Detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III)

In 1901 a physician, Archibald Garrod, observed a patient with black urine. He used this simple observation to demonstrate that a single mutant gene can produce a discrete block in a biochemical pathway, which he called an “inborn error of metabolism”. Garrod’s brilliant insight anticipated by 40 years the one gene-one enzyme concept of Beadle and Tatum. In similar fashion the chemist Linus Pauling and the biochemist Vernon Ingram, through study of patients with sickle cell anemia, showed that mutant genes alter the amino acid sequences of proteins. Clearly, many fundamental advances in biology were spawned by perceptive studies of human genetic diseases (1). We began our work in 1972 in an attempt to understand a human genetic disease, familial hypercholesterolemia or FH. In these patients the concentration of cholesterol in blood is elevated many fold above normal and heart attacks occur early in life. We postulated that this dominantly inherited disease results from a failure of end-product repression of cholesterol synthesis. The possibility fascinated us because genetic defects in feedback regulation had not been observed previously in humans or animals, and we hoped that study of this disease might throw light on fundamental regulatory mechanisms. Our approach was to apply the techniques of cell culture to unravel the postulated regulatory defect in FH. These studies led to the discovery of a cell surface receptor for a plasma cholesterol transport protein called low density lipoprotein (LDL) and to the elucidation of the mechanism by which this receptor mediates feedback control of cholesterol synthesis (2,3). FH was shown to be caused by inherited defects in the gene encoding the LDL receptor, which disrupt the normal control of cholesterol metabolism. Study of the LDL receptor in turn led to the understanding of receptor-mediated endocytosis, a genera! process by which cells communicate with each other through internalization of regulatory and nutritional molecules (4). Receptor-mediated endocytosis differs from previously described biochemical pathways because it depends upon the continuous and highly controlled movement of membraneembedded proteins from one cell organelle to another in a process termed

https://science.sciencemag.org/content/sci/232/4746/34.full.pdf

A receptor-mediated pathway for cholesterol homeostasis.

Flavonoids are nearly ubiquitous in plants and are recognized as the pigments responsible for the colors of leaves, especially in autumn. They are rich in seeds, citrus fruits, olive oil, tea, and red wine. They are low molecular weight compounds composed of a three-ring structure with various substitutions. This basic structure is shared by tocopherols (vitamin E). Flavonoids can be subdivided according to the presence of an oxy group at position 4, a double bond between carbon atoms 2 and 3, or a hydroxyl group in position 3 of the C (middle) ring. These characteristics appear to also be required for best activity, especially antioxidant and antiproliferative, in the systems studied. The particular hydroxylation pattern of the B ring of the flavonoles increases their activities, especially in inhibition of mast cell secretion. Certain plants and spices containing flavonoids have been used for thousands of years in traditional Eastern medicine. In spite of the voluminous literature available, however, Western medicine has not yet used flavonoids therapeutically, even though their safety record is exceptional. Suggestions are made where such possibilities may be worth pursuing.

The Effects of Plant Flavonoids on Mammalian Cells:Implications for Inflammation, Heart Disease, and Cancer

A B S T R AC T BACKGROUND The order and magnitude of pathologic processes in Alzheimer’s disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer’s disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease. METHODS In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant’s age at baseline assessment and the parent’s age at the onset of symptoms of Alzheimer’s disease to calculate the estimated years from expected symptom onset (age of the participant minus parent’s age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes. RESULTS Concentrations of amyloid-beta (Aβ)42 in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini–Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. CONCLUSIONS We found that autosomal dominant Alzheimer’s disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer’s disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer’s disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.)

