Statins Research Articles

TAL1 hijacks MYCN enhancer that induces MYCN expression and dependence on mevalonate pathway in T-cell acute lymphoblastic leukemia.

A hallmark of T-cell acute lymphoblastic leukemia (T-ALL) is the dysregulated expression of oncogenic transcription factors (TFs), including TAL1, NOTCH1 and MYC. Rewiring of the transcriptional program disrupts the tightly controlled spatiotemporal expression of downstream target genes, thereby contributing to leukemogenesis. In this study, we first identify an evolutionarily conserved enhancer element controlling the MYCN oncogene (named enhMYCN) that is aberrantly activated by the TAL1 complex in T-ALL cells. TAL1-positive T-ALL cells are highly dependent on MYCN expression for their maintenance in vitro and in xenograft models. Interestingly, MYCN drives the expression of multiple genes involved in the mevalonate pathway, and T-ALL cells are sensitive to inhibition of HMG-CoA reductase (HMGCR), a rate-limiting enzyme of this pathway. Importantly, MYC and MYCN regulate the same targets and compensate for each other. Thus, MYCN-positive T-ALL cells display a dual dependence on the TAL1-MYCN and NOTCH1-MYC pathways. Together, our results demonstrate that enhMYCN-mediated MYCN expression is required for human T-ALL cells and implicate the TAL1-MYCN-HMGCR axis as a potential therapeutic target in T-ALL.

Triterpenoids from Protorhus longifolia Exhibit Hypocholesterolemic Potential via Regulation of Cholesterol Biosynthesis and Stimulation of Low-Density Lipoprotein Uptake in HepG2 Cells.

The increasing incidence of hypercholesterolemia-related diseases even in the presence of the currently available cholesterol-lowering drugs indicates a need to discover new therapeutic drugs. This study aimed to investigate the hypocholesterolemic potential of two triterpenoids isolated from Protorhus longifolia stem bark. In silico techniques and in vitro enzyme assays were used to evaluate the potential inhibition of cholesterol esterase and HMG-CoA reductase by the triterpenoids (ARM-2 and RA-5). The toxicity, modulation of low-density lipoprotein (LDL) uptake, and associated gene expression were determined in HepG2 hepatocytes. In silico molecular docking revealed that ARM-2 compared with RA-5 has a relatively stronger binding affinity for both enzymes. Both triterpenoids further demonstrated promising in silico drug-likeness properties and favorable ADMET profiles characterized by high intestinal absorption and lack of CYP450 enzyme inhibition. The compounds further showed, to varying degrees of efficacy, inhibition of cholesterol micellization as well as both cholesterol esterase and HMG-CoA reductase activities with IC50 values ranging from 16.4 to 41.1 μM. Moreover, enhanced hepatic cellular LDL uptake and the associated upregulation of the LDL-R and SREBP-2 gene expression were observed in the triterpenoid-treated HepG2 cells. It is evident that the triterpenoids, especially ARM-2, possess hypocholesterolemic properties, and these molecules can serve as leads or structural templates for the development of new hypocholesterolemic drugs.

The effect of a multi-component behavior change technique intervention on medication adherence among individuals on primary prevention statin therapy: a dose-finding protocol

BackgroundIn the USA, the primary cause of death and morbidity continues to be cardiovascular disease (CVD). Numerous trials have shown that statin medication reduces the likelihood of CVD events; it is a cornerstone of CVD prevention. However, studies have also indicated that up to 60% of the estimated 26.8 million Americans prescribed primary prevention statin treatment are nonadherent during the first year. Multi-component behavioral change technique (BCT) therapies have shown moderate promise in improving medication adherence as well as other positive health behaviors (such as physical activity). However, no research has looked at the duration of multi-component BCT intervention needed to result in a clinically significant improvement in statin adherence behaviors. This study aims to determine the necessary dose of a multi-component BCT intervention (defined as duration in weeks) to promote adherence to statin medication among those on primary prevention statin treatment by utilizing the modified time-to-event continuous reassessment method (TiTE-CRM).Methods and designThe study will utilize the modified TiTE-CRM in 42 participants, recruited in 14 cohorts of 3 participants each. The goal of this analysis is to identify the minimum effective dose (MED) of a multi-behavior change technique (BCT) intervention required to increase adherence to statins by 20% between baseline and follow-up periods. Using the TiTE-CRM method, the dose of the behavior intervention in weeks will be assigned to each cohort based on the performance of the prior cohort. At the end of the study, the intervention dose that has been found to be associated with a 20% increase in statin adherence among 80% of participants assigned to that dose will be identified as the MED.DiscussionIf successful, the current trial will provide additional guidance to researchers and clinicians seeking to increase statin medication adherence using a BCT intervention by identifying the dose (i.e., the duration) of an intervention required to meaningfully increase adherence.Trial registrationClinicalTrials.gov NCT05273736. Registered on March 10, 2022. https://www.clinicaltrials.gov/ct2/show/NCT05273736

