Desmosterol Concentrations Research Articles

Supplementation of Seaweed Extracts to the Diet Reduces Symptoms of Alzheimer's Disease in the APPswePS1ΔE9 Mouse Model.

We previously demonstrated that diet supplementation with seaweed Sargassum fusiforme (S. fusiforme) prevented AD-related pathology in a mouse model of Alzheimer's Disease (AD). Here, we tested a lipid extract of seaweed Himanthalia elongata (H. elongata) and a supercritical fluid (SCF) extract of S. fusiforme that is free of excess inorganic arsenic. Diet supplementation with H. elongata extract prevented cognitive deterioration in APPswePS1ΔE9 mice. Similar trends were observed for the S. fusiforme SCF extract. The cerebral amyloid-β plaque load remained unaffected. However, IHC analysis revealed that both extracts lowered glial markers in the brains of APPswePS1ΔE9 mice. While cerebellar cholesterol concentrations remained unaffected, both extracts increased desmosterol, an endogenous LXR agonist with anti-inflammatory properties. Both extracts increased cholesterol efflux, and particularly, H. elongata extract decreased the production of pro-inflammatory cytokines in LPS-stimulated THP-1-derived macrophages. Additionally, our findings suggest a reduction of AD-associated phosphorylated tau and promotion of early oligodendrocyte differentiation by H. elongata. RNA sequencing on the hippocampus of one-week-treated APPswePS1ΔE9 mice revealed effects of H. elongata on, amongst others, acetylcholine and synaptogenesis signaling pathways. In conclusion, extracts of H. elongata and S. fusiforme show potential to reduce AD-related pathology in APPswePS1ΔE9 mice. Increasing desmosterol concentrations may contribute to these effects by dampening neuroinflammation.

COVID-19 and cholesterol biosynthesis: Towards innovative decision support systems

With COVID-19 becoming endemic, there is a continuing need to find biomarkers characterizing the disease and aiding in patient stratification. We studied the relation between COVID-19 and cholesterol biosynthesis by comparing 10 intermediates of cholesterol biosynthesis during the hospitalization of 164 patients (admission, disease deterioration, discharge) admitted to the University Medical Center of Ljubljana. The concentrations of zymosterol, 24-dehydrolathosterol, desmosterol, and zymostenol were significantly altered in COVID-19 patients. We further developed a predictive model for disease severity based on clinical parameters alone and their combination with a subset of sterols. Our machine learning models applying 8 clinical parameters predicted disease severity with excellent accuracy (AUC= 0.96), showing substantial improvement over current clinical risk scores. After including sterols, model performance remained better than COVID-GRAM. This is the first study to examine cholesterol biosynthesis during COVID-19 and shows that a subset of cholesterol-related sterols is associated with the severity of COVID-19.

Amiodarone accumulates two cholesterol precursors in myocardium: A controlled clinical study.

Amiodarone is an effective antiarrhythmic drug, which interferes with cholesterol synthesis. In the human body, it inhibits two enzymes in the cholesterol-synthesis pathway, followed by increases especially in serum desmosterol and zymostenol concentrations and a decrease in that of serum lathosterol. We explored whether desmosterol and zymostenol accumulate also in myocardial tissue during amiodarone treatment. Thirty-three patients admitted for cardiac transplantation volunteered for the study. Ten patients were on amiodarone treatment (AD group) and 23 were not (control group). The groups were matched as regards demographic and clinical variables. Myocardial samples were obtained from the removed hearts from 31 patients. Cholesterol, non-cholesterol sterols and squalene were quantified by means of gas-liquid chromatography. In serum and myocardium, desmosterol was 19- and 18-fold higher and zymostenol 4- and 2-fold higher in the AD group versus the control group (p<0.001 for all). In contrast, myocardial cholesterol, squalene and lathosterol levels were lower in the AD group than in the control group (p<0.05 for all). Levels of phytosterols and cholestanol were similar in the serum and myocardium in the two groups. Levels of myocardial and serum desmosterol, zymostenol, lathosterol and phytosterols correlated with each other in both groups (p<0.05 for all). Amiodarone treatment caused the accumulation of desmosterol and zymostenol in myocardium. In particular, myocardial desmosterol concentrations were substantially elevated, which may play a part in some of the therapeutic and adverse effects of amiodarone treatment.

