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.)

/pdf/clinical-and-biomarker-changes-in-dominantly-inherited-66jpsco78g.pdf

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.

NEW MATERIAL:A compound shown by the formula I or formula II (R 1 is H, or CH 3 ; R 2 is H, lower alkyl, or alkali metal). USE: A physiologically active substance having improved cholesterol lowering action. Having improved inhibitory activity against cholesterol synthesis. PREPARATION: Monacolin K (R 1 =CH 3 ) or ML-236B (R 1 =H) shown by the formula III is treated with hydroxylase produced by a bacterium (e.g., Shizophyllum commune) belonging to the genus Schizophyllum, to give a compound shown by the formula I or formula II. COPYRIGHT: (C)1985,JPO&Japio

Monacolin k and ml-236b derivative

Mevalonolacton-derivate und verfahren zu deren herstellung

The time course of the inhibition of cholesterol synthesis by low and high doses of mevinolin and monacolin X were studied in normal human skin fibroblasts, fibroblasts without low density lipoprotein receptor and HepG2 hepatome cells. Low doses of the inhibitors (0.2 ng/mL) caused a sharp decrease in the rate of cholesterol synthesis during the firt 2–3 h, which gradually increased to about 40% during the next 6 h. Further incubation led to a decrease or stabilization of the cholesterol synthesis rate. High doses of the drugs (100 mg/mL) strongly inhibited cholesterol synthesis during the first 2–3 h, followed by a moderate increase during the next 20 h. No drug or tissue selectivity was observed.

Time response of cholesterol synthesis inhibition by compactin-related compunds.In vitro quantitation of the “Escape Phenomenon”

Fig. 1. Effect of mutastein on the formation of artificial plaque on Nichrome-steel wires by Streptococcus mutans 671 5. Experimental conditions were described in the text. 1; Control, 2; 15 ^g/ml mutastein, 3; 50 ^g/ml mutastein. It is believed to be a significant step for the induction of dental caries that cariogenic Streptococcus mutans synthesizes adhesive, insoluble glucan from sucrose and adheres to tooth surfaces to form dental plaque in the oral cavity0. This is supported by the fact that mutant strains of $. mutans defective in adhesive glucan synthesis lack cariogenicity0. Thus, inhibition of the synthesis of the adhesive, insoluble glucan is expected to be an effective means for preventing plaque formation and caries development. Mutastein, a heat-stable glycoprotein isolated from the culture filtrate of Aspergillus terreus, was identified as a specific inhibitor of glucan synthesis2). This substance suppresses significantly plaque formation and caries development in rats3), and is nowused commercially as a protective agent against caries development in humans. Two glucosyltransferases (GTase) are known to be involved in the glucan synthesis by S. mutans, one (GTase-S) that catalyzes soluble glucan synthesis and one (GTase-I) that converts soluble glucan to the adhesive, insoluble glucan4). Mutastein was reported to inhibit the latter enzyme of several strains of S. mutans2>5\\ In the present experiments, the inhibitory effect of mutastein on glucan synthesis in the cell-free enzyme system of S. mutans 6715 and the formation of artificial, dental plaque by growing cells of this strain were studied. Mutastein was isolated from the culture filtrate of A. terreus as described previously2). Briefly, the culture filtrate was adjusted to pH 3.5 with HC1 and the resultant precipitate was collected by centrifugation. The precipitate was * Present address: Central Research Laboratory, Godo Shusei Co. Ltd., Matsudo-shi, Chiba-ken 271, Japan. submitted to ammoniumsulfate precipitation and chromatography of hydroxyapatite and Toyopearl HW-65. Cell-free extracts of S. mutans 6715, containing both GTase-S and GTase-F\\ synthesized adhesive, insoluble glucan along with small amounts of nonadhesive, insoluble glucan and soluble glucan (Table 1). Mutastein inhibited adhesive, insoluble glucan synthesis by 45%at a concentration of 0.1 pgjm\\ and almost completely at 0.4 ^g/ml. On the other hand, synthesis of both nonadhesive, insoluble glucan and soluble glucan was markedly stimulated by mutastein; the activation was 3-fold for the former and 10-fold for the latter at a mutastein concentration of 0.4 ^g/rnl (Table 1). The data suggest that mutastein inhibited specifically the conversion of soluble glucan to adhesive, in-

Akira Endo

Papers

Monacolin k and ml-236b derivative

Mevalonolacton-derivate und verfahren zu deren herstellung

Time response of cholesterol synthesis inhibition by compactin-related compunds.In vitro quantitation of the “Escape Phenomenon”

Inhibitory effect of mutastein on the synthesis of artificial, dental plaque by Streptococcus mutans.

Remedies for hyperlipemia containing ml-236b metal salt as main component