Formulation and Development of Solid Dispersion System for Enhancement of Solubility and Dissolution Rate of Lovastatin

The solubility and dissolution rate of Lovastatin, a drug used for the treatment of hyperlipidaemia. Lovastatin is a selective competitive inhibitor of HMG Co-A reductase. However, its absolute bioavailability is 5%. To increase the solubility of drug solid dispersion was prepared. Solid dispersion prepared with polymer in 1:5 ratios shows the presence of amorphous form confirmed by the characterization study. Solid dispersion preliminary solubility analysis was carried out for the selection of the carrier and solid dispersion was prepared with Hydroxy Propyl Methyl Cellulose (HPMC) and Methyl Cellulose (MC). These solid dispersions were analyzed for the solubility and in-vitro dissolution profile solid dispersion of drug with polymer has shown enhanced solubility with improved dissolution rate. Further FTIR, X-Ray studies were carried out. The present investigations showed that solubility of Lovastatin Sodium was markedly increased by its solid dispersion using PVP K30 as carrier. The formulation SDF8 containing (1:8) shows highest dissolution rate. Hence the solid dispersion a way is useful technique in providing fastest onset of action of Lovastatin Sodium as well as enhanced dissolution rate. The study also shows that dissolution rate of Lovastatin can be enhanced to considerable extent by solid dispersion technique with Polymer.

Design and Formulation for Enhancement of Solubility and Dissolution Rate of Atorvastatin using Solid Dispersion

The solubility and dissolution rate of Atorvastatin, a drug used for the treatment of hyperlipidaemia. Atorvastatin is a selective competitive inhibitor of HMG Co-A reductase. However its absolute bioavailability is 5%. To increase the solubility of drug solid dispersion was prepared. Solid dispersion preliminary solubility analysis was carried out for the selection of the carrier and solid dispersion was prepared with Hydroxy Propyl Methyl Cellulose (HPMC) and Methyl Cellulose (MC). These solid dispersions were analyzed for the solubility and in-vitro dissolution profile solid dispersion of drug with polymer has shown enhanced solubility with improved dissolution rate. Further FTIR, X-Ray studies were carried out. Solid dispersion prepared with polymer in 1:5 ratios shows the presence of amorphous form confirmed by the characterization study. The present investigations showed that solubility of Atorvastatin Sodium was markedly increased by its solid dispersion using PVP K30 as carrier. The formulation SDF8 containing (1:8) shows highest dissolution rate. Hence the solid dispersion a way is useful technique in providing fastest onset of action of Atorvastatin Sodium as well as enhanced dissolution rate. The study also shows that dissolution rate of pravastatin can be enhanced to considerable extent by solid dispersion technique with Polymer.

Neuronal γ-secretase regulates lipid metabolism, linking cholesterol to synaptic dysfunction in Alzheimer’s disease

Presenilin mutations that alter γ-secretase activity cause familial Alzheimer's disease (AD), whereas ApoE4, an apolipoprotein for cholesterol transport, predisposes to sporadic AD. Both sporadic and familial AD feature synaptic dysfunction. Whether γ-secretase is involved in cholesterol metabolism and whether such involvement impacts synaptic function remains unknown. Here, we show that in human neurons, chronic pharmacological or genetic suppression of γ-secretase increases synapse numbers but decreases synaptic transmission by lowering the presynaptic release probability without altering dendritic or axonal arborizations. In search of a mechanism underlying these synaptic impairments, we discovered that chronic γ-secretase suppression robustly decreases cholesterol levels in neurons but not in glia, which in turn stimulates neuron-specific cholesterol-synthesis gene expression. Suppression of cholesterol levels by HMG-CoA reductase inhibitors (statins) impaired synaptic function similar to γ-secretase inhibition. Thus, γ-secretase enables synaptic function by maintaining cholesterol levels, whereas the chronic suppression of γ-secretase impairs synapses by lowering cholesterol levels.

