Biological consequences of statins in Candida species and possible implications for human health

2007 ◽  
Vol 35 (6) ◽  
pp. 1529-1532 ◽  
Author(s):  
K. Wikhe ◽  
C. Westermeyer ◽  
I.G. Macreadie
Keyword(s):  
Mitochondrial Dna ◽  
Side Effects ◽  
Candida Species ◽  
Candida Glabrata ◽  
Fungal Species ◽  
Fungal Colonization ◽  
Preliminary Screening ◽  
Cholesterol Levels ◽  
Essential Enzyme ◽  
Coa Reductase

The statins, simvastatin and atorvastatin are the most widely prescribed drugs. Statins lower cholesterol levels through their action on HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase, an essential enzyme for the biosynthesis of cholesterol. Fungal HMG-CoA reductases are also inhibited by statins, resulting in reduced levels of ergosterol (the fungal equivalent of cholesterol) and concomitant growth inhibition. This effect occurs in a range of fungal species and possibly affects fungal colonization of people on statin therapy. Furthermore, it may suggest that statins could have a role in new antifungal therapies. Possibly associated with the reduction in ergosterol levels, statins also inhibit respiratory growth. In the yeast, Candida glabrata, passage with statins dramatically increased the frequencies of petite mutants that were devoid of mitochondrial DNA, suggesting that statins caused a defect in the maintenance of mitochondrial DNA. These observations in C. glabrata may provide further insights into side effects of statins in humans undergoing treatment for hypercholesterolaemia. In addition, C. glabrata may be highly useful for the preliminary screening of agents to reduce statin side effects.

scholarly journals Anti-Obesity Properties of Calocybe Indica in Zebra fishes with Short-Term High-Fat Diet Induction

2021 ◽  
Vol 14 (01) ◽  
pp. 411-423
Author(s):  
Anushree Nagaraj ◽  
Sarah Andrea Wilson ◽  
Lalitha Vaidyanathan
Keyword(s):  
Side Effects ◽  
Normal Control ◽  
Whole Body ◽  
Standard Drug ◽  
Alcoholic Fatty Liver ◽  
Synthetic Drugs ◽  
Cholesterol Levels ◽  
Calocybe Indica ◽  
Complex Health Problems ◽  
Coa Reductase

Obesity, a disease involved with complex health problems, is indicated by increased BMI, triglyceride and cholesterol levels. Obese individuals are found to be highly susceptible to develop non-alcoholic fatty liver disease,cardiovascular diseases, and also type 2 diabetes mellitus. Synthetic drugs used for treating obesity have been found to be associated with side effects such as anxiety,sleeplessness,hypertension, and drug addiction. Research on natural productspossessing therapeutic biological activitieshasdiscoveredtheir potential to minimize or even completely eliminate such side effects. Medicinal properties ofCalocybe indica include antidiabetic, hypertensive, anticancer, anti-inflammatory, antibacterial, and hepatoprotective effects; however, its anti-obesity activity is obscure.In this study, the anti-obesity effects of Calocybe indicawere investigated using a diet-induced obese Zebrafish modeland compared with standard drug Atorvastatin.Results show that 200µg of C. indica was able to effectively bring down triglyceride levels (12.5± 0 mg/ml; normal control 12.7 ± 0.7 mg/ml), cholesterol (210± 15.9 mg; normal control =70.4± 0)and HMG COA Reductase levels (0.9± 0.03; normal = 1.2 ± 0.01). Excessive fat accumulation in the liver (steatohepatitis) reduced after treatment with C. indica to a greater extent than by treatment with standard drug Atorvastatin. 100 µg of C. indica was found to be optimum in decreasing the levels of the liver enzymes, AST (177.1±5.7 IU/L; normal control =177.7±43.02 IU/l), ALT (365.5±2.9 IU/L; normal control= 355.5±34.4 IU/l), and ALP (2.3±1.1μmoles of phenol liberated/mg of protein/min; normal control = 0.7±1.2 μmoles of phenol liberated/mg of protein/min).Whole-body Oil Red O staining of the zebrafishes showed that with increasing concentration of C. indica, the accumulation of triglycerides and lipids decreased.

scholarly journals A QM/MM Evaluation of the Missing Step in the Reduction Mechanism of HMG-CoA by Human HMG-CoA Reductase

Processes ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 1085
Author(s):  
Paula Mihaljević-Jurič ◽  
Sérgio F. Sousa
Keyword(s):  
Mevalonate Pathway ◽  
Atomic Level ◽  
Amino Acid Residues ◽  
Protonation State ◽  
Primary Target ◽  
Cholesterol Levels ◽  
The Subject ◽  
Electron Reduction ◽  
Dynamics Simulations ◽  
Coa Reductase