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Clinical and Biomarker Changes in Dominantly Inherited Alzheimer’s Disease

Natural killer T (NKT) lymphocytes express an invariant T cell antigen receptor (TCR) encoded by the Valpha14 and Jalpha281 gene segments. A glycosylceramide-containing alpha-anomeric sugar with a longer fatty acyl chain (C26) and sphingosine base (C18) was identified as a ligand for this TCR. Glycosylceramide-mediated proliferative responses of Valpha14 NKT cells were abrogated by treatment with chloroquine-concanamycin A or by monoclonal antibodies against CD1d/Vbeta8, CD40/CD40L, or B7/CTLA-4/CD28, but not by interference with the function of a transporter-associated protein. Thus, this lymphocyte shares distinct recognition systems with either T or NK cells.

http://science.sciencemag.org/content/sci/278/5343/1626.full.pdf

CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides.

Binding of modified lipoproteins including oxidized low density lipoprotein (oxidized LDL) to cell surface receptors is an initial step of conversion of monocyte-derived macrophages into lipid-laden foam cells, a key cellular component in the early lesions of atherosclerosis. We have searched for microbial metabolites that inhibit oxidized LDL-induced lipid accumulation in macrophages and isolated three compounds from a strain of Bacillus sp. as inhibitors of oxidized LDL binding. By chemical and spectroscopic analyses, these metabolites were shown to be related to the cyclic lipopeptide iturin C. Two of these compounds were novel metabolites having long chain β-amino acid moieties of different length. These agents, at concentrations ranging from 5 to 20 μM, inhibited cell surface binding of oxidized 125I-LDL, resulting in reduced intracellular accumulation and degradation of the lipoprotein as well as in reduced cholesteryl ester formation from [14C]oleate in macrophages J774.

Inhibition of the Binding of Oxidized Low Density Lipoprotein to the Macrophages by Iturin C-related Compounds.

PROBLEM TO BE SOLVED: To link the energy of a process or device (information on the amount of emitted CO 2 ) with information on production (the number of pieces, operational status, quality) to compute and manage the amount of emitted CO 2 for each product and for each lot; and to manage and analyze the amount of emitted CO 2 in each process through which products or lots pass to reduce the amounts of CO 2 emission for each product and for each lot. SOLUTION: A production energy management system includes: a production management system which manages production information on products; and an energy management system which manages energy information related to the production of the products and information on the operational status of production facilities. The production energy management system executes various energy analyses related to the production on the basis of the production information of the production management system, the energy information of the energy management system, and information on the operational status of the production facilities. COPYRIGHT: (C)2010,JPO&INPIT

Production energy management system

Modulation of the plasma cholesteryl ester transfer by stachybotramide

/pdf/inhibition-of-15-lipoxygenase-by-orobol-fbbr3k8rp9.pdf

Inhibition of 15-lipoxygenase by orobol.

Hydroxybenzoic and phthalic acids and their related compounds were tested for inhibitory activity to brain glutamate decarboxylase. Of mono-, di-, and trihydroxybenzoic acids, gallic acid was the most inhibitory, giving 50% inhibition at a concentration of 0.17 mm. Dihydroxybenzoic acids were less inhibitory than the trihydroxyacids but more than monohydroxybenzoic acids. Of the phthalic acid-related compounds tested, 4, 5-dihydroxyisophthalic acid was the most potent inhibitor, producing 50% inhibition at 0.61 μm. The inhibition of these compounds was competitive with respect to L-glutamate. The Ki values were 0.02, 1.2 and 4.9 pM for 4, 5-dihydroxyisophthalic acid, 5-hydroxyisophthalic acid and gallic acid, respectively. When administered intraventricularly to mice, 4, 5-dihydroxyisophthalic acid produced a significant decrease in the γ-aminobutyric acid content of the brain, resulting in induction of convulsions.

Akira Endo

Papers

Inhibition of the Binding of Oxidized Low Density Lipoprotein to the Macrophages by Iturin C-related Compounds.

Production energy management system

Modulation of the plasma cholesteryl ester transfer by stachybotramide

Inhibition of 15-lipoxygenase by orobol.

Inhibition of brain glutamate decarboxylase by 4,5-dihydroxyisophthalic acid and related compounds.