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Advances in Clinical and Experimental... Oct 2021Atherosclerosis (AS), a chronic inflammatory disease, is a major contributor to deaths worldwide. Ganoderic acid A (GAA) has been widely applied for various diseases due...
BACKGROUND
Atherosclerosis (AS), a chronic inflammatory disease, is a major contributor to deaths worldwide. Ganoderic acid A (GAA) has been widely applied for various diseases due to its excellent anti-inflammatory properties.
OBJECTIVES
To investigate the underlying mechanism of GAA inhibition of inflammation and lipid deposition in human monocyte (THP-1) cells.
MATERIAL AND METHODS
The Cell Counting Kit-8 (CCK-8) assay was used to assess the potential effect of GAA on the viability of THP-1 cells. The release of inflammatory cytokines and oxidative stress was measured using enzyme-linked immunosorbent assay (ELISA) and the corresponding kit, respectively. The levels of lipid deposition and total cholesterol (TC) were also evaluated. Next, the scavenger receptors and proteins in Notch1/PPARă/CD36 signaling were measured with western blot. As Notch1 was overexpressed in the THP-1 cells induced by oxidized low-density lipoprotein (ox-LDL), the above assays were performed again to confirm the underlying mechanism.
RESULTS
Ganoderic acid A suppressed ox-LDL-induced inflammation and oxidative stress in THP-1 cells. At the same time, it inhibited the TC level and lipid deposition. The effects of GAA on alleviating inflammation, oxidative stress and lipid accumulation were relieved after the overexpression of Notch1 in the treated cells, and the effects of GAA on alleviating inflammation, oxidative stress and lipid accumulation were diminished. The PPARă activator also weakened the effects of GAA on relieving inflammation, oxidative stress and lipid accumulation in ox-LDL-induced THP-1 cells.
CONCLUSIONS
Ganoderic acid A inhibits ox-LDL-induced macrophage inflammation and lipid deposition in THP-1 cells through Notch1/PPARă/CD36 signaling, which may provide theoretical guidance for the clinical applications of GAA in AS treatment.
Topics: CD36 Antigens; Heptanoic Acids; Humans; Inflammation; Lanosterol; Lipoproteins, LDL; Macrophages; PPAR gamma; Receptor, Notch1; Signal Transduction; THP-1 Cells
PubMed: 34329545
DOI: 10.17219/acem/137914 -
Annals of Translational Medicine Nov 2020Cataracts, the leading cause of vision impairment worldwide, arise from abnormal aggregation of lens proteins. According to the World Health Organization, cataracts... (Review)
Review
Cataracts, the leading cause of vision impairment worldwide, arise from abnormal aggregation of lens proteins. According to the World Health Organization, cataracts cause more than 40% of blindness cases. As the population ages, the prevalence of cataracts will increase rapidly. Although cataract surgery is regarded as effective, it still suffers from complications and high cost, and could not meet the increasingly surgery demand. Therefore, pharmacological treatment for cataracts is a cheaper and more readily available option for patients, which is also a hot topic for years. Anti-cataract drug screening was previously mainly based on the specific pathogenic factors: oxidative stress, excess of quinoid substances, and aldose reductase (AR) activation. And several anti-cataract drugs have been applied in the clinic, while the effect is still unsatisfied. Makley and Zhao recently identified two kinds of novel pharmacological substances (25-hydroxycholesterol, lanosterol) that can reverse lens opacity by dissolving the aggregation of crystallin proteins, indicating that protein aggregation is not an endpoint and could be reversed with specific small-molecule drugs, significantly boosting the development of the cataract pharmacopeia and being regarded as a new dawn for cataract treatment. Our team built a novel optimized platform and had screened several potential therapeutic agents from a collection of lanosterol derivatives. In this review, we would mainly focus on the advancement of cataract pharmacotherapy based on the targets for anti-cataract drugs.
