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M Noronha

Publications and source records attributed to M Noronha.

At least 19 recordsLinked to original sources
PubMed2001

Engineering the pH-optimum of a triglyceride lipase: from predictions based on electrostatic computations to experimental results.

The optimisation of enzymes for particular purposes or conditions remains an important target in virtually all protein engineering endeavours. Here, we present a successful strategy for altering the pH-optimum of the triglyceride lipase cutinase from Fusarium solani pisi. The computed electrostatic pH-dependent potentials in the active site environment are correlated with the experimentally observed enzymatic activities. At pH-optimum a distinct negative potential is present in all the lipases and esterases that we studied so far. This has prompted us to propose the "The Electrostatic Catapult Model" as a model for product release after cleavage of the ester bond. The origin of the negative potential is associated with the titration status of specific residues in the vicinity of the active site cleft. In the case of cutinase, the role of Glu44 was systematically investigated by mutations into Ala and Lys. Also, the neighbouring Thr45 was mutated into Proline, with the aim of shifting the spatial location of Glu44. All the charge mutants displayed altered titration behaviour of active site electrostatic potentials. Typically, the substitution of the residue Glu44 pushes the onset of the active site negative potential towards more alkaline conditions. We, therefore, predicted more alkaline pH optima, and this was indeed the experimentally observed. Finally, it was found that the pH-dependent computed Coulombic energy displayed a strong correlation with the observed melting temperatures of native cutinase.

Amino Acid Sequence↗
PubMed1991

Triiodothyronine causes rapid reversal of alpha 1/cyclic adenosine monophosphate synergism on brown adipocyte respiration and type II deiodinase activity.

Previous studies have shown that thyroid status affects the response of brown adipose tissue (BAT) to the sympathetic nervous system. For example, hypothyroidism is associated with the development of a marked synergism between alpha 1- and beta-adrenergic pathways to stimulate type II iodothyronine 5'-deiodinase activity. Hypothyroidism also attenuates the respiratory response (thermogenesis) of isolated brown adipocytes to norepinephrine. To explore the interactions of the sympathetic nervous system and thyroid status in these cells, we compared the thermogenic and 5'-deiodinase responses to adrenergic agonists in isolated brown adipocytes from hypothyroid rats during treatment with 3,5,3'-triiodothyronine (T3). The fivefold synergism of alpha 1- and beta-adrenergic catecholamines to increase the deiodinase activity was progressively reduced, reaching a control euthyroid value of unity after 5 days of T3 treatment. Hypothyroidism reduced both the O2max (twofold to threefold) and increased the concentration of agonist required for 50% stimulation (10-fold) for both norepinephrine and forskolin. In hypothyroid cells, there was a twofold synergism between the alpha 1-agonist cirazoline and forskolin to increase respiration, which was blocked by prazosin and reproduced by the calcium ionophore, A23187. This synergistic effect of the alpha 1-agonist was lost within 2 days of T3 administration. These studies identify a second Ca(2+)-dependent intra-adrenergic synergism, which functions to ameliorate the reduced cyclic adenosine monophosphate (cAMP) responsiveness of the hypothyroid brown adipocyte.

Adipose Tissue, Brown↗
PubMed1987

Early infantile epileptic encephalopathy with suppression burst: Ohtahara syndrome.

Eleven infants with neonatal onset of intractable epilepsy are described, who showed the clinical and electroencephalographic features of Ohtahara syndrome. With time, transition to West and Lennox-Gastaut syndromes occurred. No cause could be found in eight cases. All nine survivors are severely mentally and physically handicapped and continue to have seizures. Early infantile epileptic encephalopathy represents the earliest of the age-dependent epileptic encephalopathies.

Age Factors↗
PubMed1983

Sequential changes from minimal pancreatic inflammation to advanced alcoholic pancreatitis.

A correlation of several clinical parameters and pancreatitis morphological alterations observed in chronic alcoholics with and without pancreatic is presented. Three groups of patients were studied: asymptomatic chronic alcoholics (24); non-alcoholic controls (10); and cases with advanced chronic pancreatitis (6). Clinical, biochemical and functional studies were performed. Morphological studies were made on surgical biopsy specimens in light and electron microscopy. The results of this study showed: 1) fat accumulates within pancreatic acinar cells in alcoholics drinking more than 80 g of ethanol per day; 2) ultrastructural changes found in acinar cells of the alcoholics are similar to those described for liver cells; 3) the alterations found in alcoholics without pancreatitis are also observed in those with advanced chronic pancreatitis. An attempt to correlate the sequential changes in the histopathology of alcoholic pancreatic disease with the clinical picture and secretory patterns was made. According to these observations, admitting the ultrastructural similarities between the liver and the pancreas and the recently demonstrated abnormalities of lipid metabolism in pancreatic cells in experimental animal research, the authors postulate a toxic-metabolic mechanism as a likely hypothesis for the pathogenesis of chronic alcoholic inflammation of the pancreas.