Statins are important drugs in the regulation of cholesterol levels in the human body that have as a primary target the enzyme β-hydroxy-β-methylglutaryl-CoA reductase (HMGR). This enzyme plays a crucial role in the mevalonate pathway, catalyzing the four-electron reduction of HMG-CoA to mevalonate. A second reduction step of this reaction mechanism has been the subject of much speculation in the literature, with different conflicting theories persisting to the present day. In this study, the different mechanistic hypotheses were evaluated with atomic-level detail through a combination of molecular dynamics simulations (MD) and quantum mechanics/molecular mechanics (QM/MM) calculations. The obtained Gibbs free activation and Gibbs free reaction energy (15 kcal mol−1 and −40 kcal mol−1) show that this hydride step takes place with the involvement of a cationic His405 and Lys639, and a neutral Glu98, while Asp715 remains in an anionic state. The results provide an atomic-level portrait of this step, clearly demonstrating the nature and protonation state of the amino acid residues involved, the energetics associated, and the structure and charge of the key participating atoms in the several intermediate states, finally elucidating this missing step.

scholarly journals Molds in museum environments: Biodeterioration of art photographs and wooden sculptures

2013 ◽  
Vol 65 (3) ◽  
pp. 955-962 ◽  
Author(s):  
Milica Ljaljevic-Grbic ◽  
M. Stupar ◽  
Jelena Vukojevic ◽  
Ivana Maricic ◽  
Natasa Bungur
Keyword(s):  
Aspergillus Niger ◽  
Indoor Air ◽  
Trichoderma Viride ◽  
Fungal Species ◽  
Chaetomium Globosum ◽  
Fungal Colonization ◽  
Cellulolytic Activity ◽  
Cultural Center ◽  
Fungal Propagules ◽  
Alternaria Sp

Pieces of art stored in museum depots and display rooms are subject to fungal colonization that leads to bio-deterioration processes. Deteriorated wooden sculptures and art photographs temporarily stored in the quarantine room of the Cultural Center of Belgrade were subject to mycological analyses. Twelve fungal species were identified on the wooden substratum and five species were detected on photograph surfaces. Trichoderma viride, Chaetomium globosum and Alternaria sp. were the fungi with proven cellulolytic activity detected on the examined cellulose substrata. Indoor air mycobiota were estimated to 210.09 ? 8.06 CFU m-3, and the conidia of fungus Aspergillus niger were the dominant fungal propagules in the air of the examined room.

scholarly journals Wild Apple-Associated Fungi and Bacteria Compete to Colonize the Larval Gut of an Invasive Wood-Borer Agrilus mali in Tianshan Forests

2021 ◽  
Vol 12 ◽  
Author(s):  
Tohir A. Bozorov ◽  
Zokir O. Toshmatov ◽  
Gulnaz Kahar ◽  
Daoyuan Zhang ◽  
Hua Shao ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Inhibitory Concentration ◽  
Fungal Species ◽  
Gut Bacteria ◽  
Recent Analysis ◽  
Fungal Colonization ◽  
Antifungal Compound ◽  
Concentration Method ◽  
Malus Sieversii ◽  
Wood Borer

The gut microflora of insects plays important roles throughout their lives. Different foods and geographic locations change gut bacterial communities. The invasive wood-borer Agrilus mali causes extensive mortality of wild apple, Malus sieversii, which is considered a progenitor of all cultivated apples, in Tianshan forests. Recent analysis showed that the gut microbiota of larvae collected from Tianshan forests showed rich bacterial diversity but the absence of fungal species. In this study, we explored the antagonistic ability of the gut bacteria to address this absence of fungi in the larval gut. The results demonstrated that the gut bacteria were able to selectively inhibit wild apple tree-associated fungi. Among them, Pseudomonas synxantha showed strong antagonistic ability, producing antifungal compounds. Using different analytical methods, such as column chromatography, mass spectrometry, HPLC, and NMR, an antifungal compound, phenazine-1-carboxylic acid (PCA), was identified. Activity of the compound was determined by the minimum inhibitory concentration method and electron microscopy. Moreover, our study showed that the gut bacteria could originate from noninfested apple microflora during infestation. Overall, the results showed that in newly invaded locations, A. mali larvae changed their gut microbiota and adopted new gut bacteria that prevented fungal colonization in the gut.

scholarly journals The The Effects of Cinnamaldehyde (Cinnamon Derivatives) and Nystatin on Candida Albicans and Candida Glabrata

