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Porokeratoses (PK) are a group of uncommon dermatoses characterized by abnormal epidermal differentiation due to a disorder of the mevalonate metabolic pathway. Several clinical subtypes exist that can be associated with the same patient or affect different patients within a family and could, therefore, be different expressions of one disease. All PK subtypes share a common histopathologic finding, the cornoid lamella, a vertical stack of parakeratotic corneocytes embedded in an orthokeratotic horny layer. PK often affects immunosuppressed patients, in whom the course may parallel the level of immunosuppression. The pathogenesis of PK, which had long remained mysterious, has been recently unraveled after discovering pathogenic variants of genes involved in the mevalonate metabolic pathway. The disease is due to germline pathogenic variants of genes of this pathway but requires a second‐hit event to manifest; therefore, PK is considered a dominantly inherited but recessively expressed condition. The prognosis of PK is usually favorable, even though the lesions progress to keratinocyte carcinomas in 7%–16% of patients. The treatment of PK was based on physical (ablative) procedures and various (topical or systemic) treatments, whose efficacy is nevertheless inconsistent and often temporary. The discovery of the metabolic pathway involved in the pathogenesis of PK paved the way for the elaboration of new topical treatments (combination of statins and cholesterol), which are more regularly efficacious compared with older treatments, even though the management of some patients with PK may still be challenging. [ABSTRACT FROM AUTHOR]

Background: Lovastatin, the main lipid-lowering component in red yeast rice, is a golden anti-lipid drug, but its long-term application is continuously challenged by potential skeletal muscle atrophy. Daidzein, an isoflavone derived from soybeans and many Chinese medicines, shows therapeutic potential in treating muscle-related diseases and metabolic disorders. However, whether daidzein can improve lovastatin-induced muscle atrophy and the specific mechanism needs to further study. Methods: Lovastatin-induced mice and zebrafish muscle atrophy models were used to validate the protective effect of daidzein in vivo. And the lovastatin-induced C2C12 myotube atrophy model was employed to validate the therapeutic efficacy and investigate the specific mechanism of daidzein in vitro. We combined specific siRNA targeting FOXO3a and AMPK-selective inhibitor, agonist to elucidate AMPK/FOXO3a-dependent muscle-protective mechanism of daidzein. The anti-atrophy effects of daidzein through blockage of abnormal activation of AMPK/FOXO3a was presented in Immunofluorescence, H&E staining, Western blot, qRT-PCR. Serum creatine kinase level was detected by ELISA and we used mouse muscle grip instrument to detect the strength of mouse muscles. Results: In this study, we demonstrated that daidzein could dose-dependently alleviate lovastatin-induced mice skeletal muscle atrophy, reduce serum creatine kinase, and improve muscle grip strength in mice. Mechanistically, daidzein inhibited lovastatin-induced FOXO3a phosphorylation caused by AMPK activation, thereby inhibiting FOXO3a nuclear translocation to restrain the expression of muscle-related proteins Atrogin-1 and MuRF-1. In C2C12 myotube, administration of AMPK-selective inhibitor Compound C recapitulated the therapeutic effects of daidzein against lovastatin-induced myotubes atrophy, while the anti-atrophy effects of daidzein were lost in the presence of AMPK-selective agonist MK-3903. In lovastatin-induced mice muscle atrophy models, Compound C elicited similar anti-atrophy effects as daidzein, but this effect was not potentiated when it was applied in combination with daidzein, suggesting that daidzein exerted therapeutic efficacy dependent on blockage of AMPK activity. Conclusions: Our study identified daidzein as an effective component that ameliorated lovastatin-induced skeletal muscle atrophy through blockage of abnormal activation of AMPK/FOXO3a and transcriptional activation of genes encoding downstream muscle-related proteins. Our results also highlighted the therapeutic potential by regulating the AMPK/FOXO3a axis in management of statin-induced myotoxicity. [ABSTRACT FROM AUTHOR]

Atherosclerosis (AS) is a chronic inflammation vascular disease, with its ongoing progression can lead to the onset of cardiovascular diseases. Traditional drug therapy is limited by poor drug delivery, insufficient drug accumulation, and notable toxic side effects. In addition, the failure to receive an early AS diagnosis is primarily responsible for the delayed treatment, which subsequently contributes to the high frequency of life‐threatening cardiovascular events. In this work, a macrophage membranes (MM)‐camouflaged reactive oxygen species (ROS)‐sensitive nanotheranostic platform (LC‐MM) is constructed to improve AS target diagnosis and treatment efficacy. Thanks to the strong antioxidant properties of carbon dots (CDs), CDs as drug carriers for lovastatin aimed to synergistically treat AS by reducing ROS accumulation and suppressing inflammatory responses in vitro and in vivo are employed. The active functions of MM coupled with the ROS‐responsiveness of LC nanoplatform are expected to enhance the efficacy of nanotherapy, particularly to reduce lipid deposition, macrophage infiltration, necrotic core size, collagen content, pro‐inflammatory cytokines, and oxidative stress accumulation. Moreover, the near‐infrared emission properties inherited from CDs facilitated precise fluorescence (FL) imaging for AS plaques. Thus, the biomimetic nanotheranostic agent LC‐MM represented a powerful platform for safe and effective AS management. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the ability of pentoxifylline when compared to lovastatin and chlorpromazine as nephroprotective substances in cases of renal ischemia and reperfusion syndrome (IRI). A total of 36 adult male animals were randomly allocated into four groups (untreated control group, pentoxifylline group, lovastatin group, and chlorpromazine group), each consisting of nine animals. All groups were submitted to experimental ischemia and reperfusion procedures. The animals were evaluated 24, 72 and 120 hours after IRI, including physical examinations, serum urea and creatinine measurements, as well as histopathological, morphometric, and stereological analyses of the renal tissue. Results indicated that 24 hours after IRI, only chlorpromazine was effective in controlling azotemia. At the 72-hour mark, both chlorpromazine and pentoxifylline exhibited efficacy. After 120 hours, all three substances demonstrated renal protective qualities. Pentoxifylline was the most effective in preserving the structural integrity of kidney tissue, followed by chlorpromazine. In conclusion, all three treatments (pentoxifylline, chlorpromazine, and lovastatin) were effective. Pentoxifylline proved to be promising in the response against acute tubular necrosis, although chlorpromazine presented earlier renoprotective effects in terms of maintaining renal function. [ABSTRACT FROM AUTHOR]