Lipoproteins and cholesterol homeostasis in paediatric nephrotic syndrome patients.

IntroductionThe aim of this study was to investigate lipoprotein particle distributions and the likelihood of achieving cholesterol homeostasis in the remission phase of nephrotic syndrome (NS) in paediatric patients. We hypothesized that lipoprotein particle distributions moved toward less atherogenic profile and that cholesterol homeostasis was achieved.Materials and methodsThirty-three children, 2 to 9 years old with NS were recruited. Blood sampling took place both in the acute phase and during remission. Serum low-density lipoprotein particles (LDL) and high-density lipoprotein particles (HDL) were separated using non-denaturing polyacrylamide gradient gel (3-31%) electrophoresis. Serum non-cholesterols sterols (NCSs), desmosterol, lathosterol, 7-dehydrocholesterol (7-DHC), campesterol and β-sitosterol were measured by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS).ResultsAll patients had desirable serum HDL cholesterol concentrations during remission. The dominant lipoprotein diameters and LDL subclass distribution did not change significantly during follow-up. In contrast, HDL lipoprotein particle distribution shifted towards larger particles. The absolute concentration of desmosterol was significantly lower during remission (P = 0.023). β-sitosterol concentration markedly increased during remission (P = 0.005). Desmosterol/β-sitosterol (P < 0.001) and 7-DHC/β-sitosterol (P = 0.005) ratios significantly declined during disease remission.ConclusionsFavourable changes in the serum lipid profiles, HDL particle subclass distribution and cholesterol metabolism in paediatric patients with NS during remission took place. For the first time, we found that cholesterol homeostasis changed in favour of increased cholesterol absorption during disease remission. Nevertheless, complete cholesterol homeostasis was not achieved during disease remission.

Desmosterol and 7-dehydrocholesterol concentrations in post mortem brains of depressed people: The role of trazodone

Major depressive disorder (MDD) is a common, disabling, and heterogeneous condition that responds unpredictably to current treatments. We previously showed an association between depressive symptoms and plasma concentrations of two cholesterol precursors, desmosterol and 7-dehydrocholesterol (7DHC). Here, we measured total cholesterol and sterol concentrations with mass spectrometry in postmortem brain samples from depressed and control subjects. Mean (±SEM) desmosterol concentration was 8.9 ± 0.97 ng/mg in the depressed versus 10.7 ± 0.72 ng/mg in the control group. The mean of the posterior probability distribution for the difference in desmosterol concentration between the two groups was 2.36 (95% highest density interval [HDI] 0.59–4.17). Mean 7DHC concentrations, 12.5 ± 4.1 ng/mg in the depressed versus 5.4 ± 0.74 ng/mg in the control group, were unlikely to be different (95% HDI, [−1.37–0.34]). We found that presence of trazodone in the peri-mortem toxicology screen accounted for the observed difference in desmosterol concentrations. We also observed extremely high 7DHC levels in all 4 subjects who had taken trazodone. Trazodone has been recently found to inhibit 7-dehydrocholesterol reductase and alter sterol concentrations in rodents, cell culture, human fibroblasts, and blood. In this study, we demonstrate for the first time that trazodone alters human brain sterol composition. Given congenital deficiency of 7-dehydrocholesterol reductase results in Smith-Lemli-Opitz syndrome, our findings support the hypothesis that this commonly used medication may have previously unappreciated risks.

Can non-cholesterol sterols indicate the presence of specific dysregulation of cholesterol metabolism in patients with colorectal cancer?

