitant normalization of gut glutaminase activity. The reduction of ammonia (by OP) leads to a reduction in intracranial hypertension in models of ALF and is associated with an improvement in inflammation and nitric oxide availability in the context of cirrhosis. Studies to date have indicated that it is safe and patient studies in minimal HE and overt HE are underway to establish OP as a treatment for this major complication of liver disease.
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ABSTRACT Background and Aims: Introduction: In the brain Ammonia is detoxified to glutamine through the action of astrocytic glutamine synthase. This glutamine transported to the neurons serves as an energy source via neuronal... more
ABSTRACT Background and Aims: Introduction: In the brain Ammonia is detoxified to glutamine through the action of astrocytic glutamine synthase. This glutamine transported to the neurons serves as an energy source via neuronal mitochondrial glutaminase (Kglutaminase) producing ammonia. Accumulating ammonia may become neurotoxic, an effect partly modulated by TLR4. Therefore increasedbrain K-glutaminase activity and ammonia generation could produce neuronal dysfunction. Aim: To assess the expression and activity of neuronal K-glutaminase in ALF and determine whether this involves TLR4-dependent pathways. Methods: Study 1: 3 groups of mice studied. Healthy: n = 6; ALF induced by acetaminophen (APAP) (500 mg/kg IP): n = 7; and ALF treated with STM 28, a TLR4 antagonist. The animals were sacrificed after 8-hour or at coma. Study 2: 4 groups of mice studied [WT control: n=10, WT (NH3), n = 10 (using NH4Cl in diet); TLR4 ko control (TLR4−/−), n = 6; TLR4−/−(NH3) n = 13]. Arterial ammonia and frontal cortex brain water were measured. Brain was snap frozen for PCR and brain sections were stained for Glase. Results: Study 1: ALF induced significant increase in ammonia and brain water in the APAP group compared with controls (345+/-32 vs. 132+/-11 umol/L, p = 0.002) (83.6+/-2.3% vs. 76.3+/-2.6%, p = 0.05) respectively. Immunohistochemistry of brain slices showed significantly increased K-Glase expression in the neurons in the frontal cortex, hippocampus and cerebellum of the ALF treated animals compared with healthy controls. Glase activity was significantly increased in ALF treated groups compared with controls (7.9+/-0.2 vs 6.2+/-0.7 p < 0.03) and reduced significantly in the STM 28 animals (p < 0.03) in parallel with reduced brain water and time to coma (p < 0.01 each). Study 2: Hyperammonemia resulted in a significant increase in brain water in WT animals compared with TLR4−/− cohort (p 0.02), Glase expression and activity was significantly reduced in the TLR4−/− hyperammonemic animals compared with the WT hyperammonemic group (8.5+/-0.4 vs 7.2+/-0.1, p = 0.01). Conclusions: The study shows for the first time a potential role of neuronal production of aMmonia by increased expression of Glase. Reduction of brain inflammation using TLR4 antagonist or a knocking out TLR4 results in reduction of Glase expression, activity and reduction in brain edema suggesting a potential role of TLR4 signalling in the modulation of increased neuronal Glase in ALF. Further studies should address the mechanisms involved and whether Glase may be a target of therapy.
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Infection with hepatitis B virus (HBV) results in disparate degrees of tissue injury: the virus can either replicate without pathological consequences or trigger immune-mediated necroinflammatory liver damage. We investigated the... more
Infection with hepatitis B virus (HBV) results in disparate degrees of tissue injury: the virus can either replicate without pathological consequences or trigger immune-mediated necroinflammatory liver damage. We investigated the potential for myeloid-derived suppressor cells (MDSCs) to suppress T cell-mediated immunopathology in this setting. Granulocytic MDSCs (gMDSCs) expanded transiently in acute resolving HBV, decreasing in frequency prior to peak hepatic injury. In persistent infection, arginase-expressing gMDSCs (and circulating arginase) increased most in disease phases characterized by HBV replication without immunopathology, whilst L-arginine decreased. gMDSCs expressed liver-homing chemokine receptors and accumulated in the liver, their expansion supported by hepatic stellate cells. We provide in vitro and ex vivo evidence that gMDSCs potently inhibited T cells in a partially arginase-dependent manner. L-arginine-deprived T cells upregulated system L amino acid transporte...
