scholarly journals Effect of 26-Oxygenosterols from Ganoderma lucidum and Their Activity as Cholesterol Synthesis Inhibitors

2005 ◽  
Vol 71 (7) ◽  
pp. 3653-3658 ◽  
Author(s):  
Hassan Hajjaj ◽  
Catherine Macé ◽  
Matthew Roberts ◽  
Peter Niederberger ◽  
Laurent B. Fay
Keyword(s):  
Ganoderma Lucidum ◽  
Cholesterol Synthesis ◽  
Biological Effects ◽  
Cholesterol Biosynthesis ◽  
Blood Cholesterol ◽  
Ganoderic Acid ◽  
Isolation And Identification ◽  
Medicinal Fungus ◽  
Lower Blood Cholesterol

ABSTRACT Ganoderma lucidum is a medicinal fungus belonging to the Polyporaceae family which has long been known in Japan as Reishi and has been used extensively in traditional Chinese medicine. We report the isolation and identification of the 26-oxygenosterols ganoderol A, ganoderol B, ganoderal A, and ganoderic acid Y and their biological effects on cholesterol synthesis in a human hepatic cell line in vitro. We also investigated the site of inhibition in the cholesterol synthesis pathway. We found that these oxygenated sterols from G. lucidum inhibited cholesterol biosynthesis via conversion of acetate or mevalonate as a precursor of cholesterol. By incorporation of 24,25-dihydro-[24,25-3H2]lanosterol and [3-3H]lathosterol in the presence of ganoderol A, we determined that the point of inhibition of cholesterol synthesis is between lanosterol and lathosterol. These results demonstrate that the lanosterol 14α-demethylase, which converts 24,25-dihydrolanosterol to cholesterol, can be inhibited by the 26-oxygenosterols from G. lucidum. These 26-oxygenosterols could lead to novel therapeutic agents that lower blood cholesterol.

scholarly journals Discovery of Ganoderma lucidum triterpenoids as potential inhibitors against Dengue virus NS2B-NS3 protease

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Shiv Bharadwaj ◽  
Kyung Eun Lee ◽  
Vivek Dhar Dwivedi ◽  
Umesh Yadava ◽  
Aleksha Panwar ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Ganoderma Lucidum ◽  
Denv Infection ◽  
Ganoderic Acid ◽  
Medicinal Fungus ◽  
Infection Inhibition ◽  
Dynamics Simulations ◽  
Potential Inhibitors ◽  
Ns3 Protease

AbstractDengue virus (DENV) infection causes serious health problems in humans for which no drug is currently available. Recently, DENV NS2B-NS3 protease has been proposed as a primary target for anti-dengue drug discovery due to its important role in new virus particle formation by conducting DENV polyprotein cleavage. Triterpenoids from the medicinal fungus Ganoderma lucidum have been suggested as pharmacologically bioactive compounds and tested as anti-viral agents against various viral pathogens including human immunodeficiency virus. However, no reports are available concerning the anti-viral activity of triterpenoids from Ganoderma lucidum against DENV. Therefore, we employed a virtual screening approach to predict the functional triterpenoids from Ganoderma lucidum as potential inhibitors of DENV NS2B-NS3 protease, followed by an in vitro assay. From in silico analysis of twenty-two triterpenoids of Ganoderma lucidum, four triterpenoids, viz. Ganodermanontriol (−6.291 kcal/mol), Lucidumol A (−5.993 kcal/mol), Ganoderic acid C2 (−5.948 kcal/mol) and Ganosporeric acid A (−5.983 kcal/mol) were predicted to be viral protease inhibitors by comparison to reference inhibitor 1,8-Dihydroxy-4,5-dinitroanthraquinone (−5.377 kcal/mol). These results were further studied for binding affinity and stability using the molecular mechanics/generalized Born surface area method and Molecular Dynamics simulations, respectively. Also, in vitro viral infection inhibition suggested that Ganodermanontriol is a potent bioactive triterpenoid.

IN VIVO INHIBITION OF CHOLESTEROL BIOSYNTHESIS BY A MITOCHONDRIAL EXTRACT

1961 ◽  
Vol 39 (4) ◽  
pp. 747-755 ◽  
Author(s):  
B. B. Migicovsky
Keyword(s):  
Cholesterol Synthesis ◽  
Cholesterol Biosynthesis ◽  
Liver Mitochondria ◽  
Blood Cholesterol ◽  
Active Principle ◽  
Aqueous Extracts ◽  
Inhibitory Substance ◽  
Cholesterol Levels ◽  
Mitochondrial Extract

Aqueous extracts of liver mitochondria were administered to rats by intraperitoneal, subcutaneous, and oral routes, and C14-acetate or mevalonate was injected intraperitoneally 3 hours later. Cholesterol synthesis in vivo from C14-acetate was depressed by the inhibitory substance in the mitochondrial extracts. Synthesis from C14-mevalonate was not inhibited.Active extracts were prepared from livers of rat, rabbit, pig, and sheep. An inhibitory substance is present in blood serum and administration of active mitochondrial extracts depressed blood cholesterol levels. Pending its identification, the active principle has been provisionally termed I.C.S. (inhibitor of cholesterol synthesis).

