25-Hydroxycholesterol inhibits Hantavirus infection by reprogramming cholesterol metabolism.

Hantavirus causes two types of acute diseases: hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. It is a major health concern due to its high mortality and lack of effective treatment. Type I interferon treatment has been suggested to be effective against hantavirus when treated in advance. Interferons induce multiple interferon-stimulated genes (ISGs), whose products are highly effective at resisting and controlling viruses. A product of ISGs, the enzyme cholesterol 25-hydroxylase (CH25H), catalyzes the oxidation of cholesterol to 25-hydroxycholesterol (25HC). 25HC can inhibit multiple enveloped-virus infections, but the mechanism is largely unknown, and whether 25HC plays an important role in regulating hantavirus remains unexplored. In this study, we show that Hantaan virus (HTNV), the prototype hantavirus, induced CH25H gene in infected cells. Overexpression of CH25H and treatment with 25HC, inhibited HTNV infection, possibly by lowering 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG-CoA reductase, HMGCR), which inhibits cholesterol biosynthesis. In addition, cholesterol-lowering drugs such as HMGCR-targeting statins have potent hantavirus inhibitory effects. Our results indicate that 25HC and some statins are potential antiviral agents effective against hantavirus infections. This study provides evidence that targeting cholesterol metabolism is promising in developing specific hantavirus antivirals and indicates the possibility of repurposing FDA-approved cholesterol-lowering drug, statins for treating hantavirus infection.

From Studio to Rehab: A Debilitating Form of Anti-HMGCR Myopathy.

Immune-mediated necrotizing myopathy is a subtype of immune-mediated myopathy associated with or without statin use. Statins, or HMG-CoA reductase inhibitors, are the most prescribed medications for dyslipidemia. The statin-associated myopathic syndromes range from asymptomatic elevations in creatine kinase to severe debilitating muscle weakness with associated rhabdomyolysis and elevated liver enzymes. Clinical improvement occurs upon discontinuation of statins, but some patients do not recover completely. Diagnostic tests include electromyography, muscle biopsy, myositis autoantibody panel, and antibodies against the HMGCR. Here, we present a case of anti-HMGCR-related myopathy associated with atorvastatin.

Lipid alterations in chronic liver disease and liver cancer.

Lipids are a complex and diverse group of molecules with crucial roles in many physiological processes, as well as in the onset, progression, and maintenance of cancers. Fatty acids and cholesterol are the building blocks of lipids, orchestrating these crucial metabolic processes. In the liver, lipid alterations are prevalent as a cause and consequence of chronic hepatitis B and C virus infections, alcoholic hepatitis, and non-alcoholic fatty liver disease and steatohepatitis. Recent developments in lipidomics have also revealed that dynamic changes in triacylglycerols, phospholipids, sphingolipids, ceramides, fatty acids, and cholesterol are involved in the development and progression of primary liver cancer. Accordingly, the transcriptional landscape of lipid metabolism suggests a carcinogenic role of increasing fatty acids and sterol synthesis. However, limited mechanistic insights into the complex nature of the hepatic lipidome have so far hindered the development of effective therapies.

Functional study of SCCD pathogenic gene UBIAD1 (Review).

Schnyder's crystalline corneal dystrophy (SCCD) is a rare autosomal dominant genetic disorder that is characterized by progressive corneal opacity, owing to aberrant accumulation of cholesterol and phospholipids in the cornea. A number of SCCD affected families have been reported in the world since 1924, when it was first described. In 2007, the molecular basis of SCCD was demonstrated to be associated with a tumor suppressor, UbiA prenyltransferase domain­containing 1 (UBIAD1), which was isolated from the bladder mucosa and demonstrated to be involved in vitamin K2 and CoQ10 biosynthesis. This sterol triggers the binding of UBIAD1 to 3­hydroxy­3­methyl­glutaryl coenzyme A reductase (HMGCR) at endoplasmic reticulum (ER) membranes, which is regulated by an intracellular geranylgeranyl diphosphate (GGpp) molecule. The inability of SCCD­associated UBIAD1 to bind GGpp results in the consistent binding of UBIAD1 to HMGCR at ER membranes. This binding leads to HMGCRs being redundant. Therefore, they cannot be degraded through ER­associated degradation to synthesize abundant cholesterol in tissue cells. Excess corneal cholesterol accumulation thus leads to SCCD disease. After decades, the efforts of numerous ophthalmologists and scientists have helped clarify the molecular basis and pathogenesis of SCCD, which has guided the effective diagnosis and treatment of this genetic disorder. However, more studies need to be conducted to understand the pathogenesis of SCCD disease from a genetic basis by studying the defective gene, UBIAD1. Results would guide effective diagnosis and treatment of the inherited eye disease.

