Inflammation, cellular and redox signalling mechanisms in cancer and degenerative diseases

Strategies for the intervention and prevention of cancers, diabetes, cardiovascular disease, HIV/AIDS and diseases of overt inflammation including neurodegenerative diseases (Alzheimer's and Parkinson's disease) require an understanding of the basic molecular mechanism(s) by prophylactic agents (dietary antioxidant factors from food plants and medicinal plants in this context) that may potentially prevent or reverse the promotion or progression of the diseases. Inflammation, cellular and redox signalling mechanisms play major roles in the pathophysiology of numerous disease states.Stem cell transplants may afford an alternative treatment for such debilitating neural diseases as Alzheimer's disease (AD) and Parkinson's disease, hormonal diseases such as diabetes mellitus, and traumas such as spinal cord injuries. This holds great promise for diabetes, given the associated complications such as heart disease, stroke, peripheral vascular disease, diabetic retinopathy, kidney disease and birth defects. With increasing constraints hindering the use of embryonic cells for neurotransplantation, stem cells, more particularly blood stem cells due to their differentiative potential and easy access, stand to be the method of choice. Advances in embryonic stem cell research however still hold much promise. Stem cells can now be indefinitely multiplied in number and cryopreserved without loss of their potential. Professor Hwang and his group at the College of Veterinary Medicine of the Seoul National University, South Korea have reported an impressive improvement in the efficiency of stem cell derivation from blastocysts from 5 per cent to 35 per cent and showed that the stem cell lines could differentiate into somatic cells of the ectoderm, mesoderm and endoderm lineages.

Peroxisomes and the fatty liver of malnutrition: an hypothesis 1-3

Peroxisomes play a role in hepatic á-oxidation of fat, a process that results in the production of hydrogen per-oxide. The fatty infiltration of the liver that occurs in severely malnourished children remains unexplained. We observed an almost total absence of peroxisomes in the hepatocytes of these children. We suggest that lack of available peroxisomes could contribute to the development of fatty liver.(AU)

Fasting glucose production in the smaller of twins with epinephrine-deficient hypoglycemia

The possibility that insufficient glucose production or availability of gluconeogenic substrates could account for fasting hypoglycemia was investigated in three children with epinephrine deficiency. Each had been born the smaller of discordant identical twins, and the unaffected twins served as controls. Fasting plasma glucose production was measured by constant infusion of U-[13]C-glucose under steady-state conditions and was compared with availability of potential glucose sources estimated from respiratory calorimetry and excretory nitrogen. The average rate of glucose production was 2.6 mg/kg/min in the affected twins after they became symptomatic and 2.9 mg/kg/min in the control twins after comparable fasting. Plasma alanine was lower in the affected twins during this interval (average: 0.11 mM versus 0.16 mM), but not earlier prior to decreased plasma glucose; alanine correlated with plasma glucose in a similar way in both groups (r = 0.77). Plasma urea production was 0.30 versus 0.15 mg urea N/kg/min. The calculated availability of potential gluconeogenic amino acids was 1.2 versus 0.6 mg/kg/min. Availability of glycerol, estimated from respiratory calorimetry was 0.4 mg/kg/min in both groups. In two of the twin pairs, net oxidation of carbohydrate (glycogen) was, by design, relatively small under these conditions (0.1 and 0.4 mg/kg/min in the affected and control twins, respectively). Gluconeogenesis therefore accounted for the majority of glucose production. The unaccounted remaining major gluconeogenic source is assumed to be recycled substrates from unoxidized pyruvate. Infusion of excess alanine in these two pairs increased plasma glucose and glucose production similarly in both the affected and control twins. This change was associated with an abnormally large increase in plasma alanine. In the third twin pair, net oxidation of carbohydrate was greater in the affected twin (1.8 versus 1.3 mg/kg/min) and possible glucose sources exceeded total glucose production during hypoglycemia. Earlier during fasting, net oxidation of carbohydrate in this twin was 5.8 mg/kg/min versus 3.1 mg/kg/min in the control. Plasma glucose production measured simultaneously was 4.3 versus 3.8 mg/kg/min, being less than the rate of carbohydrtae oxidation in the affected twin. It is concluded that the abnormal fasting metabolism observed in these children with decreased epinephrine was not primarily a consequence of deficient glucose production or lack of potential gluconeogenic substrates. Initial persistent oxidation of glycogen and subsequent increased utilization of protein during hypoglycemia indicate failure to conserve these limited net sources of pyruvate(AU)

Fasting energy utilization in the smaller of twins with epinephrine-deficient hypoglycemia

