Dantrolene and coenzyme Q10 as a suggested combination therapy to statin-induced myopathy in high fat diet rats: A possible interference with ROS/ TGF-ß / Smad4 signaling pathway.

One of the major hitches for statins' utilization is the development of myotoxicity. Versatile studies reported that the underlining molecular mechanisms including coenzyme Q10 (CoQ10)/ubiquinone depletion, as well as the disturbance in the cytoplasmic Ca2+ homeostasis. Therefore, we investigated the consequences of supplementing CoQ10 and dantrolene, a cytoplasmic Ca2+ reducing agent, in combination with simvastatin. This adjuvant therapy normalized the simvastatin-mediated elevation in serum ALT, AST, CK-MM, as well as tissue Ca2+ content, in addition to suppressing the simvastatin-mediated oxidative stress in simvastatin-treated rats, while having no effect upon statin-induced antihyperlipidemic effect. Additionally, the combination inhibited the simvastatin-induced TGF-ß/ Smad4 pathway activation. Collectively, the current study emphasizes on the potential utilization of dantrolene and CoQ10 as an adjuvant therapy to statins treatment for improving their side effect profile.

Platelet rich fibrin and simvastatin-loaded pectin-based 3D printed-electrospun bilayer scaffold for skin tissue regeneration.

Designing multifunctional wound dressings is a prerequisite to prevent infection and stimulate healing. In this study, a bilayer scaffold (BS) with a top layer (TL) comprising 3D printed pectin/polyacrylic acid/platelet rich fibrin hydrogel (Pec/PAA/PRF) and a bottom nanofibrous layer (NL) containing Pec/PAA/simvastatin (SIM) was produced. The biodegradable and biocompatible polymers Pec and PAA were cross-linked to form hydrogels via Ca2+ activation through galacturonate linkage and chelation, respectively. PRF as an autologous growth factor (GF) source and SIM together augmented angiogenesis and neovascularization. Because of 3D printing, the BS possessed a uniform distribution of PRF in TL and an average fiber diameter of 96.71 ± 18.14 nm was obtained in NL. The Young's modulus of BS was recorded as 6.02 ± 0.31 MPa and its elongation at break was measured as 30.16 ± 2.70 %. The wound dressing gradually released growth factors over 7 days of investigation. Furthermore, the BS significantly outperformed other groups in increasing cell viability and in vivo wound closure rate (95.80 ± 3.47 % after 14 days). Wounds covered with BS healed faster with more collagen deposition and re-epithelialization. The results demonstrate that the BS can be a potential remedy for skin tissue regeneration.

Exploring peripheral biomarkers of response to simvastatin supplementation in schizophrenia.

Schizophrenia is one of the most debilitating mental disorders, and its diagnosis and treatment present significant challenges. Several clinical trials have previously evaluated the effectiveness of simvastatin, a lipid-lowering medication, as a novel add-on treatment for schizophrenia. However, treatment effects varied highly between patients and over time. In the present study, we aimed to identify biomarkers of response to simvastatin in recent-onset schizophrenia patients. To this end, we profiled relevant immune and metabolic markers in patient blood samples collected in a previous clinical trial (ClinicalTrials.gov: NCT01999309) before simvastatin add-on treatment was initiated. Analysed sample types included serum, plasma, resting-state peripheral blood mononuclear cells (PBMCs), as well as PBMC samples treated ex vivo with immune stimulants and simvastatin. Associations between the blood readouts and clinical endpoints were evaluated using multivariable linear regression. This revealed that changes in insulin receptor (IR) levels induced in B-cells by ex vivo simvastatin treatment inversely correlated with in vivo effects on cognition at the primary endpoint of 12 months, as measured using the Brief Assessment of Cognition in Schizophrenia scale total score (standardised ß ± SE = -0.75 ± 0.16, P = 2.2 × 10-4, Q = 0.029; n = 21 patients). This correlation was not observed in the placebo group (ß ± SE = 0.62 ± 0.39, P = 0.17, Q = 0.49; n = 14 patients). The candidate biomarker explained 53.4 % of the variation in cognitive outcomes after simvastatin supplementation. Despite the small sample size, these findings suggest a possible interaction between the insulin signalling pathway and cognitive effects during simvastatin therapy. They also point to opportunities for personalized schizophrenia treatment through patient stratification.