Repurposing Antihypertensive and Statin Medications for Spinal Pain: A Mendelian Randomization Study.

Mendelian randomization (MR) study. To examine whether antihypertensive medications (beta-blockers, calcium channel blockers, and angiotensin-converting enzyme inhibitors) and statins can be repurposed to prevent or treat spinal pain (back or neck pain). Observational studies and a recent MR study have found associations between elevated blood pressure and a greater risk of back pain. Observational studies have found associations between hyperlipidemia and statin use and greater risk of back pain. No prior MR studies have examined the effects of antihypertensives or statins on spinal pain. This was a two-sample MR study using publicly available summary statistics from large-scale genome-wide association studies (GWAS). Sample sizes in exposure GWASs were n=757,601 (systolic blood pressure) and n=173,082 (low-density lipoprotein cholesterol), and n=1,028,947 for the outcome GWAS of spinal pain defined as health care seeking for any spinal pain-related diagnosis. Genes and cis-acting variants were identified as proxies for the drug targets of interest. MR analyses used inverse-variance weighted meta-analysis. The threshold for statistical significance after correction for multiple testing was P <0.0125. No statistically significant associations of these medications with spinal pain were found. However, findings were suggestive of a protective effect of beta-blockers on spinal pain risk (odds ratio [OR] 0.84, 95% confidence interval [CI] 0.72-0.98; P =0.03), and calcium channel blockers on greater spinal pain risk (OR 1.12, 95% CI 1.02-1.24; P =0.02). A protective effect of beta-blockers on spinal pain was suggested in the current study, consistent with findings from observational studies of various other pain phenotypes. The detrimental effect of calcium channel blockers on spinal pain suggested in the current study must be interpreted in the context of conflicting directions of effect on nonspinal pain phenotypes in other observational studies.This Mendelian randomization study examined whether antihypertensive medications (beta-blockers, calcium channel blockers, and angiotensin-converting enzyme inhibitors) and statins can be repurposed to prevent or treat spinal.This was a two-sample MR study using publicly available summary statistics from large-scale genome-wide association studies ranging size from 173,082 to 1,028,947 adults.While no statistically significant associations were found, a protective effect of beta-blockers on spinal pain was suggested (odds ratio [OR] 0.84, 95% confidence interval [CI] 0.72 to 0.98; p= 0.03), as was a detrimental effect of calcium channel blockers on spinal pain (OR 1.12, 95% CI 1.02 to 1.24; p= 0.02).

Statins in Cancer Prevention and Therapy.

Statins, a class of HMG-CoA reductase inhibitors best known for their cholesterol-reducing and cardiovascular protective activity, have also demonstrated promise in cancer prevention and treatment. This review focuses on their potential applications in head and neck cancer (HNC), a common malignancy for which established treatment often fails despite incurring debilitating adverse effects. Preclinical and clinical studies have suggested that statins may enhance HNC sensitivity to radiation and other conventional therapies while protecting normal tissue, but the underlying mechanisms remain poorly defined, likely involving both cholesterol-dependent and -independent effects on diverse cancer-related pathways. This review brings together recent discoveries concerning the anticancer activity of statins relevant to HNC, highlighting their anti-inflammatory activity and impacts on DNA-damage response. We also explore molecular targets and mechanisms and discuss the potential to integrate statins into conventional HNC treatment regimens to improve patient outcomes.

