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:  The physiology of yellowtail fed a non‐fishmeal diet was examined, with a specific interest in the role of taurine in disease resistance and cholesterol metabolism. Decrease of disease resistance in fish fed a non‐fishmeal diet was confirmed by mortality due to natural infection with pseudotuberculosis and artificial infection with Lactococcus garvieae. It is suggested that the most important symptoms related to decrease of disease resistance in fish fed a non‐fishmeal diet is anemia. Anemia was improved by supplementation with taurine. Significant elevation of relative expression of HMG‐CoA reductase mRNA in fish fed a non‐fishmeal diet suggests that cholesterol synthesis would be activated and not dysfunctional. Plasma cholesterol of these fish was elevated to the levels of control fish by supplementation of both cholesterol and taurine. These results suggest that hypocholesterolemia observed in fish fed a non‐fishmeal diet compared with a fishmeal diet would be caused by insufficient dietary cholesterol and decrease of endogenous cholesterol due to the lack of dietary taurine.

Hypercholesterolemia is a leading cause of cardiovascular disease and mortality in men and women throughout the USA and abroad. The development of statins (HMG-CoA reductase inhibitors) to lower plasma atherogenic cholesterol levels and improve cardiovascular outcomes represents one of the greatest contributions to clinical science in the twentieth century, although residual risk remains even among statin-treated patients. Our understanding of lipid metabolism took a giant leap forward in 2003 with the discovery of proprotein convertase subtilsin/kexin type 9 (PCSK9), a low abundance circulating protein with an outsized effect on the regulation of plasma cholesterol levels. Evolocumab and alirocumab represent the first two US Food and Drug Administration-approved fully human monoclonal antibodies that target PCSK9, which not only lower low-density lipoprotein (LDL) cholesterol to unprecedented levels, but also further improve important cardiovascular outcomes. Small interfering RNA (siRNA) molecules now represent the next generation of drugs designed to antagonize PCSK9. Inclisiran is a siRNA specific for PCSK9 that prevents translation of PCSK9 messenger RNA, leading to decreased concentrations of the protein and lower concentrations of LDL cholesterol. The ORION clinical development program includes several completed and ongoing clinical trials designed to evaluate the safety and efficacy of inclisiran and test its ability to improve hard cardiovascular outcomes. This review discusses the mechanisms of action of inclisiran, examines the current evidence, and provides a comparison of similarities and differences relative to the PCSK9 inhibitors.

Clear cell renal cell carcinoma (ccRCC) is the most representative subtype of renal cancer. CircRNA acts as a kind of ceRNA to play a role in regulating microRNA (miRNA) in many cancers. However, the potential pathogenesis role of the regulatory network among circRNA/miRNA/mRNA is not clear and has not been fully explored. CircRNA expression profile data were obtained from GEO datasets, and the differentially expressed circRNAs (DECs) were identified through utilizing R package (Limma) firstly. Secondly, miRNAs that were regulated by these circRNAs were predicted by using Cancer-specific circRNA database and Circular RNA Interactome. Thirdly, some related genes were identified by intersecting targeted genes, which was predicted by a web tool (miRWalk) and differentially expressed genes, which was obtained from TCGA datasets. Function enrichment was analyzed, and a PPI network was constructed by Cytoscape software and DAVID web set. Subsequently, ten hub-genes were screened from the network, and the overall survival time in patients of ccRCC with abnormal expression of these hub-genes were completed by GEPIA web set. In the last, a circRNA/miRNA/mRNA regulatory network was constructed, and potential compounds and drug which may have the function of anti ccRCC were forecasted by taking advantage of CMap and PharmGKB datasets. Six DECs (hsa_circ_0029340, hsa_circ_0039238, hsa_circ_0031594, hsa_circ_0084927, hsa_circ_0035442, hsa_circ_0025135) were obtained and six miRNAs (miR-1205, miR-657, miR-587, miR-637, miR-1278, miR-548p) which are regulated by three circRNAs (hsa_circ_0084927, hsa_circ_0035442, hsa_circ_0025135) were also predicted. Then 497 overlapped genes regulated by these six miRNAs above had been predicted, and function enrichment analysis revealed these genes are mainly linked with some regulation functions of cancers. Ten hub-genes (PTGER3, ADCY2, APLN, CXCL5, GRM4, MCHR1, NPY5R, CXCR4, ACKR3, MTNR1B) have been screened from a PPI network. PTGER3, ADCY2, CXCL5, GRM4 and APLN were identified to have a significant effect on the overall survival time of patients with ccRCC. Furthermore, one compound (josamycin) and four kinds of drugs (capecitabine, hmg-coa reductase inhibitors, ace Inhibitors and bevacizumab) were confirmed as potential therapeutic options for ccRCC by CMap analysis and pharmacogenomics analysis. This study implies the potential pathogenesis of the regulatory network among circRNA/miRNA/mRNA and provides some potential therapeutic options for ccRCC.