The anti-hyperlipidemic effects of Poria cocos (Schw.) Wolf extract: Modulating cholesterol homeostasis in hepatocytes via PPARα pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Poria cocos (Schw.) Wolf (Polyporaceae, P.cocos), which is born on the pine root, has a history of more than two thousand years of medicine in China. P.cocos was first recorded in the Shennong's Herbal Classic, studies have proved its lipid-lowering effect. AIM OF STUDY: The aim of study was to investigate the underlying mechanism of P.cocos extract on hyperlipidemia. MATERIALS AND METHODS: Male Sprague-Dawley (SD) rats aged 9-12 weeks were intraperitoneally (IP) injected with Triton-WR 1339 to establish an acute hyperlipidemia model. At 0 h and 20 h after the model was established, low and high doses of P.cocos extract or simvastatin were given twice. After 48 h, the rats were sacrificed, and liver and serum samples were collected for analysis. The cell model was constructed by treating L02 cells with 1% fat emulsion-10% FBS-RPMI 1640 medium for 48 h. At the same time, low and high doses of P.cocos extract and simvastatin were administered. Oil red O staining was used to evaluate the lipid accumulation in the cells, and H&E staining was used to evaluate the liver lesions of rats. Real-time quantitative PCR and western blotting were used to detect the expressions of lipid metabolism-related genes. RESULTS: P.cocos extract relieved lipid accumulation in vitro and alleviated hyperlipidemia in vivo. Both gene and protein expressions of peroxisome proliferator-activated receptor α (PPARα) were shown to be up-regulated by P.cocos extract. Additionally, P.cocos extract down-regulated the expressions of fatty acid synthesis-related genes sterol regulatory element-binding protein-1 (SREBP-1), Acetyl-CoA Carboxylase 1 (ACC1) and fatty acid synthase (FAS), while up-regulated the expressions of cholesterol metabolism-related genes liver X receptor-α (LXRα), ATP-binding cassette transporter A1 (ABCA1), cholesterol 7alpha-hydroxylase (CYP7A1) and low density lipoprotein receptor (LDLR), which were reversed by the treatment with the PPARα inhibitor GW6471. CONCLUSION: P.cocos extract ameliorates hyperlipidemia and lipid accumulation by regulating cholesterol homeostasis in hepatocytes through PPARα pathway. This study provides evidence that supplementation with P.cocos extract could be a potential strategy for the treatment of hyperlipidemia.

[Diosgenin alleviates NAFLD induced by a high-fat diet in rats via mTOR/SREBP-1c/HSP60/MCAD/SCAD signaling pathway].

This study aims to observe the effects of diosgenin on the expression of mammalian target of rapamycin(mTOR), sterol regulatory element-binding protein-1c(SREBP-1c), heat shock protein 60(HSP60), medium-chain acyl-CoA dehydrogenase(MCAD), and short-chain acyl-CoA dehydrogenase(SCAD) in the liver tissue of the rat model of non-alcoholic fatty liver disease(NAFLD) and explore the mechanism of diosgenin in alleviating NAFLD. Forty male SD rats were randomized into five groups: a control group, a model group, low-(150 mg·kg~(-1)·d~(-1)) and high-dose(300 mg·kg~(-1)·d~(-1)) diosgenin groups, and a simvastatin(4 mg·kg~(-1)·d~(-1)) group. The rats in the control group were fed with a normal diet, while those in the other four groups were fed with a high-fat diet. After feeding for 8 weeks, the body weight of rats in the high-fat diet groups increased significantly. After that, the rats were administrated with the corresponding dose of diosgenin or simvastatin by gavage every day for 8 weeks. The levels of triglyceride(TG), total cholesterol(TC), alanine transaminase(ALT), and aspartate transaminase(AST) in the serum were determined by the biochemical method. The levels of TG and TC in the liver were measured by the enzyme method. Oil-red O staining was employed to detect the lipid accumulation, and hematoxylin-eosin(HE) staining to detect the pathological changes in the liver tissue. The mRNA and protein levels of mTOR, SREBP-1c, HSP60, MCAD, and SCAD in the liver tissue of rats were determined by real-time fluorescence quantitative polymerase chain reaction(RT-qPCR) and Western blot, respectively. Compared with the control group, the model group showed increased body weight, food uptake, liver index, TG, TC, ALT, and AST levels in the serum, TG and TC levels in the liver, lipid deposition in the liver, obvious hepatic steatosis, up-regulated mRNA and protein expression levels of mTOR and SREBP-1c, and down-regulated mRNA and protein expression levels of HSP60, MCAD, and SCAD. Compared with the model group, the rats in each treatment group showed obviously decreased body weight, food uptake, liver index, TG, TC, ALT, and AST levels in the serum, TG and TC levels in the liver, lessened lipid deposition in the liver, ameliorated hepatic steatosis, down-regulated mRNA and protein le-vels of mTOR and SREBP-1c, and up-regulated mRNA and protein levels of HSP60, MCAD, and SCAD. The high-dose diosgenin outperformed the low-dose diosgenin and simvastatin. Diosgenin may prevent and treat NAFLD by inhibiting the expression of mTOR and SREBP-1c and promoting the expression of HSP60, MCAD, and SCAD to reduce lipid synthesis, improving mitochondrial function, and promoting fatty acid ß oxidation in the liver.

