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Non-Congenital Acquired Myopathies
Published in Maher Kurdi, Neuromuscular Pathology Made Easy, 2021
Statins are inhibitors for HMG-CoA reductase, an enzyme that catalyzes the conversion of HMG-CoA to mevalonic acid, the precursor of cholesterol. They lower the cholesterol and LDL levels in the blood. They could interrupt cholesterol metabolism causing damage to the muscle sarcolemma and mitochondria, allowing the influx of calcium to the cells resulting in myonecrosis.
Mevalonic aciduria
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
The pathway is regulated via feedback inhibition by cholesterol of the synthesis of mevalonic acid at the 3-hydroxy-3-methylglutaryl-CoA (HMG CoA) reductase step. When cholesterol, which is ingested or derived from plasma low-density lipoproteins (LDL), downregulates HMG CoA reductase, nonsterol isoprenoid synthesis is preserved by inhibition of squalene synthetase and more distal enzymes, further limiting the incorporation of farnesylpyrophosphate into cholesterol. The initial enzymes in the nonsterol branches of the pathway have a very high affinity for farnesylpyrophosphate [26, 27].
Atherosclerosis
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
Many drugs inhibit cholesterol synthesis, such as 2-phenylbutyric acid and derivatives.19,64,132,198,461,541,542,626,700 Application of this drug in clinical trials has resulted in toxic manifestations. Derivatives of this compound reduce acetyl-CoA formation. The currently employed clofibrate has some effect on cholesterol biosynthesis at the level of 3-hydroxy-3-methylglutaryl-CoA reductase.21 There are some other drugs blocking cholesterol synthesis at other steps. Benzmalacene (N-[l-methyl-2,3-bis(p-chlorophenyl)propyl]maleamic acid or 4-[2,3-bis(4-chlorophenyl)-l-methylpropyl]amino]-4-oxo-2-butenoic acid) inhibits the incorporation of mevalonic acid into cholesterol in rat liver homogenates. However, benzamalacene given to animals has a toxic effect and results in liver damage.207,304 This drug has been among the first compounds used clinically. It is structurally related to a series of nonsteroidal estrogens and estogen antagonists.
The Effects of Sterol-Related Signaling Pathways on Glioma
Published in Nutrition and Cancer, 2022
Masoumeh Eslahi, Parisa Maleki Dana, Fatemeh Sadoughi, Jamal Hallajzadeh, Zatollah Asemi, Mehran Sharifi, Mohammad Ali Mansournia, Bahman Yousefi
Based on several experimental studies on colon and prostate cancer, phytosterols have been suggested as anti-carcinogenic compounds (20,21). Sterols have different functions such as controlling the fluidity of membrane and permeability. A specific function of sterols has been observed in the proliferation of cell and signal transduction in some plants. Besides, they modulate the activity of membrane-bound enzymes (19). One of the most important features of cellular growth is the sustained production of lipids. The biochemical and biophysical properties of membrane-based processes such as vesicle traffic, receptor signaling, and assembly of protein complexes are highly dependent on the sterol composition of cellular membranes (22). Findings according to the profiling of cancer tissues (23) and in vitro cell line models have shown that cholesterol metabolism has a critical role in the origins of cancer as well as drug resistance (24). Mevalonic acid, farnesyl pyrophosphate, and geranylgeranyl pyrophosphate are essential for cell growth and division and produced in the early steps of cholesterol biosynthesis. Cancer cells highly depend on isoprenylated molecules for cell growth. Several experiments have shown that they target the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA-reductase) with statins and prenylation enzymes as well as farnesyl transferase inhibitor (25). Contrary to the normal differentiated tissues of the nervous system, brain tumors exhibit a high rate of de novo sterol synthesis.
Statins as an adjunctive therapy for COVID-19: the biological and clinical plausibility
Published in Immunopharmacology and Immunotoxicology, 2021
Tarek Kashour, Rabih Halwani, Yaseen M. Arabi, M. Rizwan Sohail, John C. O’Horo, Andrew D. Badley, Imad M. Tleyjeh
Statins represent an interesting group of lipid lowering medications, which possess several pleotropic effects. Statins are competitive and reversible inhibitors of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase. The enzyme converts HMG-CoA into mevalonic acid, which is the substrate for cholesterol biosynthesis. They are the most effective oral drugs for reducing plasma cholesterol and have been shown to improve cardiovascular outcomes in primary and secondary prevention trials as well as slowing the progression and possibly regression of atherosclerosis [24–28]. Patients with familial hypercholesterolemia (FH) have increased lifelong risk of CVD that reach about 100-fold in comparison to healthy individuals at age of 20–40 and hence they might be at increased risk for acquiring COVID-19 disease [29]. In their recent publication, the International Lipid Expert Panel (ILEP) and the European FH Patient Network (FH Europe) recommended the continuation of statin therapy and other lipid lowering treatments for patients with COVID-19 disease but to pay special attention regarding possible drug interactions with other concomitant medications used for COVID-19 disease [29].
National survey of Japanese patients with mevalonate kinase deficiency reveals distinctive genetic and clinical characteristics
Published in Modern Rheumatology, 2019
Takayuki Tanaka, Kohei Yoshioka, Ryuta Nishikomori, Hidemasa Sakai, Junya Abe, Yuriko Yamashita, Ryugo Hiramoto, Akira Morimoto, Eiichi Ishii, Hirokazu Arakawa, Utako Kaneko, Yusei Ohshima, Nami Okamoto, Osamu Ohara, Ikue Hata, Yosuke Shigematsu, Tomoki Kawai, Takahiro Yasumi, Toshio Heike
All patients showed vigorous acute-phase responses during attacks, with elevated leukocyte counts (median, 19,250/μL) and CRP levels (median, 14.5 mg/dL) (Table 2). Increased serum IgD or IgA was observed in 56 and 60% of patients, respectively. Urinary mevalonic acid excretion was elevated in all patients examined (Table 2). All patients tested showed MVK activity ≤2% of that in healthy controls (data not shown). Stimulation of IL-1β secretion by LPS was significantly elevated in MKD PBMCs (Figure 2). All patients harbored homozygous or compound heterozygous disease-causing variants of the MVK gene. All parents examined harbored one of the heterozygous variants shared by the patients (data not shown). Notably, five of the ten genetic variants were specific to this cohort (Figure 3) and were considered pathogenic based on their absence from the Exome Aggregation Consortium database, and from at least one of two function prediction programs: Polyphen 2 or Mutation Taster (data not shown). Disease-causing variants commonly found in Europe (i.e. V377I, I268T, H20P/N, and P167L) [6,7] were not detected in our patients.