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1
Zhao, Chunyan, e Karin Dahlman-Wright. "Liver X receptor in cholesterol metabolism". Journal of Endocrinology 204, n. 3 (16 ottobre 2009): 233–40. http://dx.doi.org/10.1677/joe-09-0271.
Abstract (sommario):
The liver X receptors (LXRs) are nuclear receptors that are activated by endogenous oxysterols, oxidized derivatives of cholesterol. There are two isoforms of LXR, LXRα (NR1H3) and LXRβ (NR1H2). Both LXRα and LXRβ regulate gene expression by binding to DNA sequences associated with target genes as heterodimers with isoforms of the retinoid X receptor (RXR), RXRα (NR2B1), RXRβ (NR2B2), and RXRγ (NR2B3). LXRs act as cholesterol sensors: when cellular oxysterols accumulate as a result of increasing concentrations of cholesterol, LXR induces the transcription of genes that protect cells from cholesterol overload. In this review, we summarize the roles of LXRs in controlling cholesterol homeostasis, including their roles in bile acid synthesis and metabolism/excretion, reverse cholesterol transport, cholesterol biosynthesis and uptake, and cholesterol absorption/excretion in the intestine. The overlapping and distinct roles of the LXRα and LXRβ isoforms, and the potential use of LXRs as attractive targets for treatment of cardiovascular disease are also discussed.
2
Reboldi, Andrea, e Eric Dang. "Cholesterol metabolism in innate and adaptive response". F1000Research 7 (16 ottobre 2018): 1647. http://dx.doi.org/10.12688/f1000research.15500.1.
Abstract (sommario):
It has been long recognized that cholesterol is a critical molecule in mammalian cell biology, primarily for its contribution to the plasma membrane’s composition and its role in assuring proper transmembrane receptor signaling as part of lipid rafts. Efforts have also been made to characterize the cholesterol biosynthetic pathway, cholesterol homeostasis, and cholesterol-derived metabolites in order to gain insights into their dysregulation during metabolic diseases. Despite the central role cholesterol metabolism plays in shaping human health, its regulation during immune activation, such as immune response to pathogens or autoimmune/autoinflammatory diseases, is poorly understood. The immune system is composed of several type of cells with distinct developmental origin, life span, molecular requirements, and gene expressions. It is unclear whether the same array of cholesterol metabolism regulators are equally employed by different immune cells and whether distinct cholesterol metabolites have similar biological consequences in different immune cells. In this review, we will describe how cholesterol metabolism is controlled during the adaptive and the innate immune response and the role for intracellular and extracellular receptors for cholesterol and its derivatives.
3
Bilai, I. M., M. I. Romanenko e D. H. Ivanchenko. "Study on the influence of 7-β-hydroxy-γ-aryloxypropylxanthinyl-8-thioalkanic acid derivatives on the lipid metabolism in experiment". Zaporozhye Medical Journal 23, n. 3 (7 giugno 2021): 411–16. http://dx.doi.org/10.14739/2310-1210.2021.3.207465.
Abstract (sommario):
Statin side effects are not a rare occurrence, in particular dyspeptic disorders, insomnia, headache, skin erythema, rash are often noted. All of this determines scientists to find new effective and low-toxic hypolipidemic agents. Various natural and synthetic xanthine derivatives have been recognized as therapeutically potential compounds and reported to control various diseases. Therefore, the study of new xanthine derivatives and their hypolipidemic effects, which would have a significant therapeutic effect with minimal side effects, is relevant. The aim of the study was to examine the effect of 7-β-hydroxy-γ-aryloxypropylxanthinyl-8-thioalkanic acid derivatives on lipidogram parameters in experimental laboratory rats. Materials and methods. The objects of the study were 7-β-hydroxy-γ-aryloxypropylxanthinyl-8-thioalkanic acid derivatives. The experiments were performed in white laboratory Wistar rats weighing 180–220 g. Experimental modeling of hyperlipidemia – tween model: intraperitoneal administration of tween-80 at a dose of 200 mg/100 g body weight. The test compounds were administered orally, simultaneously with tween, at a dose of 1/10 of LD50 (previously calculated by Prozorovsky express method) for 6 days. The following indicators of lipidogram were determined: total cholesterol (TC), high-density lipoprotein cholesterol (HDL cholesterol), low-density lipoprotein cholesterol (LDL cholesterol), triglycerides (TG) and atherogenic index of plasma: TC – HDL cholesterol / HDL cholesterol. The experiments were carried out with respect to Bioethical rules and norms. Results. The studies have shown data on the hypolipidemic activity of 7-β-hydroxy-γ-aryloxypropylxanthinyl-8-thioalkane acid derivatives. According to the conditional efficiency index Ʃ, which included the overall percentage of the following indicators – total cholesterol, low-density lipoprotein cholesterol and triglycerides, the leading compounds were 2439 (87.47 %), 6047 (82.30 %). The reference drug atorvastatin had a value of 82.98 %. Conclusions. The major compound was 2439 identified among all compared to the control group. The prospect of further research is a more detailed study on the ability of xanthine derivatives to exhibit hypolipidemic effects and to influence oxidative stress in various hyperlipidemic models.
4
Nunomura, Satoshi, Makoto Makishima e Chisei Ra. "Liver X receptors and immune regulation". BioMolecular Concepts 1, n. 5-6 (1 dicembre 2010): 381–87. http://dx.doi.org/10.1515/bmc.2010.030.
Abstract (sommario):
AbstractRecent studies suggest that homeostasis of lipid metabolism is crucial for the function of various immune cells. Oxygenated derivatives of cholesterol (oxysterols) are well-known regulators of lipid metabolism and have diverse functions, such as inhibition of cholesterol synthesis, efflux of intracellular cholesterol, synthesis of cholesterol esters, and activation of liver X receptors (LXRs). In this review, we introduce novel roles of the oxysterol receptors LXRs in the immune system, including regulation of inflammatory responses, T cell expansion, immunoglobulin production, and antitumor responses. We also discuss lipid-mediated signaling as a potential target for treatment of immune diseases.
5
Pirmoradi, Leila, Nayer Seyfizadeh, Saeid Ghavami, Amir A. Zeki e Shahla Shojaei. "Targeting cholesterol metabolism in glioblastoma: a new therapeutic approach in cancer therapy". Journal of Investigative Medicine 67, n. 4 (14 febbraio 2019): 715–19. http://dx.doi.org/10.1136/jim-2018-000962.
Abstract (sommario):
Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor known with a poor survival rate despite current advances in the field of cancer. Additional research into the pathophysiology of GBM is urgently needed given the devastating nature of this disease. Recent studies have revealed the unique cellular physiology of GBM cells as compared with healthy astrocytes. Intriguingly, GBM cells are incapable of de novo cholesterol synthesis via the mevalonate pathway. Thus, the survival of GBM cells depends on cholesterol uptake via low-density lipoprotein receptors (LDLRs) in the form of apolipoprotein-E-containing lipoproteins and ATP-binding cassette transporter A1 (ABCA1) that efflux surplus cholesterol out of cells. Liver X receptors regulate intracellular cholesterol levels in neurons and healthy astrocytes through changes in the expression of LDLR and ABCA1 in response to cholesterol and its derivatives. In GBM cells, due to the dysregulation of this surveillance pathway, there is an accumulation of intracellular cholesterol. Furthermore, intracellular cholesterol regulates temozolomide-induced cell death in glioblastoma cells via accumulation and activation of death receptor 5 in plasma membrane lipid rafts. The mevalonate pathway and autophagy flux are also fundamentally related with implications for cell health and death. Thus, via cholesterol metabolism, the mevalonate pathway may be a crucial player in the pathogenesis and treatment of GBM where our current understanding is still lacking. Targeting cholesterol metabolism in GBM may hold promise as a novel adjunctive clinical therapy for this devastating cancer.
6
Roth, Andrew T., Jennifer A. Philips e Pallavi Chandra. "The role of cholesterol and its oxidation products in tuberculosis pathogenesis". Immunometabolism 6, n. 2 (aprile 2024): e00042. http://dx.doi.org/10.1097/in9.0000000000000042.
Abstract (sommario):
Mycobacterium tuberculosis causes tuberculosis (TB), one of the world’s most deadly infections. Lipids play an important role in M. tuberculosis pathogenesis. M. tuberculosis grows intracellularly within lipid-laden macrophages and extracellularly within the cholesterol-rich caseum of necrotic granulomas and pulmonary cavities. Evolved from soil saprophytes that are able to metabolize cholesterol from organic matter in the environment, M. tuberculosis inherited an extensive and highly conserved machinery to metabolize cholesterol. M. tuberculosis uses this machinery to degrade host cholesterol; the products of cholesterol degradation are incorporated into central carbon metabolism and used to generate cell envelope lipids, which play important roles in virulence. The host also modifies cholesterol by enzymatically oxidizing it to a variety of derivatives, collectively called oxysterols, which modulate cholesterol homeostasis and the immune response. Recently, we found that M. tuberculosis converts host cholesterol to an oxidized metabolite, cholestenone, that accumulates in the lungs of individuals with TB. M. tuberculosis encodes cholesterol-modifying enzymes, including a hydroxysteroid dehydrogenase, a putative cholesterol oxidase, and numerous cytochrome P450 monooxygenases. Here, we review what is known about cholesterol and its oxidation products in the pathogenesis of TB. We consider the possibility that the biological function of cholesterol metabolism by M. tuberculosis extends beyond a nutritional role.
7
Karolczak, Kamil, e Cezary Watala. "The Mystery behind the Pineal Gland: Melatonin Affects the Metabolism of Cholesterol". Oxidative Medicine and Cellular Longevity 2019 (10 luglio 2019): 1–8. http://dx.doi.org/10.1155/2019/4531865.