Colorectal cancer (CRC) is a highly prevalent malignancy. Previous studies suggested that cholesterol might play a signficant role in malignant transformation and proliferation. Non-cholesterol sterols (NCS), which are transported by serum lipoproteins alongside cholesterol, are regarded as cholesterol synthesis and absorption markers. Quantification of NCS in serum and HDL fraction (NCSHDL), could provide a better insight into the cholesterol metabolism. The aim of this study was to examine the status of cholesterol synthesis and cholesterol absorption markers in serum and HDL fraction and explore their interrelation in CRC patients. Current study was designed as observational, case-control study. The study included 73 CRC patients and 95 healthy subjects. NCS and NCSHDL concentrations were determined by HPLC-MS/MS. Based on NCS and NCSHDL concentrations, different cholesterol homeostasis indices were calculated. Patients had significantly lower NCS (P<0.001) and NCSHDL concentrations (P<0.001 for desmosterolHDL; P<0.05 for lathosterolHDL, P=0.001 for campesterolHDL, P<0.001 for β-sitosterolHDL). NCSHDL/NCS (P<0.005 for desmosterolHDL/desmosterol; P<0.05 for lathosterolHDL/lathosterol; P<0.001 for both β-sitosterolHDL/β-sitosterol and campesterolHDL/campesterol) and synthesis to absorption ratio (CSI/CAI) (P<0.005) were increased in CRC patients. Additionally, low serum concentrations of desmosterol (P<0.001; OR=0.329; 95%CI (0.199–0.542)) and campesterol (P<0.001; OR=0.540; 95%CI (0.424–0.687)) were independent predictors of CRC presence. Our data suggest that cholesterol homeostasis in CRC is shifted towards increased synthesis. Relative abundance of NCS in HDL particles is increased, suggesting the possible overproduction of cholesterol precursors in peripheral tissues.

Association between non-cholesterol sterol concentrations and Achilles tendon thickness in patients with genetic familial hypercholesterolemia

BackgroundFamilial hypercholesterolemia (FH) is a genetic disorder that result in abnormally high low-density lipoprotein cholesterol levels, markedly increased risk of coronary heart disease (CHD) and tendon xanthomas (TX). However, the clinical expression is highly variable. TX are present in other metabolic diseases that associate increased sterol concentration. If non-cholesterol sterols are involved in the development of TX in FH has not been analyzed.MethodsClinical and biochemical characteristics, non-cholesterol sterols concentrations and Aquilles tendon thickness were determined in subjects with genetic FH with (n = 63) and without (n = 40) TX. Student-t test o Mann–Whitney test were used accordingly. Categorical variables were compared using a Chi square test. ANOVA and Kruskal–Wallis tests were performed to multiple independent variables comparison. Post hoc adjusted comparisons were performed with Bonferroni correction when applicable. Correlations of parameters in selected groups were calculated applying the non-parametric Spearman correlation procedure. To identify variables associated with Achilles tendon thickness changes, multiple linear regression were applied.ResultsPatients with TX presented higher concentrations of non-cholesterol sterols in plasma than patients without xanthomas (P = 0.006 and 0.034, respectively). Furthermore, there was a significant association between 5α-cholestanol, β-sitosterol, desmosterol, 24S-hydroxycholesterol and 27-hydroxycholesterol concentrations and Achilles tendon thickness (p = 0.002, 0.012, 0.020, 0.045 and 0.040, respectively).ConclusionsOur results indicate that non-cholesterol sterol concentrations are associated with the presence of TX. Since cholesterol and non-cholesterol sterols are present in the same lipoproteins, further studies would be needed to elucidate their potential role in the development of TX.

Desmosterol accumulation in users of amiodarone.

