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Dive into the research topics where Richard J. Cenedella is active.

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Featured researches published by Richard J. Cenedella.


Lipids | 2009

Cholesterol synthesis inhibitor U18666A and the role of sterol metabolism and trafficking in numerous pathophysiological processes.

Richard J. Cenedella

The multiple actions of U18666A have enabled major discoveries in lipid research and contributed to understanding the pathophysiology of multiple diseases. This review describes these advances and the utility of U18666A as a tool in lipid research. Harry Rudney’s recognition that U18666A inhibited oxidosqualene cyclase led him to discover a pathway for formation of polar sterols that he proved to be important regulators of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase. Laura Liscum’s recognition that U18666A inhibited the egress of cholesterol from late endosomes and lysosomes led to greatly improved perspective on the major pathways of intracellular cholesterol trafficking. The inhibition of cholesterol trafficking by U18666A mimicked the loss of functional Niemann–Pick type C protein responsible for NPC disease and thus provided a model for this disorder. U18666A subsequently became a tool for assessing the importance of molecular trafficking through the lysosomal pathway in other conditions such as atherosclerosis, Alzheimer’s disease, and prion infections. U18666A also provided animal models for two important disorders: petite mal (absence) epilepsy and cataracts. This was the first chronic model of absence epilepsy. U18666A is also being used to address the role of oxidative stress in apoptosis. How can one molecule have so many effects? Perhaps because of its structure as an amphipathic cationic amine it can interact and inhibit diverse proteins. Restricting the availability of cholesterol for membrane formation through inhibition of cholesterol synthesis and intracellular trafficking could also be a mechanism for broadly affecting many processes. Another possibility is that through intercalation into membrane U18666A can alter membrane order and therefore the function of resident proteins. The similarity of the effects of natural and enantiomeric U18666A on cells and the capacity of intercalated U18666A to increase membrane order are arguments in favor of this possibility.


Survey of Ophthalmology | 1996

Cholesterol and cataracts

Richard J. Cenedella

Inherited defects in enzymes of cholesterol metabolism and use of drugs which inhibit lens cholesterol biosynthesis can be associated with cataracts in animals and man. The basis of this relationship apparently lies in the need of the lens to satisfy its sustained requirement for cholesterol by on-site synthesis, and impairing this synthesis can lead to alteration of lens membrane structure. Lens membrane contains the highest cholesterol content of any known membrane. The Smith-Lemli-Opitz syndrome, mevalonic aciduria, and cerebrotendinous xanthomatosis all involve mutations in enzymes of cholesterol metabolism, and affected patients can develop cataracts. Two established models of rodent cataracts are based on treatment with inhibitors of cholesterol biosynthesis. The long-term ocular safety of the very widely used vastatin class of hypocholesterolemic drugs is controversial. Some vastatins are potent inhibitors of cholesterol biosynthesis by animal lenses, can block cholesterol accumulation by these lenses and can produce cataracts in dogs. Whether these drugs inhibit cholesterol biosynthesis in human lenses at therapeutic doses is unknown. Results of clinical trials of 1-5 years duration in older patient populations indicate high ocular safety. However, considering the slow life-long growth of the lens and its continuing need for cholesterol, longterm safety of the vastatins should perhaps be viewed in units of 10 or 20 years, particularly with younger patients.


Experimental Eye Research | 1979

Mechanism of cataract production by 3-β(2-diethylaminoethoxy) androst-5-en-17-one hydrochloride, U18666A: An inhibitor of cholesterol biosynthesis

Richard J. Cenedella; George G. Bierkamper

Abstract The present report describes a new model for cataract research induced by a compound (3-β(2-diethylaminoethoxy) androst-5-en-17-one hydrochloride; i.e. U18666A) which inhibits the enzymatic reduction of desmosterol to cholesterol and provides information on the possible mechanism of cataractogenesis. Treatment of the new born rat with U18666A results in nuclear cataracts appearing between 15 and 25 days of age. This cataract is apparently unrelated to accumulation of desmosterol, since this sterol was not detected in opaque lenses until long after their first appearance. Rather, development of this opacity could involve a selective reduction in the concentrations of γ-crystallin, the smallest of the four classes of water-soluble crystallins and the single major constituent of the rat lens after water. The observed lowering of γ-crystallin levels in opaque lens is apparently explained by a differential reduction in protein synthesis measured from [ 3 H]leucine injected intraocularly. This differential effect could be explained by marked changes in the intracellular concentration of Na + and K + ions in opaque lens; Na + levels greatly increased and K + decreased. Recent reports indicate that decreasing the intracellular ratio of K + Na + in lens results in a shift of protein synthesis from lower to higher molecular weight species. In view of this information and the results of the present study, we suggest that the development and/or progression of the cataracts induced by U18666A could be related to a selective block in formation of γ-crystallin secondary to alteration in the levels of Na + and K + ions in lens.