The possible role of epinephrine deficiency in abnormal utilization of energy sources during fasting was investigated in three pairs of discordant identical twins with recurrent fasting hypoglycemia. The hypoglycemic twins, ages 2, 8 and 9 years, each had beens smaller at birth. Defective epinephrine responsiveness to hypoglycemia was established by administration of 2-deoxyglucose, 50 mg/kg, i.v. In the control twins, this resulted in a rapid increase of plasma glucose (+39 mg/100 ml), free fatty acids (+0.3 mM), and urinary epinephrine (+224 ng/mg creatine). These changes did not occur in the affected twins. Fasting metabolism in the epinephrine-deficient twins was compared to the unaffected twins as controls. Oxidation of carbohydrate and fat were estimated from hourly measurements of oxygen consumption and carbon dioxide production, and utilization of protein was determined from nitrogen excretion. PLasma glucose decreased more rapidly in the affected twins during the 8 hours prior to appearance of symptoms. During this period, carbohydrate was oxidized more rapidly than in the controls (average: 3.1 versus 1.7 mg/kg/min). Plasma á-hydroxybutyrate and free fatty acids was frequently less in relation to glucose. Symptoms occurred when the sum of both glucose and á-hydroxybutyrate was lower than in the controls. Urinary epinephrine excretion increased from an average baseline of 18 to a maximum of 134 ng/mg creatinine in the control twins. The average maximum urinary epinephrine reached in the deficient twins was only 51 ng/mg creatinine, in spite of lower glucose. Plasma insulin decreased in relation to glucose below 40 mg/100 ml in the control twins (r = 0.65), but this did not occur in the deficient twins (r = -0.38). Cortisol and growth hormone responses were similar in the two groups. THerefore, the consequences of inability to increase epinephrine when availability of glucose became acutely limiting were inappropriate persistent oxidation of carbohydrate, decreased circulating alternate substrates from fat, and lack of suppression of insulin. (AU)

Rhein, a selective inhibitor of the DPNH-flavin step in mitochondrial electron transport

Previous findings in the literature that rhein inhibits DPNH-linked mitochondrial oxidations by acting in the DPNH dehydrogenase region of the respiratory chain have been confirmed and extended. In the micromolar range rhein inhibits DPNH oxidase and DPNH-ferricyanide activities and the energy-linked reduction of DPNH by succinate in membrane preparations from heart, as wellas the DPNH dehydrogenase and transhydrogenase activities of the soluble, purified enzyme. The inhibition of the activities of the soluble enzyme are purely competitive with respect to substrate. These facts localize the primary inhibition site of rhein between substrate and FMN. In heart ETP a second noncompetitive inhibition is also present but is detectable only at very low (<10æM) rhein concentrations. Rhein also inhibits DPNH dehydrogenase in Candida utilis mitochondria and the purified enzyme from liver. On conversion of the heart enzyme to the low molecule weight DPNH-cytochrome reductase the typical effect of rhein disappears and is replaced by a slight stimulation or inhibition, depending on the electron acceptor used, showing that the substrate binding site is modified in this form of the enzyme. In beef liver mitochondria DPNH oxidation may appear insensitive to rhein, probably because of the strong binding of rhein to other proteins. To a lesser extent unspecific binding of rhein and resultant interference with the inhibition of DPNH dehydrogenase is also shown by BSA and by proteins in heart ETP. Rhein also inhibits transhydrogenations in mitochondria and at higher concentrations lactate and malate dehydrogenases but has no effect on sccinate, alcohol (liver nad yeast), and glucose-6-p dehydrogenases or on Neuospora DPN-ase, glucose-6-phosphatase, and amine oxidase. (SUMMARY)

Studies on hypoglycin toxicity in rats. I. Changes in hepatic ultrastructure

Hypoglycin is a toxic amino acid found in the unripe ackee fruit. The ackee is a popular item of diet in Jamaica and has been proposed as a cause of the so-called vomiting sickness. Hypoglycin is thought to act by inhibiting the oxidation of long-chain fatty acids, uncoupling oxidative phosphorylation, and interfering with gluconeogenesis. Hypoglycin was given intraperitoneally to rats in a dose of 10 mg/100 g, and samples of liver taken at hourly intervals up to 5 hr were studied with the electron microscope and compared with controls. The major ultrastructural findings in the hypoglycin-treated rats were progressive mitochondrial swelling with loss of granules and pallor of the matrix, followed by incorporation into autophagic vacuoles. These findings correlate well with the reported biochemical mechanisms.(AU)