Functions of reactive oxygen species in apoptosis and ganoderic acid biosynthesis in Ganoderma lucidum

2019 ◽  
Vol 366 (23) ◽  
Author(s):  
Jing Zhu ◽  
Fengli Wu ◽  
Sining Yue ◽  
Chen Chen ◽  
Shuqi Song ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Ganoderma Lucidum ◽  
Reactive Oxygen ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Activity Levels ◽  
Oxygen Species ◽  
Ganoderic Acid ◽  
Medicinal Fungus ◽  
Intracellular Ros ◽  
Ga Biosynthesis

ABSTRACT Ganoderma lucidum is a medicinal fungus that is widely used in traditional medicine. Fungal PacC is recognized as an important transcription factor that functions during adaptation to environmental pH, fungal development and secondary metabolism. Previous studies have revealed that GlPacC plays important roles in mycelial growth, fruiting body development and ganoderic acid (GA) biosynthesis. In this study, using a terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) assay, we found that the apoptosis level was increased when PacC was silenced. The transcript and activity levels of caspase-like proteins were significantly increased in the PacC-silenced (PacCi) strains compared with the control strains. Silencing PacC also resulted in an increased reactive oxygen species (ROS) levels (∼2-fold) and decreased activity levels of enzymes involved in the antioxidant system. Further, we found that the intracellular ROS levels contributed to apoptosis and GA biosynthesis. Adding N-acetyl-cysteine and vitamin C decreased intracellular ROS and resulted in the inhibition of apoptosis in the PacCi strains. Additionally, the GA biosynthesis was different between the control strains and the PacCi strains after intracellular ROS was eliminated. Taken together, the findings showed that silencing PacC can result in an intracellular ROS burst, which increases cell apoptosis and GA biosynthesis levels. Our study provides novel insight into the functions of PacC in filamentous fungi.

EFFECT OF STARVATION ON CHOLESTEROL BIOSYNTHESIS IN VITRO

1955 ◽  
Vol 33 (1) ◽  
pp. 858-866 ◽  
Author(s):  
B. B. Migicovsky ◽  
J. D. Wood
Keyword(s):  
Particulate Matter ◽  
Cholesterol Synthesis ◽  
Cholesterol Biosynthesis ◽  
Liver Homogenate ◽  
Normal Liver ◽  
Synthetic Activity ◽  
Liver Homogenates

The components of centrifugal fractionation of liver homogenates from normal and starved rats were examined for cholesterol synthesis and inhibition thereof. Normal liver particulate matter fractions obtained between 700 to 9000 × g and 9000 to 140,000 × g were active with respect to cholesterol synthesis in the presence of clear supernate obtained by centrifugation at 140,000 × g. The particles alone did not synthesize cholesterol. Particles from liver homogenate of starved rats, recombined with clear supernate from starved rats, lacked synthetic activity but clear supernate from liver homogenate of starved rats showed some activity in the presence of normal particles. Degradation of cholesterol occurred with liver particles (700–9000 × g) from both normal and starved rats: the latter preparation also inhibited cholesterol synthesis. Preliminary incubation of clear supernate from normal rats with particles from starved rats, followed by recentrifugation at 140,000 × g, produced a supernate with synthetic activity equal to that obtained with untreated supernate. Preliminary incubation with normal particles gave a supernate with less synthetic activity. This indicated another difference between particulate matter from normal and starved rats.

scholarly journals The anti-tubercular activity of simvastatin is mediated by cholesterol-driven autophagy via the AMPK-mTORC1-TFEB axis

2020 ◽  
Vol 61 (12) ◽  
pp. 1617-1628
Author(s):  
Natalie Bruiners ◽  
Noton K. Dutta ◽  
Valentina Guerrini ◽  
Hugh Salamon ◽  
Ken D. Yamaguchi ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Mevalonate Pathway ◽  
Biological Effects ◽  
Cholesterol Biosynthesis ◽  
Cholesterol Homeostasis ◽  
Infection Model ◽  
Protein Prenylation ◽  
Macrophage Infection