2019 ◽  
Vol 7 (7) ◽  
pp. 1067-1070 ◽  
Author(s):  
Sedigheh Bakhtiari ◽  
Soudeh Jafari ◽  
Jamileh Bigom Taheri ◽  
Tahereh Sadat Jafarzadeh Kashi ◽  
Zahra Namazi ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Minimum Inhibitory Concentration ◽  
Candida Species ◽  
Candida Glabrata ◽  
Inhibitory Concentration ◽  
Fungal Infections ◽  
Fungal Growth ◽  
Minimum Fungicidal Concentration ◽  
Microdilution Method

BACKGROUND: Candida species are the most common opportunistic fungal infections. Today, cinnamon plants have been considered for anti-Candida properties. AIM: This study aimed to investigate the effectiveness of cinnamaldehyde extract (from cinnamon derivatives) on Candida albicans and Candida glabrata species and comparison with nystatin. MATERIAL AND METHODS: In this study, cinnamaldehyde and nystatin were used. The specimens included Candida albicans and Candida glabrata. Minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) were measured for each one by the microdilution method. This experiment was repeated three times. RESULTS: Cinnamaldehyde extract at a concentration of 62.5 μl/ml was able to prevent the growth of Candida albicans, at a concentration of 93.7 μl/ml, causing Candida albicans to disappear, at 48.8 μl/ml, to prevent the growth of Candida glabrata, and in the concentration of 62.5 μl/ml, causes the loss of Candida glabrata. In comparison, nystatin at 0.5 μg/ml concentration prevented the growth of Candida albicans, at concentrations of 1 μg/ml causing Candida albicans to be destroyed, at 4 μg/ml concentration to prevent the growth of Candida glabrata, and at a concentration of 8 μg/ml causes the loss of Candida glabrata. The results were the same every three times. CONCLUSIONS: Although cinnamaldehyde extract had an effect on fungal growth in both Candida albicans and Candida glabrata with a fatal effect; the effect on these two species was lower than nystatin.

Inhibition of recombinant enzyme 3-hydroxy-3-methylglutaryl-CoA reductase from Candida glabrata by α-asarone-based synthetic compounds as antifungal agents

2019 ◽  
Vol 292 ◽  
pp. 64-67 ◽  
Author(s):  
Dulce Andrade-Pavón ◽  
Jossue Ortiz-Álvarez ◽  
Eugenia Sánchez-Sandoval ◽  
Joaquín Tamariz ◽  
César Hernández-Rodríguez ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Antifungal Agents ◽  
Recombinant Enzyme ◽  
Synthetic Compounds ◽  
Coa Reductase

Randomized phase II study of gefitinib alone or with simvastatin in previously treated advanced non-small cell lung cancer (NSCLC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8057-8057
Author(s):  
J. Han ◽  
S. Lee ◽  
T. Yun ◽  
Y. Moon ◽  
I. Park ◽  
...  
Keyword(s):  
Survival Data ◽  
Membrane Receptors ◽  
Skin Reactions ◽  
Unselected Patient ◽  
Cholesterol Levels ◽  
Randomized Phase Ii ◽  
Previously Treated ◽  
Coa Reductase ◽  
Unselected Patient Population

8057 Background: Statins reduce not only serum cholesterol levels but also mevalonate synthesis by inhibiting HMG-CoA reductase. Mevalonate is a precursor of several cellular major products including dolichol, geranylpyrophosphate (GPP) and farnesyl-pyrophosphate (FPP). Dolichol has a stimulatory effect on DNA synthesis and is linked to several tumor cell proteins. GPP and FPP cause isoprenylation of Ras and Rho those regulate signal transduction of several membrane receptors crucial for cell proliferation, differentiation, and apoptosis, which result in resistance to gefitinib. Thus depletion of mevalonate metabolites may enhance gefitinib activity in NSCLC. This study compared gefitinib alone with gefitinib plus simvastatin in patients with recurrent NSCLC after at least one chemotherapy. Methods: Between May 2006 and September 2008, 107 patients (51% male, 74% adenocarcinoma, 50% never-smoker, 54% more than two prior regimens) were randomly assigned to gefitinib alone (250 mg/d orally, n=53) or gefitinib plus simvastatin (250mg/d and 40 mg/d orally, respectively, n=54). A cycle was considered as 4 weeks of treatment. Therapy was continued until disease progression or intolerable toxicities. The primary end point was to assess response rate. Secondary end points included time to progression and survival. Median follow-up was 10.1 months. Results: Efficacy was similar for gefitinib and gefitinib plus simvastatin groups. Objective tumor response rates (RR) were 31.5% (95% CI, 19.1 to 43.9) and 32.1% (95% CI, 19.5 to 44.7); median PFS were 1.9 and 2.0 months; and median OS were 9.5 and 12.7 months, respectively. In subgroup analysis, gefitinib plus simvastatin showed a trend for higher RR than gefitinib alone in non-adenocarcinoma group (38.5% vs. 7.7%, p=0.08). Adverse events at both arms were generally mild (grade 1 or 2) and consisted mainly of skin reactions. Conclusions: Gefitinib combined with simvastatin did not improved efficacy compared to gefitinib alone in this unselected patient population, but showed a trend for higher efficacy in non-adenocarcinoma patients. Although it is preliminary, gefitinib combined with simvastatin showed slightly increased OS. Updated survival data will be presented. No significant financial relationships to disclose.

