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Microbial Cell Factories May 2024Lovastatin has widespread applications thanks to its multiple pharmacological effects. Fermentation by filamentous fungi represents the major way of lovastatin...
BACKGROUND
Lovastatin has widespread applications thanks to its multiple pharmacological effects. Fermentation by filamentous fungi represents the major way of lovastatin production. However, the current lovastatin productivity by fungal fermentation is limited and needs to be improved.
RESULTS
In this study, the lovastatin-producing strains of Aspergillus terreus from marine environment were screened, and their lovastatin productions were further improved by genetic engineering. Five strains of A. terreus were isolated from various marine environments. Their secondary metabolites were profiled by metabolomics analysis using Ultra Performance Liquid Chromatography-Mass spectrometry (UPLC-MS) with Global Natural Products Social Molecular Networking (GNPS), revealing that the production of secondary metabolites was variable among different strains. Remarkably, the strain of A. terreus MJ106 could principally biosynthesize the target drug lovastatin, which was confirmed by High Performance Liquid Chromatography (HPLC) and gene expression analysis. By one-factor experiment, lactose was found to be the best carbon source for A. terreus MJ106 to produce lovastatin. To improve the lovastatin titer in A. terreus MJ106, genetic engineering was applied to this strain. Firstly, a series of strong promoters was identified by transcriptomic and green fluorescent protein reporter analysis. Then, three selected strong promoters were used to overexpress the transcription factor gene lovE encoding the major transactivator for lov gene cluster expression. The results revealed that compared to A. terreus MJ106, all lovE over-expression mutants exhibited significantly more production of lovastatin and higher gene expression. One of them, LovE-b19, showed the highest lovastatin productivity at a titer of 1512 mg/L, which represents the highest production level reported in A. terreus.
CONCLUSION
Our data suggested that combination of strain screen and genetic engineering represents a powerful tool for improving the productivity of fungal secondary metabolites, which could be adopted for large-scale production of lovastatin in marine-derived A. terreus.
Topics: Lovastatin; Aspergillus; Genetic Engineering; Fermentation; Aquatic Organisms
PubMed: 38724934
DOI: 10.1186/s12934-024-02396-z -
BMC Pulmonary Medicine May 2024Simvastatin (Sim), a hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been widely used in prevention and treatment of cardiovascular diseases....
BACKGROUND
Simvastatin (Sim), a hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been widely used in prevention and treatment of cardiovascular diseases. Studies have suggested that Sim exerts anti-fibrotic effects by interfering fibroblast proliferation and collagen synthesis. This study was to determine whether Sim could alleviate silica-induced pulmonary fibrosis and explore the underlying mechanisms.
METHODS
The rat model of silicosis was established by the tracheal perfusion method and treated with Sim (5 or 10 mg/kg), AICAR (an AMPK agonist), and apocynin (a NOX inhibitor) for 28 days. Lung tissues were collected for further analyses including pathological histology, inflammatory response, oxidative stress, epithelial mesenchymal transformation (EMT), and the AMPK-NOX pathway.
RESULTS
Sim significantly reduced silica-induced pulmonary inflammation and fibrosis at 28 days after administration. Sim could reduce the levels of interleukin (IL)-1β, IL-6, tumor necrosis factor-α and transforming growth factor-β1 in lung tissues. The expressions of hydroxyproline, α-SMA and vimentin were down-regulated, while E-cad was increased in Sim-treated rats. In addition, NOX4, p22pox, p40phox, p-p47phox/p47phox expressions and ROS levels were all increased, whereas p-AMPK/AMPK was decreased in silica-induced rats. Sim or AICAR treatment could notably reverse the decrease of AMPK activity and increase of NOX activity induced by silica. Apocynin treatment exhibited similar protective effects to Sim, including down-regulating of oxidative stress and inhibition of the EMT process and inflammatory reactions.
CONCLUSIONS
Sim attenuates silica-induced pulmonary inflammation and fibrosis by downregulating EMT and oxidative stress through the AMPK-NOX pathway.
Topics: Animals; Male; Rats; Acetophenones; Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Disease Models, Animal; Epithelial-Mesenchymal Transition; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lung; NADPH Oxidase 4; NADPH Oxidases; Oxidative Stress; Pneumonia; Pulmonary Fibrosis; Ribonucleotides; Signal Transduction; Silicon Dioxide; Silicosis; Simvastatin; Transforming Growth Factor beta1
PubMed: 38720270
DOI: 10.1186/s12890-024-03014-9 -
European Journal of Pharmaceutical... May 2024Non-alcoholic steatohepatitis (NASH) is characterized by liver inflammation, fat accumulation, and collagen deposition. Due to the limited availability of effective...