Objective: Studies have demonstrated that administering statins promptly following myocardial ischemia/reperfusion (MI/R) can confer cardioprotective benefits. This study investigates whether Lovastatin can modulate the Yes-associated protein/Transcriptional co-activator with PDZ-binding motif (YAP/TAZ) signaling pathway to mitigate cardiomyocyte injury caused by hypoxia/reoxygenation (H/R). Methods: The in vitro MI/R model was established by H/R in rat myocardial H9c2 cells, and the cells were pretreated with varying doses of Lovastatin before reoxygenation. The extent of cellular injury was evaluated by measuring the myocardial enzyme content and cell viability. The levels of oxidative stress and inflammatory factors were quantified by enzyme-linked immunosorbent assay (ELISA). Mitochondrial function was evaluated by detecting mitochondrial reactive oxide species (ROS), oxygen consumption rate (OCR), mitochondrial permeability transition pore (MPTP), adenosine 5′-triphosphate (ATP), mitochondrial membrane potential (MMP), and Ca2+. Western blotting (WB) and immunofluorescence assays were applied to detect the proteins related to apoptosis, autophagy, and YAP/TAZ signaling. YAP overexpression plasmid (Ov-YAP) was constructed for mechanism verification. Results: H/R leads to a reduction in H9c2 cell viability, and an elevation in the contents of myocardial enzymes, inflammatory factors, and oxidative stress. The apoptosis and autophagy were increased, and yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) expression levels were up-regulated in the H/R group. Nevertheless, all these changes were dose-dependently reversed by Lovastatin. Meanwhile, Lovastatin restored the levels of MMP, ATP, MPTP opening, and Ca2+, and reduced OCR in H9c2 cells exposed to H/R. Nevertheless, Ov-YAP markedly attenuated the function of Lovastatin on apoptosis, autophagy, inflammation, and oxidative stress in H9c2 cells exposed to H/R. Conclusion: The result indicated that Lovastatin played a protective role in H/R-induced H9c2 cells by inhibiting YAP/TAZ signaling. [ABSTRACT FROM AUTHOR]

[Display omitted] • Actin cytoskeleton is involved in a variety of cellular processes. • Dynamic changes in actin act as key regulators of cellular signaling. • Actin reorganization on signaling is rarely explored due to lack of suitable assay. • Quantitation of F-actin by high magnification imaging and image reconstruction. • Actin quantitation is applied in a range of processes: signaling to pathogen entry. The actin cytoskeleton is involved in a large number of cellular signaling events in addition to providing structural integrity to the cell. Actin polymerization is a key event during cellular signaling. Although the role of actin cytoskeleton in cellular processes such as trafficking and motility has been extensively studied, the reorganization of the actin cytoskeleton upon signaling has been rarely explored due to lack of suitable assays. Keeping in mind this lacuna, we developed a confocal microscopy based approach that relies on high magnification imaging of cellular F-actin, followed by image reconstruction using commercially available software. In this review, we discuss the context and relevance of actin quantitation, followed by a detailed hands-on approach of the methodology involved with specific points on troubleshooting and useful precautions. In the latter part of the review, we elucidate the method by discussing applications of actin quantitation from our work in several important problems in contemporary membrane biology ranging from pathogen entry into host cells, to GPCR signaling and membrane-cytoskeleton interaction. We envision that future discovery of cell-permeable novel fluorescent probes, in combination with genetically encoded actin-binding reporters, would allow real-time visualization of actin cytoskeleton dynamics to gain deeper insights into active cellular processes in health and disease. [ABSTRACT FROM AUTHOR]

Fragile X syndrome (FXS) is the primary hereditary cause of intellectual disability and autism spectrum disorder. It is characterized by exacerbated neuronal excitability, and its correction is considered an objective measure of treatment response in animal models, a marker albeit rarely used in clinical trials. Here, we used an extensive transcranial magnetic stimulation (TMS) battery to assess the neurophysiological effects of a therapy combining two disease‐modifying drugs, lovastatin (40 mg) and minocycline (100 mg), administered alone for 8 weeks and in combination for 12 weeks, in 19 patients (mean age of 23.58 ± 1.51) with FXS taking part in the LOVAmix trial. The TMS battery, which included the resting motor threshold, short‐interval intracortical inhibition, long‐interval intracortical inhibition, corticospinal silent period, and intracortical facilitation, was completed at baseline after 8 weeks of monotherapy (visit 2 of the clinical trial) and after 12 weeks of dual therapy (visit 4 of the clinical trial). Repeated measure ANOVAs were performed between baseline and visit 2 (monotherapy) and visit 3 (dual therapy) with interactions for which monotherapy the participants received when they began the clinical trial. Results showed that dual therapy was associated with reduced cortical excitability after 20 weeks. This was reflected by a significant increase in the resting‐motor threshold after dual therapy compared to baseline. There was a tendency for enhanced short‐intracortical inhibition, a marker of GABAa‐mediated inhibition after 8 weeks of monotherapy compared to baseline. Together, these results suggest that a combined therapy of minocycline and lovastatin might act on the core neurophysiopathology of FXS. This trial was registered at clinicaltrials.gov (NCT02680379). Lay Summary: Individuals with fragile X syndrome (FXS), the primary hereditary cause of intellectual disability and autism spectrum disorder, often have overly excited brains, which is linked to their symptoms. In this study, we used noninvasive brain stimulation to understand how brain excitability changes with treatment in individuals with FXS while participating in the LOVAmix clinical trial (NCT02680379), which combined two disease‐modifying drugs. After 20 weeks of combined therapy, our participants showed signs of lower brain activity, suggesting that combining minocycline and lovastatin might act on the underlying biology that causes the symptoms experienced by individuals with FXS. [ABSTRACT FROM AUTHOR]

Simvastatin is a widely used statin medication that is commonly prescribed to lower cholesterol levels and reduce the risk of cardiovascular events. It is marketed under the brand name Zocor and is known for its effectiveness in treating high cholesterol and managing cardiovascular disease. Monacolin J is an important precursor used to synthesize simvastatin and is mainly produced by chemical methods in industry. Here, monacolin J was synthesized through an enzymatic method under optimized reaction conditions. One recombinant Escherichia coli BL21 (DE3) strain containing lovastatin hydrolase (encoded by CDV55_102090) from Aspergillus turcosus was constructed, which effectively transformed 100 g/L of lovastatin to monacolin J within 3.5 h at pH 8.0 and 30 °C, with a conversion rate of >99.8%. Furthermore, the T5010, the temperature at which the residual activity was half of the initial enzymatic activity after 10 min of heat treatment, was >50 °C, indicating the tremendous potential of this bioprocess for synthesizing monacolin J at an industrial scale. [ABSTRACT FROM AUTHOR]