Adult↗
PubMed1981

Alcohol and the pancreas. I. Clinical associations and histopathology of minimal pancreatic inflammation.

Fat accumulation within pancreatic acinar cells was observed by examination in patients consuming more than 30 gm./day of ethanol. Ultrastructural changes within the cell are described in these alcoholics without clinical pancreatitis, changes which are similar to those seen in the hepatocytes of alcoholics. The mechanisms which induce these ultrastructural changes and accumulation of fat in the pancreatic acinar cell are not apparent at present. A toxic metabolic mechanism is an attractive hypothesis for these effects.

Adult↗
PubMed1981

Alcohol and the pancreas. II. Pancreatic morphology of advanced alcoholic pancreatitis.

The histopathology of advanced chronic alcoholic pancreatitis is dominated by cellular degeneration, atrophy and fibrosis. Sequential changes in the histopathology of alcoholic pancreatic disease has been defined and traced from initial injury to end-stage disease. These sequential histopathologies have been correlated with clinical syndrome and secretory patterns. The data are more consistent with a toxic-metabolic pathogenesis of alcoholic pancreatitis than the previous Big Duct and Small Duct hypotheses.

Adult↗
PubMed1976

[The secretin test with the standard dose and high dose in chronic pancreatitis].

Sequential standard (1.0 U/kg) and augmented (4.0-5.0 U/kg) secretin response of the pancreas has been briefly compared in normal subjects and in pathologic series. The results of sequential testing led to the conclusion that, for clinical purposes, the standard test is sufficient for the diagnosis of well established pancreatic pathologies causing gross destruction of the parenchyma, while the augmented test is of particular value when the response to 1 U/kg produces equivocal results, since a higher stimulation enhances the masked secretory deficiency. The application of the augmented stimulus in alcoholic patients suggested the hypothesis that the post-secretin response pattern of minimal pancreatic inflammatory pathology is hypersecretion. Repeated observations in alcoholic hypersecretors will provide physiologic data elucidating the evolution of pancreatic pathology towards the end stages of chronic pancreatitis.

Alcoholism↗
PubMed1976

[Standard and Augmented Secretin Tests in Chronic Pancreatitis].

The response of the pancreas to standard (1.0 U/kg) and augmented (4.0-5.0 U/kg) doses of secretin was compared in normal subjects and patients. The results of the investigation showed that for clinical purposes the standard test is sufficient for the diagnosis of pancreatic diseases causing gross destruction of the parenchyma. The augmented test is of particular value when the response to 1 U/kg produces equivocal results, since greater stimulation enhances the masked secretory deficiency. The effect of the augmented stimulus in alcoholic patients suggests the hypothesis that the post-secretin response pattern of minimal pancreatic inflammatory disease is hypersecretion. Repeated observation is alcoholic hypersecretors has provided data which can explain the evolution of pancreatic pathology in the terminal stages of chronic pancreatitis.

Alcoholism↗
PubMed1975

Standard and augmented secretin testing in chronic pancreatic alcoholic disease.

Sequential standard (1.0 U./kg.) and augmented (4.0-5.0 U./kg.) secretin response to the pancreas has been briefly compared in normal subjects and in patients with combinations of alcoholism, cirrhosis and alcoholic pancreatitis. The results of sequential testing led to the conclusion that, for clinical purposes, the standard test is adequate for the diagnosis of well established pancreatic pathologies causing gross destruction of the parenchyma. The augmented test is of particular value when the response to 1 U./kg. produced equivocal results, inasmuch as augmented stimulation enhances the masked secretory deficiency. The administration of the augmented stimulus to alcoholic patients yielded data which suggest a new hypothesis of pathogenesis for alcoholic pancreatitis, e.g., the postsecretin response pattern of minimal pancreatic inflammatory pathology is hypersecretion. Alcohol is thought to induce fatty degeneration of the pancreatic cell initially. Continued injury leads to necrosis and fibrosis.

Alcoholism↗