Abstract (sommario):
Melatonin may be considered a cardioprotective agent. Since atherogenesis is partly associated with the metabolism of lipoproteins, it seems plausible that melatonin affects cardiovascular risk by modulating the metabolism of cholesterol and its subfractions. Moreover, cholesterol-driven atherogenesis can be hypothetically reduced by melatonin, mainly due to the minimalization of harmful reactions triggered in the cardiovascular system by the reactive oxygen species-induced toxic derivatives of cholesterol. In this review, we attempted to summarize the available data on the hypolipemizing effects of melatonin, with some emphasis on the molecular mechanisms underlying these reactions. We aimed to attract readers’ attention to the numerous gaps of knowledge present in the reviewed field and the essential irrelevance between the findings originating from different sources: clinical observations and in vitro mechanistic and molecular studies, as well as preclinical experiments involving animal models. Overall, such inconsistencies make it currently impossible to give a reliable opinion on the action of melatonin on the metabolism of lipoproteins.
8
SHAND, JOHN H., e DAVID W. WEST. "The effect of fibric acid derivatives on cholesterol metabolism in rat liver". Biochemical Society Transactions 22, n. 2 (1 maggio 1994): 110S. http://dx.doi.org/10.1042/bst022110s.
9
Schroepfer, George J. "Oxysterols: Modulators of Cholesterol Metabolism and Other Processes". Physiological Reviews 80, n. 1 (1 gennaio 2000): 361–554. http://dx.doi.org/10.1152/physrev.2000.80.1.361.
Abstract (sommario):
Oxygenated derivatives of cholesterol (oxysterols) present a remarkably diverse profile of biological activities, including effects on sphingolipid metabolism, platelet aggregation, apoptosis, and protein prenylation. The most notable oxysterol activities center around the regulation of cholesterol homeostasis, which appears to be controlled in part by a complex series of interactions of oxysterol ligands with various receptors, such as the oxysterol binding protein, the cellular nucleic acid binding protein, the sterol regulatory element binding protein, the LXR nuclear orphan receptors, and the low-density lipoprotein receptor. Identification of the endogenous oxysterol ligands and elucidation of their enzymatic origins are topics of active investigation. Except for 24,25-epoxysterols, most oxysterols arise from cholesterol by autoxidation or by specific microsomal or mitochondrial oxidations, usually involving cytochrome P-450 species. Oxysterols are variously metabolized to esters, bile acids, steroid hormones, cholesterol, or other sterols through pathways that may differ according to the type of cell and mode of experimentation (in vitro, in vivo, cell culture). Reliable measurements of oxysterol levels and activities are hampered by low physiological concentrations (∼0.01–0.1 μM in plasma) relative to cholesterol (∼5,000 μM) and by the susceptibility of cholesterol to autoxidation, which produces artifactual oxysterols that may also have potent activities. Reports describing the occurrence and levels of oxysterols in plasma, low-density lipoproteins, various tissues, and food products include many unrealistic data resulting from inattention to autoxidation and to limitations of the analytical methodology. Because of the widespread lack of appreciation for the technical difficulties involved in oxysterol research, a rigorous evaluation of the chromatographic and spectroscopic methods used in the isolation, characterization, and quantitation of oxysterols has been included. This review comprises a detailed and critical assessment of current knowledge regarding the formation, occurrence, metabolism, regulatory properties, and other activities of oxysterols in mammalian systems.
10
Gylling, Helena, e Tatu A. Miettinen. "The effect of plant stanol- and sterol-enriched foods on lipid metabolism, serum lipids and coronary heart disease". Annals of Clinical Biochemistry: International Journal of Laboratory Medicine 42, n. 4 (1 luglio 2005): 254–63. http://dx.doi.org/10.1258/0004563054255605.
Abstract (sommario):
Phytosterols are plant sterols, mainly campesterol and sitosterol, and their respective stanols (5α-saturated derivatives), which chemically resemble cholesterol. They are present in a normal diet and are absorbed proportionally to cholesterol, but to a much lesser extent, such that less than 0.1% of serum sterols are plant sterols. Phytosterols inhibit intestinal cholesterol absorption, and fat-soluble plant stanol esters were introduced as a functional food for lowering serum cholesterol in the early 1990s; plant sterol esters entered the market at the end of the 1990s. Inhibition of the intestinal absorption of cholesterol stimulates cholesterol synthesis, a factor which limits serum cholesterol lowering to about 10% with phytosterols. Enrichment of the diet with plant stanol esters reduces absorption and serum concentrations of both cholesterol and plant sterols, whereas enrichment of the diet with plant sterol esters, especially in combination with statins, lowers serum cholesterol but increases serum plant sterol levels. Recent studies have suggested that high-serum plant sterol levels may be associated with increased coincidence of coronary heart disease. Estimates of coronary heart disease reduction by 20-25% with plant sterols/stanols is based mainly on short-term studies. Long-term cholesterol lowering, needed for the prevention of coronary heart disease, may be successful with plant stanol esters, which lower serum cholesterol in both genders over at least a year.
11
Mehtiev, A. R., V. I. Fedchenko, Ya V. Tkachev, V. P. Timofeev e A. Yu Misharin. "Regulation of cholesterol biosynthesis and metabolismin Hep G2 cells by δ8(14)-15-ketoergostane derivatives". Biomeditsinskaya Khimiya 56, n. 5 (2010): 576–86. http://dx.doi.org/10.18097/pbmc20105605576.
Abstract (sommario):
The comparative study of effects of 5α-cholest-8(14)-en-15-on-3β-ol (I), (22E)-5α-ergosta-8(14),22-dien-15-on-3β-ol (II), (22S,23S)-22,23-oxido-5α-ergost-8(14)-en-15-on-3β-ol (III) and (22R,23R)-22,23-oxido-5α-ergost-8(14)-en-15-on-3β-ol (IV) on HMG-CoA reductase, CYP27A1 and CYP3A4 genes expression in Hep G2 cells was performed. In the contrast to 15-ketocholestane derivative (I), 15-ketoergostane derivatives (II - IV) decreased the HMG- CoA reductase mRNA level; (22R,23R)-22,23-oxido-5α-ergost-8(14)-en-15-on-3β-ol (IV) significantly increased CYP3A4 mRNA level (320% from control). Ketosterol (II) was found to be a more potent inhibitor of cholesterol biosynthesis in Hep G2 cells at a prolong incubation, compared with ketosterol (I). The side chain conformation of compounds (I) - (IV) was evaluated by computational modeling; the correlation between biological activity of these compounds and conformational flexibility of their side chains was found. The results obtained indicated that Δ8(14)-15-ketoergostane derivatives may be used as a sterol biosynthesis and metabolism regulators in liver cells.
12
Dobrzyn, Pawel. "CoA in Health and Disease". International Journal of Molecular Sciences 23, n. 8 (15 aprile 2022): 4371. http://dx.doi.org/10.3390/ijms23084371.
Abstract (sommario):
Coenzyme A (CoA) and its thioester derivatives are crucial components of numerous biosynthetic and degradative pathways of the cellular metabolism (including fatty acid synthesis and oxidation, the Krebs cycle, ketogenesis, cholesterol and acetylcholine biosynthesis, amino acid degradation, and neurotransmitter biosynthesis), post-translational modifications of proteins, and the regulation of gene expression [...]
13
Li, Xiaoyue, Beibei Zeng, Lu Wen, Yingcai Zhao, Zhaojie Li, Changhu Xue, Tiantian Zhang e Yuming Wang. "Sea Cucumber Saponins Derivatives Alleviate Hepatic Lipid Accumulation Effectively in Fatty Acids-Induced HepG2 Cells and Orotic Acid-Induced Rats". Marine Drugs 20, n. 11 (10 novembre 2022): 703. http://dx.doi.org/10.3390/md20110703.
Abstract (sommario):
The sulfated echinoside A (EA) and holothurin A (HA) are two prominent saponins in sea cucumber with high hemolytic activity but also superior lipid-lowering activity. Deglycosylated derivatives EA2 and HA2 exhibit low hemolysis compared to EA and HA, but their efficacies on lipid metabolism regulation remains unknown. In this study, fatty acids-treated HepG2 cells and orotic acid-treated rats were used to investigate the lipid-lowering effects of sea cucumber saponin derivatives. Both the saponin and derivatives could effectively alleviate lipid accumulation in HepG2 model, especially EA and EA2. Moreover, though the lipid-lowering effect of EA2 was not equal with EA at the same dosage of 0.05% in diet, 0.15% dosage of EA2 significantly reduced hepatic steatosis rate, liver TC and TG contents by 76%, 41.5%, and 63.7%, respectively, compared to control and reversed liver histopathological features to normal degree according to H&E stained sections. Possible mechanisms mainly included enhancement of fatty acids β-oxidation and cholesterol catabolism through bile acids synthesis and excretion, suppression of lipogenesis and cholesterol uptake. It revealed that the efficacy of EA2 on lipid metabolism regulation was dose-dependent, and 0.15% dosage of EA2 possessed better efficacy with lower toxicity compared to 0.05% dosage of EA.
14
Egbewande, Folake A., Martin C. Sadowski, Claire Levrier, Kaylyn D. Tousignant, Jonathan M. White, Mark J. Coster, Colleen C. Nelson e Rohan A. Davis. "Identification of Gibberellic Acid Derivatives That Deregulate Cholesterol Metabolism in Prostate Cancer Cells". Journal of Natural Products 81, n. 4 (23 febbraio 2018): 838–45. http://dx.doi.org/10.1021/acs.jnatprod.7b00929.
15
Guerrero-Ospina, Juan Camilo, Nasly Jimena Garay, Beatriz Restrepo, Nelsy Loango, Maria Elena Maldonado-Celis e Patricia Landazuri. "Modulation by Passiflora edulisof intracellular triglycerides and cholesterol in SW480 colorectal cancer cell lines and their metastatic derivatives (SW620)". Boletin Latinoamericano y del Caribe de Plantas Medicinales y Aromaticas 23, n. 2 (30 marzo 2024): 214–28. http://dx.doi.org/10.37360/blacpma.24.23.2.15.