The rise of drug-resistant tuberculosis poses a major risk to public health. Statins, which inhibit both cholesterol biosynthesis and protein prenylation branches of the mevalonate pathway, increase anti-tubercular antibiotic efficacy in animal models. However, the underlying molecular mechanisms are unknown. In this study, we used an in vitro macrophage infection model to investigate simvastatin’s anti-tubercular activity by systematically inhibiting each branch of the mevalonate pathway and evaluating the effects of the branch-specific inhibitors on mycobacterial growth. The anti-tubercular activity of simvastatin used at clinically relevant doses specifically targeted the cholesterol biosynthetic branch rather than the prenylation branches of the mevalonate pathway. Using Western blot analysis and AMP/ATP measurements, we found that simvastatin treatment blocked activation of mechanistic target of rapamycin complex 1 (mTORC1), activated AMP-activated protein kinase (AMPK) through increased intracellular AMP:ATP ratios, and favored nuclear translocation of transcription factor EB (TFEB). These mechanisms all induce autophagy, which is anti-mycobacterial. The biological effects of simvastatin on the AMPK-mTORC1-TFEB-autophagy axis were reversed by adding exogenous cholesterol to the cells. Our data demonstrate that the anti-tubercular activity of simvastatin requires inhibiting cholesterol biosynthesis, reveal novel links between cholesterol homeostasis, the AMPK-mTORC1-TFEB axis, and Mycobacterium tuberculosis infection control, and uncover new anti-tubercular therapy targets.

INHIBITION OF CHOLESTEROL BIOSYNTHESIS BY A MITOCHONDRIAL EXTRACT

1960 ◽  
Vol 38 (4) ◽  
pp. 339-346 ◽  
Author(s):  
B. B. Migicovsky
Keyword(s):  
Cholesterol Synthesis ◽  
Cholesterol Biosynthesis ◽  
Inhibitory Effect ◽  
Homeostatic Mechanism ◽  
Heat Labile ◽  
Mitochondrial Extract

Cholesterol biosynthesis was effectively inhibited by an extract of mitochondria disrupted with sonic oscillations. The inhibitory effect occurred both in vivo and in vitro. The inhibitor substance was heat-labile, and could be prepared from mitochondria from livers of normal or starved rats. The inhibition appeared to be of the competitive type. The locus of the inhibition in the chain of reactions from acetate to cholesterol appeared to be between acetoacetate and mevalonate. It is suggested that the inhibitor substance present in the mitochondrion represents, in part, the homeostatic mechanism that controls cholesterol synthesis by the liver.

Production of a new triterpenoid disaccharide saponin from sequential glycosylation of ganoderic acid A by 2 Bacillus glycosyltransferases

2021 ◽  
Vol 85 (3) ◽  
pp. 687-690
Author(s):  
Te-Sheng Chang ◽  
Chien-Min Chiang ◽  
Jiumn-Yih Wu ◽  
Yu-Li Tsai ◽  
Huei-Ju Ting
Keyword(s):  
Ganoderma Lucidum ◽  
Aqueous Solubility ◽  
Ganoderic Acid ◽  
Medicinal Fungus

ABSTRACT Ganoderic acid A (GAA) is a lanostane-type triterpenoid, isolated from medicinal fungus Ganoderma lucidum, and possesses multiple bioactivities. In the present study, GAA was sequentially biotransformed by 2 recently discovered Bacillus glycosyltransferases (GT), BtGT_16345 and BsGT110, and the final product was purified and identified as a new compound, GAA-15,26-O-β-diglucoside, which showed 1024-fold aqueous solubility than GAA.

scholarly journals Oncogenic role of SOX9-DHCR24-cholesterol biosynthesis axis in IGH-BCL2 positive diffuse large B-cell lymphomas

Blood ◽  
2021 ◽  
Author(s):  
Yajie Shen ◽  
Jingqi Zhou ◽  
Kui Nie ◽  
Shuhua Cheng ◽  
Zhengming Chen ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Line ◽  
Cholesterol Synthesis ◽  
Cholesterol Biosynthesis ◽  
Cholesterol Content ◽  
B Cell Lymphomas ◽  
Tumor Load ◽  
Large B Cell

Although oncogenicity of the stem cell regulator SOX9 has been implicated in many solid tumors, its role in lymphomagenesis remains largely unknown. In this study, we showed that SOX9 is overexpressed preferentially in a subset of diffuse large B-cell lymphomas (DLBCL) harboring IGH-BCL2 translocations. SOX9 positivity in DLBCL correlates with advanced stage of disease. Silencing of SOX9 decreased cell proliferation, induced G1/S arrest and increased apoptosis of DLBCL cells, both in vitro and in vivo. Whole transcriptome analysis and CHIP-seq assays identified DHCR24, a terminal enzyme in cholesterol biosynthesis, as a direct target of SOX9, which promotes cholesterol synthesis by increasing DHCR24 expression. Enforced expression of DHCR24 was capable of rescuing the phenotypes associated with SOX9 knockdown in DLBCL cells. In DLBCL cell line xenograft models, SOX9 knockdown resulted in lower DHCR24 level, reduced cholesterol content and decreased tumor load. Pharmacological inhibition of cholesterol synthesis also inhibited DLBCL xenograft tumorigenesis, the reduction of which is more pronounced in DLBCL cell line with higher SOX9 expression, suggesting that it may be addicted to cholesterol. In summary, our study demonstrates that SOX9 can drive lymphomagenesis through DHCR24 and the cholesterol biosynthesis pathway. This SOX9-DHCR24-cholesterol biosynthesis axis may serve as a novel treatment target for DLBCL.