The cost-effectiveness of icosapent ethyl in combination with statin therapy compared with statin alone for cardiovascular risk reduction.

AIMS: The aim of this study was to estimate the cost-effectiveness, from the perspective of the Australian public healthcare system, of icosapent ethyl in combination with statin therapy compared with statin alone for the prevention of cardiovascular disease. METHODS AND RESULTS: A Markov model populated with data from the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial was designed to predict the effectiveness and costs of icosapent ethyl in combination with statins compared with statins alone over a 20-year time horizon. Data inputs for costs and utilities were sourced from published sources. The annual costs of icosapent ethyl were assumed to be AUD1637 (USD2907) per person. All future costs and outcomes were discounted annually by 5%. The main outcome of interest was incremental cost-effectiveness ratios in terms of cost per quality adjusted life year (QALY) gained and per year of life saved (YoLS). Over a 20-year time horizon, compared with statin alone, icosapent ethyl in combination with statin was estimated to cost an additional AUD$13,022 per person, but led to 0.338 YoLS and 0.289 QALYs gained (all discounted). These equated to incremental cost-effectiveness ratios of AUD45,036 per QALY gained and AUD38,480 per YoLS. Sub-analyses for primary and secondary prevention were AUD96,136 and AUD35,935 per QALY gained, respectively. The results were sensitive to time-horizon, age related trends and the acquisition price of icosapent ethyl. CONCLUSION: Compared with statin alone, icosapent ethyl in combination with statin therapy is likely to be cost-effective in the prevention of cardiovascular disease assuming a willingness-to-pay threshold of AUD50,000 per QALY gained, especially in the secondary preventive setting.

RNA-binding protein hnRNPR reduces neuronal cholesterol levels by binding to and suppressing HMGCR.

Recent studies have identified multiple RNA-binding proteins tightly associated with lipid and neuronal cholesterol metabolism and cardiovascular disorders. However, the role of heterogeneous nuclear ribonucleoprotein R (hnRNPR) in cholesterol metabolism and homeostasis, whether it has a role in regulating 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), is largely unknown. This research identifies hnRNPR as a repressor of HMGCR. Knockdown and overexpression of hnRNPR in cultured neuroblastoma cell (N2a) and MN1 cell lines enhances and inhibits HMGCR in vitro, respectively. hnRNPR may exert its repressive activity on HMGCR mRNA and protein levels by using its RNA recognition motif (RRM) in recognizing and modulating the stability of HMGCR transcript. Our RNA immunoprecipitation and luciferase reporter assays demonstrate a direct interaction between hnRNPR and HMGCR mRNA. We also demonstrated that hnRNR binds to the 3' untranslated region (3' UTR) of HMGCR and reduces its translation, while hnRNPR silencing increases HMGCR expression and cholesterol levels in MN1 and N2a cells. Overexpression of HMGCR significantly restores the decreased cholesterol levels in hnRNPR administered cells. Taken together, we identify hnRNPR as a novel post-transcriptional regulator of HMGCR expression in neuronal cholesterol homeostasis.

Statins in risk-reduction and treatment of cancer.

Statins, which are competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, reduce cholesterol blood levels and the risk of developing cardiovascular diseases and their related complications. In addition to this main activity, statins show pleiotropic effects such as antioxidant, anti-inflammatory and antiproliferative properties, with applications in many pathologies. Based on their antiproliferative properties, in vitro and in vivo studies have investigated their effects on various types of cancer (i.e., breast cancer, prostate cancer, colorectal cancer, ovarian cancer, lung cancer) with different genetic and molecular characteristics. Many positive results were obtained, but they were highly dependent on the physiochemical properties of the statins, their dose and treatment period. Combined therapies of statins and cytotoxic drugs have also been tested, and synergistic or additive effects were observed. Moreover, observational studies performed on patients who used statins for different pathologies, revealed that statins reduced the risk of developing various cancers, and improved the outcomes for cancer patients. Currently, there are many ongoing clinical trials aimed at exploring the potential of statins to lower the mortality and the disease-recurrence risk. All these results are the foundation of new treatment directions in cancer therapy.

Comparing the serum TAG response to high-dose supplementation of either DHA or EPA among individuals with increased cardiovascular risk: the ComparED study.