Abstract (sommario):
Cancer cells modify lipid metabolism to proliferate, Passiflora edulis (P. edulis) fruit juice (ZuFru) has antitumor activity, but whether a mechanism is through modulation of cell lipids is unknown. To establish if ZuFru modifies cholesterol and triglycerides in SW480 and SW620. ZuFru composition was studied by phytochemical march; antiproliferative activity by sulforhodamine B, cholesterol, and triglycerides by Folch method. Zufru contains anthocyanins, flavonoids, alkaloids, and tannins. Cell lines showed differences in their growth rate (p=0.049). At 39.6 μg/mL of ZuFru, cell viability was decreased: SW480 (45.6%) and SW620 (45.1%). In SW480, cholesterol (44.6%) and triglycerides (46.5%) decreased; In SW620, cholesterol decreased 14.8% and triglycerides increased 7%,with significant differences for both lines. Antiproliferative activity of ZuFru could be associated with the inhibition of intracellular biosynthesis of cholesterol and triglycerides in SW480. Action mechanisms need to be further investigated
16
Maxumova, M. A., I. A. Sobenin, M. I. Balabolkin e A. N. Orekhov. "Atherogenic characteristics of oral sugar-reducing sulfonylurea derivatives". Problems of Endocrinology 40, n. 3 (15 dicembre 1994): 8–10. http://dx.doi.org/10.14341/probl11986.
Abstract (sommario):
The authors have examined the effects of sulfonylurea drugs glybenclamide and glypizide and of their analogs manilil and minidiab on cholesterol levels in murine peritoneal macrophages. Both glybenclamide and glypizide had a direct atherogenic effect on cultured murine peritoneal macrophages. A similar effect was observed in vivo: blood sera of diabetics after a single intake of 5 mg of manilil or minidiab increased the atherogenic potential of cultured murine peritoneal macrophages.
17
Ayavire, Fernando, Jose Miguel Fonseca, Felipe Salas, Julio Benites, Chukwuemeka R. Nwokocha, Adrian Paredes, Fredi Cifuentes e Javier Palacios. "Ascorbic supplementation attenuates juglone induced metabolic derangement". Boletin Latinoamericano y del Caribe de Plantas Medicinales y Aromaticas 20, n. 2 (30 marzo 2021): 195–202. http://dx.doi.org/10.37360/blacpma.21.20.2.15.
Abstract (sommario):
Juglone derivatives like 2-(4-hydroxyphenyl) amino-1,4-naphthoquinone (Q7) are used as antitumor agents, and act through reactive oxygen species (ROS) generation. Such may lead to abnormal lipid metabolism and ROS dysregulation. The objective of this study was to evaluate the effect of ascorbate on the metabolism of lipids and carbohydrates following Q7-induced oxidative stress. Male Wistar rats were administered Q7 (10 mg/Kg) and/or ascorbate (500 mg/Kg) orally for 20 days. Rats treated with Q7 showed an increase in serum triglycerides, VLDL cholesterol and lipid peroxidation levels. When Q7 treatment was followed up by ascorbate (500 mg/Kg) administration, we observed a reduction in serum triglycerides, VLDL cholesterol and lipid peroxidation. The oral administration of ascorbate reduced the Q7-induced increases in lipids, and postprandial glycemia. This could be associated with the redox activity of ascorbate that reduced the oxidative stress induced by Q7. We thus conclude that ascorbate modulates the Q7-induced increase of lipid and carbohydrate metabolism.
18
Akhmetshina, Alena, Dagmar Kratky e Elizabeth Rendina-Ruedy. "Influence of Cholesterol on the Regulation of Osteoblast Function". Metabolites 13, n. 4 (21 aprile 2023): 578. http://dx.doi.org/10.3390/metabo13040578.
Abstract (sommario):
Bone is a dynamic tissue composed of cells, an extracellular matrix, and mineralized portion. Osteoblasts are responsible for proper bone formation and remodeling, and function. These processes are endergonic and require cellular energy in the form of adenosine triphosphate (ATP), which is derived from various sources such as glucose, fatty acids, and amino acids. However, other lipids such as cholesterol have also been found to play a critical role in bone homeostasis and can also contribute to the overall bioenergetic capacity of osteoblasts. In addition, several epidemiological studies have found a link between elevated cholesterol, cardiovascular disease, an enhanced risk of osteoporosis, and increased bone metastasis in cancer patients. This review focuses on how cholesterol, its derivatives, and cholesterol-lowering medications (statins) regulate osteoblast function and bone formation. It also highlights the molecular mechanisms underlying the cholesterol–osteoblast crosstalk.
19
Miettinen e Gylling. "Non-Nutritive Bioactive Constituents of Plants: Phytosterols". International Journal for Vitamin and Nutrition Research 73, n. 2 (1 marzo 2003): 127–34. http://dx.doi.org/10.1024/0300-9831.73.2.127.
Abstract (sommario):
Normal human diet contains small amounts of phytosterols, mainly sitosterol and campesterol. Intestinal absorption of these plant sterols is low, about one tenth of that of cholesterol, such that their serum concentrations are also low, about 0.1 to 1% of the cholesterol levels. Like cholesterol they are transported by lipoproteins, mainly by LDL, and secreted unchanged in bile. Addition of plant sterols, or especially of their delta-5 saturated derivatives plant stanols into diet as fat-soluble esters inhibit cholesterol absorption and lower serum cholesterol similarly in short-term studies. Long-term consumption of plant stanol esters lowers serum cholesterol to the extent expected to reduce clinical manifestation of coronary heart disease by over 20% without detectable side effecs, cholesterol lowering being especially effective in combination with cholesterol synthesis inhibitors statins.
20
Wielkoszyński, Tomasz, Jolanta Zalejska-Fiolka, Joanna K. Strzelczyk, Aleksander J. Owczarek, Armand Cholewka, Katarzyna Kokoszczyk e Agata Stanek. "5α,6α-Epoxyphytosterols and 5α,6α-Epoxycholesterol Increase Nitrosative Stress and Inflammatory Cytokine Production in Rats on Low-Cholesterol Diet". Oxidative Medicine and Cellular Longevity 2020 (8 giugno 2020): 1–9. http://dx.doi.org/10.1155/2020/4751803.
Abstract (sommario):
Objective. Oxidized cholesterol derivatives are compounds with proven atherogenic and mutagenic effects. However, little is known about the effect of oxidized plant sterol derivatives (oxyphytosterols), whose structure is similar to the one of oxycholesterols. Our previous studies indicate that they have a similar profile of action, e.g., both exacerbate disorder of lipid metabolism and oxidative stress in experimental animals. The aim of the present study was to assess the effect of epoxycholesterol and epoxyphytosterols (mainly sitosterol) on the severity of nitrosative stress and the concentration of selected proinflammatory cytokines in blood and liver tissue of rats on a low-cholesterol diet. Material and Methods. Forty-five male Wistar rats were fed with feed containing 5α,6α-epoxyphytosterols (ES group, n: 15), 5α,6α-epoxycholesterol (ECh group, n: 15), and oxysterol-free feed (C group, n: 15) for 90 days (daily dose of oxysterols: 10 mg/kg). At the end of the experiment, nitrotyrosine, TNF-α, IL-1β, IL-6, and lipid metabolism parameters were determined in blood serum. Furthermore, nitrotyrosine, TNF-α, cholesterol, and triglyceride content were determined in liver homogenates. Results. Serum nitrotyrosine, IL-1β, and TNF-α concentrations as well as TNF-α content in the liver were significantly higher in both groups exposed to oxysterols (ECh and ES groups) as compared to the C group. The serum IL-6 level and nitrotyrosine content in the liver were significantly higher in the ECh group, as compared to the C and ES groups. There was evidence to support the dyslipidemic effect of studied compounds. Conclusions. The results indicate that oxidized plant sterols have a similar toxicity profile to that of oxycholesterols, including nitrosative stress induction, proinflammatory effect, and impaired lipid metabolism.
21
Olkkonen, Vesa M. "New Functions for Oxysterols and Their Cellular Receptors". Lipid Insights 2 (gennaio 2008): LPI.S866. http://dx.doi.org/10.4137/lpi.s866.
Abstract (sommario):
Oxysterols are naturally occurring oxidized derivatives of cholesterol, or by-products of cholesterol biosynthesis, with multiple biologic functions. These compounds display cytotoxic, pro-apoptotic, and pro-inflammatory activities and may play a role in the pathology of atherosclerosis. Their functions as intermediates in the synthesis of bile acids and steroid hormones, and as readily transportable forms of sterol are well established. During the past decade, however, novel physiologic activities of oxysterols have emerged. They are now thought to act as endogenous regulators of gene expression in lipid metabolism. Recently, new intracellular oxysterol receptors have been identified and novel functions of oxysterols in cell signaling discovered, evoking novel interest in these compounds in several branches of biomedical research.
22
Martín-Acebes, Miguel A., Nereida Jiménez de Oya e Juan-Carlos Saiz. "Lipid Metabolism as a Source of Druggable Targets for Antiviral Discovery against Zika and Other Flaviviruses". Pharmaceuticals 12, n. 2 (21 giugno 2019): 97. http://dx.doi.org/10.3390/ph12020097.
Abstract (sommario):
The Zika virus (ZIKV) is a mosquito-borne flavivirus that can lead to birth defects (microcephaly), ocular lesions and neurological disorders (Guillain-Barré syndrome). There is no licensed vaccine or antiviral treatment against ZIKV infection. The effort to understand the complex interactions of ZIKV with cellular networks contributes to the identification of novel host-directed antiviral (HDA) candidates. Among the cellular pathways involved in infection, lipid metabolism gains attention. In ZIKV-infected cells lipid metabolism attributed to intracellular membrane remodeling, virion morphogenesis, autophagy modulation, innate immunity and inflammation. The key roles played by the cellular structures associated with lipid metabolism, such as peroxisomes and lipid droplets, are starting to be deciphered. Consequently, there is a wide variety of lipid-related antiviral strategies that are currently under consideration, which include an inhibition of sterol regulatory element-binding proteins (SREBP), the activation of adenosine-monophosphate activated kinase (AMPK), an inhibition of acetyl-Coenzyme A carboxylase (ACC), interference with sphingolipid metabolism, blockage of intracellular cholesterol trafficking, or a treatment with cholesterol derivatives. Remarkably, most of the HDAs identified in these studies are also effective against flaviviruses other than ZIKV (West Nile virus and dengue virus), supporting their broad-spectrum effect. Considering that lipid metabolism is one of the main cellular pathways suitable for pharmacological intervention, the idea of repositioning drugs targeting lipid metabolism as antiviral candidates is gaining force.