Journal of Biological Chemistry | 1999

Direct Evidence for Immiscible Cholesterol Domains in Human Ocular Lens Fiber Cell Plasma Membranes

Robert F. Jacob; Richard J. Cenedella; Mason Rp

The molecular structure of human ocular lens fiber cell plasma membranes was examined directly using small angle x-ray diffraction approaches. A distinct biochemical feature of these membranes is their high relative levels of free cholesterol; the mole ratio of cholesterol to phospholipid (C/P) measured in these membranes ranges from 1 to 4. The organization of cholesterol in this membrane system is not well understood, however. In this study, the structure of plasma membrane samples isolated from nuclear (3.3 C/P) and cortical (2.4 C/P) regions of human lenses was evaluated with x-ray diffraction approaches. Meridional diffraction patterns obtained from the oriented membrane samples demonstrated the presence of an immiscible cholesterol domain with a unit cell periodicity of 34.0 Å, consistent with a cholesterol monohydrate bilayer. The dimensions of the sterol-rich domains remained constant over a broad range of temperatures (5–20 °C) and relative humidity levels (31–97%). In contrast, dimensions of the surrounding sterol-poor phase were significantly affected by experimental conditions. Similar structural features were observed in membranes reconstituted from fiber cell plasma membrane lipid extracts. The results of this study indicate that the lens fiber cell plasma membrane is a complex structure consisting of separate sterol-rich and -poor domains. Maintenance of these separate domains may be required for the normal function of lens fiber cell plasma membrane and may interfere with the cataractogenic aggregation of soluble lens proteins at the membrane surface.


European Journal of Cancer | 1977

Studies of the mechanism of carcass fat depletion in experimental cancer

Raymond C. Kralovic; E.Andrew Zepp; Richard J. Cenedella

Abstract Loss of body fat is commonly associated with both experimental and human cancers. A direct effect of cancer upon free fatty acid mobilization from host adipose tissue could potentially explain this lipid depletion. Rates of free fatty acid (FFA) production were measured in epididymal adipose tissue removed from normal-control rats and rats bearing the Walker 256 carcinoma either intramuscularly (i.m.) or intraperitoneally (i.p.). By the 4th day after i.p. transplantation and by the time the i.m. tumor mass reached 4% of body weight (b.w.), basal lipolytic rates were 2–3 times higher in adipose tissue from tumor bearing than age matched control rats. Body neutral lipids were not yet significantly reduced at this early time. The high rates of adipose tissue lipolysis were maintained as the cancer progressed and body neutral lipids became significantly reduced once the i.m. tumor attained 6–7% of b.w. The mechanism by which cancer causes this increased fatty acid mobilization is yet unclear. The Walker 256 tumor might produce a lipolytic factor which directly stimulates adipose tissue lipolysis, since ascites serum from i.p. tumor bearing rats could stimulate adipose tissue lipolysis in vitro . However, blood serum from tumor bearing rats did not seem to stimulate adipose tissue lipolysis in vitro more than blood serum from control rats. Severe chronic stress seems an unlikely explanation for the early stimulated lipolysis in cancer, particularly the i.p. tumor. However, rats with even small i.m. tumors, although appearing stress free, possessed enlarged adrenal glands and somewhat atrophied thymus glands, classic markers for the presence of a stress situation. The cancer, in some unknown manner, might induce some special stress reaction.