Studies have shown that the reduction in serum TAG concentrations with long-chain n-3 fatty acid supplementation is highly variable among individuals. The objectives of the present study were to compare the proportions of individuals whose TAG concentrations lowered after high-dose DHA and EPA, and to identify the predictors of response to both modalities. In a double-blind, controlled, crossover study, 154 men and women were randomised to three supplemented phases of 10 weeks each: (1) 2·7 g/d of DHA, (2) 2·7 g/d of EPA and (3) 3 g/d of maize oil, separated by 9-week washouts. As secondary analyses, the mean intra-individual variation in TAG was calculated using the standard deviation from the mean of four off-treatment samples. The response remained within the intra-individual variation (±0·25 mmol/l) in 47 and 57 % of participants after DHA and EPA, respectively. Although there was a greater proportion of participants with a reduction >0·25 mmol/l after DHA than after EPA (45 υ. 32 %; P 0·25 mmol/l after both DHA and EPA had higher non-HDL-cholesterol, TAG and insulin concentrations compared with other responders at baseline (all P < 0·05). In conclusion, supplementation with 2·7 g/d DHA or EPA had no meaningful effect on TAG concentrations in a large proportion of individuals with normal mean TAG concentrations at baseline. Although DHA lowered TAG in a greater proportion of individuals compared with EPA, the magnitude of TAG lowering among them was similar.

Anti-HMG-CoA reductase myopathy, an undesirable evolution of statin induced myopathy: a case report.

Statins are commonly used lipid lowering agents which play a pivotal role in reducing cardiovascular morbidity and mortality. Often well tolerated, these HMG-CoA reductase (HMGCR) inhibitors can sometimes cause severe muscle weakness and elevated creatinine kinase (CK) often labeled as statin intolerance or statin induced myopathy. These symptoms improve after discontinuation of the offending drug along with normalization of the enzyme levels. However, an entity called Immune Mediated Necrotizing Myopathy (IMNM), a type of autoimmune mediated myopathy, has been recognized and characterized in patients with history of statin exposure where there is persistence of proximal muscle weakness, CK elevation and myofiber necrosis can be seen on muscle biopsy even after stopping statins. With the increased use of statins, there seems to be a higher incidence of IMNM cases in recent years. Here we discuss a case of anti-HMG-CoA myopathy, one of the three recognized types of IMNM that has been more commonly associated with statin exposure and highly responsive to immunotherapy.

Experimental Drugs for Neuropathic Pain.

BACKGROUND: Neuropathic pain (NP) is an important public health problem and despite recent progress in the understanding, diagnosis, pathophysiological mechanisms and the treatment of NP, many patients remain refractory to pharmacotherapy. OBJECTIVE: Currently used drugs have limited efficacy and dose-limiting adverse effects, and thus there is a substantial need for further development of novel medications for its treatment. Alternatively, drugs approved for use in diseases other than NP can be applied as experimental for NP conditions. This paper covers advances in the field of NP treatment. RESULTS: The prime focus of this paper is on drugs with well-established pharmacological activity whose current therapeutic applications are distinct from NP. These drugs could be a potential novel treatment of NP. Data from preclinical studies and clinical trials on these experimental drugs are presented. The development of advanced methods of genomics enabled to propose new targets for drugs which could be effective in the NP treatment. CONCLUSION: Experimental drugs for NP can be a treatment option which should be tailor-made for each individual on the basis of pain features, previous therapies, associated clinical conditions, recurrence of pain, adverse effects, contraindications and patients' preferences. At present, there are only some agents which may have potential as novel treatments. Increasing knowledge about mechanisms underlying NP, mechanisms of drug action, as well as available data from preclinical and clinical studies make botulinum toxin A, minocycline, ambroxol, statins and PPAR agonists (ATx086001) promising potential future treatment options.

Necrotizing Autoimmune Myopathy: Clinicopathologic Study from a Single Tertiary Care Centre.