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Shtanova, L. Ya, S. P. Vesеlsky, P. I. Yanchuk, O. V. Tsymbalyuk, O. F. Moroz, E. M. Reshetnik, V. S. Moskvina, O. V. Shablykina, О. V. Kravchenko e V. P. Khilya. "Benzodiazepinе derivative methanindiazenone modulates lipid metabolism in the liver of rats with rotenone-induced Parkinson’s syndrome". Fiziolohichnyĭ zhurnal 69, n. 6 (10 novembre 2023): 77–87. http://dx.doi.org/10.15407/fz69.06.077.
Abstract (sommario):
Parkinson’s disease (PD) is a neurodegenerative condition for which the exact causes remain elusive, and no effective treatments currently exist. The pathogenesis of PD is believed to involve oxidative stress, mitochondrial dysfunction, and lipid metabolism disorders. A benzodiazepine derivative JM-20 has demonstrated protective effects on mitochondria in both neurons and peripheral tissues of rats with rotenoneinduced Parkinson’s syndrome (PS). This study aimed to analyze bile composition and assess the impact of a new benzodiazepine derivative, methanindiazenone, on lipid metabolism in the liver of rats subjected to the rotenone model of PS. The results indicated that, compared to the control group, bile concentration of phospholipids, cholesterol, cholesterol esters, and triglycerides decreased by 24.3, 26.2, 25.8, and 27.5%, respectively. With methanindiazenone treatment at doses of 0.5 and 1.0 mg/kg, all these metrics reverted to the control level. However, in the rotenone+methanindiazenone 2.0 mg/kg group, the levels of phospholipids, cholesterol, and cholesterol esters (except for triglycerides) surpassed the control values by 33, 28.1, 28.4 and 33.5%, respectively. Methanindiazenone positively impacted the motor behavior of rats with the rotenone model of PS and enhanced their survival rates. Therefore, at doses of 0.5 and 1.0 mg/kg, methanindiazenone not only improved lipid metabolism in the liver but also the overall well-being of rats with the rotenone model of PS. However, a 2 mg/kg dose of methanindiazenone displayed toxic effects, as seen from the increased content of phospholipids, cholesterol, and cholesterol esters in bile. Hence, methanindiazenone holds potential as a therapeutic agent for PS and possibly other neurodegenerative diseases related to lipid metabolism impairment, but its use should be limited to doses of 0.5 and 1.0 mg/kg.
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Kazymyrko, V. K., L. M. Ivanitska, T. S. Silantieva e V. V. Kutovyi. "UNIVERSAL THEORY OF ATHEROSCLEROSIS PATHOGENESIS". Likarska sprava, n. 7-8 (31 dicembre 2019): 3–12. http://dx.doi.org/10.31640/jvd.7-8.2019(1).
Abstract (sommario):
The paper shows that atherosclerosis results from disturbed cholesterol homeostasis in the body, the development of systemic stromal-vascular lipid-protein dystrophy (or lipidosis, or cholesterolosis) complicated by extracellular focal lipid deposits with a predominant cholesterol in the interstitial tissue of the inner arterial and aortic layer. These deposits are foreign to this body tissue. They induce the development of chronic productive granulomatous inflammation in it – granulomatosis around endogenous foreign bodies. Cholesterol deposition is promoted by a positive cholesterol balance in the body; increased permeability of the endothelium in hemodynamically vulnerable parts of the arteries, where blood components, including LP, infiltrate their wall; a lack of hydrolytic enzymes in the cell lysosomes that could destroy the steroid nucleus of the cholesterol molecule. Being essential for each specific organism (for building membranes, the formation of bile acids, the synthesis of steroid hormones, vitamin D3), cholesterol, if exceeded, can increase the probability of developing atherosclerosis. Genetic mechanisms are implicated in the disturbed lipid protein metabolism in the human body. Hyperlipoproteinemias (HLPs) are known to be the most common metabolic disorders. The dystrophy under consideration results from primary HLP types IIa, IIb, III, IV, V, as well as secondary HLPs in patients with various medical conditions associated with an increase in blood LDL and / or VLDL and/or a decrease in HDL. A reduced cholesterol efflux from peripheral tissues due to a decreased HDL content and the development of lipidosis are seen in diabetes, obesity, physical inactivity, stress, puberty, menopause, hypertriglyceridemia, cigarette smoking, uremia, treatment with anabolic steroids, beta-adrenergic blocking agents, gestagens, and the use of contraceptives. The most pronounced manifestations of dystrophy are characteristic of HLP types IIA, IIb, III, but its moderate development complicated by atherosclerosis also occurs in types IV and V, which are accompanied by increased blood VLDL. Mutations of LDL receptor genes, apoprotein genes lead to the development of stromal vascular dystrophy and atherosclerosis. A number of rare genetic disorders of sterol metabolism accompany impaired metabolism of cholesterol and its esters: hepatic lipase deficiency (with accumulation of VLDL and IDLs); a deficiency in lysosomal hydrolase of cholesterol esters with impaired LDL metabolism (Wolman disease); cholesterol ester accumulation disease; cerebrotendinous xanthomatosis; cerebral cholesterolosis; Toichlander and Hand Schüler Christian syndromes. The main factor contributing to the development of inflammation in the inner vascular wall of arteries and aorta in atherosclerosis is the cyclic hydrocarbonic structure of cholesterol, which cannot be cleaved in the lysosomes of MPs. The leading role of the cyclic hydrocarbonic structure of cholesterol, which is insoluble and indestructible by MPs, in the induction of atherosclerosis-related inflammation is confirmed by the fact of the atherogenic action of cholesterol derivatives having its structure. An important factor in inflammatory morphogenesis is the lipoprotein dyscolloidosis occurring in the arterial intima and the physical and chemical metamorphosis of cholesterol. A colloidal solution, solid crystals of free cholesterol and liquid crystals of cholesterol esters have a pronounced phlogogenic and sclerogenic effect on the interstitial tissue of the arterial intima.
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Rudzite, Vera, Edite Jurika, Janis Jirgensons, Inga Herpfer, Günter Weiss, Helmut Wachter e Dietmar Fuchs. "The Influence of Kynurenine and Its Metabolites on Lipid Metabolism". Pteridines 8, n. 3 (settembre 1997): 201–5. http://dx.doi.org/10.1515/pteridines.1997.8.3.201.
Abstract (sommario):
Summary Incorporation of fatty acids into phospholipids has been investigated using samples of rat liver tissue homogenate, Krebs-Ringer-phosphate buffer (pH=7.4) containing 0.3% albumin, fatty acid mixture and glycerol. The addition of L-kynurenine (4 nmoljg wet weight) to incubation medium induced an increase of palmitic, oleic and linolenic acid and decrease of linoleic and arachidonic acid incorporation into phospholipids. These changes of fatty acid incorporation into phospholipids were followed by increase of cholesterol and decrease of phospholipids content in samples. The addition of 3-hydroxykynurenine (1.8 and 4 nmoljg wet weight), 3-hydroxyanthranilic acid (2.2 and 4 nmoljg wet weight) ,1n..:l quinolinic acid (2.4 and 4 nmoljg wet weight) to incubation medium for phospholipid biosynthesis ill vitro induced a decrease of stearic, palrnitic and linoleic acid and an increase of oleic and especially arachidonic acid incorporation into phospholipids. These changes were accompanied by a decrease of cholesterol content in samples. The influence of kynurenine on fatty acid incorporation into phospholipids was similar to that of neopterin observed earlier. The other tryptophan degradation products behaved similar to the reduced pteridine derivatives. Our results allow to suggest that L-kynurenine decreases, while 3-hydroxykynurenine, 3-hydroxyanthranilic acid and quinolinic acid increase membrane fluidity in the studied concentrations.
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Gugliucci, Alejandro. "Triglyceride-Rich Lipoprotein Metabolism: Key Regulators of Their Flux". Journal of Clinical Medicine 12, n. 13 (29 giugno 2023): 4399. http://dx.doi.org/10.3390/jcm12134399.
Abstract (sommario):
The residual risk for arteriosclerotic cardiovascular disease after optimal statin treatment may amount to 50% and is the consequence of both immunological and lipid disturbances. Regarding the lipid disturbances, the role of triglyceride-rich lipoproteins (TRLs) and their remnants has come to the forefront in the past decade. Triglycerides (TGs) stand as markers of the remnants of the catabolism of TRLs that tend to contain twice as much cholesterol as compared to LDL. The accumulation of circulating TRLs and their partially lipolyzed derivatives, known as “remnants”, is caused mainly by ineffective triglyceride catabolism. These cholesterol-enriched remnant particles are hypothesized to contribute to atherogenesis. The aim of the present narrative review is to briefly summarize the main pathways of TRL metabolism, bringing to the forefront the newly discovered role of apolipoproteins, the key physiological function of lipoprotein lipase and its main regulators, the importance of the fluxes of these particles in the post-prandial period, their catabolic rates and the role of apo CIII and angiopoietin-like proteins in the partition of TRLs during the fast-fed cycle. Finally, we provide a succinct summary of the new and old therapeutic armamentarium and the outcomes of key current trials with a final outlook on the different methodological approaches to measuring TRL remnants, still in search of the gold standard.
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Salter, A. M. "Regulation of gene transcription by fatty acids". Proceedings of the British Society of Animal Science 2007 (aprile 2007): 261. http://dx.doi.org/10.1017/s1752756200021645.