Non-alcoholic steatohepatitis (NASH) is characterized by liver inflammation, fat accumulation, and collagen deposition. Due to the limited availability of effective treatments, there is a pressing need to develop innovative strategies. Given the complex nature of the disease, employing combination approaches is essential. Hedgehog signaling has been recognized as potentially promoting NASH, and cholesterol can influence this signaling by modifying the conformation of PTCH1 and SMO activity. HSP90 plays a role in the stability of SMO and GLI proteins. We revealed significant positive correlations between Hedgehog signaling proteins (Shh, SMO, GLI1, and GLI2) and both cholesterol and HSP90 levels. Herein, we investigated the novel combination of the cholesterol-lowering agent lovastatin and the HSP90 inhibitor PU-H71 in vitro and in vivo. The combination demonstrated a synergy score of 15.09 and an MSA score of 22.85, as estimated by the ZIP synergy model based on growth inhibition rates in HepG2 cells. In a NASH rat model induced by thioacetamide and a high-fat diet, this combination therapy extended survival, improved liver function and histology, and enhanced antioxidant defense. Additionally, the combination exhibited anti-inflammatory and anti-fibrotic potential by influencing the levels of TNF-α, TGF-β, TIMP-1, and PDGF-BB. This effect was evident in the suppression of the Col1a1 gene expression and the levels of hydroxyproline and α-SMA. These favorable outcomes may be attributed to the combination's potential to inhibit key Hedgehog signaling molecules. In conclusion, exploring the applicability of this combination contributes to a more comprehensive understanding and improved management of NASH and other fibrotic disorders.
PubMed: 38714237
DOI: 10.1016/j.ejps.2024.106792 -
Frontiers in Immunology 2024In the face of continued growth in the elderly population, the need to understand and combat age-related cardiac decline becomes even more urgent, requiring us to...
BACKGROUND
In the face of continued growth in the elderly population, the need to understand and combat age-related cardiac decline becomes even more urgent, requiring us to uncover new pathological and cardioprotective pathways.
METHODS
We obtained the aging-related genes of heart failure through WGCNA and CellAge database. We elucidated the biological functions and signaling pathways involved in heart failure and aging through GO and KEGG enrichment analysis. We used three machine learning algorithms: LASSO, RF and SVM-RFE to further screen the aging-related genes of heart failure, and fitted and verified them through a variety of machine learning algorithms. We searched for drugs to treat age-related heart failure through the DSigDB database. Finally, We use CIBERSORT to complete immune infiltration analysis of aging samples.
RESULTS
We obtained 57 up-regulated and 195 down-regulated aging-related genes in heart failure through WGCNA and CellAge databases. GO and KEGG enrichment analysis showed that aging-related genes are mainly involved in mechanisms such as Cellular senescence and Cell cycle. We further screened aging-related genes through machine learning and obtained 14 key genes. We verified the results on the test set and 2 external validation sets using 15 machine learning algorithm models and 207 combinations, and the highest accuracy was 0.911. Through screening of the DSigDB database, we believe that rimonabant and lovastatin have the potential to delay aging and protect the heart. The results of immune infiltration analysis showed that there were significant differences between Macrophages M2 and T cells CD8 in aging myocardium.
CONCLUSION
We identified aging signature genes and potential therapeutic drugs for heart failure through bioinformatics and multiple machine learning algorithms, providing new ideas for studying the mechanism and treatment of age-related cardiac decline.
Topics: Heart Failure; Humans; Aging; Machine Learning; Algorithms; Gene Expression Profiling; Databases, Genetic; Computational Biology; Gene Regulatory Networks; Transcriptome
PubMed: 38686376
DOI: 10.3389/fimmu.2024.1367235 -
Scientific Reports Apr 2024Chronic stress is associated with major depressive disorder (MDD). Increased glucocorticoid levels caused by uncontrolled release through the...
Chronic stress is associated with major depressive disorder (MDD). Increased glucocorticoid levels caused by uncontrolled release through the hypothalamic‒pituitary‒adrenal (HPA) axis can cause changes in the lipid content of the cellular plasma membrane. These changes are suspected to be involved in the development of depressive disorders. St. John's wort extract (SJW) Ze 117 has long been used as an alternative to synthetic antidepressants. Part of its effect may be due to an effect on the cellular lipid composition and thus on the properties of plasma membranes and receptor systems embedded therein. In this study, we investigated the effect of Ze 117 on that of dexamethasone and simvastatin. Dexamethasone increases the fluidity of C6 cell plasma membranes. This effect is counteracted by administration of Ze 117. Here we demonstrate that this is not due to a change in C16:1/16:0 and C18:1/18:0 ratios in C6 cell fatty acids. On the other hand, Ze 117 increased the cellular cholesterol content by 42.5%, whereas dexamethasone reduced cholesterol levels similarly to simvastatin. Lowering cholesterol levels by dexamethasone or simvastatin resulted in decreased β-arrestin 2 recruitment to the 5-HT receptor. This effect was counterbalanced by Ze 117, whereas the SJW extract had little effect on β-arrestin 2 recruitment in non-stressed cells. Taken together, in C6 cells, Ze 117 induces changes in membrane fluidity through its effect on cellular cholesterol metabolism rather than by affecting fatty acid saturation. This effect is reflected in an altered signal transduction of the 5-HT receptor under Ze 117 administration. The current in vitro results support the hypothesis that Ze 117 addresses relevant parts of the cellular lipid metabolism, possibly explaining some of the antidepressant actions of Ze 117.