BACKGROUND: Idiopathic inflammatory myopathies (IIMs) are a group of chronic, autoimmune disorders which include a new entity, necrotizing autoimmune myopathy (NAM). NAM lacks inflammation and presents with markedly elevated creatinine phosphokinase (CPK) levels. It is associated with connective tissue diseases (CTDs), statin use, malignancies, and most cases are idiopathic. OBJECTIVES: The objectives of this study are to describe the clinicopathologic features in muscle biopsy-proven cases of NAM. To emphasize the role of laboratory parameters such as CPK levels and myositis profile in the diagnosis of NAM. MATERIALS AND METHODS: This is a retrospective study including 15 patients of NAM diagnosed on muscle biopsy over a period of 2 years. The slides of the biopsies were reviewed, and clinical data, electromyography findings, and CPK levels were obtained. Myositis profile was done. RESULTS: Necrotizing myopathy accounted for 13.63% (15 cases) of total inflammatory myopathies (110 cases) in the study. These were grouped into CTD-associated NAM, statin-associated NAM, paraneoplastic NAM and idiopathic NAM which was the common type. All cases presented with progressive proximal muscle weakness and had markedly elevated CPK levels. Anti-3-hydroxy-3-methyl-glutaryl-coenzyme A reductase and antisignal recognition particle antibodies were seen to be positive in six patients. Muscle biopsies showed predominant fiber necrosis with significant fiber degeneration and regeneration in the absence of inflammation. All patients received immunotherapy with significant improvement was seen in six patients with two mortalities. CONCLUSION: Necrotizing myopathy is a new addition to the spectrum of IIM. Clinicopathologic correlation is important for appropriate diagnosis. It is found to be refractory to corticosteroids monotherapy. The course of illness is not uniform, and in some patients, there can be rapid worsening with mortality.

Detection of autoantibodies to 3-hydroxy-3-methylglutaryl-coenzyme a reductase by ELISA in a reference laboratory setting.

BACKGROUND: We investigated the performance of an ELISA for the detection of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) IgG antibodies in immune-mediated necrotizing myopathies (IMNM). METHODS: Patients positive for HMGCR antibodies (n=61) or negative (n=78) by protein immunoprecipitation (IP), and healthy controls (n=100) were used to evaluate the ELISA. Unique consecutive serum samples (n=155) received at ARUP Laboratories for HMGCR IgG testing by ELISA were also investigated and analysed for serum muscle enzymes (aldolase, creatine kinase, and myoglobin). The ELISA's sensitivity, specificity, and percentage agreement were assessed relative to IP. Correlation between specific muscle enzyme concentration and the presence of HMGCR antibody was determined. RESULTS: Overall agreement between ELISA and IP was 93.4%. Using the IP as reference, the sensitivity and specificity of the ELISA was 95.1%, and 100%, respectively. Inter- and intra-assay coefficient of variation of the ELISA was <10.0%, and ≤15.0%, respectively. In the consecutive cohort, 21 (13.6%) samples tested positive for HMGCR IgG. Concentrations of aldolase, creatine kinase, and myoglobin were significantly higher (all p<0.0001) in patients positive for HMGCR antibodies at the time of evaluation. CONCLUSIONS: We confirm significant reliability of HMGCR antibodies as measured by the ELISA for the evaluation of IMNM.

Pravastatin induces cell cycle arrest and decreased production of VEGF and bFGF in multiple myeloma cell line / Pravastatina induz parada no ciclo celular e diminuição na produção de VEGF e bFGF em linhagem de Mieloma Multiplo

Abstract Multiple myeloma (MM) is a B cell bone marrow neoplasia characterized by inflammation with an intense secretion of growth factors that promote tumor growth, cell survival, migration and invasion. The aim of this study was to evaluate the effects of pravastatin, a drug used to reduce cholesterol, in a MM cell line.Cell cycle and viability were determinate by Trypan Blue and Propidium Iodide. IL6, VEGF, bFGF and TGFβ were quantified by ELISA and qRT-PCR including here de HMG CoA reductase. It was observed reduction of cell viability, increase of cells in G0/G1 phase of the cell cycle and reducing the factors VEGF and bFGF without influence on 3-Methyl-Glutaryl Coenzyme A reductase expression.The results demonstrated that pravastatin induces cell cycle arrest in G0/G1 and decreased production of growth factors in Multiple Myeloma cell line.

Resumo O Mieloma Múltiplo é uma neoplasia de linfócitos B da medula óssea, caracterizada por inflamação com uma intensa secreção de fatores de crescimento que promovem o aumento do volume do tumor, sobrevivência celular, migração e invasão. O objetivo deste estudo foi avaliar os efeitos da pravastatina, uma droga usada para reduzir o colesterol, em um linhagem de MM. O ciclo celular e viabilidade foram determinadas por Trypan Blue e iodeto de propídio. IL6, VEGF, bFGF e TGF foram quantificadas por ELISA e qRT-PCR, incluindo aqui de HMG CoA redutase. Observou-se a redução da viabilidade das células, aumento de células na fase G0/G1 do ciclo celular e redução no VEGF e bFGF, sem influência na expressão da enzima 3-Metil-Glutaril Coenzima A redutase. Os resultados demonstraram que a pravastatina induz parada no ciclo celular em G0/G1 e diminuição da produção de fatores de crescimento em várias linhas de células de Mieloma.