HMG-CoA reductase inhibitors (statins) are the most effective pharmacological means of reducing cardiovascular disease risk. The most common side effect of statin use is skeletal muscle myopathy, which may be exacerbated by exercise. Hypercholesterolemia and training status are factors that are rarely considered in the progression of myopathy. The purpose of this study was to determine the extent to which acute and chronic exercise can influence statin-induced myopathy in hypercholesterolemic (ApoE-/-) mice. Mice either received daily injections of saline or simvastatin (20 mg/kg) while: 1) remaining sedentary (Sed), 2) engaging in daily exercise for two weeks (novel, Nov), or 3) engaging in daily exercise for two weeks after a brief period of training (accustomed, Acct) (2x3 design, n = 60). Cholesterol, activity, strength, and indices of myofiber damage and atrophy were assessed. Running wheel activity declined in both exercise groups receiving statins (statin x time interaction, p<0.05). Cholesterol, grip strength, and maximal isometric force were significantly lower in all groups following statin treatment (statin main effect, p<0.05). Mitochondrial content and myofiber size were increased and 4-HNE was decreased by exercise (statin x exercise interaction, p<0.05), and these beneficial effects were abrogated by statin treatment. Exercise (Acct and Nov) increased atrogin-1 mRNA in combination with statin treatment, yet enhanced fiber damage or atrophy was not observed. The results from this study suggest that exercise (Nov, Acct) does not exacerbate statin-induced myopathy in ApoE-/- mice, yet statin treatment reduces activity in a manner that prevents muscle from mounting a beneficial adaptive response to training.

Mevastatin (HMG-CoA reductase inhibitor) isolated from Penicillium citrinum is known to the first statin that inhibitor of cholesterol synthesis. Recently, several clinical reports of other statins suggest its role on reducing the severity of psoriasis, but the available evidence on cellular/molecular level of mevastatin is unclear. Thus, this study was to determine the molecular/cellular mechanism of mevastatin using TNF-α/IL-17A stimulated HaCaT cells. First, the safety and effectiveness of mevastatin were confirmed through the comparative experiment of five statin derivatives. Mevastatin decreased mRNA levels of cytokines (IL-1α/β, IL-6, and IL-8), chemokine (CC motif) ligand 20 (CCL20), and keratin proteins (Keratin 5/14/6/16) known to be overexpressed in psoriasis. In addition, mevastatin significantly reduced phosphorylation of NF-κB, MAPKs and STAT3 in TNF-α/IL-17 signaling pathway. Moreover, mevastatin specifically suppressed keratin 5/14 proteins expressed in the keratinocyte differentiation process of the basal layer and keratin 6A/16 overexpressed in patients with psoriasis. These results imply that mevastatin not only can inhibit psoriasis-induced inflammatory cytokines and chemokines, but also can suppress psoriasis-related keratin proteins.