Journal of Biological Chemistry | 2001

Evidence for Distinct Cholesterol Domains in Fiber Cell Membranes from Cataractous Human Lenses

Robert F. Jacob; Richard J. Cenedella; R. Preston Mason

Previous studies in our laboratory have provided direct evidence for the existence of distinct cholesterol domains within the plasma membranes of human ocular lens fiber cells. The fiber cell plasma membrane is unique in that it contains unusually high concentrations of cholesterol, with cholesterol to phospholipid (C/P) mole ratios ranging from 1 to 4. Since membrane cholesterol content is disturbed in the development of cataracts, it was hypothesized that perturbation of cholesterol domain structure occurs in cataracts. In this study, fiber cell plasma membranes were isolated from both normal (control) and cataractous lenses and assayed for cholesterol and phospholipid. Control and cataractous whole lens membranes had C/P mole ratios of 3.1 and 1.7, respectively. Small angle x-ray diffraction approaches were used to directly examine the structural organization of the cataractous lens plasma membrane versus control. Both normal and cataractous oriented membranes yielded meridional diffraction peaks corresponding to a unit cell periodicity of 34.0 Å, consistent with the presence of immiscible cholesterol domains. However, comparison of diffraction patterns indicated that cataractous lens membranes contained more pronounced and better defined cholesterol domains than controls, over a broad range of temperature (5–40 °C) and relative humidity (52–92%) levels. In addition, diffraction analyses of the sterol-poor regions of cataractous membranes indicated increased membrane rigidity as compared with control membranes. Modification of the membrane lipid environment, such as by oxidative insult, is believed to be one potential mechanism for the formation of highly resolved cholesterol domains despite significantly reduced cholesterol content. The results of this x-ray diffraction study provide evidence for fundamental changes in the lens fiber cell plasma membrane structure in cataracts, including the presence of more prominent and highly ordered, immiscible cholesterol domains.


Toxicology and Applied Pharmacology | 1972

Studies on the hepatomegaly caused by the hypolipidemic drugs nafenopin and clofibrate

Robert B. Beckett; Raul Weiss; Robert E. Stitzel; Richard J. Cenedella

Abstract Clofibrate (ethyl- p -chlorophenoxyisobutyrate) and nafenopin (2 methyl-2-( p -(1,2,3,4-tetrahydro-1-naphthyl) phenoxy)-propionate), structurally similar hypolipidemic phenolic ethers, were given po to adult male mice at 25 or 100 mg/kg/day once daily for 7 or 14 consecutive days. Both compounds increased liver weights; however, on a milligram basis nafenopin was 6 to 7 times as potent as clofibrate. Light microscopic exmination of livers from treated mice indicated that with both drugs hepatocytes in the centrilobular area were swollen, of finer cytoplasmic granularity and contained somewhat more acidophilic staining material. The microsomal drug-metabolizing enzymes of the smooth endoplasmic reticulum were not markedly affected by drug pretreatment. Hypertrophy of hepatocytes seems a reasonable explanation for the modest increase in liver size following treatment with clofibrate; however, this mechanism would seem inadequate to explain totally the very marked hepatomegaly seen with nafenopin. Measurements of hepatic DNA content after 1 and 2 wk treatment with 100 mg/kg/day of nafenopin showed approximately 30 and 50% increases, respectively, in the DNA content of the total liver. Apparently the hepatomegaly resulting from treatment with nafenopin is explained by an increase in hepatocyte cell number in addition to increases in hepatocyte size.


Experimental Eye Research | 1983

Source of cholesterol for the ocular lens, studied with U18666A: A cataract-producing inhibitor of lipid metabolism

Richard J. Cenedella

Cholesterol is the major lipid component of the ocular lens. The source of lens cholesterol during the first month of post-natal life of the rat was investigated by use of U18666A, a potent inhibitor of cholesterol biosynthesis which can also produce cataracts. Lenses from rats treated with U18666A at a level known to produce cataracts were of smaller size and accumulated total sterol at about one-half the rate of untreated controls. The lens content of phospholipid also lagged behind that of controls. Desmosterol accounted for 50-75% of the total sterol in lens of all treated rats, this paralleled the percent content of desmosterol in liver and serum of these animals. Lenses taken from 20-day-old treated rats and incubated in vitro synthesized little digitonide-precipitable sterol (DPS) from 3H2O as compared to lenses from age-matched controls. The steady state concentration of U18666A in lens was found to be 1-2 X 10(-6) M; this concentration almost completely blocked sterol synthesis in vitro when added to normal lenses. Although U18666A inhibited lens synthesis in vitro of phospholipids from 1,3-[3H]-glycerol and 32Pi, it did so only at levels much higher than those encountered in vivo. Thus, the changes seen in lens phospholipids appear secondary to the decreases in sterols. Since lenses of treated rats synthesized little if any sterol but accumulated sterol at one-half the rate of control lens, we conclude that during early post-natal development of the rat the ocular lens possesses the potential to satisfy about one-half of its sterol requirements from sources outside of the lens, perhaps from lipoproteins in aqueous humor. This conclusion is consistent with our earlier work which indicated that the rats lens can furnish 50-100% of its total cholesterol by synthesis de novo during the first two weeks of life and less thereafter. The relationship of the inhibition of sterol synthesis to production of the U18666A-induced cataract is discussed.