scholarly journals Relationships between pharmacotherapy-induced metabolic changes and improved psychopathology in schizophrenia: data from a mirtazapine and first-generation antipsychotics combination trial

2013 ◽  
Vol 16 (7) ◽  
pp. 1661-1666 ◽  
Author(s):  
Viacheslav Terevnikov ◽  
Jan-Henry Stenberg ◽  
Jari Tiihonen ◽  
Evgeni Chukhin ◽  
Marina Joffe ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Side Effects ◽  
First Generation ◽  
Metabolic Effects ◽  
Open Label ◽  
Double Blind ◽  
Cholesterol Levels ◽  
Syndrome Scale ◽  
Negative Syndrome

Abstract Clinical efficacy and metabolic side-effects of antipsychotics seem to correlate with each other. In this study, interrelationship of similar metabolic effects of mirtazapine and its earlier reported desirable effects on psychopathology in first-generation antipsychotics (FGAs)-treated schizophrenia were explored. Symptomatic FGAs-treated patients with schizophrenia received a 6-wk double-blind treatment with add-on mirtazapine (n = 20) or placebo (n = 16), followed by a 6-wk open-label mirtazapine treatment. Mirtazapine (but not placebo) induced an increase in body weight and cholesterol levels. The latter was associated with a clinical improvement in all (sub)scales of the Positive and Negative Syndrome Scale [PANSS; an increase of cholesterol by 1 mmol/l predicted 7 points reduction on the PANSS total score (r = 0.85, p = 0.001)]. In schizophrenia, mirtazapine-induced weight gain and increase of total cholesterol are associated with the improved efficacy of mirtazapine-FGAs combination – a novel observation with possible clinical and theoretical implications.

scholarly journals Cohort Study of Airway Mycobiome in Adult Cystic Fibrosis Patients: Differences in Community Structure between Fungi and Bacteria Reveal Predominance of Transient Fungal Elements

2015 ◽  
Vol 53 (9) ◽  
pp. 2900-2907 ◽  
Author(s):  
Rolf Kramer ◽  
Annette Sauer-Heilborn ◽  
Tobias Welte ◽  
Carlos A. Guzman ◽  
Wolf-Rainer Abraham ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Fungal Spores ◽  
Rare Event ◽  
Single Strand Conformation Polymorphism ◽  
Fungal Species ◽  
Fungal Communities ◽  
Fungal Colonization ◽  
Molecular Fingerprinting ◽  
High Exposure ◽  
Entire Cohort

The respiratory mycobiome is an important but understudied component of the human microbiota. Like bacteria, fungi can cause severe lung diseases, but their infection rates are much lower. This study compared the bacterial and fungal communities of sputum samples from a large cohort of 56 adult patients with cystic fibrosis (CF) during nonexacerbation periods and under continuous antibiotic treatment. Molecular fingerprinting based on single-strand conformation polymorphism (SSCP) analysis revealed fundamental differences between bacterial and fungal communities. Both groups of microorganisms were taxonomically classified by identification of gene sequences (16S rRNA and internal transcript spacer), and prevalences of single taxa were determined for the entire cohort. Major bacterial pathogens were frequently observed, whereas fungi of known pathogenicity in CF were detected only in low numbers. Fungal species richness increased without reaching a constant level (saturation), whereas bacterial richness showed saturation after 50 patients were analyzed. In contrast to bacteria, a large number of fungal species were observed together with high fluctuations over time and among patients. These findings demonstrated that the mycobiome was dominated by transient species, which strongly suggested that the main driving force was their presence in inhaled air rather than colonization. Considering the high exposure of human airways to fungal spores, we concluded that fungi have low colonization abilities in CF, and colonization by pathogenic fungal species may be considered a rare event. A comprehensive understanding of the conditions promoting fungal colonization may offer the opportunity to prevent colonization and substantially reduce or even eliminate fungus-related disease progression in CF.

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