Effect of foxtail millet supplementation in comparison to atorvastatin on high-fat diet-induced hyperlipidemia in rats

Background: Hyperlipidemia can be defined as an increased concentration of lipids in the blood. Foxtail millet (FTM) is a nutrient-rich cereal containing several phytochemicals which have possible lipid-lowering and glucose-lowering abilities. Atorvastatin is an HMG Co-A Reductase Inhibitor commonly prescribed for Hyperlipidemia. Aims and Objectives: The aim of this study was to compare the hypolipidemic effect of FTM with that of Atorvastatin in Sprague–Dawley rats. Materials and Methods: Twelve 12 male Sprague–Dawley rats were segregated into Group-A and Group-B with six (6) rats in each group. The rats in both groups were fed high-fat diet for 21 days and for the next 21 days the 6 rats in Group-A were fed FTM in the form of pellets, the 6 rats in Group-B were administered Atorvastatin in a dose of 5 mg/kg. The body weight (BW) and lipid profiles of the rats were measured at three stages-day 0, day 21, and day 42. Results: FTM showed an 18.1% rise in high-density lipoprotein (HDL-C). It showed a fall in BW, total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL-C), and very LDL (VLDL-C) which were 15.5%, 14.0%, 12.8%, 18.3%, and 16.0%, respectively. With Atorvastatin the rise in HDL-C was 13.4%. The fall in BW, TC, TG, LDL-C, and VLDL-C was 30.2%, 30.5%, 24.9%, 27.5%, and 34.4%, respectively. Conclusion: The present study results showed that FTM had a noticeable positive effect on the lipid profile and BW in Dyslipidemia in comparison to Atorvastatin.

Statin as Repurposed Drug in Ovarian Cancer: A Comprehensive Review.

With a prevalence rate of 6.6 per 100,000 women, ovarian cancer is the third most lethal gynecological tumor in the world. Several factors like family history, nulliparity, late menopause, genetic mutation, and an unhealthy lifestyle contribute to increasing the risk of ovarian cancer development. Novel research studies suggest that ovarian cancer may be caused by changes in the lipid metabolic profile that trigger inflammatory responses. Moreover, ovarian cancer patients will eventually experience chemoresistance. Statin, a competitive inhibitor of HMG-CoA reductase that is a lipid-lowering drug with pleiotropic effects, seems to be the best choice to deal with this therapeutic issue. The aim of this review is to highlight the pharmacotherapeutic potential of statins, especially the repurposing of statin drugs for antitumor mechanisms. This review will also provide a brief summary of the meta-analysis, and case-control observational studies carried out to examine the impact of statins on risk reduction and survival in ovarian cancer patients. Furthermore, this review will discuss the nanotechnological approach for improving the drug's bioavailability and safe and targeted delivery with controlled release of active ingredients, making statins more effective in preventing and treating ovarian cancer.

Addressing Cardiovascular Risk Across the Arc of a Woman's Life: Sex-Specific Prevention and Treatment.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in womenin the United States of America. Despite this, women are underdiagnosed, less often receive preventive care, and are undertreated for CVD compared to men. There has been an increase in sex-specific risk factors and treatments over the past decade; however, sex-specific recommendations have not been included in the guidelines. We aim to highlight recent evidence behind thedifferential effect of traditional risk factors and underscore sex-specific risk factors with an intention to promote awareness, improve risk stratification, and early implementation of appropriate preventive therapies in women. Women are prescribed fewer antihypertensives and lipid-lowering agents and receive less cardiovascular care as compared to men. Additionally, pregnancy complications have been associated with increased cardiovascular mortality later in life. Findings from theARIC study suggest that there is a perception of lower risk of cardiovascular disease in women. The SWEDEHEART study which investigated sex differences in treatment, noted a lower prescription of guideline-directed therapy in women. Women are less likely to be prescribed statin medications by their providers in both primary and secondary prevention as they are considered lower risk than men, while also being more likely to decline and discontinue treatment. A woman's abnormal response to pregnancy may serve as her first physiological stress test which can have implications on her future cardiovascular health. This was supported by the CHAMPs study noting a higher premature cardiovascular risk after maternal complications. Adverse pregnancy outcomes have been associated with a 1.5-4.0 fold increase in future cardiovascular events in multiple studies. In this review, we highlight the differences in traditional risk factors and their impact on women. Furthermore, we address the sex-specific risk factors and pregnancy-associated complications that increase the risk of CVD in women. Adherence to GDMT may have implications on overall mortality in women. An effort to improve early recognition of CVD risk with implementation of aggressive risk factor control and lifestyle modification should be emphasized. Future studies should specifically report on differences in outcomes between males and females. Increased awareness and knowledge on sex-specific risks and prevention are likely to lower the prevalence and improve outcomes of CVD in women.