Abstract (sommario):
Dietary lipids have the capacity to regulate many aspects of metabolism in a manner depend on chain length and the number, and position, of double bonds in the fatty acids they contain. For example, while long chain saturated fatty acids increase plasma cholesterol, polyunsaturated fatty acids (PUFA) have the opposite effect. PUFA also have a major impact on the activity of enzymes associated with carbohydrate metabolism and lipid biosynthesis and oxidation. The role of fatty acids as substrates in these pathways, and their conversion to eicosanoids, with different levels of activity depending on the parent molecule, represents two mechanisms whereby they exert such effects. However, more recently it has been established that fatty acids and/or their derivatives also have direct effects on the expression of genes for proteins regulating carbohydrate and lipid metabolism.
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Pavlík, Vojtěch, Veronika Machalová, Martin Čepa, Romana Šínová, Barbora Šafránková, Jaromír Kulhánek, Tomáš Drmota et al. "Retinoic Acid Grafted to Hyaluronic Acid Activates Retinoid Gene Expression and Removes Cholesterol from Cellular Membranes". Biomolecules 12, n. 2 (25 gennaio 2022): 200. http://dx.doi.org/10.3390/biom12020200.
Abstract (sommario):
All-trans-retinoic acid (atRA) is a potent ligand that regulates gene expression and is used to treat several skin disorders. Hyaluronic acid (HA) was previously conjugated with atRA (HA-atRA) to obtain a novel amphiphilic compound. HA-atRA forms micelles that incorporate hydrophobic molecules and facilitate their transport through the skin. The aim of this study was to determine the influence of HA-atRA on gene expression in skin cells and to compare it with that of unbound atRA. Gene expression was investigated using microarrays and a luciferase system with a canonical atRA promoter. HA-atRA upregulated gene expression similarly to atRA. However, HA-atRA activated the expression of cholesterol metabolism genes, unlike atRA. Further investigation using HPLC and filipin III staining suggested that the treated cells induced cholesterol synthesis to replenish the cholesterol removed from the cells by HA-atRA. HA modified with oleate (HA-C18:1) removed cholesterol from the cells similarly to HA-atRA, suggesting that the cholesterol removal stemmed from the amphiphilic nature of the two derivatives. HA-atRA induces retinoid signaling. Thus, HA-atRA could be used to treat skin diseases, such as acne and psoriasis, where the combined action of atRA signaling and anti-inflammatory cholesterol removal may be potentially beneficial.
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Hall, Iris H., David J. Reynolds, O. T. Wong, A. Sood e B. F. Spielvogel. "The Effects of Boron Derivatives on Lipid Absorption from the Intestine and on Bile Lipids and Bile Acids of Sprague Dawley Rats". Metal-Based Drugs 2, n. 2 (1 gennaio 1995): 65–72. http://dx.doi.org/10.1155/mbd.1995.65.
Abstract (sommario):
N,N-dimethyl-n-octadecylamine borane 1¯ at 8 mg/kg/day, tetrakis-u-(trimethylamine boranecarboxylato)-bis(trimethyl-carboxyborane)-dicopper(II) 2¯ at 2.5 mg/kg/day and trimethylamine-carboxyborane 3¯ at 8 mg/kg/day were evaluated for their effects on bile lipids, bile acids, small intestinal absorption of cholesterol and cholic acid and liver and small intestinal enzyme activities involved in lipid metabolism. The agent administered orally elevated rat bile excretion of lipids, e.g. cholesterol and phospholipids, and compounds 2¯ and 3¯ increased the bile flow rate. These agents altered the composition of the bile acids, but there was no significant increase in lithocholic acid which is most lithogenic agent in rats. The three agents did decrease cholesterol absorption from isolated in situ intestinal duodenum loops in the presence of drug. Hepatic and small intestinal mucosa enzyme activities, e.g. ATP-dependent citrate lyase, acyl CoA cholesterol acyl transferase, cholsterol-7-α -hydroxylase, sn glycerol-3-phosphate acyl transferase, phosphatidylate phosphohydrolase, and lipoprotein lipase, were reduced. However, the boron derivatives 1¯ and 3¯ decreased hepatic HMG-CoA reductase activity, the regulatory enzyme for cholesterol synthesis, but the compounds had no effects on small intestinal mucosa HMG-CoA reductase activity. There was no evidence of hepatic cell damage afforded by the drugs based on clinical chemistry values which would induce alterations in bile acid concentrations after treatment of the rat.
30
Mehtiev, A. R., V. I. Fedchenko, Ya V. Tkachev, V. P. Timofeev e A. Yu Misharin. "Regulation of cholesterol biosynthesis and metabolism in Hep G2 cells by Δ8(14)-15-ketoergostane derivatives". Biochemistry (Moscow) Supplement Series B: Biomedical Chemistry 4, n. 3 (19 agosto 2010): 251–57. http://dx.doi.org/10.1134/s1990750810030066.
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Fuior, Elena Valeria, Evangelia Zvintzou, Theodosios Filippatos, Katerina Giannatou, Victoria Mparnia, Maya Simionescu, Anca Violeta Gafencu e Kyriakos E. Kypreos. "Peroxisome Proliferator-Activated Receptor α in Lipoprotein Metabolism and Atherosclerotic Cardiovascular Disease". Biomedicines 11, n. 10 (3 ottobre 2023): 2696. http://dx.doi.org/10.3390/biomedicines11102696.
Abstract (sommario):
Peroxisome proliferator-activated receptors (PPARs) are a group of ligand-binding transcription factors with pivotal action in regulating pleiotropic signaling pathways of energetic metabolism, immune responses and cell proliferation and differentiation. A significant body of evidence indicates that the PPARα receptor is an important modulator of plasma lipid and lipoprotein metabolism, with pluripotent effects influencing the lipid and apolipoprotein cargo of both atherogenic and antiatherogenic lipoproteins and their functionality. Clinical evidence supports an important role of PPARα agonists (fibric acid derivatives) in the treatment of hypertriglyceridemia and/or low high-density lipoprotein (HDL) cholesterol levels, although the effects of clinical trials are contradictory and point to a reduction in the risk of nonfatal and fatal myocardial infarction events. In this manuscript, we provide an up-to-date critical review of the existing relevant literature.
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Goncharov, N. P. "Androgens: A lecture". Problems of Endocrinology 42, n. 4 (15 agosto 1996): 28–31. http://dx.doi.org/10.14341/probl12071.
Abstract (sommario):
Androgens (Greek aner, andros - male and genesis - origin) - compounds with the properties of the male sex hormone testosterone (T). T (androst-4-en-17p-ol-3-one; molecular mass 288.41) is a derivative of androstane. In 1935, Laker from 100 kg of testes of bulls for the first time isolated 10 mg of a pure substance, which he called testosterone. Its biological activity was 10 times higher than that of androsterone known at that time. Based on a number of studies, it has been suggested that T is a 17-dihydro derivative of androstenedione. Soon, the hypothetical structure of T was deciphered and its synthesis was carried out. This was a prologue for the synthesis of dozens of derivatives of T with desired properties. Later, a large number of natural androgens secreted by the testes and adrenal glands, as well as their metabolic products excreted in the urine, were isolated from various biological environments of humans and animals. Biosynthesis and metabolism of androgens. Using various methods, including chemical-analytical, radioisotope, chromatographic, perfusion of testes, studying metabolic products excreted in the urine, it was possible to develop a conceptual scheme of androgen synthesis. Cholesterol ester, accumulated by Leydig cells of the testis, is a source of androgen formation.
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Stawarska, Agnieszka, Małgorzata Czerwonka, Małgorzata Jelińska, Iga Piasecka e Barbara Bobrowska-Korczak. "The Influence of Supplementation with Zinc in Micro and Nano Forms on the Metabolism of Fatty Acids in Livers of Rats with Breast Cancer". Nutrients 13, n. 11 (27 ottobre 2021): 3821. http://dx.doi.org/10.3390/nu13113821.
Abstract (sommario):
The aim of this study was to investigate the effect of zinc supplementation (in the form of nano or microparticles) on the profile and metabolism of fatty acids in the liver microsomes of rats with induced breast cancer. The activity of desaturases (Δ5, Δ6, Δ9) and the level of cholesterol and its oxidized derivatives were measured. The aim of this study was also to determine the effect of various forms of zinc supplements on rats that were on 5-, 12- and 15-hydroxyeicosatetraenoic (5-, 12- and 15-HETE) and hydroxyoctadecadienoic (HODE) acids, and the level of prostaglandin E2 (PGE2). Female Spraque-Dawley rats (n = 24) were divided into 2 groups that were supplemented with zinc in the micro form (342 nm) or nano form (99 nm) particles, respectively, and a group with a standard diet (control group). All animals received 7,12-dimethylbenz[a]anthracene twice for the induction of breast cancer. Dietary nano-Zn supplementation increased vaccenic acid content (p = 0.032) and decreased Δ6-desaturase activity (p = 0.006), whereas micro-Zn increased cholesterol (p = 0.006), ∑COPs (total cholesterol-oxidation products) (p = 0.019) and PGE2 (p = 0.028) content. Dietary enrichment with Zn microparticles resulted in lower concentrations of the metabolites 15-, 12- and 5-HETE and HODE. Our study indicates that the effect of zinc supplementation on the metabolism of fatty acids in the liver microsomes under neoplastic conditions depends on the form in which it is administered.
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He, Wen-Sen, Mei-Gui Wang, Xiao-Xia Pan, Jing-Jing Li, Cheng-Sheng Jia, Xiao-Ming Zhang e Biao Feng. "Role of plant stanol derivatives in the modulation of cholesterol metabolism and liver gene expression in mice". Food Chemistry 140, n. 1-2 (settembre 2013): 9–16. http://dx.doi.org/10.1016/j.foodchem.2013.02.062.
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Jaouadi, Oumaima, Inès Limam, Mohamed Abdelkarim, Emna Berred, Ahlem Chahbi, Mélody Caillot, Brigitte Sola e Fatma Ben Aissa-Fennira. "5,6-Epoxycholesterol Isomers Induce Oxiapoptophagy in Myeloma Cells". Cancers 13, n. 15 (26 luglio 2021): 3747. http://dx.doi.org/10.3390/cancers13153747.