Topics: Hypericum; Plant Extracts; Cholesterol; Membrane Fluidity; Dexamethasone; Cell Line, Tumor; Simvastatin; Glioma; Animals; Rats; Cell Membrane; Receptor, Serotonin, 5-HT1A; Fatty Acids
PubMed: 38684848
DOI: 10.1038/s41598-024-60562-0 -
Pharmaceuticals (Basel, Switzerland) Mar 2024Cardiovascular disease is a global health concern and reducing plasma LDL-C levels is a major goal in cardiovascular prevention. Our study aimed to evaluate the...
The Lipid-Lowering Efficacy of a Nutraceutical Combination Including Leucoselect Phytosome, Red Yeast Rice, Policosanol and Folic Acid in Dyslipidaemia Patients: Real-World Insights.
BACKGROUND
Cardiovascular disease is a global health concern and reducing plasma LDL-C levels is a major goal in cardiovascular prevention. Our study aimed to evaluate the effectiveness of a nutraceutical formulation including leucoselect phytosome, red yeast rice, policosanol and folic acid on LDL-c levels in patients at low cardiovascular risk with dyslipidemia.
MATERIALS AND METHODS
We prospectively enrolled all consecutive patients with dyslipidemia at low cardiovascular risk who were unresponsive to diet and physical activity. Clinical assessments and laboratory analyses, encompassing lipid profile, hepatic function, and CPK levels, were performed at baseline prior to initiating treatment and repeated at the 12-week mark following administration of the study nutraceutical.
RESULTS
Sixty (60) consecutive patients (mean age 48.02 ± 10.1 years; 60% male) were included. At the 12-week follow-up, a statistically significant reduction in Total Cholesterol (13.1%) and LDL-c serum level (20.4%) was observed. Hepatic and muscular function remain stable over the time. The adherence to therapy was 99% and the persistence was maximum.
CONCLUSIONS
The nutraceutical formulation including leucoselect phytosome red yeast rice, policosanol and folic acid significantly reduced the LDL-c plasma levels, consistent with previous research showing that the bioactive component in red yeast rice-lovastatin-is effective in addressing problems with lipid metabolism. Importantly, it was safe and well-tolerated among patients with dyslipidemia in a real-world setting.
PubMed: 38675408
DOI: 10.3390/ph17040447 -
International Journal of Molecular... Apr 2024The solute carrier organic anion transporter family member 1B1 () encodes the organic anion-transporting polypeptide 1B1 (OATP1B1 protein) that transports statins to...
The solute carrier organic anion transporter family member 1B1 () encodes the organic anion-transporting polypeptide 1B1 (OATP1B1 protein) that transports statins to liver cells. Common genetic variants in , such as *5, cause altered systemic exposure to statins and therefore affect statin outcomes, with potential pharmacogenetic applications; yet, evidence is inconclusive. We studied common and rare variants in up to 64,000 patients from UK Biobank prescribed simvastatin or atorvastatin, combining whole-exome sequencing data with up to 25-year routine clinical records. We studied 51 predicted gain/loss-of-function variants affecting OATP1B1. Both *5 alone and the *15 haplotype increased LDL during treatment (beta*5 = 0.08 mmol/L, = 6 × 10; beta*15 = 0.03 mmol/L, = 3 × 10), as did the likelihood of discontinuing statin prescriptions (hazard ratio*5 = 1.12, = 0.04; HR*15 = 1.05, = 0.04). *15 and *20 increased the risk of General Practice (GP)-diagnosed muscle symptoms (HR*15 = 1.22, = 0.003; HR*20 = 1.25, = 0.01). We estimated that genotype-guided prescribing could potentially prevent 18% and 10% of GP-diagnosed muscle symptoms experienced by statin patients, with *15 and *20, respectively. The remaining common variants were not individually significant. Rare variants in increased LDL in statin users by up to 1.05 mmol/L, but replication is needed. We conclude that genotype-guided treatment could reduce GP-diagnosed muscle symptoms in statin patients; incorporating further variants into clinical prediction scores could improve LDL control and decrease adverse events, including discontinuation.