Synergistic anticancer therapy via ferroptosis using modified bovine serum albumin nanoparticles loaded with sorafenib and simvastatin.

Ferroptosis is a non-apoptotic cell death pathway characterized by the accumulation of lipid-peroxy radicals within the affected cells. Here, we investigate the synergistic capacity of sorafenib (SOR) and simvastatin (SIM) to trigger ferroptosis for cancer therapy. For precise in-vivo delivery, SOR + SIM was ratiometrically loaded in bovine serum albumin nanoparticles (BSA-NPs) modified with 4-carboxy phenylboronic acid (CPBA). The developed CPBA-BSA(SOR + SIM)-NPs revealed size of 175.2 ± 12.8 nm, with PDI of 0.22 ± 0.03 and Z-potential of -29.6 ± 4.8 mV. Significantly, CPBA-BSA(SOR + SIM)-NPs exhibited > 2 and > 5-fold reduction in IC50 values compared to individual SOR and SIM treatments respectively, in all tested cell lines. Moreover, CPBA-BSA(SOR + SIM)-NPs treated cells exhibited decrease in glutathione levels, increase in malonaldehyde levels and depolarization of mitochondrial membrane potential (JC-1 assay). Pharmacokinetic analysis revealed enhanced AUC0-∞ and MRT levels for SOR and SIM when administered as CPBA-BSA(SOR + SIM)-NPs compared to free drugs. Crucially, in in-vivo experiments, CPBA-BSA(SOR + SIM)-NPs led to a significant reduction in tumor volume compared to various control groups. Histological and biomarker analyses underscore their biocompatibility for clinical applications. In conclusion, this study highlights the potential of CPBA-BSA(SOR + SIM)-NPs as a promising strategy for inducing ferroptosis in cancer cells, concurrently improving drug delivery and therapeutic efficacy. This approach opens new avenues in cancer treatment.

Potential Effect of Baobab's Polyphenols as Antihyperlipidemic Agents: In Silico Study.

Adansonia digitata L. is an African tree commonly called baobab. This tree is effectively used in traditional medicine to treat cardiovascular disorders. Hyperlipidemia is a well-known cardiovascular risk factor associated with the increased incidence of mortality worldwide. This study aimed to demonstrate the mechanism of baobab polyphenols in the activities of hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and pancreatic lipase as lipid metabolic enzymes. Molecular docking and an incentive for drug design showed that all the polyphenols in baobab bound to the proteins with higher affinity and a lower binding energy compared with simvastatin as the positive control (ΔG: from -5.5 kcal/mol to -6.5 kcal/mol). The same polyphenols exhibited a considerable binding affinity to pancreatic lipase (ΔG: from -7.5 kcal/mol to -9.8 kcal/mol) in comparison with the control and HMG-CoA reductase. Quercetin showed the best docking score from the selected Baobab polyphenols (ΔG = -9.8 kcal/mol). The root mean square deviation (RMSD) results indicated that stable epicatechin and quercetin complexes were demonstrated with HMG-CoA reductase, and other less stable complexes were developed using rutin and chlorogenic acid. Moreover, the analysis of the root mean square fluctuation (RMSF) simulation results was consistent with that of the RMSD. The RMSF value for all the baobab polyphenols, including the crystal control ligand, was kept between 0.80 and 8.00 Å, similarly to simvastatin, and less than 4.8 Å for pancreatic lipase. Chlorogenic acid, quercetin, epicatechin, and rutin had negative ΔG binding scores from highest to lowest. The same ligands displayed more negative ΔG binding scores than those observed in HMG-CoA reductase and crystal control ligand (methoxyundecyl phosphinic acid) in their simulation with pancreatic lipase. In conclusion, baobab polyphenols interact with HMG-CoA reductase and pancreatic lipase to inhibit their substrate binding and block their activity.

Reshaping the gut microbiome and bile acid composition by Gyejibongnyeong-hwan ameliorates western diet-induced dyslipidemia.