Modeling of hydrophobic tetrapeptides as a competitive inhibitor for HMG-CoA reductase

This study presents a modeling of hydrophobic tetrapeptides acting in a competitive manner against 3‑hydroxy-3-methylglutaryl coenzyme A reductase. This enzyme catalyzes the reductive deacylation of 3‑hydroxy-3-methylglutaryl coenzyme A to mevalonate, using two molecules of nicotinamide adenine dinucleotide phosphate as cofactors, and this reaction represents the rate-limiting step in cholesterol biosynthesis. Thus, it is a target of many investigations in order to control a cholesterol level because the elevated cholesterol level is known as a risk factor of hypercholesterolemia. In previous studies, the two hypocholesterolemic peptides were isolated from soy glicinin. Based on these sequences, a number of the tri-, tetra-, hexa- and heptapeptides were designed in order to improve their inhibitory activities. The peptide fragmentation was applied as a main tool in design. Using the developed design method, a new recognized motif in the designed tetrapeptides was identified. According to the design parameter, the IIIP peptide possessed the most rigid structure among the new designed tetrapeptides. The circular dichroism study confirmed that the observed predominant conformation of the IIIP peptide was close to the type I of a β-turn. The IIIP peptide was determined as the strongest inhibitor among the new designed tetrapeptides. The kinetic study revealed the competitive HMGR inhibition by the peptide, which acted as a bisubstrate blocking an access of HMG-CoA and NADPH to their binding sites. The correlation coefficient (r2) between the predicted and observed peptide activities of 0.91 suggests wide possibilities of the proposed approach to design new peptides that may differ from the previously designed peptides in the recognized motif, sequences, lengths and structural preferences.

Systematic Screening of Associations between Medication Use and Risk of Neurodegenerative Diseases Using a Mendelian Randomization Approach.

Systematically assessing the causal associations between medications and neurodegenerative diseases is significant in identifying disease etiology and novel therapies. Here, we investigated the putative causal associations between 23 existing medication categories and major neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). A two-sample mendelian randomization (MR) approach was conducted. Estimates were calculated using the inverse-variance weighted (IVW) method as the main model. A sensitivity analysis and a pleiotropy analysis were performed to identify potential violations. Genetically predisposition to antihypertensives (OR = 0.809, 95% CI = 0.668-0.981, p = 0.031), thyroid preparations (OR = 0.948, 95% CI = 0.909-0.988, p = 0.011), and immunosuppressants (OR = 0.879, 95% CI = 0.789-0.979, p = 0.018) was associated with a decreased risk of AD. Genetic proxies for thyroid preparations (OR = 0.934, 95% CI = 0.884-0.988, p = 0.017), immunosuppressants (OR = 0.825, 95% CI = 0.699-0.973, p = 0.022), and glucocorticoids (OR = 0.862, 95% CI = 0.756-0.983, p = 0.027) were causally associated with a decreased risk of PD. Genetically determined antithrombotic agents (OR = 1.234, 95% CI = 1.042-1.461, p = 0.015), HMG CoA reductase inhibitors (OR = 1.085, 95% CI = 1.025-1.148, p = 0.005), and salicylic acid and derivatives (OR = 1.294, 95% CI = 1.078-1.553, p = 0.006) were associated with an increased risk of ALS. We presented a systematic view concerning the causal associations between medications and NDs, which will promote the etiology discovery, drug repositioning and patient management for NDs.

New insights into the therapeutic potentials of statins in cancer.

The widespread clinical use of statins has contributed to significant reductions of cardiovascular morbidity and mortality. Increasing preclinical and epidemiological evidences have revealed that dyslipidemia is an important risk factor for carcinogenesis, invasion and metastasis, and that statins as powerful inhibitor of HMG-CoA reductase can exert prevention and intervention effects on cancers, and promote sensitivity to anti-cancer drugs. The anti-cancer mechanisms of statins include not only inhibition of cholesterol biosynthesis, but also their pleiotropic effects in modulating angiogenesis, apoptosis, autophagy, tumor metastasis, and tumor microenvironment. Moreover, recent clinical studies have provided growing insights into the therapeutic potentials of statins and the feasibility of combining statins with other anti-cancer agents. Here, we provide an updated review on the application potential of statins in cancer prevention and treatment and summarize the underneath mechanisms, with focuses on data from clinical studies.