Oxidative stress hurts the survival of transplanted mesenchymal stem cells (MSCs). Lipopolysaccharide (LPS) preconditioning inhibits apoptotic death in MSCs. Also, Lovastatin's protective effect was reported on MSCs. Here, we investigated the potential of LPS and Lovastatin combination therapy on the survival and proliferation of MSCs. MSCs harvested from adult rats (240–260 g) femur and tibia bone marrow. Third passage MSCs were divided into 6 groups control group, LPS, LPS + Lovastatin (10 and 15 µM), and Lovastatin (10 and 15 µM). Cell survival and proliferation were assessed using an MTT assay 24 h after LPS, Lovastatin, or LPS + Lovastatin treatment. Also, Malondialdehyde (MDA) as a lipid peroxidation marker and antioxidant enzymes such as Glutathione peroxidase (GPX) and Superoxide dismutase (SOD) activity levels evaluated. Finally, the expression level of tumor protein P53 (P53) and octamer-binding transcription factor 4 (OCT4) genes were measured by qRT-PCR test. Lovastatin 10 μM potentiated proliferation and survival of MSCs. It can increase the activity of GPX and SOD. 10 µM Lovastatin could not affect MDA amounts but decreased the expression levels of P53 and Oct4 significantly. Nevertheless, treatment with LPS reduced the survival and proliferation of MSCs, along with a significant reduction in GPX activity. LPS + Lovastatin could increase SOD activity, however, GPX enzyme activity and MSCs proliferation did not change so, and it was not effective. We propose Lovastatin at the dose of 10 µM as a suitable combination agent to increase the survival and proliferation of MSCs in oxidative stress conditions. [ABSTRACT FROM AUTHOR]

A pH responsive non‐isocyanate polyurethane‐acrylate (NIPUA) is synthesized through utilizing palm olein and sunflower oil as feedstock. The unsaturated acyl chains of both vegetable oils are converted into epoxy rings through epoxidation and subjected to carbonation with binary catalytic system under a solventless and mild condition to produce the cyclic carbonates. The cyclic carbonates were reacted with 1,4‐butanediamine and itaconic acid to produce the NIPUA. The intermediates and product were characterized by FTIR spectroscopy, NMR spectroscopy and gel permeation chromatography. The NIPUA was incorporated with poly(vinyl pyrrolidone) (PVP) to form a polymer carrier system loaded with a hydrophobic model drug, lovastatin (LOV). All NIPUA/PVP preformulations demonstrated pH responsiveness, with 1 to 2‐folds enhanced solubility at pH 7.4 compared to pH 2.0. NIPUA/PVP exhibited solubility enhancer effect by significantly enhanced solubility (2–4 times) compared to pure LOV, LOV‐loaded PVP, and Medostatin tablets at both pH levels. LOV‐loaded NIPUA/PVP exhibited lower enthalpy energy in DSC thermogram than LOV‐loaded PVP, indicating disruption of LOV's crystalline structure. In MTT assay, IC50 values were 30.76 μg mL−1 for pure LOV and 273.53 μg mL−1 for NIPUA/PVP, demonstrating the potential of NIPUA as an environmentally friendly, pH responsive drug carrier for controlled release of poorly water‐soluble drugs. [ABSTRACT FROM AUTHOR]

Our study focused on developing and optimizing β-CD-based microparticulate carrier systems to enhance lovastatin's solubility and systemic availability (LST). Specifically, we designed solid dispersions, inclusion complexes, and hydrogel microparticles as carrier systems. Fourier-transform infrared spectroscopy (FTIR) studies were conducted to ensure drug–polymer interactions and ingredient compatibility. Additionally, we investigated the physical state, thermal stability, topology, internal morphology, and particle size using techniques such as powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), transmission electron microscopy (TEM), zeta size, and zeta potential. Our results confirmed the formation of compatible and thermally stable networks within an acceptable particle size range. The entrapment efficiency and product yield fell within 83.50–88.50% and 87–90.50%, respectively. Notably, all developed formulations exhibited a significant increase in solubility at pH 6.8 compared to LST commercial Tablets, as indicated by the regression coefficient (R2) for the release of LST following first-order kinetics. We compared LST commercial tablets with our optimized formulations (SD3 and HA3) for pharmacokinetic evaluation. SD3 demonstrated a Cmax of 63.64 µg/ml, an AUC o-t of 555.79 µg/ml.h, and a half-life (t1/2) of 7.3 h. In contrast, HA3 exhibited superior pharmacokinetic parameters with a Cmax of 93.543 µg/ml, an AUC o-t of 1154.35 µg/ml.h, and a t1/2 of 10.33 h. These results indicate the efficient release of LST from the developed carrier systems, supported by increased Cmax and lower tmax values. Furthermore, biochemical and histopathological studies on our optimized formulations confirmed their biocompatibility. Our findings demonstrate our developed β-CD-based microparticulate carrier systems' effectiveness in enhancing lovastatin's solubility, systemic availability, and biocompatibility. [ABSTRACT FROM AUTHOR]

Enteric methanogenesis in ruminants is identified as one of the primary anthropogenic sources of total atmospheric methane. Recent evidence suggests that rumen methanogenesis is significantly suppressed by lovastatin. Nevertheless, it has not been reported whether the methane reduction by lovastatin depends on ruminant livestock type, nor has fiber degradability been examined. The current research aimed to analyze the in vitro effect of lovastatin on the major fermentation end-products, gas production (GP) kinetics, and fiber degradation of a forage-based diet using rumen inoculum from sheep, goats, and cows. The experiment was conducted as a 3 × 3 factorial arrangement of treatments (dose of lovastatin: 0, 80, and 160 mg/L and three inoculum sources) in a completely randomized design. The results suggested that lovastatin did not affect the GP kinetics parameters. The anti-methanogenic properties of lovastatin were variable depending on dose and inoculum source. Lovastatin demonstrated a superior methane-lowering effect in sheep rumen inoculum compared with goat and cow inocula. The total volatile fatty acid (VFA) production was unaffected by lovastatin, but changes in acetate and valerate proportions were registered. Remarkably, lovastatin decreased the NH3-N concentration with goat and sheep inocula and the in vitro neutral fiber detergent (NDF) degradation for all inoculum sources. [ABSTRACT FROM AUTHOR]

Lovastatin (LS) is the cholesterol-lowering drug in the statin class, but it has poor oral bioavailability due to its high metabolism and low solubility, which affect its clinical efficacy. To overcome limitations associated with LS, the current study sought to develop a transdermal nanoemulsion using linseed oil and finally convert it into a nanogel formulation. Nanoemulsion (NE) was prepared using the spontaneous titration method. Different components of NE were selected based on solubility study and pseudo ternary phase diagrams were constructed using the titration method to determine the concentration range of components. Carbopol 934 was used to convert NE to nanogel (NG). The NE was selected based on the stability study and the composition of optimized NE consists of oil phase as 10%w/w linseed oil, 35%w/w Tween 80, and Polyethylene glycol 400 in 1:1 as Smix, and 55%w/w aqueous phase as water. The optimized NE (NE3) was characterized for various parameters and the formulation NE3 was found with desired globular size (108.9 ± 3.12 nm), polydispersity index 0.257 ± 0.015, zeta potential (−16.93 ± 1.12 mV), and spherical morphology. NE3 was combined with carbopol 934 to convert into NG and further characterized for pH, rheological behavior, and in vitro permeation study. The in vitro drug permeation study showed that the NG (33.69 ± 0.75 μg/cm²/h) and NE (36.63 ± 0.55 μg/cm²/h) have maximum permeation flux rate as compared to LS suspension (6.41 ± 1.13 μg/cm²/hours). These results conclude that the NG formulation of LS can be a safe and effective alternative to an oral formulation of LS with enhanced permeation characteristics for transdermal delivery. [ABSTRACT FROM AUTHOR]