Amiodarone is an effective and widely used antiarrhythmic drug with many possible adverse effects including hypercholesterolaemia and hepatotoxicity. Our aim was to evaluate how long-term amiodarone treatment affects cholesterol metabolism. The study population consisted of 56 cardiac patients, of whom 20 were on amiodarone (amiodarone + group) and 36 did not use the drug (amiodarone - group). We also studied a control group of 124 individuals selected randomly from the population. Cholesterol metabolism was evaluated by analysis of serum noncholesterol sterols by gas-liquid chromatography and gas chromatography-mass spectrometry. Comparisons of serum lipids and noncholesterol sterols across the three groups showed increased serum triglyceride in users of amiodarone but no statistically significant group differences in total, LDL or HDL cholesterol or serum proprotein convertase subtilisin/kexin type 9 concentrations. Nor did the groups differ in the ratios of cholestanol or plant sterols to cholesterol in serum, suggesting that cholesterol absorption was unaltered. However, all users of amiodarone had very markedly elevated serum desmosterol concentrations: the desmosterol-to-cholesterol ratio (102 × μmol mmol-1 ) averaged 1030.7 ± 115.7 (mean ± SE) in the amiodarone + group versus 82.7 ± 3.4 and 75.9 ± 1.4 in the amiodarone - and the population control groups (P < 0.001), respectively. Use of amiodarone was associated with on average 12-fold serum desmosterol concentrations compared with the control groups. This observation is fully novel and suggests that amiodarone interferes with the conversion of desmosterol to cholesterol in the cholesterol synthesis pathway. Whether accumulation of desmosterol plays a role in amiodarone-induced hepatotoxicity deserves to be studied in the future.

Plasma sterols and depressive symptom severity in a population-based cohort.

Convergent evidence strongly suggests major depressive disorder is heterogeneous in its etiology and clinical characteristics. Depression biomarkers hold potential for identifying etiological subtypes, improving diagnostic accuracy, predicting treatment response, and personalization of treatment. Human plasma contains numerous sterols that have not been systematically studied. Changes in cholesterol concentrations have been implicated in suicide and depression, suggesting plasma sterols may be depression biomarkers. Here, we investigated associations between plasma levels of 34 sterols (measured by mass spectrometry) and scores on the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR16) scale in 3117 adult participants in the Dallas Heart Study, an ethnically diverse, population-based cohort. We built a random forest model using feature selection from a pool of 43 variables including demographics, general health indicators, and sterol concentrations. This model comprised 19 variables, 13 of which were sterol concentrations, and explained 15.5% of the variation in depressive symptoms. Desmosterol concentrations below the fifth percentile (1.9 ng/mL, OR 1.9, 95% CI 1.2–2.9) were significantly associated with depressive symptoms of at least moderate severity (QIDS-SR16 score ≥10.5). This is the first study reporting a novel association between plasma concentrations cholesterol precursors and depressive symptom severity.

Mitochondrial dysfunctions in 7-ketocholesterol-treated 158N oligodendrocytes without or with α-tocopherol: Impacts on the cellular profil of tricarboxylic cycle-associated organic acids, long chain saturated and unsaturated fatty acids, oxysterols, cholesterol and cholesterol precursors

In multiple sclerosis (MS) a process of white matter degradation leading to demyelination is observed. Oxidative stress, inflammation, apoptosis, necrosis and/or autophagy result together into a progressive loss of oligodendrocytes. 7-ketocholesterol (7KC), found increased in the cerebrospinal fluid of MS patients, triggers a rupture of RedOx homeostasis associated with mitochondrial dysfunctions, aptoptosis and autophagy (oxiapoptophagy) in cultured murine oligodendrocytes (158N). α-tocopherol is able to mild the alterations induced by 7KC partially restoring the cellular homeostasis. In presence of 7KC, the amount of adherent 158N cells was decreased and oxidative stress was enhanced. An increase of caspase-3 and PARP degradation (evidences of apoptosis), and an increased LC3-II/LC3-I ratio (criterion of autophagy), were detected. These events were associated with a decrease of the mitochondrial membrane potential (ΔΨm) and by a decrease of oxidative phosphorylation revealed by reduced NAD+ and ATP. The cellular lactate was higher while pyruvate, citrate, fumarate, succinate (tricarboxylic acid (TCA) cycle intermediates) were significantly reduced in exposed cells, suggesting that an impairment of mitochondrial respiratory functions could lead to an increase of lactate production and to a reduced amount of ATP and acetyl-CoA available for the anabolic pathways. The concentration of sterol precursors lathosterol, lanosterol and desmosterol were significantly reduced together with satured and unsatured long chain fatty acids (C16:0 − C18:0, structural elements of membrane phospholipids). Such reductions were milder with α-tocopherol. It is likely that the cell death induced by 7KC is associated with mitochondrial dysfunctions, including alterations of oxidative phosphorylation, which could result from lipid anabolism dysfunctions, especially on TCA cycle intermediates. A better knowledge of mitochondrial associated dysfunctions triggered by 7KC will contribute to bring new information on the demyelination processes which are linked with oxidative stress and lipid peroxidation, especially in MS.