Gyejibongnyeong-hwan (GBH), a traditional Chinese medicine, is used in clinical practice to treat blood stasis in metabolic diseases. Herein, we examined the effects of GBH on dyslipidemia and investigated the underlying mechanisms by focusing on modulation of the gut microbiota-bile acid axis by GBH. We utilized a Western diet-induced dyslipidemia mouse model and divided animals into the following four groups (n = 5 each): the normal chow diet, vehicle control (WD), simvastatin (Sim, 10 mg/kg/day simvastatin; positive control), and GBH (GBH, 300 mg/kg/day) groups. The drugs were administered for 10 weeks, and morphological changes in the liver and aorta were analyzed. The mRNA expression of genes related to cholesterol metabolism, gut microbiota, and bile acid profiles were also evaluated. The GBH group showed significantly lower levels of total cholesterol, accumulation of lipids, and inflammatory markers in the liver and aorta of Western diet-fed mice. Low-density lipoprotein cholesterol levels were significantly lower in the GBH group than in the WD group (P < 0.001). The expression of cholesterol excretion-associated genes such as liver X receptor alpha and ATP-binding cassette subfamily G member 8, as well as the bile acid synthesis gene cholesterol 7 alpha-hydroxylase, which lowers cholesterol in circulation, was increased. Furthermore, GBH inhibited the intestinal farnesoid X receptor (FXR)-fibroblast growth factor 15 signaling pathway through the interactions of gut microbiota with bile acids acting as FXR ligands, which included chenodeoxycholic acid and lithocholic acid. Overall, GBH improved dyslipidemia induced by a Western diet by modulating the gut microbiota-bile acid axis.

Simvastatin Reduces Doxorubicin-Induced Cardiotoxicity: Effects beyond Its Antioxidant Activity.

This study aimed to evaluate if Simvastatin can reduce, and/or prevent, Doxorubicin (Doxo)-induced cardiotoxicity. H9c2 cells were treated with Simvastatin (10 µM) for 4 h and then Doxo (1 µM) was added, and the effects on oxidative stress, calcium homeostasis, and apoptosis were evaluated after 20 h. Furthermore, we evaluated the effects of Simvastatin and Doxo co-treatment on Connexin 43 (Cx43) expression and localization, since this transmembrane protein forming gap junctions is widely involved in cardioprotection. Cytofluorimetric analysis showed that Simvastatin co-treatment significantly reduced Doxo-induced cytosolic and mitochondrial ROS overproduction, apoptosis, and cytochrome c release. Spectrofluorimetric analysis performed by means of Fura2 showed that Simvastatin co-treatment reduced calcium levels stored in mitochondria and restored cytosolic calcium storage. Western blot, immunofluorescence, and cytofluorimetric analyses showed that Simvastatin co-treatment significantly reduced Doxo-induced mitochondrial Cx43 over-expression and significantly increased the membrane levels of Cx43 phosphorylated on Ser368. We hypothesized that the reduced expression of mitochondrial Cx43 could justify the reduced levels of calcium stored in mitochondria and the consequent induction of apoptosis observed in Simvastatin co-treated cells. Moreover, the increased membrane levels of Cx43 phosphorylated on Ser368, which is responsible for the closed conformational state of the gap junction, let us to hypothesize that Simvastatin leads to cell-to-cell communication interruption to block the propagation of Doxo-induced harmful stimuli. Based on these results, we can conclude that Simvastatin could be a good adjuvant in Doxo anticancer therapy. Indeed, we confirmed its antioxidant and antiapoptotic activity, and, above all, we highlighted that Simvastatin interferes with expression and cellular localization of Cx43 that is widely involved in cardioprotection.

Caffeine Supplementation and FOXM1 Inhibition Enhance the Antitumor Effect of Statins in Neuroblastoma.

High-risk neuroblastoma exhibits transcriptional activation of the mevalonate pathway that produces cholesterol and nonsterol isoprenoids. A better understanding of how this metabolic reprogramming contributes to neuroblastoma development could help identify potential prevention and treatment strategies. Here, we report that both the cholesterol and nonsterol geranylgeranyl-pyrophosphate branches of the mevalonate pathway are critical to sustain neuroblastoma cell growth. Blocking the mevalonate pathway by simvastatin, a cholesterol-lowering drug, impeded neuroblastoma growth in neuroblastoma cell line xenograft, patient-derived xenograft (PDX), and TH-MYCN transgenic mouse models. Transcriptional profiling revealed that the mevalonate pathway was required to maintain the FOXM1-mediated transcriptional program that drives mitosis. High FOXM1 expression contributed to statin resistance and led to a therapeutic vulnerability to the combination of simvastatin and FOXM1 inhibition. Furthermore, caffeine synergized with simvastatin to inhibit the growth of neuroblastoma cells and PDX tumors by blocking statin-induced feedback activation of the mevalonate pathway. This function of caffeine depended on its activity as an adenosine receptor antagonist, and the A2A adenosine receptor antagonist istradefylline, an add-on drug for Parkinson's disease, could recapitulate the synergistic effect of caffeine with simvastatin. This study reveals that the FOXM1-mediated mitotic program is a molecular statin target in cancer and identifies classes of agents for maximizing the therapeutic efficacy of statins, with implications for treatment of high-risk neuroblastoma. SIGNIFICANCE: Caffeine treatment and FOXM1 inhibition can both enhance the antitumor effect of statins by blocking the molecular and metabolic processes that confer statin resistance, indicating potential combination therapeutic strategies for neuroblastoma. See related commentary by Stouth et al., p. 2091.