Topics: Humans; Liver-Specific Organic Anion Transporter 1; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Exome Sequencing; United Kingdom; Male; Female; Biological Specimen Banks; Middle Aged; Aged; Simvastatin; Treatment Outcome; Atorvastatin; Polymorphism, Single Nucleotide; UK Biobank
PubMed: 38674010
DOI: 10.3390/ijms25084426 -
Heliyon Apr 2024The prevalence of obesity and its primary associated comorbidities, such as type 2 diabetes and fatty liver disease, has reached epidemic proportions, with no successful...
The prevalence of obesity and its primary associated comorbidities, such as type 2 diabetes and fatty liver disease, has reached epidemic proportions, with no successful treatment available at present. Heat shock protein 90 (HSP90), a crucial chaperone, plays a key role in lipogenesis (DNL) by stabilizing and maintaining sterol regulatory element binding protein (SREBP) activity. Kongensin A (KA), derived from , inhibits RIP3-mediated necrosis, showing promise as an anti-necrotic and anti-inflammatory agent. It is not yet clear if KA, acting as an HSP90 inhibitor, can enhance hyperlipidemia, hepatic steatosis, and insulin resistance in obese individuals by controlling lipid metabolism. In this study, we first found that KA can potentially decrease lipid content at the cellular level. C57BL/6J mice were given a high-fat diet (HFD) and received KA and lovastatin through oral administration for 7 weeks. KA improved hyperlipidemia, fatty liver, and insulin resistance, as well as reduced body weight in diet-induced obese (DIO) mice, with no significant alteration in food intake. , KA suppressed DNL and reduced the amounts of mSREBPs. KA promoted mSREBP degradation via the FBW7-mediated ubiquitin-proteasome pathway. KA decreased the level of -Akt Ser308, and -GSK3β Ser9 by inhibiting the interaction between HSP90β and Akt. Overall, KA enhanced hyperlipidemia, hepatic steatosis, and insulin resistance by blocking SREBP activity, thereby impacting the FBW7-controlled ubiquitin-proteasome pathway.
PubMed: 38655315
DOI: 10.1016/j.heliyon.2024.e29367 -
Clinical and Translational Medicine Apr 2024
Topics: Humans; Female; Mifepristone; Leiomyoma; Simvastatin; Receptors, Progesterone; Signal Transduction; Drug Synergism; Uterine Neoplasms
PubMed: 38649749
DOI: 10.1002/ctm2.1672 -
PloS One 2024This study comprehensively evaluated the causal relationship between different types of statins use and knee/hip osteoarthritis (OA) using a two-sample and multivariate...
OBJECTIVE
This study comprehensively evaluated the causal relationship between different types of statins use and knee/hip osteoarthritis (OA) using a two-sample and multivariate Mendelian randomization (MR) method.
METHODS
MR analysis was conducted using publicly available summary statistics data from genome-wide association studies (GWAS) to assess the causal associations between total statins use (including specific types) and knee/hip OA. The primary analysis utilized the inverse variance-weighted (IVW) method, with sensitivity analysis conducted to assess robustness. Multivariable MR (MVMR) analysis adjusted for low-density lipoprotein cholesterol (LDL-C), intermediate-density lipoprotein cholesterol (IDL-C), high-density lipoprotein cholesterol (HDL-C), and body mass index (BMI).
RESULTS
The MR analysis revealed a significant inverse association between genetically predicted total statins use and the risk of knee OA (OR = 0.950, 95%CI: 0.920-0.982, p = 0.002) as well as hip OA (OR = 0.932, 95%CI: 0.899-0.966, p <0.001). Furthermore, this study highlighted a reduced risk of knee/hip OA with the use of atorvastatin and simvastatin. Rosuvastatin use was associated with a decreased risk of hip OA but showed no association with knee OA. MVMR results indicated no correlation between exposure factors and outcomes after adjusting for LDL-C or IDL-C. HDL-C may not significantly contribute to statin-induced osteoarthritis, while BMI may play an important role.
CONCLUSION
This study provides compelling evidence of the close relationship between statin use and a reduced risk of knee/hip OA, particularly with atorvastatin and simvastatin. LDL-C and IDL-C may mediate these effects. These findings have important implications for the clinical prevention and treatment of knee/hip OA.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Mendelian Randomization Analysis; Osteoarthritis, Knee; Osteoarthritis, Hip; Genome-Wide Association Study; Cholesterol, LDL; Simvastatin; Body Mass Index; Cholesterol, HDL; Polymorphism, Single Nucleotide; Risk Factors
PubMed: 38648228
DOI: 10.1371/journal.pone.0297766