Background: Lovastatin, a type of statin usually considered as a lipid‐lowering drug that lowers blood cholesterol and low‐density lipoprotein cholesterol levels, has been rediscovered to have anticancer activity. Fewer studies exist regarding the effect of lovastatin on esophageal squamous cell carcinoma (ESCC). Methods: Here, we report that lovastatin shows anticancer effect on ESCC By affecting the mitochondrial autophagy pathway. Moreover, based on proteomics and computer molecular simulations found that RAB38 and RAB27A may be a target of lovastatin. Results: We observed that autophagy of mitochondria is inhibited by lovastatin, affecting esophageal squamous cell proliferation. There is a possible link between the expression of RAB38, RAB27A and immune cell invasion in esophageal cancer. Conclusions: These results demonstrate the huge potential of lovastatin as an RAB38, RAB27A inhibitor in esophageal cancer chemotherapy and chemoprevention. [ABSTRACT FROM AUTHOR]

Chuen-Chau Chang,1– 3,&ast; Chun-Chieh Yeh,4,5 Cheng Tiong,6,7 Mao-Feng Sun,8 Jaung-Geng Lin,8 Yih-Giun Cherng,3,9 Ta-Liang Chen,2,3,10,&ast; Chien-Chang Liao1– 3,8,11 1Department of Anesthesiology, Taipei Medical University Hospital, Taipei, Taiwan; 2Anesthesiology and Health Policy Research Center, Taipei Medical University Hospital, Taipei, Taiwan; 3Department of Anesthesiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 4Department of Surgery, China Medical University Hospital, Taichung, Taiwan; 5Department of Surgery, University of Illinois, Chicago, IL, USA; 6Division of Gastroenterology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan; 7Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 8School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan; 9Department of Anesthesiology, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan; 10Department of Anesthesiology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; 11Research Center of Big Data and Meta-Analysis, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan&ast;These authors contributed equally to this workCorrespondence: Chien-Chang Liao, Department of Anesthesiology, Taipei Medical University Hospital, 252 Wuxing St, Taipei, 110, Taiwan, Email ccliao@tmu.edu.tw; jacky48863027@yahoo.com.twObjective: Sustained hyperlipidemia contributes to fatty liver and liver cirrhosis. Red yeast rice (RYR) effectively improved the lipid profile; however, the effects of RYR on the risk of incident liver cirrhosis remain to be elucidated. We aimed to evaluate the beneficial effects of RYR use on the risk and outcome of liver cirrhosis.Patients and methods: We identified 156,587 adults who had newly diagnosed hyperlipidemia in 2010– 2016 from health insurance data in this retrospective cohort study. Using propensity score matching, we selected 34,367 patients who used RYR and 34,367 patients who used lovastatin. Events of incident liver cirrhosis that occurred in the two cohorts during the follow-up period of 2010– 2019 were identified. We calculated adjusted hazard ratios (HRs) and 95% confidence intervals (Cis) for liver cirrhosis risk associated with RYR use in the multiple Cox proportional hazard model.Results: Compared with patients who used lovastatin, patients who used RYR had a decreased risk of liver cirrhosis (HR 0.60, 95% CI 0.57– 0.63), and this association was significant in various subgroups. A biological gradient relationship between the frequency of RYR use and decreased liver cirrhosis was observed (p for trend < 0.0001). Reduced postcirrhosis jaundice (HR 0.56, 95% CI 0.43– 0.72), ascites (HR 0.37, 95% CI 0.28– 0.50), hepatic coma (HR 0.36, 95% CI 0.26– 0.50), and mortality (HR 0.48, 95% CI 0.38– 0.61) were also associated with RYR use.Conclusion: We demonstrated the beneficial effects of RYR use on the risk and outcome of liver cirrhosis; however, the lack of compliance data should be considered. However, our study did not infer causality or claim the superiority of RYR over lovastatin.Keywords: hyperlipidemia, liver cirrhosis, lovastatin, outcome, red yeast rice, risk

Abstract 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.

Background: Evidence suggests that statins can improve survival outcomes and ameliorate treatment-related side-effects in certain malignancies. Statins exhibit various mechanisms of action, including apoptosis induction, proliferation inhibition, tumor radiosensitization, lipid production suppression, and anti-inflammatory effects. This trial aimed to assess the impact of lovastatin on patients with locally advanced head and neck squamous cell carcinoma (HNSCC) undergoing definitive chemoradiation. Method: In this double-blinded randomized phase 2 clinical trial, 35 patients were randomly allocated to receive either 80 mg of lovastatin daily in conjunction with chemoradiotherapy (case group, n=18) or a placebo (control group, n=17). Primary outcomes included the response rate (RR) after three months, the occurrence of acute and late side-effects, median progression-free survival (PFS), and overall survival (OS). Results: The complete RR was slightly higher in the statin group (83.3% vs. 64.7%), although it did not reach statistical significance (P = 0.592). Acute adverse events did not significantly differ between the two groups. Grade 3 dermatitis occurred more frequently in the placebo group (35.3% vs. 11.1%), while grade 3 mucositis was more common in the statin group (38.9% vs. 11.8%). The median OS was 22 months (confidence interval (CI) 95% = 6.3-37.6) in the statin group and 17 months (CI 95% = 4.9-29.1) in the control group (P = 0.50). Median PFS was 20 months (CI 95% = 15.8-24.1) in the statin group and 15 months (CI 95% = 8.2-21.7) in the control group (P = 0.609). Conclusion: Combining lovastatin with chemoradiation augments the therapeutic effect in HNSCC. Larger-scale studies incorporating advanced radiotherapy techniques and baseline lipid profile assessments are necessary to investigate statins' efficacy in HNSCC further. [ABSTRACT FROM AUTHOR]