Antihyperlipidemic potential of dietary supplementation with carnosine in high-fat diet-fed rats.

OBJECTIVE: The aim of this study was to investigate the hypolipidemic effects of carnosine and a commercial carnosine supplement on lipid status, liver and kidney function, and inflammation associated with dyslipidemia in rats with high-fat diet-induced hyperlipidemia. MATERIALS AND METHODS: The study was conducted on adult male Wistar rats, divided into control and experimental groups. Animals were kept in standard laboratory conditions and according to groups were treated with saline, carnosine, carnosine dietary supplement, simvastatin, and their combinations. All substances were prepared fresh every day and used by oral gavage. RESULTS: Treatment with a carnosine-based supplement significantly improved total and LDL cholesterol levels in serum, especially in the combination with simvastatin as a conventional drug in dyslipidemia treatment. The effect of carnosine on the metabolism of triglycerides was not as evident as in the case of cholesterol. Nevertheless, the values of the atherogenic index showed that the combinations of carnosine and carnosine supplement with simvastatin were the most effective in lowering this comprehensive lipid index. Dietary carnosine supplementation resulted also in anti-inflammatory effects, as demonstrated by immunohistochemical analyses. Besides, the good safety profile of carnosine in terms of its effect on liver and kidney functions was also confirmed. CONCLUSIONS: The use of carnosine supplements in preventing and/or treatment of metabolic disorders requires further investigations into the mechanisms of action and potential interactions with conventional therapy.

Strontium and simvastatin dual loaded hydroxyapatite microsphere reinforced poly(ε-caprolactone) scaffolds promote vascularized bone regeneration.

The promotion of vascular network formation in the early stages of implantation is considered a prerequisite for successful functional bone regeneration. In this study, we successfully constructed 3D printed scaffolds with strong mechanical strength and a controllable pore structure that can sustainably release strontium (Sr) ions and simvastatin (SIM) for up to 28 days by incorporation of Sr2+ and SIM-loaded hydroxyapatite microspheres (MHA) into a poly(ε-caprolactone) (PCL) matrix. In vitro cell experiments showed that Sr-doped scaffolds were beneficial to the proliferation and osteogenic differentiation of bone mesenchymal stem cells (BMSCs), an appropriate dose of SIM was beneficial to cell proliferation and angiogenesis, and a high dose of SIM was cytotoxic. The Sr- and SIM-dual-loaded scaffolds with an appropriate dose significantly induced osteogenic differentiation of BMSCs and tube formation of human umbilical vein endothelial cells (HUVECs) in vitro and promoted vascular network and functional bone formation in vivo. Ribose nucleic acid (RNA) sequencing analysis suggested that the mechanism of promotion of vascularized bone regeneration by fabricated scaffolds is that dual-loaded Sr2+ and SIM can upregulate osteogenic and vasculogenic-related genes and downregulate osteoclast-related genes, which is beneficial for vascular and new bone regeneration. The 3D printed composite scaffolds loaded with high-stability and low-cost inorganic Sr2+ ions and SIM small-molecule drugs hold great promise in the field of promoting vascularized bone regeneration.

Simvastatin therapy in higher dosages deteriorates bone quality: Consistent evidence from population-wide patient data and interventional mouse studies.