DiazaCon reduces black-tailed prairie dog reproduction in Colorado

Context Black-tailed prairie dogs (Cynomus ludovicianus) often come into conflict with humans in urban natural areas adjacent to private property by destroying plants and denuding the landscape. There is a diversity of attitudes related to urban prairie dog management in Colorado and interest in non-lethal methods is increasing. Therefore, the development of non-lethal methods that allow the existence of prairie dogs and mitigate damage related to population density is needed. Aims The efficacy of DiazaCon (20,25-diazacholesterol dihydrochloride, a cholesterol analogue) as an oral contraceptive bait for reducing reproduction in black-tailed prairie dogs was tested. Persistence of DiazaCon in black-tailed prairie dogs 11 months after initial application was also determined. Methods Prairie dogs were baited with DiazaCon-coated rolled oats or control bait for 10 days over a 20-day period in November 2007 on one control and one treatment site. Sites were randomly assigned to a treatment group. Visual counts were used 8 months post-treatment (June/July 2008) to determine pup:adult ratios on both sites. Prairie dogs on both sites were trapped 11 months post-treatment (September/October 2008) to gather mass and age data to assess juvenile:adult ratios and to collect blood samples for determination of serum cholesterol and desmosterol concentrations. Key results DiazaCon treatment reduced the number of pups per adult by 95.5% when compared with the control site in June/July 2008 (0.09±0.02, n=10, number of observation days) versus 2.0±0.2 (n=10). Free serum cholesterol levels in treated animals (370.7µgmL–1) were lower than control animal levels (411.6µgmL–1, P&lt;0.015), while treated desmosterol levels (14.5µgmL–1) were higher than controls (0.35µgmL–1, P&lt;0.02) 11 months after ingestion of DiazaCon bait. However, these differences would likely not have been sufficient to prevent successful breeding in the upcoming breeding season. Conclusions DiazaCon is an effective contraceptive in black-tailed prairie dogs. It is probably reversible and will likely affect breeding success for only one breeding season. DiazaCon may provide an additional tool to help manage urban populations of prairie dogs in locations where lethal control is unacceptable. Implications The need for further research into secondary hazards to non-target animals, such as predators, is discussed. Recommendations for field application are also discussed.

A comparative study of the effects of cholesterol and desmosterol on zwitterionic DPPC model membranes

Desmosterol is a direct biosynthetic precursor of cholesterol in Bloch biochemical pathway of cholesterol biosynthesis and differs with cholesterol only by a double bond in carbon 24. In this study, we aimed to research for the first time comparative effects of cholesterol and its precursor desmosterol on dipalmitoyl phosphatidylcholine (DPPC) multilamellar vesicles (MLVs) by utilizing Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). Our DSC studies reveal that with the addition of increasing desmosterol and cholesterol concentrations into pure DPPC MLVs, the pretransition disappears, the main phase transition shifts to lower temperatures and then disappears. While the main phase transition is abolished at 25mol% concentration of desmosterol, this disappearance of the main phase transition occurs at cholesterol concentration above 30mol%. Our FTIR studies show that both desmosterol and cholesterol decrease the order in the gel phase, whereas they increase it in the liquid crystalline phase. Importantly, we found that the effect of desmosterol on membrane order is weaker than that of cholesterol in both phases. Moreover, desmosterol and cholesterol increase the dynamics of DPPC membranes in the gel phase, while they decrease it in the liquid crystalline phase. Both sterols also induce a decrease in the wavenumber values of the CO stretching and PO2− antisymmetric double stretching bands of DPPC both in the gel and liquid crystalline phases, which points out hydrogen bonding in between the hydroxyl group of both sterols and the carbonyl and phosphate groups of DPPC membranes.