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Statins are 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors widely used in the treatment of hyperlipidemia. The inhibition of HMG-CoA reductase in the mevalonate pathway leads to the suppression of cell proliferation and induction of apoptosis. The cyclic GMP-AMP synthase (cGAS) stimulator of the interferon genes (STING) signaling pathway has been suggested to not only facilitate inflammatory responses and the production of type I interferons (IFN), but also activate other cellular processes, such as apoptosis. It has not been studied, however, whether cGAS-STING activation is involved in the apoptosis induced by statin treatment in human colorectal cancer cells. In this study, we reported that lovastatin impaired mitochondrial function, including the depolarization of mitochondrial membrane potential, reduction of oxygen consumption, mitochondrial DNA (mtDNA) integrity, and mtDNA abundance in human colorectal cancer HCT116 cells. The mitochondrial dysfunction markedly induced ROS production in mitochondria, whereas the defect in mitochondria respiration or depletion of mitochondria eliminated reactive oxygen species (ROS) production. The ROS-induced oxidative DNA damage by lovastatin treatment was attenuated by mitochondrial-targeted antioxidant mitoquinone (mitoQ). Upon DNA damage, mtDNA was released into the cytosol and bound to DNA sensor cGAS, thus activating the cGAS-STING signaling pathway to trigger a type I interferon response. This effect was not activated by nuclear DNA (nuDNA) or mitochondrial RNA, as the depletion of mitochondria compromised this effect, but not the knockdown of retinoic acid-inducible gene-1/melanoma differentiation-associated protein 5 (RIG-I/MDA5) adaptor or mitochondrial antiviral signaling protein (MAVS). Moreover, lovastatin-induced apoptosis was partly dependent on the cGAS-STING signaling pathway in HCT116 cells as the knockdown of cGAS or STING expression rescued cell viability and mitigated apoptosis. Similarly, the knockdown of cGAS or STING also attenuated the antitumor effect of lovastatin in the HCT116 xenograft model in vivo. Our findings suggest that lovastatin-induced apoptosis is at least partly mediated through the cGAS-STING signaling pathway by triggering mtDNA accumulation in the cytosol in human colorectal cancer HCT116 cells. [ABSTRACT FROM AUTHOR]

Statins, in the role of anti-cancer agents, have been used in many types of cancers with results in some cases promising while, in others, disappointing. The purpose of this review is to identify and highlight data from literature on the successes or failure of using statins as anti-cancer agents. We asked ourselves the following two questions: 1. Could statins, which are taken mostly to reduce cardiovascular risk, guarantee a lower incidence or a better cancer disease prognosis, concerning local recurrence, metastasis or mortality? 2. Does statins intake (before and/or after cancer diagnosis) improve the prognosis or increase the chemotherapeutic action when combined with other anticancer therapies? For the first question twenty-seven manuscripts have been selected, for the second one, twenty-eight. There are data which correlate statins with a possible tumor suppressive action among the following cancers: breast, lung, prostate and head and neck. Lastly, for gastric cancer and colorectal there is no evidence of a correlation. The onco-suppressive efficacy of statins is mainly related to the histopathological and/or molecular characteristics of the tumor cells, which have different characteristics. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Simple Summary: Cerebral alterations have been identified in Chagas disease since its discovery. Meningoencephalitis and stroke were verified in patients and experimental models of infection. Our group previously described brain microvasculopathy in mice caused by Trypanosoma cruzi (Y strain) infection, which was characterized by endothelial dysfunction, a reduction in perfused capillaries, and increased leukocyte rolling and adhesion. Nowadays, nifurtimox and benznidazole are still the only options for Chagas disease treatment, but the high rate of side-effect occurrence may lead patients to treatment interruption. In the search for better treatment alternatives, statins show promising effects. The literature shows evidence that statins present anti-inflammatory activity and the ability to improve endothelial function, and they could also have trypanocidal activity. All these indicate that it could be an interesting drug to treat cerebral microvasculopathy in Chagas disease. In this paper, we investigate the effect of lovastatin on microcirculation damage and brain inflammation caused by acute experimental T. cruzi infection. Here, we report that lovastatin prevented the increase in F4/80+ cells and ICAM-1 levels in the brain caused by acute infection with T. cruzi, suggesting an anti-inflammatory activity of lovastatin. Neurological commitment is a neglected manifestation of Chagas disease (CD). Meningoencephalitis mainly affects children and immunosuppressed patients, while stroke can occur with or without cardiac compromise. One of the possible causes of stroke development is microvascular commitment. Our group previously described that experimental Trypanossoma cruzi acute infection leads to cerebral microvasculopathy. This condition is characterized by decreased capillary density, increased leukocyte rolling and adhesion, and endothelial dysfunction. CD was discovered 114 years ago, and until today, only two drugs have been available for clinical treatment: benznidazole and nifurtimox. Both present a high cure rate for the acute phase (80%) and small cure rate for the chronic phase (20%). In addition, the high occurrence of side-effects, without proper medical follow-up, can result in treatment abandonment. Therefore, the search for new therapeutic schemes is necessary. Statins are drugs already used in the clinic that have several pleiotropic effects including endothelial function improvement, anti-inflammatory action, as well as trypanocidal effects, making them a potential alternative treatment for brain microvasculopathy in CD. Here, we investigate the effect of lovastatin (LOV) on brain microvasculopathy and inflammatory parameters. Swiss Webster mice were intraperitoneally inoculated with the Y strain of T. cruzi. Treatment with lovastatin (20 mg/kg/day) was initiated 24 h after the infection and continued for 14 consecutive days. We observed that LOV treatment did not affect parasitemia, brain microcirculation alterations, or the reduction in cerebral blood flow caused by T. cruzi infection. Also, LOV did not prevent the increased number of CD3+ cells and eNOS levels in the T. cruzi-infected brain. No alterations were observed on VCAM-1 and MCP-1 expressions, neither caused by infection nor LOV treatment. However, LOV prevented the increase in F4/80+ cells and ICAM-1 levels in the brain caused by acute infection with T. cruzi. These results suggest an anti-inflammatory activity of LOV, but more studies are needed to elucidate the role of LOV in CD acute infection. [ABSTRACT FROM AUTHOR]

Abstracts: Air pollution, a global health concern, has been associated with adverse effects on human health. In particular, particulate matter (PM), which is a major contributor to air pollution, impacts various organ systems including the skins. In fact, PM has been suggested as a culprit for accelerating skin aging and pigmentation. In this study, using single-cell RNA sequencing, IL-24 was found to be highly upregulated among the differentially expressed genes commonly altered in keratinocytes and fibroblasts of ex vivo skins exposed to PM. It was verified that PM exposure triggered the expression of IL-24 in keratinocytes, which subsequently led to a decrease in type I procollagen expression and an increase in MMP1 expression in fibroblasts. Furthermore, long-term treatment of IL-24 induced cellular senescence in fibroblasts. Through high-throughput screening, we identified chemical compounds that inhibit the IL-24-STAT3 signaling pathway, with lovastatin being the chosen candidate. Lovastatin not only effectively reduced the expression of IL24 induced by PM in keratinocytes but also exhibited a capacity to restore the decrease in type I procollagen and the increase in MMP1 caused by IL-24 in fibroblasts. This study provides insights into the significance of IL-24, illuminating mechanisms behind PM-induced skin aging, and proposes IL-24 as a promising target to mitigate PM-associated skin aging.