BACKGROUND: Combining mouse experiments with big data analysis of the Austrian population, we investigated the association between high-dose statin treatment and bone quality. METHODS: The bone microarchitecture of the femur and vertebral body L4 was measured in male and ovariectomized female mice on a high-fat diet containing simvastatin (1.2 g/kg). A sex-specific matched big data analysis of Austrian health insurance claims using multiple logistic regression models was conducted (simvastatin 60-80 mg/day vs. controls; males: n = 138,666; females: n = 155,055). RESULTS: High-dose simvastatin impaired bone quality in male and ovariectomized mice. In the trabecular femur, simvastatin reduced bone volume (µm3: ♂, 213 ± 15 vs. 131 ± 7, p < 0.0001; ♀, 66 ± 7 vs. 44 ± 5, p = 0.02) and trabecular number (1/mm: ♂, 1.88 ± 0.09 vs. 1.27 ± 0.06, p < 0.0001; ♀, 0.60 ± 0.05 vs. 0.43 ± 0.04, p = 0.01). In the cortical femur, bone volume (mm3: ♂, 1.44 ± 0.03 vs. 1.34 ± 0.03, p = 0.009; ♀, 1.33 ± 0.03 vs. 1.12 ± 0.03, p = 0.0002) and cortical thickness were impaired (µm: ♂, 211 ± 4 vs. 189 ± 4, p = 0.0004; ♀, 193 ± 3 vs. 169 ± 3, p < 0.0001). Similar impairments were found in vertebral body L4. Simvastatin-induced changes in weight or glucose metabolism were excluded as mediators of deteriorations in bone quality. Results from mice were supported by a matched cohort analysis showing an association between high-dose simvastatin and increased risk of osteoporosis in patients (♂, OR: 5.91, CI: 3.17-10.99, p < 0.001; ♀, OR: 4.16, CI: 2.92-5.92, p < 0.001). CONCLUSION: High-dose simvastatin dramatically reduces bone quality in obese male and ovariectomized female mice, suggesting that direct drug action accounts for the association between high dosage and increased risk of osteoporosis as observed in comparable human cohorts. The underlying pathophysiological mechanisms behind this relationship are presently unknown and require further investigation.

Hederagenin Exerts Potential Antilipemic Effect via p38MAPK Pathway in Oleic Acid-induced HepG2 cells and in Hyperlipidemic Rats.

Hederagenin, a natural compound distributed in many medicinal plants, has a variety of pharmacological properties including anti-bacteria, anti-inflammation, anti-oxidation, and anti- apoptosis.. The aim of this study was to evaluate the effects of hederagenin on decreasing blood lipid and anti-oxidative stress in oleic acid-induced HepG2 cells and hyperlipidemic rats, and explore underlying mechanisms. In vitro, TG was used as the index to verify the lipid-lowering effect of hederagenin in oleic acid-induced HepG2 cells. In vivo, TC, TG, LDL-C, and HDL-C were used as direct indicators to study the antilipemic effect of hederagenin in hyperlipidemic rats. MDA, SOD, and GSH-PX were measured to analyze the anti-oxidative effect of hederagenin. The signaling pathways of anti-oxidation were evaluated using Western blot. Our results showed that hederagenin (250µmol/L) increased significantly TG clearance rate. In addition, treatment with hederagenin, XZK and simvastatin reduced effectively TC, TG, LDL-C and MDA content, and increased HDL-C, SOD and GSH-PX in HFD rats. Moreover, the phosphorylation level of p38 MAPK was inhibited after administration of hederagenin, XZK and simvastatin. Our results revealed that hederagenin possessed beneficial potentials for hypolipidemic effects, especially in TG clearance. The mechanism might be associated with inhibition of lipid absorption, reduction of lipid oxidation, and down-regulation of p38MAPK phosphorylation.

Biochemistry and Nanomechanical Properties of Human Colon Cells upon Simvastatin, Lovastatin, and Mevastatin Supplementations: Raman Imaging and AFM Studies.

One of the most important areas of medical science is oncology, which is responsible for both the diagnostics and treatment of cancer diseases. Over the years, there has been an intensive development of cancer diagnostics and treatment. This paper shows the comparison of normal (CCD-18Co) and cancerous (CaCo-2) cell lines of the human gastrointestinal tract on the basis of nanomechanical and biochemical properties to obtain information on cancer biomarkers useful in oncological diagnostics. The research techniques used were Raman spectroscopy and imaging and atomic force microscopy (AFM). In addition, the studies also included the effect of the statin compounds─mevastatin, lovastatin, and simvastatin─and their influence on biochemical and nanomechanical changes of cell properties using Raman imaging and AFM techniques. The cytotoxicity of statins was determined using XTT tests.

Anti-Obesity Effects of Aqueous Extracts of Sunbanghwalmyung-Eum in High-Fat- and High-Cholesterol-Diet-Induced Obese C57BL/6J Mice.