Additive effects of lupin protein and phytic acid on aortic calcification in ApoE deficient mice

Lupin proteins have repeatedly been shown to exhibit lipid lowering properties and reduce aortic calcification in atherosclerosis models. Despite many efforts on its identification, the component which is responsible for the observed effects is still under debate. Phytic acid which is generally associated with lupin protein isolates has currently been described as bioactive plant compound. The objective of the study was to determine the role of associated phytic acid for the described lupin protein effects.A two-factorial study with ApoE knockout mice was conducted in which mice received lupin protein isolate or casein with or without phytase. Phytic acid was added to the casein diets to a final concentration identical to the lupin protein diets. Here we show that the serum concentrations of cholesterol, lathosterol and desmosterol were lower and the faecal bile acid excretion was higher in the groups fed lupin proteins than in the groups fed casein (p < 0.05). Mice that received the lupin protein diet containing phytic acid were characterized by a lower aortic calcification than mice of the other three groups (p < 0.05). In conclusion, our results show that the cholesterol lowering properties of lupin protein isolate were not caused by phytic acid. However, the hypocalcific action of lupin proteins appears to depend on the combination of lupin proteins and phytic acid.

Protective role of plant sterol and stanol esters in liver inflammation: insights from mice and humans.

The inflammatory component of non–alcoholic steatohepatitis (NASH) can lead to irreversible liver damage. Therefore there is an urgent need to identify novel interventions to combat hepatic inflammation. In mice, omitting cholesterol from the diet reduced hepatic inflammation. Considering the effects of plant sterol/stanol esters on cholesterol metabolism, we hypothesized that plant sterol/stanol esters reduces hepatic inflammation. Indeed, adding plant sterol/stanol esters to a high-fat-diet reduced hepatic inflammation as indicated by immunohistochemical stainings and gene expression for inflammatory markers. Finally, adding sterol/stanol esters lowered hepatic concentrations of cholesterol precursors lathosterol and desmosterol in mice, which were highly elevated in the HFD group similarly as observed in severely obese patients with NASH. In vitro, in isolated LPS stimulated bone marrow derived macrophages desmosterol activated cholesterol efflux whereas sitostanol reduced inflammation. This highly interesting observation that plant sterol/stanol ester consumption leads to complete inhibition of HFD-induced liver inflammation opens new venues in the treatment and prevention of hepatic inflammation.

Aging Induces Tissue‐Specific Changes in Cholesterol Metabolism in Rat Brain and Liver

Disturbance of cholesterol homeostasis in the brain is coupled to age-related brain dysfunction. In the present work, we studied the relationship between aging and cholesterol metabolism in two brain regions, the cortex and hippocampus, as well as in the sera and liver of 6-, 12-, 18- and 24-month-old male Wistar rats. Using gas chromatography-mass spectrometry, we undertook a comparative analysis of the concentrations of cholesterol, its precursors and metabolites, as well as dietary-derived phytosterols. During aging, the concentrations of the three cholesterol precursors examined (lanosterol, lathosterol and desmosterol) were unchanged in the cortex, except for desmosterol which decreased (44%) in 18-month-old rats. In the hippocampus, aging was associated with a significant reduction in lanosterol and lathosterol concentrations at 24months (28 and 25%, respectively), as well as by a significant decrease of desmosterol concentration at 18 and 24months (36 and 51%, respectively). In contrast, in the liver we detected age-induced increases in lanosterol and lathosterol concentrations, and no change in desmosterol concentration. The amounts of these sterols were lower than in the brain regions. In the cortex and hippocampus, desmosterol was the predominant cholesterol precursor. In the liver, lathosterol was the most abundant precursor. This ratio remained stable during aging. The most striking effect of aging observed in our study was a significant decrease in desmosterol concentration in the hippocampus which could reflect age-related reduced synaptic plasticity, thus representing one of the detrimental effects of advanced age.