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This study assessed the involvement of metabolic factors (anthropometric indices, insulin resistance (IR) and adipocytokines) in the prediction of portal hypertension, esophageal varices and risk of variceal bleeding in cirrhotic... more
This study assessed the involvement of metabolic factors (anthropometric indices, insulin resistance (IR) and adipocytokines) in the prediction of portal hypertension, esophageal varices and risk of variceal bleeding in cirrhotic patients. Two prospective and retrospective cohorts of cirrhotic patients were selected (n = 357). The first prospective cohort (n = 280) enrolled consecutively in three centers, underwent upper gastrointestinal endoscopy, seeking evidence of esophageal varices. Clinical, anthropometric, liver function tests, ultrasonographic, and metabolic features were recorded at the time of endoscopy, patients were followed-up every 6 months until death, liver transplantation or variceal bleeding. The second retrospective cohort (n = 48 patients) had measurements of the hepatic venous pressure gradient (HVPG). Statistical analyses of the data were with the SPSS package. The presence of esophageal varices was independently associated with lower platelet count, raised HOM...
Research Interests: Egypt, Multivariate Analysis, Insulin Resistance, Humans, Blood Glucose, and 15 moreLiver Cirrhosis, Insulin, Female, Male, Aged, Middle Aged, Gastrointestinal Endoscopy, Adiponectin, Adult, Biological markers, Chi Square Distribution, Logistic Models, Liver function tests, Esophageal and gastric varices, and Cardiovascular medicine and haematology
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Liver failure is characterized by endothelial dysfunction, which results in hemodynamic disturbances leading to renal failure. Albumin infusion improves hemodynamics and prevents renal dysfunction in advance liver failure. These effects... more
Liver failure is characterized by endothelial dysfunction, which results in hemodynamic disturbances leading to renal failure. Albumin infusion improves hemodynamics and prevents renal dysfunction in advance liver failure. These effects are only partly explained by the oncotic properties of albumin. This study was designed to test the hypothesis that albumin exerts its beneficial effects by stabilising endothelial function. In vivo: systemic hemodynamics, renal function, markers of endothelial dysfunction (ADMA) and inflammation were studied in analbuminaemic and Sprague-Dawley rats, 6-weeks after sham/bile duct ligation surgery. In vitro: human umbilical vein endothelial cells were stimulated with LPS with or without albumin. We studied protein expression and gene expression of adhesion molecules, intracellular reactive oxygen species, and cell stress markers. Compared to controls, analbuminaemic rats had significantly greater hemodynamic deterioration after bile duct ligation, resulting in worse renal function and shorter survival. This was associated with significantly greater plasma renin activity, worse endothelial function, and disturbed inflammatory response. In vitro studies showed that albumin was actively taken up by endothelial cells. Incubation of albumin pre-treated endothelial cells with LPS was associated with significantly less activation compared with untreated cells, decreased intracellular reactive oxygen species, and markers of cell stress. These results show, for the first time, that absence of albumin is characterised by worse systemic hemodynamics, renal function and higher mortality in a rodent model of chronic liver failure and illustrates the important non-oncotic properties of albumin in protecting against endothelial dysfunction.