Sunbanghwalmyung-eum (SBH) is a traditional herbal medicine that exhibits various pharmacological properties, such as antioxidant, anti-inflammatory, and anticancer activities. In this study, we investigated the systemic anti-obesity effects of an aqueous extract of SBH in the liver, adipose, and muscle tissue from high-fat and high-cholesterol diet (HFHCD)-induced obese C57BL/6J mice. After 6 weeks of an HFHCD, the mice were continuously fed HFHC with oral administration of SBH (100 mg/kg/day), Sim (simvastatin, 5 mg/kg/day, positive control), or water (HFHC only) for another 6 weeks. Our results showed that SBH attenuated the HFHCD-induced body weight gain and fat accumulation in the liver, and improved plasma lipid levels, such as those of triglycerides (TGs), blood total cholesterol (TC), and low-density lipoprotein (LDL-c). SBH and Sim inhibited the inflammation accompanied by obesity via decreasing inflammatory cytokine interleukin (IL)-1ß, tumor necrosis factor α (TNFα), and monocyte chemoattractant protein 1 (MCP1). Moreover, SBH downregulated the expression of protein levels of adipogenic-related factors, including peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), in the liver, adipose, and muscle tissue. The SBH and Sim treatment also significantly upregulated the phosphorylation of AMP-activated protein kinase α (AMPKα) in the liver and hormone-sensitive lipase (HSL) in the adipose tissue. Overall, the effects of SBH on HFHCD-induced obesity were similar to or more potent than those of simvastatin. These results indicated that SBH has great potential as a therapeutic herbal medicine for obesity.

Pharmacological effects of Artocarpus lakoocha methanol extract on inhibition of squalene synthase and other downstream enzymes of the cholesterol synthesis pathway.

CONTEXT: Artocarpus lakoocha Roxb. (Moraceae) is reported to possess antioxidant, anti-inflammatory, and anti-skin ageing agents. OBJECTIVE: This study evaluates the pharmacological effects of A. lakoocha leaves methanol extract on enzymes involved in the cholesterol synthesis pathway in high-fat diet-induced hyperlipidemic rats. MATERIALS AND METHODS: Twenty-four male Wistar rats, weighing approximately 180-220 g, were divided into four groups: control, diseased (hyperlipidemic), A. lakoocha leaves extract treated, and simvastatin treated. The rats were fed with high-fat diet for 2 months to induce hyperlipidaemia, afterward, experimental groups received A. lakoocha leaves methanol extract (250 mg/kg) and simvastatin (10 mg/kg) orally until the 89th day of the experiment, while the diseased group continued to receive high-fat diet along with normal saline. RESULTS: It was found that A. lakoocha extract significantly lowered the serum total cholesterol, triglycerides, and low-density lipoprotein (LDL) levels, while effectively increasing serum high-density lipoprotein (HDL) levels as compared to the diseased group (p ≤ 0.05). The mRNA expression levels of squalene synthase and HMG-CoA reductase were found to be effectively down-regulated after the treatment with A. lakoocha leaves extract (17.45 ± 2.48 vs. 31.91 ± 5.292 and 5.85 ± 3.164 vs. 37.37 ± 6.492) and simvastatin (7.148 ± 0.76 vs. 31.91 ± 5.292, and 3.098 ± 2.09 vs. 37.37 ± 6.492) as compared to the diseased group. DISCUSSION AND CONCLUSIONS: The results suggested that A. lakoocha leaves extract have observable beneficial effects on inhibition of enzymes involved in cholesterol synthesis pathway and improve lipid profile analogous to simvastatin.

Human carboxylesterase 1A plays a predominant role in the hydrolytic activation of remdesivir in humans.

Remdesivir, an intravenous nucleotide prodrug, has been approved for treating COVID-19 in hospitalized adults and pediatric patients. Upon administration, remdesivir can be readily hydrolyzed to form its active form GS-441524, while the cleavage of the carboxylic ester into GS-704277 is the first step for remdesivir activation. This study aims to assign the key enzymes responsible for remdesivir hydrolysis in humans, as well as to investigate the kinetics of remdesivir hydrolysis in various enzyme sources. The results showed that remdesivir could be hydrolyzed to form GS-704277 in human plasma and the microsomes from human liver (HLMs), lung (HLuMs) and kidney (HKMs), while the hydrolytic rate of remdesivir in HLMs was the fastest. Chemical inhibition and reaction phenotyping assays suggested that human carboxylesterase 1 (hCES1A) played a predominant role in remdesivir hydrolysis, while cathepsin A (CTSA), acetylcholinesterase (AchE) and butyrylcholinesterase (BchE) contributed to a lesser extent. Enzymatic kinetic analyses demonstrated that remdesivir hydrolysis in hCES1A (SHUTCM) and HLMs showed similar kinetic plots and much closed Km values to each other. Meanwhile, GS-704277 formation rates were strongly correlated with the CES1A activities in HLM samples from different individual donors. Further investigation revealed that simvastatin (a therapeutic agent for adjuvant treating COVID-19) strongly inhibited remdesivir hydrolysis in both recombinant hCES1A and HLMs. Collectively, our findings reveal that hCES1A plays a predominant role in remdesivir hydrolysis in humans, which are very helpful for predicting inter-individual variability in response to remdesivir and for guiding the rational use of this anti-COVID-19 agent in clinical settings.