Identification of a new plasma biomarker of Alzheimer's disease using metabolomics technology

We performed unbiased analysis of steroid-related compounds to identify novel Alzheimer's disease (AD) plasma biomarkers using liquid chromatography-atmospheric pressure chemical ionization-mass spectroscopy. The analysis revealed that desmosterol was found to be decreased in AD plasma versus controls. To precisely quantify variations in desmosterol, we established an analytical method to measure desmosterol and cholesterol. Using this LC-based method, we discovered that desmosterol and the desmosterol/cholesterol ratio are significantly decreased in AD. Finally, the validation of this assay using 109 clinical samples confirmed the decrease of desmosterol in AD as well as a change in the desmosterol/cholesterol ratio in AD. Interestingly, we could also observe a difference between mild cognitive impairment and control. In addition, the decrease of desmosterol was somewhat more significant in females. Receiver operating characteristic (ROC) analysis between controls and AD, using plasma desmosterol shows a score of 0.80, indicating a good discrimination power for this marker in the two reference populations and confirms the potential usefulness of measuring plasma desmosterol levels for diagnosing AD. Further analysis showed a significant correlation of plasma desmosterol with Mini-Mental State Examination scores. Although larger sample populations will be needed to confirm this diagnostic marker sensitivity, our studies demonstrate a sensitive and accurate method of detecting plasma desmosterol concentration and suggest that plasma desmosterol could become a powerful new specific biomarker for early and easy AD diagnosis.

Feeding of grey squirrels (Sciurus carolinensis) with the contraceptive agent DiazaCon™: effect on cholesterol, hematology, and blood chemistry

Grey squirrels (Sciurus carolinensis) are an invasive species in Britain and Italy. They have replaced native red squirrels (Sciurus vulgaris) throughout most of Britain, and cause damage to trees. Currently, lethal control is used to manage grey squirrel populations in Britain, but nonlethal methods might be more acceptable to the public. One such method is contraception with 20,25-diazacholesterol dihydrochloride (DiazaCon™). DiazaCon™ inhibits the conversion of desmosterol to cholesterol, resulting in increasing desmosterol concentrations and decreasing cholesterol concentrations. Because cholesterol is needed for the synthesis of steroid reproductive hormones, such as progesterone and testosterone, inhibition of cholesterol synthesis indirectly inhibits reproduction. Desmosterol is used as a marker of efficacy in laboratory studies with species that do not reproduce readily in captivity. Grey squirrels were gavaged with a DiazaCon™ solution for 2 days, and then fed DiazaCon™-coated peanuts for an additional 8 days at target doses of 50 and 100 mg DiazaCon™ per kg body weight. There was a significant difference in cholesterol concentrations in the treatment groups compared to the control group. Cholesterol was reduced by ≥ 40% for 2 months in both treatment groups. There were no differences among groups with respect to blood chemistry and hematology parameters, and mean values are reported. The mean overall dose of DiazaCon™ received was 29.0 ± 1.6 and 55.3 ± 4.3 mg/kg in the low (50 mg/kg) and high dose (100 mg/kg) groups, respectively. DiazaCon™ might provide an effective, acceptable alternative to lethal control.

Cholesterol metabolism, endothelial dysfunction, and carotid artery stiffness in type 1 diabetes

Background Type 1 diabetes is associated with increased risk of cardiovascular diseases and altered metabolism of cholesterol. We studied whether the markers of arterial stiffness reflecting preclinical atherosclerosis are related to markers of cholesterol metabolism in type 1 diabetes. Methods In eighteen type 1 diabetes subjects aged from 20 to 56 years, serum squalene and non-cholesterol sterols were measured with gas–liquid chromatography, and carotid arterial stiffness (elastic and Young’s modulus, beta index, distensibility, and compliance), intima-media thickness (IMT), and brachial artery endothelial function (flow-mediated dilatation, FMD) were measured with ultrasound imaging. Results Variables of arterial stiffness were not related to serum lipids or HbA 1c except Young’s modulus and compliance to triglycerides ( r = 0.541 and r = −0.552, p < 0.05 for both, respectively). Stiffness of carotid artery was related to mean blood pressure (elastic modulus r = 0.590, distensibility r = −0.486, p < 0.05 for both). Stiffness of carotid artery was associated with serum desmosterol concentration, marker of cholesterol synthesis (e.g. compliance r = −0.600, p < 0.01), and with markers of cholesterol absorption (e.g. distensibility and sitosterol to cholesterol ratio r = 0.628, p < 0.01), and the associations between absorption markers and arterial stiffness remained significant after adjustment on age and mean blood pressure. Conclusions Carotid arterial stiffness was associated with markers of cholesterol metabolism, but not with serum lipid levels. Low absorption-high synthesis of cholesterol was related to increased arterial stiffness. Cholesterol metabolism seems to play a role in vascular health beyond serum lipids in type 1 diabetes.