Abstract (sommario):
Multiple myeloma (MM) is an incurable plasma cell malignancy with frequent patient relapse due to innate or acquired drug resistance. Cholesterol metabolism is reported to be altered in MM; therefore, we investigated the potential anti-myeloma activity of two cholesterol derivatives: the 5,6 α- and 5,6 β-epoxycholesterol (EC) isomers. To this end, viability assays were used, and isomers were shown to exhibit important anti-tumor activity in vitro in JJN3 and U266 human myeloma cell lines (HMCLs) and ex vivo in myeloma patients’ sorted CD138+ malignant cells. Moreover, we confirmed that 5,6 α-EC and 5,6 β-EC induced oxiapoptophagy through concomitant oxidative stress and caspase-3-mediated apoptosis and autophagy. Interestingly, in combination treatment a synergistic interaction was observed between 5,6 α-EC and 5,6 β-EC on myeloma cells. These data highlight a striking anti-tumor activity of 5,6 α-EC and 5,6 β-EC bioactive molecules against human myeloma cells, paving the way for their potential role in future therapeutic strategies in MM.
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Muzyko, E. A., V. N. Perfilova, A. A. Nesterova, K. V. Suvorin e I. N. Tyurenkov. "EFFECT OF THE GABA DERIVATIVE SUCCICARD ON THE LIPID AND CARBOHYDRATE METABOLISM IN THE OFFSPRING OF RATS WITH EXPERIMENTAL PREECLAMPSIA IN EARLY AND LATE ONTOGENY". Pharmacy & Pharmacology 8, n. 5 (2 marzo 2021): 325–35. http://dx.doi.org/10.19163/2307-9266-2020-8-5-325-335.
Abstract (sommario):
Maternal preeclampsia can bring about metabolic disorders in the offspring at different stages of ontogeny. Up to date, no ways of preventive pharmacological correction of lipid and carbohydrate metabolism disorders developing in different periods of ontogeny in the children born to mothers with this pregnancy complication, have been developed.The aim of the experiment was to study the effect of the gamma-aminobutyric acid derivative succicard (22 mg/kg) and its reference drug pantogam (50 mg) administered per os in the course of treatment in puberty (from 40 to 70 days after birth), on the parameters of lipid and carbohydrate metabolism in the offspring of the rats with experimental preeclampsia, in different periods of ontogeny.Materials and methods. To assess the activity of lipid and carbohydrate metabolism in the offspring, an oral glucose tolerance test was performed at 40 days, 3, 6, 12 and 18 months of age. The level of glycosylated hemoglobin was measured at the age of 6, 12, and 18 months, and the concentrations of total cholesterol, high-density lipoprotein cholesterol and triglycerides were tested at 40 days, 3, 6, 12, and 18 months of age.Results. The offspring of the rats with experimental preeclampsia, were found out to have lipid and carbohydrate metabolism disturbances during early (40 days and 3 months of age) and late (6, 12, and 18 months of age) ontogeny. In comparison with the offspring of healthy females, these disturbances were manifested by significantly higher levels of glucose revealed during the oral glucose tolerance test, by high glycosylated hemoglobin in males, and with elevated concentration of total cholesterol and triglycerides and a low level of high-density lipoprotein cholesterol in the negative control rats. Both the gamma-aminobutyric acid derivative succicard and its reference drug pantogam, reduced the negative effect of experimental preeclampsia on lipid and carbohydrate metabolism in the offspring in late ontogeny (6, 12 and 18 months of age). The effectiveness of succicard was either higher or comparable with pantogam.Conclusion. Thus, the negative impact manifestations of experimental preeclampsia on lipid and carbohydrate metabolism, are revealed in the offspring in early (40 days and 3 months) and late (6, 12 and 18 months of age) ontogeny. The gamma-aminobutyric acid derivative succicard reduces the negative effect of experimental preeclampsia. Based on this finding, the drug implies the possibility of the development of a safe and highly effective medicine for preventive correction of lipid and carbohydrate metabolism disorders in the children born to mothers with preeclampsia.
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Adekenov, Sergazy, Václav Mareška, Vladimir Ivanov, O. V. Maslova, Aidos Doskaliyev, M. Z. Shaidarov e Vojtech Spiwok. "Hypolipidemic Activity of Sesquiterpene Lactones and their Derivatives". Open Access Macedonian Journal of Medical Sciences 11, A (1 luglio 2023): 251–62. http://dx.doi.org/10.3889/oamjms.2023.11650.
Abstract (sommario):
BACKGROUND: Despite the available range of lipid-lowering drugs, mainly of synthetic origin, the problem of atherosclerosis therapy and its manifestations remain unresolved. Bioinformatics methods, in particular molecular docking, are considered as a promising direction in terms of developing effective original lipid-lowering drugs. Today, as a promising source of natural lipid-lowering agents, it is advisable to consider natural terpenoids, namely sesquiterpene lactones, which are distinguished by a wide range of pharmacological activity. This article presents the results of a virtual and biological screening of the lipid-lowering activity of sesquiterpene γ-lactones and their chemically modified derivatives. AIM: The aim is to evaluate the lipid-lowering properties of samples of sesquiterpene γ-lactones and their derivatives by virtual and biological screening methods. METHODS: Molecular modeling of the binding energy of the “ligand-target” complex (docking). Molecular docking of the lipid-lowering activity of sesquiterpene γ-lactones and their derivatives was performed using the Glide program from the developer of the Schrodinger Small-Molecule Drug Discovery package using the Extra Precision algorithm (https://www.schrodinger.com/glide). The effect of sesquiterpene lactones on the expression of genes for key enzymes of lipid metabolism in the liver was studied in an in vivo model of hyperlipidemia caused by an atherogenic diet. CONCLUSION: Virtual screening of the lipid-lowering activity of sesquiterpene γ-lactones and their derivatives by molecular docking revealed a number of promising compounds (matricin, matricarin, grossmisin oxime, austricin oxime, 5β (H)-austricin) receptor interactions on the enzyme system cholesterol 7α-hydroxylase (CYP7A1). New mechanisms of lipid-lowering activity for sesquiterpene γ-lactones were proposed, which were established in the study of gene expression of key enzymes of lipid metabolism in the liver in a model of hyperlipidemia caused by an atherogenic diet in rats under in vivo conditions.
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Dowdy, Tyrone, Tomohiro Yamasaki, Aiguo Li, Lumin Zhang, Faris Zaibaq, Adrian Lita, Mark Gilbert e Mioara Larion. "DDDR-09. TARGETED DYSREGULATION OF SPHINGOLIPID RHEOSTAT BALANCE IN IDH1MUT GLIOMAS TRIGGERS PRO-APOPTOTIC METABOLIC AND SIGNALING ACTIVITY". Neuro-Oncology 24, Supplement_7 (1 novembre 2022): vii100. http://dx.doi.org/10.1093/neuonc/noac209.374.
Abstract (sommario):
Abstract BACKGROUND IDHwt gliomas exhibit sphingolipid rheostat balance that permits tumors to evade apoptosis by elevating the sphingosine-1-phosphate (S1P)-to-ceramide ratio. Overexpression of sphingosine kinase (SPHK) and consequent accumulation of S1P contribute to progression, chemoresistance, migration, and metastasis in malignant glioblastoma (GBM). We discovered that IDH1mut gliomas present a characteristic sphingolipid rheostat in which pro-apoptotic ceramides and sphingosines are elevated over oncopotent S1P. This characteristic involves inherent silencing of the SPHK2; obliging spheroids to rely on SPHK1 exclusively. We postulated that targeting this unique metabolic vulnerability would abrogate the growth-promoting and anti-apoptotic effects of S1P. METHODS IDH1mut glioma cell lines (TS603, BT142 & NCH1681) and empty vector-induced normal human astrocytes (NHAEV) were cultured and treated with a combination of SPHK1 inhibitor, N,N-dimethylsphingosine and C17-sphingosine to dysregulate sphingolipid rheostat. Biostatic response (i.e., IC50) was measured via spectrophotometric assay. Metabolic and signaling mechanisms were investigated by LC-MS lipidomic and RNA sequencing analysis. Mechanism of apoptosis was determined via western-blotting. RESULTS Following combination treatment, a global increase in ceramides, sphingosines, and their derivatives over S1P was detected in the sphingolipid rheostat. A decline in growth-promoting MAPK signaling enzymes and elevation of enzymes indicative of mitochondria-driven apoptosis occurred. Elevation of TNFα-related regulatory enzymes (NR1H3, MYLIP, INSIG, ABCA1) negatively impacted cholesterol homeostasis along with catalytic enzymes involved in cholesterol (and isoprenoid) biosynthesis. The effective concentration against IDH1mut spheroids was not cytotoxic to NHA spheroids. CONCLUSION The combination treatment potentiated a pro-apoptotic shift in sphingolipidome and revealed a novel mechanism of drug action involving concomitant global attenuation of cholesterol metabolism. While previous studies reported that decreasing cholesterol in gliomas compromises viability and induces apoptosis a link between cholesterol and sphingolipid metabolism remains unknown. Our data demonstrated that targeting sphingolipid rheostat triggers a cascade of pro-apoptotic signaling and metabolic activity that lower the threshold for apoptosis in IDHmut gliomas.
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Wu, Di, Mingjuan Gu, Zhuying Wei, Chunling Bai, Guanghua Su, Xuefei Liu, Yuefang Zhao, Lei Yang e Guangpeng Li. "Myostatin Knockout Regulates Bile Acid Metabolism by Promoting Bile Acid Synthesis in Cattle". Animals 12, n. 2 (15 gennaio 2022): 205. http://dx.doi.org/10.3390/ani12020205.