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Acute-on-chronic liver failure (ACLF) is a newly defined clinical entity with significant morbidity and mortality (~40-90 % at 1 year dependent on need for organ support at presentation). It defines a presentation with acute severe liver... more
Acute-on-chronic liver failure (ACLF) is a newly defined clinical entity with significant morbidity and mortality (~40-90 % at 1 year dependent on need for organ support at presentation). It defines a presentation with acute severe liver injury, often with multiorgan dysfunction, on a background of previously known or unknown cirrhosis. In its severest form, it is almost indistinguishable from acute liver failure, as similarly in around 5 % may rapidly progress to intracranial hypertension and cerebral oedema culminating in coma and/or death. Our understanding of such cerebral sequelae is currently limited to clinical observation, though our knowledge base is rapidly expanding since recent consensus clinical definition and guidance. Moreover, there are now animal models of ACLF and imaging modalities to better characterize events in the brain that occur with ACLF. However, as yet there has been little in the way of interventional study of this condition which are much needed. In thi...
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... 498507. [9] JC Parajo, JL Alonso and AB Moldes, Production of lactic acid from lignocellulose in a single stage of hydrolysis and fermentation. Food Biotechnol., 11 (1997), pp. 4558. ... 109113. [12] VP Lewis and ST Yang,... more
... 498507. [9] JC Parajo, JL Alonso and AB Moldes, Production of lactic acid from lignocellulose in a single stage of hydrolysis and fermentation. Food Biotechnol., 11 (1997), pp. 4558. ... 109113. [12] VP Lewis and ST Yang, Continuous propionic acid fermentation by ...
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In liver failure, ammonia homeostasis is dependent upon the function of the ammonia metabolising enzymes, glutamine synthetase (GS) and glutaminase (GA) but data about their protein expression and activity are lacking. The aims of this... more
In liver failure, ammonia homeostasis is dependent upon the function of the ammonia metabolising enzymes, glutamine synthetase (GS) and glutaminase (GA) but data about their protein expression and activity are lacking. The aims of this study were to determine the protein expression and activity of GS and GA in individual organs in a rat model of chronic liver disease and to test whether the treatment with the ammonia-lowering agent ornithine phenylacetate (OP) modulates their activities. 49 SD rats were studied 35 days after sham-operation or bile duct ligation (BDL). The BDL group received: L-ornithine (0.6 mg/kg/day), Phenylacetate (0.6 mg/kg/day), OP (0.6 mg/kg/day) or placebo (saline) for 5 days prior to sacrifice. Arterial ammonia, amino acids and liver biochemistry were measured. Expressions of GS and GA were determined by Western-blotting and activities by end-point methods in liver, muscle, gut, kidney, lung, and frontal cortex. In BDL rats, hepatic GS enzyme activity was reduced by more than 80% compared to sham rats. Further, in BDL rats GA activity was reduced in liver but increased in the gut, muscle and frontal cortex compared to sham rats. OP treatment resulted in a reduction in hyperammonemia in BDL rats, associated with increased GS activity in the muscle and reduced gut GA activity. In a rat model of chronic liver failure, hyperammonemia is associated with inadequate compensation by liver and muscle GS activity and increased gut GA activity. OP reduces plasma ammonia by increasing GS in the muscle and reducing GA activity in the gut providing additional insights into its mechanism of its action. GS and GA may serve as important future therapeutic targets for hyperammonemia in liver failure.
Research Interests: Hepatology, Liver, Animals, Male, Ammonia, and 6 moreClinical Sciences, Rats, Glutaminase, End Stage Liver Disease, Bile ducts, and Ligation
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Hyperammonemia is thought to be central in the pathophysiology of hepatic encephalopathy in patients suffering from liver failure. The purpose of this article is to explore existing treatment options that help lower ammonia levels in... more
Hyperammonemia is thought to be central in the pathophysiology of hepatic encephalopathy in patients suffering from liver failure. The purpose of this article is to explore existing treatment options that help lower ammonia levels in patients and alleviate symptoms of hepatic encephalopathy. There are two ways to approach modulating ammonia levels and its effect on the brain. The first targets ammonia levels itself and the second targets inflammation, which makes the brain susceptible to the deleterious effect of ammonia. Recent studies provide new evidence for the use of lactulose, probiotics and rifaximin, as well as closure of large portosystemic shunts in the treatment of hepatic encephalopathy. Over the past 20 years or so, many new approaches to treat hepatic encephalopathy have been developed based upon better understanding of interorgan ammonia metabolism. Reduction in ammonia can be achieved by targeting its production, absorption or elimination. This review will primarily focus on these strategies that reduce ammonia levels in liver failure patients.