The effect of 8 weeks of physical training on muscle performance and maximal fat oxidation rates in patients treated with simvastatin and coenzyme Q10 supplementation.

Statins are prescribed for the treatment of elevated cholesterol, but they may negatively affect metabolism, muscle performance, and the response to training. Coenzyme Q10 (CoQ10) supplementation may alleviate these effects. Combined simvastatin and CoQ10 treatment during physical training has never been tested. We studied the response to 8 weeks training (maximal oxygen uptake ( V̇O2max${\dot{V}_{{{\rm{O}}_{\rm{2}}}{\rm{max}}}}$ ), fat oxidation (MFO), the workload at which MFO occurred, and muscle strength) in statin naive dyslipidaemic patients who received simvastatin (40 mg/day) with (S + Q, n = 9) or without (S + Pl, n = 10) CoQ10 supplementation (2 × 200 mg/day) or placebo (Pl + Pl, n = 7) in a randomized, double-blind placebo-controlled study. V̇O2max${\dot{V}_{{{\rm{O}}_{\rm{2}}}{\rm{max}}}}$ and maximal workload increased with training (main effect of time, P < 0.05). MFO increased from 0.29 ± 0.10, 0.26 ± 0.10, and 0.38 ± 0.09 to 0.42 ± 0.09, 0.38 ± 0.10 and 0.48 ± 0.16 g/min in S + Q, S + Pl, and Pl + Pl, respectively (main effect of time, P = 0.0013). The workload at MFO increased from 75 ± 25, 56 ± 23, and 72 ± 17 to 106 ± 25, 84 ± 13 and 102 ± 31 W in S + Q, S + Pl, and Pl + Pl, respectively (main effect of time, P < 0.0001). Maximal voluntary contraction and rate of force development were unchanged. Exercise improved aerobic physical capacity and simvastatin with or without CoQ10 supplementation did not inhibit this adaptation. The similar increases in MFO and in the workload at which MFO occurred in response to training shows that the ability to adapt substrate selection and oxidation rates is preserved with simvastatin treatment, despite the potential negative impact of simvastatin at the mitochondrial level. CoQ10 supplementation does not augment this adaptation. KEY POINTS: Simvastatins are prescribed for treatment of elevated cholesterol, but they may negatively affect metabolism, muscle performance and the response to training. Coenzyme Q10 (CoQ10) supplementation may alleviate some of these effects. We found that simvastatin treatment does not negatively affect training-induced adaptations of substrate oxidation during exercise. Likewise, maximal oxygen uptake increases with physical training also in patients in treatment with simvastatin. CoQ10 supplementation in simvastatin-treated patients presents no advantage in the adaptations to physical training Simvastatin treatment decreases plasma concentrations of total CoQ10, but this can be alleviated by simultaneous supplementation with CoQ10.

Hypolipidemic and reduced nitrergic effects of p-hydroxycinnamic diesters extracted from Copernicia prunifera in mice challenged by a high-fat diet.

Dyslipidemia is a chronic non-transmissible condition that has increased due to an unhealthy lifestyle. Statins have been used as the standard treatment to control hyperlipidemia. However, side effects and high costs may be associated with its prolonged treatment, so plants derivatives have been an attractive therapy to overcome these problems. Among the compounds extracted from plants, the p-hydroxycinnamic diesters (HCE), present in carnauba wax (CW), have been found with good pharmacological properties. Therefore, this study aimed to evaluate the potential anti-hypercholesterolemic and possible toxicological effects of HCE in C57BL/6J mice under a high-fat (HF) diet. Male C57BL/6J mice were fed during 60 days under the HF diet and therefore were either treated with HCE (200 and 400 mg/kg) or simvastatin (20 mg/kg) or received saline (controls) by gavage for 30 days under the same diet. HCE treatment was able to reduce serum total cholesterol and LDL levels. Besides, this compound increased liver X receptor (LXR) and but not significantly affected IL-1ß and TNF-α liver mRNA transcription activity. In conclusion, HCE treatment was found safe and may attenuate the deleterious effects of dyslipidemia due to chronic feeding with western diets.