Accumulating results have disclosed that early brain injury (EBI) may play a major role in the determination of the outcome of aneurysmal subarachnoid hemorrhage (SAH) patients. This study is of interest to examine the efficacy of pitavastatin, a 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase) inhibitor, on SAH-induced apoptosis. A rodent double SAH model was employed. Pitavastatin was administered orally. CSF IL-1β, IL-6, IL-8 and TNF-α were measured (rt-PCR). Basilar arteries were harvested for C-Jun N-terminal kinase p46/p55 (cJNK (p46/p55)), matrix metallopeptidase-9 (MMP-9) (Western blot), caspase and Bcl-2 (rt-PCR) evaluation. Pitavastatin reduced the bioexpression of cJNK p55 compared with the SAH groups. Cleaved caspase-9a was significantly reduced in the pitavastatin-preconditioned group compared with the SAH group (p > 0.05). IL-1β and TNF-α levels were reduced in the pitavastatin-preconditioned group. Pretreatment with pitavastatin significantly reduced activated MMP-9, capsase-9a and B-cell lymphoma 2(Bcl) mRNA. Preconditioning with pitavastatin exerts its neuroprotective effect through the dual action of inhibiting cJNK(p46/p55) activation and reducing cleaved caspase-9a expression. Besides, the bioinhibition of MMP-9 may partially contribute to the neuroprotective effect. This study lends credence to the theory that statins, especially in the preconditioning status, may attenuate SAH-induced neuron apoptosis.

There is emerging evidence identifying microRNAs (miRNAs) as mediators of statin-induced cholesterol efflux, notably through the ATP-binding cassette transporter A1 (ABCA1) in macrophages. The objective of this study was to assess the impact of an HMG-CoA reductase inhibitor, pitavastatin, on macrophage miRNAs in the presence and absence of oxidized-LDL, a hallmark of a pro-atherogenic milieu. Treatment of human THP-1 cells with pitavastatin prevented the oxLDL-mediated suppression of miR-33a, -33b and -758 mRNA in these cells, an effect which was not uniquely attributable to induction of SREBP2. Induction of ABCA1 mRNA and protein by oxLDL was inhibited (30%) by pitavastatin, while oxLDL or pitavastatin alone significantly induced and repressed ABCA1 expression, respectively. These findings are consistent with previous reports in macrophages. miRNA profiling was also performed using a miRNA array. We identified specific miRNAs which were up-regulated (122) and down-regulated (107) in THP-1 cells treated with oxLDL plus pitavastatin versus oxLDL alone, indicating distinct regulatory networks in these cells. Moreover, several of the differentially expressed miRNAs identified are functionally associated with cholesterol trafficking (six miRNAs in cells treated with oxLDL versus oxLDL plus pitavastatin). Our findings indicate that pitavastatin can differentially modulate miRNA in the presence of oxLDL; and, our results provide evidence that the net effect on cholesterol homeostasis is mediated by a network of miRNAs.

3-Hydroxy-3-methylglutaric aciduria is a human autosomal recessive metabolic disorder that usually appears within the first year of life. The causes of this aciduria are lethal mutations in the gene encoding for 3-hydroxy-3-methylglutaryl coenzyme A lyase (HL). HL is a mitochondrial matrix enzyme that catalyzes the last step of ketogenesis and leucine catabolism. This gene has been mapped to chromosome 1 at locus 1pter-p33 and its genomic organisation comprises 9 exons whose sizes vary between 64-678 bp. The human cDNA sequence was reported in 1993 with the first genetic study of two Acadian-French Canadian siblings. To date, 24 mutations in 36 patients have been described; most of them are single-base substitutions causing amino acid replacements and a variety of splicing defects. In the population studied two mutations appear predominant: g.122GA (8 patients and 15 alleles) frequent in Saudi Arabia, and g.109GT (6 patients and 12 alleles), prevalent in Spain. At least seven mutations are clustered in the second half of exon 2 affecting aminoacids E37, R41 and D42 and conforming a possible hot spot. The genotype-phenotype correlation is difficult to establish since the probands received different treatments, and the onset of an acute episode frequently depends on external factors such as fasting or acute illness.