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Superimposed infection and/or inflammation precipitate renal failure in cirrhosis. This study aimed at testing the hypothesis that increased gut bacterial translocation in cirrhosis primes the kidney to the effect of superimposed... more
Superimposed infection and/or inflammation precipitate renal failure in cirrhosis. This study aimed at testing the hypothesis that increased gut bacterial translocation in cirrhosis primes the kidney to the effect of superimposed inflammation by upregulating expression of Toll-like receptor 4 (TLR4), NFκB, and cytokines. A well-characterized bile-duct ligated (BDL) model of cirrhosis, which develops renal failure following superimposed inflammatory insult with lipopolysaccharide (LPS), was used and selective gut decontamination was performed using norfloxacin. Sprague-Dawley rats were studied: Sham, Sham+LPS; BDL, BDL+LPS; an additional BDL and BDL+LPS groups were selectively decontaminated with norfloxacin. Plasma biochemistry, plasma renin activity (PRA) and cytokines and, protein expression of TLR4, NFκB, and cytokines were measured in the kidney homogenate. The kidneys were stained for TLR4, TLR2, and caspase-3. Endotoxemia was measured using neutrophil burst and Limulus amoebocyte lysate (LAL) assays. The groups treated with norfloxacin showed significant attenuation of the increase in plasma creatinine, plasma and renal TNF-α and renal tubular injury on histology. The increased renal protein expression of TLR4, NFκB, and caspase-3 in the untreated animals was significantly attenuated in the norfloxacin treated animals. PRA was reduced in the treated animals and severity of endotoxemia was also reduced. The results show for the first time that kidneys in cirrhosis show an increased expression of TLR4, NFκB, and the pro-inflammatory cytokine TNF-α, which makes them susceptible to a further inflammatory insult. This increased susceptibility to LPS can be prevented with selective decontamination, providing novel insights into the pathophysiology of renal failure in cirrhosis.
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Patients with cirrhosis frequently develop renal dysfunction, a proportion of who do not fulfill criteria for hepatorenal syndrome (HRS). We hypothesized that the kidneys in these patients would exhibit histological and biomarker evidence... more
Patients with cirrhosis frequently develop renal dysfunction, a proportion of who do not fulfill criteria for hepatorenal syndrome (HRS). We hypothesized that the kidneys in these patients would exhibit histological and biomarker evidence of kidney injury. We looked specifically for TLR expression as they may mediate kidney injury. Sixty seven subjects (6); alcoholic cirrhosis: compensated (9), acute deterioration of alcoholic cirrhosis (52)] were included. Renal dysfunction was defined as a creatinine of >133 μmol/L and/or according to the AKI network criteria. Urinary biomarkers, KIM-1, πGST, αGST and a novel biomarker, urinary TLR4 were measured. Renal biopsies were also available from eight other alcoholic cirrhosis patients (three non-HRS renal dysfunction; five HRS) that were stained for TLR4 and caspase-3. Fourteen patients developed renal dysfunction, amongst these three had type 2 HRS. KIM-1, πGST and αGST were higher in patients with acute deterioration of cirrhosis compared with patients with compensated cirrhosis, but did not differ between those with and without renal dysfunction. Urinary TLR4 was significantly higher in patients with renal dysfunction associated with infection/inflammation. Kidney biopsies from non-HRS renal dysfunction patients showed tubular damage with evidence of increased tubular expression of TLR4, and caspase-3. Minor changes were observed in HRS patients. The data provide proof of concept that renal dysfunction in patients with cirrhosis with superimposed inflammation is associated with significant tubular injury and apoptosis and with increased renal expression and urinary excretion of the TLR4, suggesting a potential role of TLR4 as mediator of renal injury.