PubMed: 33313297
DOI: 10.21037/atm-20-1960 -
Biomolecules Mar 2024Cholesterol is an essential molecule of life, and its synthesis can be inhibited by both genetic and nongenetic mechanisms. Hundreds of chemicals that we are exposed to... (Review)
Review
Cholesterol is an essential molecule of life, and its synthesis can be inhibited by both genetic and nongenetic mechanisms. Hundreds of chemicals that we are exposed to in our daily lives can alter sterol biosynthesis. These also encompass various classes of FDA-approved medications, including (but not limited to) commonly used antipsychotic, antidepressant, antifungal, and cardiovascular medications. These medications can interfere with various enzymes of the post-lanosterol biosynthetic pathway, giving rise to complex biochemical changes throughout the body. The consequences of these short- and long-term homeostatic disruptions are mostly unknown. We performed a comprehensive review of the literature and built a catalogue of chemical agents capable of inhibiting post-lanosterol biosynthesis. This process identified significant gaps in existing knowledge, which fall into two main areas: mechanisms by which sterol biosynthesis is altered and consequences that arise from the inhibitions of the different steps in the sterol biosynthesis pathway. The outcome of our review also reinforced that sterol inhibition is an often-overlooked mechanism that can result in adverse consequences and that there is a need to develop new safety guidelines for the use of (novel and already approved) medications with sterol biosynthesis inhibiting side effects, especially during pregnancy.
Topics: Humans; Sterols; Animals; Cholesterol; Biosynthetic Pathways; Lanosterol
PubMed: 38672427
DOI: 10.3390/biom14040410 -
Cell Chemical Biology Feb 2023Glioblastoma (GBM) is an aggressive adult brain cancer with few treatment options due in part to the challenges of identifying brain-penetrant drugs. Here, we...
Glioblastoma (GBM) is an aggressive adult brain cancer with few treatment options due in part to the challenges of identifying brain-penetrant drugs. Here, we investigated the mechanism of MM0299, a tetracyclic dicarboximide with anti-glioblastoma activity. MM0299 inhibits lanosterol synthase (LSS) and diverts sterol flux away from cholesterol into a "shunt" pathway that culminates in 24(S),25-epoxycholesterol (EPC). EPC synthesis following MM0299 treatment is both necessary and sufficient to block the growth of mouse and human glioma stem-like cells by depleting cellular cholesterol. MM0299 exhibits superior selectivity for LSS over other sterol biosynthetic enzymes. Critical for its application in the brain, we report an MM0299 derivative that is orally bioavailable, brain-penetrant, and induces the production of EPC in orthotopic GBM tumors but not normal mouse brain. These studies have implications for the development of an LSS inhibitor to treat GBM or other neurologic indications.
Topics: Adult; Humans; Lanosterol; Brain; Glioma; Cholesterol; Glioblastoma
PubMed: 36758549
DOI: 10.1016/j.chembiol.2023.01.005 -
Biochemical Pharmacology Feb 2022Cholesterol biosynthesis, primarily associated with eukaryotes, occurs as an essential component of human metabolism with biosynthetic deregulation a factor in cancer... (Review)
Review
Cholesterol biosynthesis, primarily associated with eukaryotes, occurs as an essential component of human metabolism with biosynthetic deregulation a factor in cancer viability. The segment that partitions between squalene and the C-end cholesterol yields the main cholesterogenesis branch subdivided into the Bloch and Kandutsch-Russell pathways. Their importance in cell viability, in normal growth and development originates primarily from the amphipathic property and shape of the cholesterol molecule which makes it suitable as a membrane insert. Cholesterol can also convert to variant oxygenated product metabolites of distinct function producing a complex interplay between cholesterol synthesis and overall steroidogenesis. In this review, we disassociate the two sides of cholesterogenesisis affecting the type and amounts of systemic sterols-one which is beneficial to human welfare while the other dysfunctional leading to misery and disease that could result in premature death. Our focus here is first to examine the cholesterol biosynthetic genes, enzymes, and order of biosynthetic intermediates in human cholesterogenesis pathways, then compare the effect of proximal and distal inhibitors of cholesterol biosynthesis against normal and cancer cell growth and metabolism. Collectively, the inhibitor studies of druggable enzymes and specific biosynthetic steps, suggest a potential role of disrupted cholesterol biosynthesis, in coordination with imported cholesterol, as a factor in cancer development and as discussed some of these inhibitors have chemotherapeutic implications.
Topics: Animals; Anticholesteremic Agents; Antineoplastic Agents; Benzylamines; Cholesterol; Humans; Lanosterol; Neoplasms; Terbinafine; Thiophenes
PubMed: 34010597
DOI: 10.1016/j.bcp.2021.114611 -
Infection and Drug Resistance 2015Efinaconazole 10% topical solution is a new triazole recently approved for the treatment of onychomycosis. It inhibits fungal lanosterol 14α-demethylase in the... (Review)
Review
Efinaconazole 10% topical solution is a new triazole recently approved for the treatment of onychomycosis. It inhibits fungal lanosterol 14α-demethylase in the ergosterol biosynthesis pathway, has potent antifungal activity against dermatophytes, as well as activity against Candida spp. and non-dermatophyte molds, and showed promising results in clinical trials. This review summarizes the mechanism of action, in vitro and in vivo data, clinical trials, safety, and quality-of-life data of efinaconazole as it applies to the treatment of onychomycosis.