Biochemical Pharmacology | 1980

Concentration-dependent effects of AY-9944 and U18666A on sterol synthesis in brain: Variable sensitivities of metabolic steps

Richard J. Cenedella

Abstract The possibility that the effects of inhibitors of sterol biosynthesis in brain are concentration dependent was examined. The drugs 3β-(2-diethylaminoethoxy) androst-5-en-17-one-HCl (U18666A) and trans -1,4-bis (2-chlorobenzylaminomethyl) cyclohexane-2HCl (AY-9944) were evaluated, because both substances markedly affect brain sterol metabolism and have been reported to alter the structure and/or function of developing brain. Incorporation of [2- 14 C]-DL-mevalonate by cell-free homogenates of rat brain into squalene and individual sterol fractions was measured in the absence and presence of a wide range of inhibitor concentrations. The qualitative and quantitative effects of U18666A and, to a lesser extent of AY-9944 on the formation of radiolabeled brain sterols were highly dependent on inhibitor concentration. The results indicate that there are two categories of metabolic steps in the pathways for sterol synthesis that were sensitive to inhibition by U18666A and AY-9944. The first category comprises steps that are located before lanosterol formation and were suppressed only by relatively high concentrations of inhibitors. At these higher inhibitor concentrations essentially all sterol synthesis was eliminated and drug effects at sites after lanosterol were therefore obscured. U18666A was over 6000 times more active than AY-9944 in inhibiting at category one sites. The second category of steps comprises those that are located late in cholesterol biosynthesis and were very sensitive to inhibition. Inhibitor effects at these late steps appeared to be drug-specific.


Cornea | 1995

Quantitation of ultraviolet light-absorbing fractions of the cornea.

Jeanne Mitchell; Richard J. Cenedella

This study attempts to measure the quantitative contribution of major chemical fractions of the whole bovine cornea to ultraviolet (UV) absorption between 240 and 300 nm, with special attention to the biologically significant range of 290-300 nm. The cornea was divided into water-insoluble, nonprotein small water-soluble, water-soluble protein, and lipid-soluble fractions. The insoluble fraction (largely collagen) was solubilized by enzymatic digestion. Solutions of individual fractions equivalent to a constant mass of fresh cornea were scanned for absorption from 240 to 300 nm. The sum of the absorbances of the individual fractions closely approximated the absorbance of whole corneas at all wavelengths examined. The extinction coefficients of the lipid and water-soluble fractions were several times greater than that of the insoluble fraction throughout the studied spectrum. Yet, because of its large mass (75% of cornea dry weight), the insoluble fraction accounted for 40-50% of UV absorbance between 240 and 280 nm. However, in the range of 290-300 nm, the water-soluble plus lipid-soluble fractions accounted for 60-65% of the total absorption, with the water- soluble proteins alone accounting for 40-45% of the total. The soluble proteins comprised only ~17% of the corneas dry weight. The special contribution of the water- soluble proteins to absorption was attributed to their relatively high tryptophan content (~ 1.6% by weight). A 54-kDa protein, identified by others as tryptophan rich, tumor-associated aldehyde dehydrogenase, accounted for ~ 30% of the total soluble protein mass. The 54-kDa soluble polypeptide together with other watersoluble proteins made the dominant contribution to the total UV-absorbing capacity of the cornea in the 290-300 nm range. We suggest the name absorbins for these proteins.

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L.H. Saxe

West Virginia University

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Daxin Tang

University of Louisville

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