Effects of Simvastatin on RBL-2H3 Cell Degranulation.

Hypercholesterolemia is a major complication of arteriosclerosis. Mast cells in arteriosclerosis plaques induce inflammatory reactions and promote arterial sclerosis. In this study, we evaluated the pharmacological effects of simvastatin (SV)-3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors on the degranulation of rat basophilic leukemia (RBL)-2H3 cells, which are commonly used as mast cell models. SV significantly decreased the degranulation induced by three types of stimulation: antigen antibody reaction (Ag-Ab), thapsigargin (Tg) serosal endoplasmic reticulum calcium ATPase (SERCA) inhibitor, and A23187 calcium ionophore. SV had a stronger inhibitory effect on degranulation induced by Ag-Ab stimulation than the other two stimulations. However, SV did not inhibit increase of intracellular Ca2+ concentrations. Mevalonate or geranylgeraniol co-treatment with SV completely prevented the inhibitory effect of SV on the degranulation induced by these stimulations. Immunoblotting results showed that SV inhibited protein kinase C (PKC) delta translocation induced by Ag-Ab but not by Tg or A23187. SV induced a reduction in active Rac1, and actin filament rearrangement. In conclusion, SV inhibits RBL-2H3 cell degranulation by inhibiting downstream signaling pathways, including the sequential degranulation pathway. These inhibitory effects were completely reversed by the addition of geranylgeraniol and might be induced by changes in the translocation of the small guanosine 5'-triphosphatase (GTPase) families Rab and Rho, which are related to vesicular transport PKC delta translocation and actin filament formation, respectively. These changes are caused by the inhibition of HMG-CoA reductase by SV following the synthesis of geranylgeranyl pyrophosphates, which play important roles in the activation of small GTPases, Rab.

Correction of the prooxidant-antioxidant balance disorders in patients with diabetic kidney disease

The present study aimed to evaluate the effect of sodium-glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin therapy on the prooxidant-antioxidant balance (PAB) in patients with diabetic kidney disease.&#x0D; Methods. A total of 88 patients with type 2 diabetes mellitus (DM) and diabetic nephropathy (DN) were included in this single-center randomized open-label prospective study. All patients were randomly divided into 2 groups: 45 patients received a standard course of treatment, which included antidiabetic drugs, renin-angiotensin-aldosterone system blockers, and HMG-CoA reductase inhibitors (statins). In addition to the standard therapy, the remaining 43 patients were prescribed the SGLT2 inhibitor dapagliflozin 10 mg per day. Patients were re-examined after 6 months of treatment. The blood PAB was calculated as the ratio of total hydroperoxides (THP) to total antioxidant activity (TAA). The level of THP and TAA was determined by the colorimetric method.&#x0D; Results. PAB was significantly elevated in type 2 DM patients with nephropathy due to TAA decrease and THP level increase when compared to the control group. The highest values of PAB were found in the late stages of DN in patients with glomerular filtration rates &lt;60 ml/min/1.73m2. In patients who received dapagliflozin, significant PAB elevation by 30,55% (р &lt; 0.05) was observed as well as THP decrease and TAA increase in blood. In the standard therapy group, no significant changes in PAB parameters were detected.&#x0D; Conclusions. Add-on treatment with dapagliflozin resulted in a more significant improvement of the PAB in patients with DN in comparison with standard treatment.

An RNA-immunoprecipitation via CRISPR/dCas13 reveals an interaction between the SARS-CoV-2 5'UTR RNA and the process of human lipid metabolism

We herein elucidate the function of SARS-CoV-2derived 5'UTR in the human cells. 5'UTR bound host cellular RNAs were immunoprecipitated by gRNA-dCas13 (targeting luciferase RNA fused to SARS-CoV-2 5'UTR) in HEK293T and A549 cells. The 5'UTR bound RNA extractions were predominantly enriched for regulating lipid metabolism. Overexpression of SARS-CoV-2 5'UTR RNA altered the expression of factors involved in the process of the human Mevalonate pathway. In addition, we found that HMG-CoA reductase inhibitors were shown to suppress SARS-CoV-2 5'UTR-mediated translation activities. In conclusion, we deduce the array of host RNAs interacting with SARS-CoV-2 5'UTR that drives SARS-CoV-2 translation and influences host metabolic pathways.