BACKGROUND: To improve the quality of red starter wine, this study explored the effects of baking red kojic rice at varying temperatures on the physicochemical characteristics of red starter wine. Baking was predicated on understanding crucial enzyme activities and starch granule structure of red kojic rice at 75, 95, and 105 °C, leading to the production of three red starter wine variants (BHQW1, BHQW2, and BHQW3). RESULTS: The results revealed an increased alcohol (increase 0.50%), total sugar (increase 0.14 g L-1), and total acid (increase 0.54 g L-1) content in red starter wine fermented using baked red kojic rice compared with the control group (wine fermented with unbaked rice, HQW). Furthermore, both the 105 °C baked red kojic rice and its resulting BHQW3 demonstrated significantly higher red color values than HQW (increase 2.03 U g-1 and 0.15 U mL-1 respectively). The highest lovastatin content was presented in red kojic rice baked at 105 °C and its corresponding fermented wine (1420.63 ± 507.9 ~g g-1 and 3368.87 ± 228.16 ~g L-1 respectively). Additionally, BHQW groups displayed higher total flavonoids and phenols content than HQW. Regarding antioxidant capacity, all BHQW groups showed stronger overall antioxidant capacity than HQW. The determination of volatile components revealed the highest content of volatile compounds in BHQW2 (2621.19 ± 548.24 ~g L-1) and significantly higher volatile esters in BHQW1 (254.46 ± 16.63 ~g L-1). Moreover, 16 volatile compounds were identified only in BHQW groups, including isoamyl caprylate, 2-ethylhexyl alcohol, and benzaldehyde. CONCLUSION: Our findings suggested that the baking technique of red kojic rice could enhance the quality of red starter wine through enhancing antioxidant properties, increasing functional components, and enriching volatile flavor compounds, thus providing a foundation for new techniques in red starter wine production. [ABSTRACT FROM AUTHOR]

One of the most important challenges in the pharmaceutical industry is to produce crystals with desired size and shape distributions, to enhance the critical quality attributes of the drug product, such as efficacy, and to improve manufacturability during downstream processing, such as filtration, drying and granulation. The paper provides a framework for effective crystal shape and size tuning, based on a systematic exploration of standard techniques, such as the linear cooling and supersaturation control (SSC), and novel methods based on the systematic combination of several techniques, namely direct nucleation control (DNC), wet milling, SSC and shape modification additives. The crystallization of lovastatin, which is notorious for its challenging needle-shaped crystals, with an extremely high aspect ratio, was used as a case study, and polypropylene glycol (PPG-4000), at different concentrations, was used as an effective shape modifier from small-scale tests studied previously. The proposed techniques were implemented in the case of seeded and unseeded systems. It was demonstrated that the combination of temperature cycling and polymer additive enhances greatly the control over the aspect ratio and crystal size distribution, compared to conventional linear cooling and SSC strategies. The implementation of wet milling at the beginning of the process, or the introduction of seeds, enhances even further the control of the critical quality attributes of the crystalline product. [Display omitted] • Developed and validated a new framework for systematic crystal shape and size tuning. • Standard cooling crystallization with a polymer additive was insufficient to improve the aspect ratio of lovastatin. • Crystal shape successfully modified using additives and Direct Nucleation Control (DNC). • The additive caused inhibition along the longest axis which resulted in an effective control of the aspect ratio. • The lowest aspect ratio was achieved using a combination of seeding, milling, additives and DNC. [ABSTRACT FROM AUTHOR]

3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase, HMGCR) is one of the rate-limiting enzymes in the mevalonate pathway required for cholesterol biosynthesis. It is an integral membrane protein of the endoplasmic reticulum (ER) but has occasionally been described in peroxisomes. By co-immunofluorescence microscopy using different HMGCR antibodies, we present evidence for a dual localization of HMGCR in the ER and peroxisomes in differentiated human monocytic THP-1 cells, primary human monocyte-derived macrophages and human primary skin fibroblasts under conditions of low cholesterol and statin treatment. Using density gradient centrifugation and Western blot analysis, we observed a truncated HMGCR variant of 76 kDa in the peroxisomal fractions, while a full-length HMGCR of 96 kDa was contained in fractions of the ER. In contrast to primary human control fibroblasts, peroxisomal HMGCR was not found in fibroblasts from patients suffering from type-1 rhizomelic chondrodysplasia punctata, who lack functional PEX7 and, thus, cannot import peroxisomal matrix proteins harboring a type-2 peroxisomal targeting signal (PTS2). Moreover, in the N–terminal region of the soluble 76 kDa C-terminal catalytic domain, we identified a PTS2-like motif, which was functional in a reporter context. We propose that under sterol-depleted conditions, part of the soluble HMGCR domain, which is released from the ER by proteolytic processing for further turnover, remains sufficiently long in the cytosol for peroxisomal import via a PTS2/PEX7-dependent mechanism. Altogether, our findings describe a dual localization of HMGCR under combined lipid depletion and statin treatment, adding another puzzle piece to the complex regulation of HMGCR. [ABSTRACT FROM AUTHOR]

Abstract Background The existence of the gut microbiota produces an “individual drug reaction.” As members of the intestinal microbiota, probiotics, although they have prebiotic functions, may accelerate the degradation of drugs, thereby affecting drug efficacy. Lovastatin is one of the well-recognized lipid-lowering drugs. Its main action site is the liver. Therefore, if it is degraded in advance by gastrointestinal probiotics, its efficacy may be reduced. Results Here, we designed a two-stage experiment in vitro and in vivo to explore the degradation of lovastatin by probiotics. In vitro, the degradation of lovastatin by 83 strains of Lactiplantibacillus plantarum and the “star strain” Lacticaseibacillus paracasei strain Shirota was investigated by high-performance liquid chromatography (HPLC). The results showed that probiotics could degrade lovastatin to varying degrees. Subsequently, we selected Lactiplantibacillus plantarum A5 (16.87%) with the strongest ability to degrade lovastatin, Lactiplantibacillus plantarum C3 (4.61%) with the weakest ability to degrade lovastatin and Lacticaseibacillus paracasei strain Shirota (17.6%) as representative probiotics for in vivo experiments. In vivo, the therapeutic effect of lovastatin combined with probiotics on golden hamsters with mixed hyperlipidemia was evaluated by measuring blood indicators, intestinal microbiota metagenomic sequencing, and the liver transcriptome. The results showed that the intake of probiotics did not affect the efficacy of lovastatin and could slow the inflammatory reaction of the liver. Conclusions The supplementation of probiotics produced beneficial metabolites in the intestine by promoting beneficial microbes. Intestinal metabolites affected the expression of the liver genes through the gut-liver axis, increased the relative content of the essential amino acids, and finally improved the liver inflammatory response of the host. This study aims to reveal the impact of probiotics on the human body from a unique perspective, suggesting the impact of taking probiotics while taking drugs. Video Abstract