scholarly journals Unripe Rubus coreanus Miquel Extract Containing Ellagic Acid Regulates AMPK, SREBP-2, HMGCR, and INSIG-1 Signaling and Cholesterol Metabolism In Vitro and In Vivo

Nutrients ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 610 ◽  
Author(s):  
Ki Hoon Lee ◽  
Eui-Seon Jeong ◽  
Goeun Jang ◽  
Ju-Ryun Na ◽  
Soyi Park ◽  
...  
Keyword(s):  
Ellagic Acid ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Cholesterol Metabolism ◽  
Plasma Cholesterol ◽  
Cholesterol Biosynthesis ◽  
Blood Cholesterol ◽  
High Cholesterol Diet ◽  
Rubus Coreanus

Our previous study demonstrated that a 5% ethanol extract of unripe Rubus coreanus (5-uRCK) has hypo-cholesterolemic and anti-obesity activity. However, the molecular mechanisms of its effects are poorly characterized. We hypothesized that 5-uRCK and one of its major bioactive compounds, ellagic acid, decrease cellular and plasma cholesterol levels. Thus, we investigated the hypocholesterolemic activity and mechanism of 5-uRCK in both hepatocytes and a high-cholesterol diet (HCD)-induced rat model. Cholesterol in the liver and serum was significantly reduced by 5-uRCK and ellagic acid. The hepatic activities of HMG-CoA and CETP were reduced, and the hepatic activity of LCAT was increased by both 5-uRCK extract and ellagic acid, which also caused histological improvements. The MDA content in the aorta and serum was significantly decreased after oral administration of 5-uRCK or ellagic acid. Further immunoblotting analysis showed that AMPK phosphorylation in the liver was induced by 5-uRCK and ellagic acid, which activated AMPK, inhibiting the activity of HMGCR by inhibitory phosphorylation. In contrast, 5-uRCK and ellagic acid suppressed the nuclear translocation and activation of SREBP-2, which is a key transcription factor in cholesterol biosynthesis. In conclusion, our results suggest that 5-uRCK and its bioactive compound, ellagic acid, are useful alternative therapeutic agents to regulate blood cholesterol.

scholarly journals Ganoderma lucidum Ethanol Extracts Enhance Re-Epithelialization and Prevent Keratinocytes from Free-Radical Injury

2020 ◽  
Vol 13 (9) ◽  
pp. 224
Author(s):  
Mario Abate ◽  
Giacomo Pepe ◽  
Rosario Randino ◽  
Simona Pisanti ◽  
Manuela Giovanna Basilicata ◽  
...  
Keyword(s):  
Free Radical ◽  
Ganoderma Lucidum ◽  
Ion Trap ◽  
Anticancer Activities ◽  
Tissue Remodelling ◽  
Ganoderic Acid ◽  
Keratinocyte Proliferation ◽  
Flight Mass Spectrometry ◽  
Ethanol Extracts

Ganoderma lucidum or Reishi is recognized as the most potent adaptogen present in nature, and its anti-inflammatory, antioxidant, immunomodulatory and anticancer activities are well known. Moreover, lately, there has been an increasing interest from pharmaceutical companies in antiaging G. lucidum-extract-based formulations. Nevertheless, the pharmacological mechanisms of such adaptogenic and regenerative actions remain unclear. The present investigation aimed to explore its molecular and cellular effects in vitro in epidermal keratinocyte cultures by applying liquid chromatography coupled to ion trap time-of-flight mass spectrometry (LCMS-IT-TOF) for analysis of ethanol extracts using ganoderic acid-A as a reference compound. The G. lucidum extract showed a keratinocyte proliferation induction accompanied by an increase of cyclic kinase protein expressions, such as CDK2 and CDK6. Furthermore, a noteworthy migration rate increase and activation of tissue remodelling factors, such as matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9), were observed. Finally, the extract showed an antioxidant effect, protecting from H2O2-induced cytotoxicity; preventing activation of AKT (protein kinase B), ERK (extracellular signal-regulated kinase), p53 and p21; and reducing the number of apoptotic cells. Our study paves the path for elucidating pharmacological properties of G. lucidum and its potential development as cosmeceutical skin products, providing the first evidence of its capability to accelerate the healing processes enhancing re-epithelialization and to protect cells from free-radical action.

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