Elevated cholesterol precursors other than cholestanol can also be a hallmark for CTX

Cerebrotendinous xanthomatosis (CTX) is an inborn error of bile acid synthesis in which hepatic conversion of cholesterol to cholic and chenodeoxycholic acids is impaired. Patients have abnormal bile alcohols in urine, normal to increased plasma cholesterol concentrations and increased concentrations of plasma cholestanol. Little is known about cholesterol precursors in CTX, however. We studied cholesterol and phytosterol profiles in two siblings with CTX during follow-up. While cholesterol concentrations were low in both patients, plasma cholestanol was 6-fold higher compared to control values. In addition, both siblings had a more than 100-fold increase in 7-dehydrocholesterol (7DHC) and 8-dehydrocholesterol (8DHC). Lathosterol, lanosterol and sitosterol were increased in both patients while concentrations of desmosterol and campesterol were normal. In addition, plasma lathosterol/cholesterol ratios were significantly elevated. After treatment with chenodeoxycholate, both patients showed a marked decrease in cholestanol, 7DHC, 8DHC, lathosterol, lanosterol and sitosterol. In addition, the lathosterol/cholesterol ratio normalized, indicating that overall cholesterol synthesis was sufficiently suppressed. This study shows that elevated cholesterol precursors, other than cholestanol, can be a hallmark for CTX.

Use of DiazaCon™ as a reproductive inhibitor for monk parakeets (Myiopsitta monachus)

Feral monk parakeet (Myiopsitta monachus) populations have become established in the United States and other countries around the world, and can cause damage to electrical facilities. Because the monk parakeet is a highly visible species and there is often public opposition to lethal control measures, non-lethal methods, such as contraception, are being developed to help control the spread of feral populations. Two gavage studies and one ad libitum nesting study were conducted to assess the efficacy of DiazaCon™ as a potential contraceptive for the monk parakeet. The first gavage study compared daily dose levels of 0, 50, 75, and 100 mg DiazaCon™ (kg bodyweight)–1 administered for 10 consecutive days. Cholesterol concentrations decreased significantly concomitant with a significant increase in desmosterol concentrations in the treated groups, but did not vary between sexes. Cholesterol and desmosterol concentrations did not differ significantly among DiazaCon™ groups, and cholesterol remained significantly suppressed 12 weeks after treatment. On the basis of these results, the second gavage study compared 5 or 10 consecutive days of DiazaCon™ administration at 50 mg kg–1 bird–1 day–1. Cholesterol concentrations decreased significantly concomitant with a significant increase in desmosterol concentrations in the treated groups, but did not vary between sexes. Cholesterol and desmosterol concentrations did not differ significantly between DiazaCon™ groups, and cholesterol remained significantly suppressed 11 weeks after treatment. Parakeets in the nesting study were fed hulled sunflower seeds treated with a target dose of 50 mg DiazaCon™ kg–1 bird–1 day–1. Birds consumed enough to receive an average dose of 34 mg kg–1 pair–1 day–1, or 17 mg kg–1 bird–1 day–1. Birds in the treated group laid an average of 1.6 ± 0.7 eggs per clutch compared with 3.9 ± 1.1 eggs per clutch in the untreated control group. None of the eggs laid by treated birds hatched compared with 1.1 ± 0.6 eggs per clutch hatching in the control group. Reproductive inhibition was effective for the length of the breeding season, at which time the study was stopped and no more data were collected. DiazaCon™ is a promising avian oral contraceptive that should be further investigated in a field setting with monk parakeets.