Continuous crystallization of lovastatin from a lovastatin-methanol solution and water as the anti-solvent in an impinging jet crystallizer is investigated using a computational fluid dynamics model. To capture the important phenomena, the model is coupled with micro-mixing, population balance, and related energy balance equations. It is implemented in OpenFOAM and validated against experimental data, where a fairly good agreement is found. The effects of key process parameters on the crystallization performance are also studied using the validated model. The results show that increasing the inlet jet velocity from 1 to 4 m/s yields a much narrower size distribution and 70% reduction in the mean crystal size. The four-fold increase in the inlet jet velocity also reduces the crystal production rate by one order of magnitude. Also, it is found that increasing the inlet supersaturation ratio from 6.8 to 8.8 nearly doubles the mean crystal size. Moreover, it results in a wider size distribution and a six-fold increase in the crystal production rate. The simulations also confirm that lower solution to anti-solvent mass flow ratios yield a wider size distribution, a larger mean crystal size and a higher crystal production rate. Increasing this ratio from 0.5 to 2 reduces the production rate by two orders of magnitude. [ABSTRACT FROM AUTHOR]

The beneficial effect of pretreatment with statins on traumatic brain injury (TBI)-induced depression and anxiety and its mechanism of action remain unclear. In this study, we combined epidemiological and experimental animal data to clarify this issue. We used the Taiwan National Health Insurance database to identify patients who were diagnosed with TBI from 2000 to 2013 and compared patients with and without statin treatment matched by age, sex, and underlying comorbidities in a 1:1 ratio. The risk of developing depression and/or anxiety was compared between patients with and without a statin using Cox proportional hazards regression. We also used a rat model to assess the effect of lovastatin pretreatment on neurobehavioral and neuropathological changes following TBI. The risk of developing depression was lower in the 41,803 patients in the statin cohort than nonstatin cohort (adjusted hazard ratio, 0.91 [95% confidence interval, 0.83–0.99]). In animal models, the lovastatin group had significantly reduced infarct volume, decreased immobility time and latency to eat, a reduced number of Fluoro- Jade-positive cells and levels of glial fibrillary acidic protein and tumor necrosis factor-alpha, and increased adenosine monophosphate -activated protein kinase (AMPK) and its upstream kinase liver kinase B1 in the hippocampal dentate gyrus. These effects were blocked in AMPK inhibitor-pretreated TBI rats. Our epidemiological data showed that a decreased risk of depression was associated with statin pretreatment, which was supported by an animal study. The underlying mechanism for this appears to involve AMPK activation in the statin pretreatment-induced alleviation of TBI. [ABSTRACT FROM AUTHOR]

Background: The effect of selegiline as an oxidase inhibitor on cell differentiation into neuron-like cells has been demonstrated by altering gene expression. Based on the results of studies on the role of statins in neurotrophin regulation, in this study, we examined the effect of lovastatin (HMG-CoA reductase inhibitor) on the differentiation of bone marrow mesenchymal cells (BMSCs) into neuron-like cells. Selegiline isanirreversible inhibitor of monoamineoxidase(MAO)typeB. Sincedopaminein thehumanbrain is metabolized primarily by MAO-B, selegiline increases dopamine levels in the central nervous system. In addition to inhibiting MAO-B, selegiline also inhibits the uptake of dopamine and norepinephrine into presynaptic nerves and increases dopamine turnover. Methods: Bone marrow mesenchymal cells were collected from 28-day-old rats and cultured under standard conditions on the medium. The experimental groups in this study were as follows: BMSCs (control); BMSCs induced with 20μM selegiline for 24 hours (experiment 1); BMSCs induced with 6 μMlovastatin for 24 hours (experiment 2); BMSCs were induced with 20 μMselegiline for 24 hours and 6 μM lovastatin for the next 24 hours (experiment 3). Real-time RT-PCR was performed to determine the mRNA levels of the nestin and NF-68 genes. Results: Real-time RT-PCR results showed that nestin and NF-68 mRNA levels were significantly increased in the co-treatment group (experiment 3) compared to the other experimental groups (P < 0.05). Conclusions: Based on the increased expression of nestin and NF-68 genes, the presence of lovastatin has a synergistic effect on neuronal differentiation and optimization of stem cell therapeutic approaches. [ABSTRACT FROM AUTHOR]

Adventitious root (AR) formation is the key to asexual reproduction; however, cytokinin (CK) hampers AR formation. But the mechanism by which CK inhibits it is still unknown. In this study, we used Malus prunifolia var. ringo apple stem cuttings that were treated with exogenous 6-benzyl adenine (6-BA) at 1 mg/L and lovastatin (CK biosynthesis inhibitor) at 1 mg/L to compare with control (untreated) cuttings. The results indicated that the control and 6-BA-treated cuttings failed to produce ARs; however, lovastatin-treated cuttings successfully produced a few ARs after 20 days (d) of treatments by increasing indole-3-acetic acid (IAA) and reducing zeatin riboside (ZR) content at several time points. The 6-BA treatment induced the expression of CK-related genes, such as MdARR3, MdARR5, MdARR5-2, MdAKH4, and MdCKX5, at most time points. However, lovastatin-treated cuttings reduced their expression, which favors AR formation. Furthermore, the expression of auxin-related genes, including MdIAA23, MdARF7, and MdARF19, was induced by lovastatin treatment. Like auxin-related genes, several root-development-related genes (MdWOX5, MdWOX11, MdLB29, and MdARRO1) were also promoted in response to lovastatin treatment that were repressed by 6-BA and control cuttings. In conclusion, lovastatin treatment supports AR formation by inhibiting CK biosynthesis inside the cuttings, as compared to the control and 6-BA-treated cuttings. This study laid the foundation for future studies on the relationship of CK biosynthesis inhibitors with adventitious rooting in apples and other crops. [ABSTRACT FROM AUTHOR]