Abstract (sommario):
Myostatin (MSTN) is a major negative regulator of skeletal muscle mass and causes a variety of metabolic changes. However, the effect of MSTN knockout on bile acid metabolism has rarely been reported. In this study, the physiological and biochemical alterations of serum in MSTN+/− and wild type (WT) cattle were investigated. There were no significant changes in liver and kidney biochemical indexes. However, compared with the WT cattle, lactate dehydrogenase, total bile acid (TBA), cholesterol, and high-density lipoprotein (HDL) in the MSTN+/− cattle were significantly increased, and glucose, low-density lipoprotein (LDL), and triglycerides (TG) were significantly decreased, indicating that MSTN knockout affected glucose and lipid metabolism and total bile acids content. Targeted metabolomic analysis of the bile acids and their derivatives was performed on serum samples and found that bile acids were significantly increased in the MSTN+/− cattle compared with the WT cattle. As the only bile acid synthesis organ in the body, we performed metabolomic analysis on the liver to study the effect of MSTN knockout on hepatic metabolism. Metabolic pathway enrichment analysis of differential metabolites showed significant enrichment of the primary bile acid biosynthesis and bile secretion pathway in the MSTN+/− cattle. Targeted metabolomics data further showed that MSTN knockout significantly increased bile acid content in the liver, which may have resulted from enhanced bile acid synthesis due to the expression of bile acid synthesis genes, cholesterol 7 alpha-hydroxylase (CYP7A1) and sterol 27-hydroxylase (CYP27A1), and upregulation in the liver of the MSTN+/− cattle. These results indicate that MSTN knockout does not adversely affect bovine fitness but regulates bile acid metabolism via enhanced bile acid synthesis. This further suggests a role of MSTN in regulating metabolism.
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HALA, D., A. AMIN, A. MIKLER e D. B. HUGGETT. "A CONSTRAINT-BASED STOICHIOMETRIC MODEL OF THE STEROIDOGENIC NETWORK OF ZEBRAFISH (DANIO RERIO)". Journal of Biological Systems 18, n. 03 (settembre 2010): 669–85. http://dx.doi.org/10.1142/s0218339010003469.
Abstract (sommario):
The metabolic process of steroidogenesis exhibits a complex biochemical network topology as the activity of various steroidogenic enzymes control cholesterol metabolism to steroid hormone derivatives. In this paper, a stoichiometric reconstruction of a sub-set of 65 reactions from the zebrafish (Danio rerio) steroidogenic network is presented and simulated using uniform reaction constraints. The reconstruction defined a set of 65 enzyme catalyzed reactions and 37 exchange or transport reactions for steroid metabolites. The reconstructed reactions were inclusive of cholesterol and androgen/estrogen metabolism. Biased (statement of network objective function) and un-biased (no statement of objective function) analyses were applied to identify network properties dependent on reaction stoichiometry. Random sampling of flux distributions through the network identified highly-correlated reaction sets that corresponded to the catalysis of steroid metabolites of physiological relevance. Subsequently, optimal flux distributions through network pathways were determined for the production of the three steroidogenic metabolites of: 11-deoxycorticosterone, testosterone and 17β-estradiol. Furthermore, flux variability analyses revealed and confirmed optimal network fluxes through physiologically feasible pathways. The stoichiometric dependence of reactions was also confirmed by conducting deletions of reactions utilized for the optimal production of 17β-estradiol. This paper demonstrates the potential application of constraint-based reconstruction and simulation techniques in enabling the construction of deterministic and predictive physiological models. This acknowledgement is poignant considering the susceptibility of the steroidogenic network to environmental and anthropogenic stressors.
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Yntema, Tess, Debby P. Y. Koonen e Folkert Kuipers. "Emerging Roles of Gut Microbial Modulation of Bile Acid Composition in the Etiology of Cardiovascular Diseases". Nutrients 15, n. 8 (12 aprile 2023): 1850. http://dx.doi.org/10.3390/nu15081850.
Abstract (sommario):
Despite advances in preventive measures and treatment options, cardiovascular disease (CVD) remains the number one cause of death globally. Recent research has challenged the traditional risk factor profile and highlights the potential contribution of non-traditional factors in CVD, such as the gut microbiota and its metabolites. Disturbances in the gut microbiota have been repeatedly associated with CVD, including atherosclerosis and hypertension. Mechanistic studies support a causal role of microbiota-derived metabolites in disease development, such as short-chain fatty acids, trimethylamine-N-oxide, and bile acids, with the latter being elaborately discussed in this review. Bile acids represent a class of cholesterol derivatives that is essential for intestinal absorption of lipids and fat-soluble vitamins, plays an important role in cholesterol turnover and, as more recently discovered, acts as a group of signaling molecules that exerts hormonal functions throughout the body. Studies have shown mediating roles of bile acids in the control of lipid metabolism, immunity, and heart function. Consequently, a picture has emerged of bile acids acting as integrators and modulators of cardiometabolic pathways, highlighting their potential as therapeutic targets in CVD. In this review, we provide an overview of alterations in the gut microbiota and bile acid metabolism found in CVD patients, describe the molecular mechanisms through which bile acids may modulate CVD risk, and discuss potential bile-acid-based treatment strategies in relation to CVD.
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Rey, Mariana, María S. Kruse, Rocío N. Magrini-Huamán, Jessica Gómez, Mario J. Simirgiotis, Alejandro Tapia, Gabriela E. Feresin e Héctor Coirini. "Tessaria absinthioides (Hook. & Arn.) DC. (Asteraceae) Decoction Improves the Hypercholesterolemia and Alters the Expression of LXRs in Rat Liver and Hypothalamus". Metabolites 11, n. 9 (27 agosto 2021): 579. http://dx.doi.org/10.3390/metabo11090579.
Abstract (sommario):
Chronic high-fat diet consumption induces hypercholesterolemia. The effect of Tessaria absinthioides (Hook. & Arn.) DC. (Asteraceae) was studied on the levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), and triglycerides, and on the expression of liver X receptors (LXRs) in a hypercholesterolemic model. Adult male rats received a normal diet (ND) or a high-fat diet (HFD; normal diet + bovine fat + cholesterol). After 14 days, rats received water (W) or a decoction of the aerial parts of T. absinthioides (Ta; 10% w/v) for 2, 4, or 6 weeks. Four and six weeks of Ta improved the levels of TC and HDL-c in HFD. After 6 weeks of Ta, the expression of LXRs in HFD was the same as that in ND in both tissues. The Ta chemical profile was studied with an ultrahigh resolution liquid chromatography Orbitrap MS analysis (UHPLC–PDA–OT-MS/MS). Fifty-one compounds were identified, of which twelve are reported for the first time. Among these compounds, caffeoylquinic acid and its derivatives could modify the lipid profile and the expression of LXRs. This is the first in vivo report of T. absinthioides, which may be a potential candidate against hypercholesterolemia.
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Deshmukh, M. B., A. R. Mulik e Savita Dhongade-Desai. "Synthesis of Some New 2-Methyl -1,4-benzothiazine-3(1H)- one Derivatives as Potential Vasodilators". E-Journal of Chemistry 1, n. 4 (2004): 206–10. http://dx.doi.org/10.1155/2004/726204.
Abstract (sommario):
The increase in the internal diameter of a blood vessel that results from relaxation of smooth muscle within the wall of the vessel is vasodilation. This causes an increase in blood flow and a decrease in systemic vascular resistance. Some substances produced by tissue deprived of fresh blood seem to be responsible for the dilation. Many products of metabolism bring about the action, CO2and acids are among them. Dilation of vessels is necessary to restore local environment of tissues and normal metabolism. It may prove to be potential in the treatment of different cardiac disorders like atherosclerosis, where, the blood vessels are narrowed due to deposition of plaque of substances like cholesterol etc. 1,4-benzothiazines have been reported to possess wide range of pharmacological and biological activities. Here, we report the synthesis and biological activity of some new arylidenehydrazino-(1H)-1,4-benzothiazines. The synthesized compounds were subjected to a prediction of biological activities. A software application (PASS) was used for this purpose. The relationship between structure and different biological activities was studied and it was found that the arylidenehydrazino-(1H)-1,4-benzothiazines are expected to be potential vasodilators.
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York, Autumn, Joseph Argus, Anjie Zhen, Nicholas Wu, Ren Sun, Scott Kitchen e Steven Bensinger. "Reprogramming lipid metabolism primes host antiviral immunity (INM7P.431)". Journal of Immunology 192, n. 1_Supplement (1 maggio 2014): 123.9. http://dx.doi.org/10.4049/jimmunol.192.supp.123.9.
Abstract (sommario):
Abstract Oxysterols, or oxidized derivatives of cholesterol, have emerged as important regulators of adaptive and innate immunity. However, the molecular mechanisms by which these lipids facilitate host defense remain indeterminate. To better understand how cellular sterol metabolism influences innate immunity, we have generated gain- and loss-of-function macrophages that have key components of sterol homeostasis perturbed. Remarkably, we find that genetic manipulation of sterol biosynthetic capacity, and cellular sterol homeostasis, intrinsically alters its innate immune program. Genetic inhibition of the sterol biosynthetic pathway renders cells intrinsically resistant to pathogen challenge. Conversely, ectopically enforcing a sterol synthetic program renders cells more susceptible to viral infections. Mechanistic studies indicate that disruption of sterol synthesis in macrophages activates an array of host defense pathways, most notably a robust type 1 IFN response and upregulation of the anti-viral proteins MX-1 and MX-2. Current studies are focused on defining how inhibition of the sterol biosynthetic pathway engages anti-viral immunity and determining if this response is broadly applicable to other cell types. These studies provide proof -of-principle evidence that direct manipulation of sterol homeostatic state of a cell is intimately associated with host defense and suggests that metabolic manipulation converts a cell from a permissive to resistant viral immune state.
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Oliveira, ML, M. Abuzer, P. Wolf, K. Cares, P. Grippo, E. Mutlu, HR Gaskins, J. Ridion e L. Tussing-Humphreys. "Diet Quality and Fecal Bile Acid Composition". Cancer Epidemiology, Biomarkers & Prevention 32, n. 6 (1 giugno 2023): 860–61. http://dx.doi.org/10.1158/1055-9965.epi-23-0365.