PubMed: 26082652
DOI: 10.2147/IDR.S69596 -
Frontiers in Genetics 2024Cataract is one of the most prevalent causes of blindness worldwide. Whilst surgery is the primary treatment for cataracts, it is not always an available option,...
Cataract is one of the most prevalent causes of blindness worldwide. Whilst surgery is the primary treatment for cataracts, it is not always an available option, particularly in developing countries. Non-surgical methods of treatment would increase treatment availability for more patients. Several studies have investigated how topical application of oxysterols, such as lanosterol, may break down aggregated proteins and restore lens transparency. However, the results are conflicting and inconclusive. In this study, we focus on combining genetic evidence for associations between lanosterol related genetic variation and cataract to explore whether lanosterol is a potentially suitable drug treatment option. Using data from 45,449 available cataract cases from the UK Biobank, with participant ages ranging from 40-69, we conducted a genetic association study (GWAS) to assess the risk of cataract. Cataract cases were defined using diagnostic and operation codes. We focused on genetic variants in the lanosterol synthase gene region. We also compared our results with previously published genetic associations of phytosterol-to-lanosterol ratios. Finally, we performed a genetic risk score analysis to test the association between lanosterol within the cholesterol synthesis pathway and the risk of cataract. No statistically significant single nucleotide polymorphisms (SNPs) associations with cataract were observed in the gene region of lanosterol synthase at a multiple testing adjusted significance threshold of < 0.05/13. The comparison between cataract risk and genetic association of 8 phytosterol-to-lanosterol GWAS results also showed no evidence to support lanosterol's protective properties for cataract risk. No statistically significant association was found between the lanosterol within the cholesterol synthesis pathway genetic risk score and cataract outcomes (OR = 1.002 = 0.568). There was no evidence observed for genetic associations between lanosterol and cataract risk. Our results do not support lanosterol's potential role in treating cataracts. Further research may be needed to address the effect of lanosterol on specific cataract subtypes.
PubMed: 38440190
DOI: 10.3389/fgene.2024.1231521 -
Molecules (Basel, Switzerland) Apr 2013Cholesterol synthesis is a ubiquitous and housekeeping metabolic pathway that leads to cholesterol, an essential structural component of mammalian cell membranes,... (Review)
Review
Cholesterol synthesis is a ubiquitous and housekeeping metabolic pathway that leads to cholesterol, an essential structural component of mammalian cell membranes, required for proper membrane permeability and fluidity. The last part of the pathway involves steroidal triterpenes with cholestane ring structures. It starts by conversion of acyclic squalene into lanosterol, the first sterol intermediate of the pathway, followed by production of 20 structurally very similar steroidal triterpene molecules in over 11 complex enzyme reactions. Due to the structural similarities of sterol intermediates and the broad substrate specificity of the enzymes involved (especially sterol-Δ24-reductase; DHCR24) the exact sequence of the reactions between lanosterol and cholesterol remains undefined. This article reviews all hitherto known structures of post-squalene steroidal triterpenes of cholesterol synthesis, their biological roles and the enzymes responsible for their synthesis. Furthermore, it summarises kinetic parameters of enzymes (Vmax and Km) and sterol intermediate concentrations from various tissues. Due to the complexity of the post-squalene cholesterol synthesis pathway, future studies will require a comprehensive meta-analysis of the pathway to elucidate the exact reaction sequence in different tissues, physiological or disease conditions. A major reason for the standstill of detailed late cholesterol synthesis research was the lack of several steroidal triterpene standards. We aid to this efforts by summarizing commercial and laboratory standards, referring also to chemical syntheses of meiosis-activating sterols.
Topics: Animals; Cholesterol; Lanosterol; Metabolomics; Models, Animal; Squalene; Steroids; Sterols; Triterpenes
PubMed: 23558541
DOI: 10.3390/molecules18044002 -
Investigative Ophthalmology & Visual... Dec 2023Epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs) is a predominant pathological process underlying fibrotic cataracts. Here we investigated the...