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Crawfish carotenoproteins and chitin are obtained by a combined process based on flotation-sedimentation and in situ lactic acid production. The carotenoprotein PF(1) obtained has a high content in essential amino acids, w-3-fatty acids,... more
Crawfish carotenoproteins and chitin are obtained by a combined process based on flotation-sedimentation and in situ lactic acid production. The carotenoprotein PF(1) obtained has a high content in essential amino acids, w-3-fatty acids, and carotene (mainly astaxanthin) and constitutes an excellent nutritional source for patients with malnutrition. The carotenoprotein PF(2) has a lower nutritional quality but with a substantial carotene content can be used as a feed for animals where coloration is required, such as salmon and trout bred under aquaculture. Chemical and spectrometric (FTIR and (13)C NMR) characterization shows the obtained chitin to be of high quality, similar to that available commercially, for medical and nutritional uses.
Research Interests: Engineering, Chromatography, Spectroscopy, Crustacea, Magnetic Resonance Spectroscopy, and 13 moreMedicine, Animals, Proteins, Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis, CHEMICAL SCIENCES, Fermentation, Electrophoresis, Fourier transform infrared spectroscopy, Gel, Agricultural and Food Chemistry, Polyacrylamide Gel, Chitin, and Procambarus Clarkii
Minimal hepatic encephalopathy (MHE) is a condition in which patients with cirrhosis of liver that has normal mental and neurological status on standard clinical examination exhibit a number of neuropsychiatric and neurophysiological... more
Minimal hepatic encephalopathy (MHE) is a condition in which patients with cirrhosis of liver that has normal mental and neurological status on standard clinical examination exhibit a number of neuropsychiatric and neurophysiological defects. Its prevalence varies up to 80% in cirrhotics .It is characterized by a specific, complex cognitive dysfunction which is independent of sleep dysfunction or problems with overall intelligence. Increasing evidence indicates that MHE is an important disorder that may seriously impair a patients daily functioning and quality of life. Psychomotor slowing, visuoconstructive disabilities, attention deficits are among the few key features while fine motor performance is also impaired. MHE may predict the development of overt hepatic encephalopathy. Various tools have been evaluated for the correct diagnosis of MHE, however, in the absence of a "gold standard", combination of test methods is recommended to most reliably diagnosed MHE. Presently, lactulose is the mainstay of treatment for MHE. However various therapies like probiotics and ornithine aspartate are under evaluation as an alternative to lactulose.
Research Interests: Pathology, Psychometrics, Cognition, Probiotics, Global Health, and 32 moreCancer, Quality of life, Treatment, Mild Cognitive Impairment, India, Activities of Daily Living, Humans, Liver Cirrhosis, Health related Quality of Life, Liver Transplantation, Differential Diagnosis, Liver Function, Incidence, Risk factors, Diagnostic Imaging, Clinical Sciences, Hepatic Encephalopathy, Prevalence, Spectrum, Survival Rate, Physical examination, Risk Factors, Liver Disease, Glutaminase, Cognition disorders, hyperammonemia, Lactulose, Automobile driving, Diagnostic Criteria, Severity of Illness Index, Neuropsychological Tests, and Attention deficit disorder with hyperactivity
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Crayfish (Procambarus clarkii) were separated by solid filtration into a proteinaceous fraction (PF-1) and a chitinous fraction (CF). The PF-1 and CF were used as starting materials for carotenoprotein-1 and carotenoprotein-2... more
Crayfish (Procambarus clarkii) were separated by solid filtration into a proteinaceous fraction (PF-1) and a chitinous fraction (CF). The PF-1 and CF were used as starting materials for carotenoprotein-1 and carotenoprotein-2 preparations, respectively. Crawfish ...