Abstract (sommario):
Background: Bile acids (BAs) are steroid metabolites generated by the liver from cholesterol. Their function is to support digestion of dietary fat, cholesterol, and fat-soluble vitamins. The gut microbiota metabolizes BAs that escape intestinal reabsorption to secondary BAs and other metabolites that are linked to increased risk of diseases including colorectal cancer (CRC). Diet plays a major role in BA metabolism and may be an important target for optimizing host-microbial BA metabolism for cancer prevention. Purpose: To examine fecal BA metabolites in relation to diet quality (Healthy Eating Index-2015, HEI-2015) among urban middle to older age adults. Methods: 135 participants were recruited from two academic medical centers. Stool, two 24-hour diet recalls, anthropometrics, and survey data were collected. Fecal BA profiling was completed using LC/MS. Diet quality was calculated using USDA's HEI-2015. Descriptive and inferential statistics were conducted. Results: Participants were 57% female, 51% African/American Black, mean age of 59.6 (±6.2) years and mean BMI of 31.4 (±6.9) kg/m2. Using USDA's cut-point for poor diet quality (HEI-2015 < 51 points), participants with poor diet quality were significantly more likely to be classified with obesity, self-report as African American/Black, report lower educational attainment, have increased secondary BAs, deoxycholic acid (DCA) and lithocholic acid (LCA), and lower 3-oxo-lithocholic acid and iso-allo-deoxycholic acid derivatives. In linear models, HEI-2015 (continuous) was a significant inverse predictor of DCA and LCA when controlling for BMI, race, and education. BMI was a significant positive predictor of DCA and LCA when controlling for HEI-2015, race, education. African American/Black was a significant inverse predictor of 3-oxo-lithocholic acid and iso-allo-deoxycholic acid when controlling for HEI-2015, BMI, and education. Conclusion. Poor diet quality and elevated BMI is associated with increased secondary BAs that have been linked to increased risk of CRC. Improving diet quality and reducing BMI may optimize host-microbial BA metabolism to prevent disease. African American/Black was an independent predicator of lower anti-inflammatory BA derivatives which warrants further investigation.
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Santana, Lidiani Figueiredo, Sandramara Sasso, Diana Figueiredo Santana Aquino, Karine de Cássia Freitas, Rita de Cássia Avellaneda Guimarães, Arnildo Pott, Valter Aragão do Nascimento, Danielle Bogo, Patrícia de Oliveira Figueiredo e Priscila Aiko Hiane. "Nutraceutic Potential of Bioactive Compounds of Eugenia dysenterica DC in Metabolic Alterations". Molecules 27, n. 8 (12 aprile 2022): 2477. http://dx.doi.org/10.3390/molecules27082477.
Abstract (sommario):
The fruit and leaves of Eugenia dysenterica DC., locally known as cagaita, are rich in antioxidant glycosylated quercetin derivatives and phenolic compounds that have beneficial effects on diabetes mellitus, hypertension and general inflammation. We conducted a literature search to investigate the nutraceutical potentials of these phenolic compounds for treating obesity, diabetes mellitus and intestinal inflammatory disease. The phenolic compounds in E. dysenterica have demonstrated effects on carbohydrate metabolism, which can prevent the development of these chronic diseases and reduce LDL (low-density lipoprotein) cholesterol and hypertension. E. dysenterica also improves intestinal motility and microbiota and protects gastric mucosa, thereby preventing inflammation. However, studies are necessary to identify the mechanism by which E. dysenterica nutraceutical compounds act on such pathological processes to support future research.
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Campia, Ivana, Valentina Sala, Joanna Kopecka, Christian Leo, Nico Mitro, Costanzo Costamagna, Donatella Caruso et al. "Digoxin and ouabain induce the efflux of cholesterol via liver X receptor signalling and the synthesis of ATP in cardiomyocytes". Biochemical Journal 447, n. 2 (26 settembre 2012): 301–11. http://dx.doi.org/10.1042/bj20120200.
Abstract (sommario):
Cardioactive glycosides exert positive inotropic effects on cardiomyocytes through the inhibition of Na+/K+-ATPase. We showed previously that in human hepatoma cells, digoxin and ouabain increase the rate of the mevalonate cascade and therefore have Na+/K+-ATPase-independent effects. In the present study we found that they increase the expression and activity of 3-hydroxy-3 methylglutaryl-CoA reductase and the synthesis of cholesterol in cardiomyocytes, their main target cells. Surprisingly this did not promote intracellular cholesterol accumulation. The glycosides activated the liver X receptor transcription factor and increased the expression of ABCA1 (ATP-binding cassette protein A1) transporter, which mediates the efflux of cholesterol and its delivery to apolipoprotein A-I. By increasing the synthesis of ubiquinone, another derivative of the mevalonate cascade, digoxin and ouabain simultaneously enhanced the rate of electron transport in the mitochondrial respiratory chain and the synthesis of ATP. Mice treated with digoxin showed lower cholesterol and higher ubiquinone content in their hearts, and a small increase in their serum HDL (high-density lipoprotein) cholesterol. The results of the present study suggest that cardioactive glycosides may have a role in the reverse transport of cholesterol and in the energy metabolism of cardiomyocytes.
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Iglesias, J., e G. F. Gibbons. "Regulation of hepatic cholesterol biosynthesis. Effects of a cytochrome P-450 inhibitor on the formation and metabolism of oxygenated sterol products of lanosterol". Biochemical Journal 264, n. 2 (1 dicembre 1989): 495–502. http://dx.doi.org/10.1042/bj2640495.
Abstract (sommario):
The involvement of oxygenated cholesterol precursors in the regulation of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity was studied by examining the effect of ketoconazole on the metabolism of mevalonic acid, lanosterol and the lanosterol metabolites, lanost-8-ene-3 beta,32-diol,3 beta-hydroxylanost-8-en-32-al and 4,4-dimethylcholesta-8,14-dien-3 beta-ol, in liver subcellular fractions and hepatocyte cultures. Inhibition of cholesterol synthesis from mevalonate by ketoconazole at concentrations up to 30 microM was due exclusively to a suppression of cytochrome P-450LDM (LDM = lanosterol demethylase) activity, resulting in a decreased rate of lanosterol 14 alpha-demethylation. No enzyme after the 14 alpha-demethylase step was affected. When [14C]mevalonate was the cholesterol precursor, inhibition of cytochrome P450LDM was accompanied by the accumulation of several labelled oxygenated sterols, quantitatively the most important of which was the C-32 aldehyde derivative of lanosterol. There was no accumulation of the 24,25-oxide derivative of lanosterol, nor of the C-32 alcohol. Under these conditions the activity of HMG-CoA reductase declined. The C-32 aldehyde accumulated to a far greater extent when lanost-8-ene-3 beta,32-diol rather than mevalonate was used as the cholesterol precursor in the presence of ketoconazole. With both precursors, this accumulation was reversed at higher concentrations of ketoconazole in liver subcellular fractions. A similar reversal was not observed in hepatocyte cultures.
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Konno, Hiroyuki, Yoshiaki Kanai, Mikiyuki Katagiri, Tami Watanabe, Akemi Mori, Tomoki Ikuta, Hiroko Tani, Shinobu Fukushima, Tomoki Tatefuji e Takuji Shirasawa. "Melinjo (Gnetum gnemonL.) Seed Extract Decreases Serum Uric Acid Levels in Nonobese Japanese Males: A Randomized Controlled Study". Evidence-Based Complementary and Alternative Medicine 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/589169.
Abstract (sommario):
Melinjo (Gnetum gnemonL.) seed extract (MSE) containingtrans-resveratrol (3,5,4′-trihydroxy-trans-stilbene) and other derivatives exerts various beneficial effects. However, its mechanism of action in humans remains unknown. In this study, we aimed to investigate beneficial effects of MSE in healthy adult males. In this double-blind, randomized controlled study, 30 males aged 35–70 years with ≤10% flow-mediated dilatation received placebo or 750 mg MSE powder for 8 weeks, and twenty-nine males (45.1±8.8years old) completed the trial. There was a significant difference in the melinjo and placebo groups. Compared with the placebo control, MSE significantly reduced serum uric acid at 4 weeks and 8 weeks (n=14and 15, resp.). HDL cholesterol was significantly increased in the melinjo group. To clarify the mechanism of MSE for reducing uric acid, we investigated xanthine oxidase inhibitory activity, angiotensin II type 1 (AT1) receptor binding inhibition rate, and agonistic activities for PPARαand PPARγ. MSE,trans-resveratrol, and a resveratrol dimer, gnetin C (GC), significantly inhibit AT1 receptor binding and exhibit mild agonistic activities for PPARαand PPARγ. In conclusion, MSE may decrease serum uric acid regardless of insulin resistance and may improve lipid metabolism by increasing HDL cholesterol.
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Fan, Guanghe, Xiaofei Wang, Cuicui Gao, Xiping Kang, Huimin Xue, Weidong Huang, Jicheng Zhan e Yilin You. "Effects of Active Ingredients in Alcoholic Beverages and Their De-Alcoholized Counterparts on High-Fat Diet Bees: A Comparative Study". Molecules 29, n. 8 (9 aprile 2024): 1693. http://dx.doi.org/10.3390/molecules29081693.
Abstract (sommario):
The mechanisms by which alcohol, alcoholic beverages, and their de-alcoholized derivatives affect animal physiology, metabolism, and gut microbiota have not yet been clarified. The polyphenol, monosaccharide, amino acid, and organic acid contents of four common alcoholic beverages (Chinese Baijiu, beer, Chinese Huangjiu, and wine) and their de-alcoholized counterparts were analyzed. The research further explored how these alcoholic beverages and their non-alcoholic versions affect obesity and gut microbiota, using a high-fat diet bee model created with 2% palm oil (PO). The results showed that wine, possessing the highest polyphenol content, and its de-alcoholized form, particularly when diluted five-fold (WDX5), markedly improved the health markers of PO-fed bees, including weight, triglycerides, and total cholesterol levels in blood lymphocytes. WDX5 treatment notably increased the presence of beneficial microbes such as Bartonella, Gilliamella, and Bifidobacterium, while decreasing Bombilactobacillus abundance. Moreover, WDX5 was found to closely resemble sucrose water (SUC) in terms of gut microbial function, significantly boosting short-chain fatty acids, lipopolysaccharide metabolism, and associated enzymatic pathways, thereby favorably affecting metabolic regulation and gut microbiota stability in bees.