PURPOSE
Epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs) is a predominant pathological process underlying fibrotic cataracts. Here we investigated the role and mechanism of lanosterol synthase (LSS), a key rate-limiting enzyme in sterol biosynthesis, in EMT of LECs.
METHODS
Human lens epithelial explants, primary rabbit LECs, and whole rat lenses were treated with TGFβ2. RNA-sequencing was conducted to explore genetic changes during fibrosis of human lens epithelial explants. Loss- and gain-of-function studies were performed in primary LECs to investigate roles and mechanisms of LSS, lanosterol and sterol regulatory element binding transcription protein 1 (SREBP1) in EMT. Rat lenses were applied to evaluate the potential effect of lanosterol on lens fibrosis. Expression of LSS, SREBP1, EMT-related regulators, and markers were analyzed by Western blot, qRT-PCR, or immunofluorescent staining.
RESULTS
LSS and steroid biosynthesis were downregulated in TGFβ2-induced lens fibrosis. LSS inhibition directly triggered EMT by inducing Smad2/3 phosphorylation and nucleus translocation, an overexpression of LSS protected LECs from EMT by inhibiting Smad2/3 activation. Moreover, LSS inhibition decreased the expression of SREBP1, which regulated EMT via intervening TGFβ2/Smad2/3 transduction. Furthermore, lanosterol protected LECs from EMT caused by both TGFβ2 treatment and LSS inhibition via suppressing Smad2/3 activation and maintained lens transparency by preventing fibrotic plaques formation.
CONCLUSIONS
We first identified that LSS protected LECs from EMT and played an antifibrotic role to maintain lens transparency. Additionally, lanosterol and sterol biosynthesis regulation might be promising strategies for preventing and treating fibrotic cataracts.
Topics: Animals; Humans; Rabbits; Rats; Cataract; Epithelial Cells; Epithelial-Mesenchymal Transition; Fibrosis; Lanosterol; Lens, Crystalline; Transforming Growth Factor beta2
PubMed: 38079167
DOI: 10.1167/iovs.64.15.12 -
European Journal of Clinical... May 2021The antifungal drugs ketoconazole and itraconazole reduce serum concentrations of 4β-hydroxycholesterol, which is a validated marker for hepatic cytochrome P450 (CYP)... (Clinical Trial)
Clinical Trial
PURPOSE
The antifungal drugs ketoconazole and itraconazole reduce serum concentrations of 4β-hydroxycholesterol, which is a validated marker for hepatic cytochrome P450 (CYP) 3A4 activity. We tested the effect of another antifungal triazole agent, fluconazole, on serum concentrations of different sterols and oxysterols within the cholesterol metabolism to see if this inhibitory reaction is a general side effect of azole antifungal agents.
METHODS
In a prospective, double-blind, placebo-controlled, two-way crossover design, we studied 17 healthy subjects (nine men, eight women) who received 400 mg fluconazole or placebo daily for 8 days. On day 1 before treatment and on day 8 after the last dose, fasting blood samples were collected. Serum cholesterol precursors and oxysterols were measured by gas chromatography-mass spectrometry-selected ion monitoring and expressed as the ratio to cholesterol (R_sterol).
RESULTS
Under fluconazole treatment, serum R_lanosterol and R_24,25-dihydrolanosterol increased significantly without affecting serum cholesterol or metabolic downstream markers of hepatic cholesterol synthesis. Serum R_4β-, R_24S-, and R_27-hydroxycholesterol increased significantly.
CONCLUSION
Fluconazole inhibits the 14α-demethylation of lanosterol and 24,25-dihydrolanosterol, regulated by CYP51A1, without reduction of total cholesterol synthesis. The increased serum level of R_4β-hydroxycholesterol under fluconazole treatment is in contrast to the reductions observed under ketoconazole and itraconazole treatments. The question, whether this increase is caused by induction of CYP3A4 or by inhibition of the catabolism of 4β-hydroxycholesterol, must be answered by mechanistic in vitro and in vivo studies comparing effects of various azole antifungal agents on hepatic CYP3A4 activity.
Topics: Adult; Age Factors; Antifungal Agents; Bile Acids and Salts; Cross-Over Studies; Cytochrome P-450 CYP3A; Double-Blind Method; Female; Fluconazole; Humans; Hydroxycholesterols; Lanosterol; Lipid Metabolism; Male; Prospective Studies; Sex Factors; Sterols; Young Adult
PubMed: 33201347
DOI: 10.1007/s00228-020-03041-5