Polypharmacy and Medication Outcome Reporting Bias in Older Patients with COVID-19

Polypharmacy, the use of multiple and potentially inappropriate medications, is an increasing problem among older adults. The global polypharmacy prevalence is 34.6% in patients with COVID-19, and polypharmacy in COVID-19 increases with age. The present paper proposes that polypharmacy in older adults with COVID-19 and other comorbid conditions is linked to the medication outcome reporting bias of randomized controlled trials. Outcome reporting bias can occur when treatment efficacy is reported as relative risk reductions, which overestimates medication benefits and exaggerates disease/illness risk reductions compared to unreported absolute risk reductions. The comorbidities common in patients with COVID-19 include high blood pressure, cardiovascular disease, dementia or cerebrovascular disease, and diabetes. Accordingly, the present paper reassesses the relative and absolute risk reductions in clinical trials from a small convenience sample of antihypertension, statin, anticoagulant, and antihyperglycemic medications. Examples demonstrate a wide gap between reported relative risk reductions and unreported absolute risk reductions in medication clinical trials. This paper concludes that medication clinical trial outcome reporting bias is an important upstream factor that contributes to biased medication benefits and poor clinical decision making, leading to polypharmacy in older adults with COVID-19 and other comorbid conditions. Public health campaigns are urgently needed to educate the public about the link between polypharmacy and medication outcome reporting bias.

Eupatilin Alleviates Hyperlipidemia in Mice by Inhibiting HMG-CoA Reductase.

Artemisia princeps (family Asteraceae) is a natural product broadly used as an antioxidative, hepatoprotective, antibacterial, and anti-inflammatory agent in East Asia. In the present study, eupatilin, the main constituent of Artemisia princeps, was investigated as an antihyperlipidemic agent. Eupatilin inhibited 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase (HCR), an enzyme that is a therapeutic target for hyperlipidemia, in an ex vivo assay using rat liver. In addition, oral administration of eupatilin significantly lowered the serum levels of total cholesterol (TC) and triglycerides (TG) in corn oil-induced and Triton WR-1339-induced hyperlipidemic mice. These results suggest that eupatilin can alleviate hyperlipidemia by inhibiting HCR.

Antihyperlipidemic mechanisms of a formula containing Curcuma xanthorrhiza, Sechium edule, and Syzigium polyanthum: In silico and in vitro studies

Herbal medicines are multi-component and can exhibit synergistic effects in the treatment of diseases. Sechium edule, Syzigium polyanthum, and Curcuma xanthorrhiza have been used in traditional medicine to reduce serum lipid levels. However, the molecular mechanism was not described clearly, especially as a mixture. Thus, we performed a network pharmacology study combined with molecular docking to find a rational explanation regarding the molecular mechanisms of this antihyperlipidemic formula. According to the network pharmacology study, we predicted that this extract mixture would act as an antihyperlipidemic agent by modulating several pathways including insulin resistance, endocrine resistance, and AMP-activated protein kinase (AMPK) signaling pathway. Based on the topology parameters, we identified 6 significant targets that play an important role in reducing lipid serum levels: HMG-CoA reductase (HMGCR), peroxisome proliferator-activated receptor alpha (PPARA), RAC-alpha serine/threonine-protein kinase (AKT1), epidermal growth factor receptor (EGFR), matrix metalloproteinase-9 (MMP9), and tumor necrosis factor-alpha (TNF). Meanwhile, 8 compounds: β-sitosterol, bisdesmethoxycurcumin, cucurbitacin D, cucurbitacin E, myricetin, phloretin, quercitrin, and rutin were the compounds with a high degree, indicating that these compounds have a multitarget effect. Our consensus docking study revealed that HMGCR was the only protein targeted by all potential compounds, and rutin was the compound with the best consensus docking score for almost all targets. The in vitro study revealed that the extract combination could inhibit HMGCR with an IC50 value of 74.26 µg/mL, indicating that HMGCR inhibition is one of its antihyperlipidemic mechanisms.