Lovastatin is a statin used to treat hypercholesterolemia and cardiovascular diseases (CVDs). It is produced by several medicinal non-pathogenic fungi, including Monascus purpureus (MP). While CVDs account for a high percentage of deaths in Iran, few studies have investigated lovastatin production in the country. This study aimed to examine the semi-industrial production of lovastatin from MP by controlling the amount of mycotoxin citrinin. Eleven treatments containing varying levels of several sources of carbon, nitrogen, and several physical factors of the fungus culture medium were tested simultaneously using a Plackett-Burman screening design. Building on Pareto chart, the Plackett-Burman test determined the contribution of each factor to the production of lovastatin and mycotoxin citrinin. As a carbon source, higher barley concentration increased lovastatin production. Lovastatin production required an increased aeration rate with a further rise in barley content. The maximum production of lovastatin (318 mg/L) and lower content of mycotoxin citrinin (48 ppb) occurred under optimized conditions (20 g/L of barley and 8 L/min of aeration). Barley and aeration rates contributed significantly to higher lovastatin and lower mycotoxin citrinin production. These findings can be used in the semi-industrial production of lovastatin with low levels of mycotoxin citrinin (less than the allowable limit). [ABSTRACT FROM AUTHOR]

The tea plant is a vital strategic forest resource in China. Dark tea produced from its leaves is an indispensable health-promoting product in western China due to its unique lipid-lowering function. Eurotium cristatum is the dominant strain in Fuzhuan brick tea (a variety of Anhua dark tea) and could produce many functional components, including lovastatin, a lipid-lowering compound. In this study, the lovastatin yield of dark tea was improved by breeding Eurotium cristatum using the protoplast fusion method. The experiments were carried out by inducing a fusion between inactivated Eurotium cristatum JH1205 and Monascus CICC5031. Among the 92 fusants screened the HPLC method, four strains (A4, A36, A54, and A76) with higher lovastatin production (more than three times as high) were obtained. The A76 strain had the highest lovastatin yield, which was 23.93 μg/mL. The location of the tea forest strongly influenced the lovastatin yield of loose dark tea. The strain bred in this study improved the lovastatin yield of loose dark tea by more than three times when compared to wild Eurotium cristatum. These results are promising for the development of tea forest resources. [ABSTRACT FROM AUTHOR]

Monascus sp. is an important food microbial resource with the production of cholesterol-lowering agent lovastatin and other healthy metabolites. However, the mycotoxin citrinin naturally produced by Monascus sp. and the insufficient productivity of lovastatin limit its large-scale use in food industry. The aim of this paper is to modify a lovastatin-producing strain Monascus pilosus GN-01 through metabolic engineering to obtain a citrinin-free M. pilosus strain with higher yield of lovastatin. The citrinin synthesis regulator gene ctnR was firstly disrupted to obtain GN-02 without citrinin production. Based on that, the lovastatin biosynthesis genes (mokC, mokD, mokE, mokF, mokH, mokI, and LaeA) were, respectively, overexpressed, and pigment-regulatory gene (pigR) was knocked out to improve lovastatin production. The results indicated ctnR inactivation effectively disrupted the citrinin release by M. pilosus GN-01. The overexpression of lovastatin biosynthesis genes and pigR knockout could lead higher contents of lovastatin, of which pigR knockout strain achieved 76.60% increase in the yield of lovastatin compared to GN-02. These studies suggest that such multiplex metabolic pathway engineering in M. pilosus GN-01 is promising for high lovastatin production by a safe strain for application in Monascus-related food. Key points: • Disruption of the regulator gene ctnR inhibited citrinin production of M. pilosus. • Synchronous overexpression of biosynthesis gene enhanced lovastatin production. • pigR knockout enhanced lovastatin of ΔctnR strain of M. pilosus. [ABSTRACT FROM AUTHOR]

Prostate cancer (PC) is the second most frequently diagnosed cancer and the fifth leading cause of cancer-related death in males worldwide. Early-stage PC patients can benefit from surgical, radiation, and hormonal therapies; however, once the tumor transitions to an androgen-refractory state, the efficacy of treatments diminishes considerably. Recently, the exploration of natural products, particularly dietary phytochemicals, has intensified in response to addressing this prevailing medical challenge. In this study, we uncovered a synergistic effect from combinatorial treatment with lovastatin (an active component in red yeast rice) and Antrodia camphorata (AC, a folk mushroom) extract against PC3 human androgen-refractory PC cells. This combinatorial modality resulted in cell cycle arrest at the G0/G1 phase and induced apoptosis, accompanied by a marked reduction in molecules responsible for cellular proliferation (p-Rb/Rb, Cyclin A, Cyclin D1, and CDK1), aggressiveness (AXL, p-AKT, and survivin), and stemness (SIRT1, Notch1, and c-Myc). In contrast, treatment with either AC or lovastatin alone only exerted limited impacts on the cell cycle, apoptosis, and the aforementioned signaling molecules. Notably, significant reductions in canonical PC stemness markers (CD44 and CD133) were observed in lovastatin/AC-treated PC3 cells. Furthermore, lovastatin and AC have been individually examined for their anti-PC properties. Our findings elucidate a pioneering discovery in the synergistic combinatorial efficacy of AC and clinically viable concentrations of lovastatin on PC3 PC cells, offering novel insights into improving the therapeutic effects of dietary natural products for future strategic design of therapeutics against androgen-refractory prostate cancer. [ABSTRACT FROM AUTHOR]

The association between the c.521T>C variant allele in SLCO1B1 (reference single nucleotide polymorphism (rs)4149056) and simvastatin-induced myotoxicity was discovered over a decade ago; however, whether this relationship represents a class effect is still not fully known. The aim of this study was to investigate the relationship between rs4149056 genotype and statin-induced myotoxicity in patients taking atorvastatin and lovastatin. Study participants were from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. A total of 233 statin-induced myopathy + rhabdomyolysis cases met the criteria for inclusion and were matched to 2,342 controls. To validate the drug response phenotype, we replicated the previously established association between rs4149056 genotype and simvastatin-induced myotoxicity. In particular, compared with homozygous T allele carriers, there was a significantly increased risk of simvastatin-induced myopathy + rhabdomyolysis in homozygous carriers of the C allele (CC vs. TT, odds ratio [OR] 4.62, 95% confidence interval [CI] 1.58-11.90, P = 0.003). For lovastatin users, homozygous carriers of the C allele were also at increased risk of statin-induced myopathy + rhabdomyolysis (CC vs. TT, OR 4.49, 95% CI 1.68-10.80, P = 0.001). In atorvastatin users, homozygous carriers of the C allele were twice as likely to experience statin-induced myopathy, though this association did not achieve statistical significance (CC vs. TT, OR 2.00, 95% CI 0.44-6.59, P = 0.30). In summary, our findings suggest that the association of rs4149056 with simvastatin-related myotoxicity may also extend to lovastatin. More data is needed to determine the extent of the association in atorvastatin users. Altogether, these data expand the evidence base for informing guidelines of pharmacogenetic-based statin prescribing practices.