3-hydroxy-3-methyl glutaryl coenzyme A reductase: an essential actor in the biosynthesis of cantharidin in the blister beetle Epicauta chinensis Laporte.

Cantharidin (C(10)H(12)O(4)) is a monoterpene defensive toxin in insects involved in chemical defence as well as in courtship and mating behaviours. It is relatively well known in the medical literature because of its high anticancer activity and as an effective therapy for molluscum contagiosum. However, little is known about its biosynthesis pathway in vivo, and no enzyme involved in cantharidin biosynthesis has been identified. The purpose of this study was to identify the crucial enzyme that is involved in the biosynthesis of cantharidin. Using the homology cloning method, a 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMGR) gene, the rate-limiting enzyme in the mevalonate pathway, was cloned from the blister beetle Epicauta chinensis. Quantitative reverse transcription PCR and gas chromatography methods revealed that the HMGR transcripts had a positive correlation with cantharidin production in the beetles (R = 0.891). RNA interference (RNAi) knockdown of HMGR mRNA expression was achieved by microinjection of a specific double-stranded RNA with more than 90% RNAi efficiency, and an apparent decrease of cantharidin production was observed. Furthermore, the HMGR mRNA was greatly upregulated by exogenous juvenile hormone III (JH III), and cantharidin production was also raised in males; however, when injecting the JH III with RNAi of HMGR mRNA at the same time, cantharidin production did not rise. These results demonstrate that HMGR is an essential enzyme in cantharidin biosynthesis in the blister beetle E. chinensis, which further verifies previous research results demonstrating that cantharidin is synthesized de novo by the mevalonate pathway in blister beetles.

[Immune-mediated necrotizing myopathy associated with antibodies to hydroxy-methyl-glutaryl-coenzyme A reductase]. / Myopathie nécrosante auto-immune associée aux anticorps anti-hydroxy-méthyl-glutaryl-coenzyme A réductase.

INTRODUCTION: Statins or 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (HMGCR) are among the most commonly prescribed treatment in France. They may be responsible for muscular intolerance with variable severity. They have been recently involved in the occurrence of an acquired inflammatory myopathy associated with anti-HMGCR antibodies. This new type of toxic myopathy remains poorly known by clinicians. OBSERVATION: We report a 61-year-old woman treated with a statin for many years who developed a lower and upper limb disabling myopathy with a rapid unfavourable course despite treatment withdrawal. Clinical history and investigations, especially including an assay for anti-HMGCR antibodies led to the diagnosis of autoimmune necrotizing myopathy with anti-HMGCR antibodies. Subsequent initiation of an immunosuppressive treatment by corticosteroids and methotrexate was effective. CONCLUSION: Statins may unmask or cause an autoimmune necrotizing myopathy associated with the presence of anti-HMGCR antibodies. Their identification is now routinely available. An immunosuppressive treatment is necessary and justified by the autoimmune nature of the disease.

Patterns of serum laboratory monitoring for safety and efficacy in patients on chronic statin therapy.

OBJECTIVE: To describe safety and efficacy laboratory monitoring of statin therapy at the University of Colorado Hospital Outpatient Clinics over a period of 3 years prior to the revised United States Food and Drug Administration statin labeling. METHODS: This retrospective, observational study evaluated serum laboratory monitoring for safety and efficacy of statin therapy between July 2008 and June 2011. Adult patients prescribed chronic statin therapy were included. The primary objective of this study was to describe the frequency of outpatient liver function tests, lipid panels, and creatine kinase for patients on chronic statin therapy. RESULTS: A total of 143 patients met study criteria. Over a 3-year period, the mean maximum frequency of measurements per patient of serum hepatic transaminases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) was higher than lipid panel measurements (5.2 ± 4.4 and 4.2 ± 2.0 respectively, p = 0.021). Only 22 of 143 patients (15.4%) had an elevation in ALT or AST. All elevations were less than three times the upper limit of normal and statin therapy was continued without changes in response to these elevations. Creatine kinase, though not a routine monitoring test, was infrequently measured (mean maximum frequency of measurements per patient 0.3 ± 0.8). CONCLUSION: Serum hepatic transaminases were routinely monitored in patients treated with chronic statin therapy. Given the absence of significant serum hepatic transaminase elevations, and clinician response to minor elevations, our data indicate that routine serum laboratory evaluations for statin toxicity are excessive.