Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients.

BACKGROUND: Bempedoic acid, an ATP citrate lyase inhibitor, reduces low-density lipoprotein (LDL) cholesterol levels and is associated with a low incidence of muscle-related adverse events; its effects on cardiovascular outcomes remain uncertain. METHODS: We conducted a double-blind, randomized, placebo-controlled trial involving patients who were unable or unwilling to take statins owing to unacceptable adverse effects ("statin-intolerant" patients) and had, or were at high risk for, cardiovascular disease. The patients were assigned to receive oral bempedoic acid, 180 mg daily, or placebo. The primary end point was a four-component composite of major adverse cardiovascular events, defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. RESULTS: A total of 13,970 patients underwent randomization; 6992 were assigned to the bempedoic acid group and 6978 to the placebo group. The median duration of follow-up was 40.6 months. The mean LDL cholesterol level at baseline was 139.0 mg per deciliter in both groups, and after 6 months, the reduction in the level was greater with bempedoic acid than with placebo by 29.2 mg per deciliter; the observed difference in the percent reductions was 21.1 percentage points in favor of bempedoic acid. The incidence of a primary end-point event was significantly lower with bempedoic acid than with placebo (819 patients [11.7%] vs. 927 [13.3%]; hazard ratio, 0.87; 95% confidence interval [CI], 0.79 to 0.96; P = 0.004), as were the incidences of a composite of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction (575 [8.2%] vs. 663 [9.5%]; hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P = 0.006); fatal or nonfatal myocardial infarction (261 [3.7%] vs. 334 [4.8%]; hazard ratio, 0.77; 95% CI, 0.66 to 0.91; P = 0.002); and coronary revascularization (435 [6.2%] vs. 529 [7.6%]; hazard ratio, 0.81; 95% CI, 0.72 to 0.92; P = 0.001). Bempedoic acid had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause. The incidences of gout and cholelithiasis were higher with bempedoic acid than with placebo (3.1% vs. 2.1% and 2.2% vs. 1.2%, respectively), as were the incidences of small increases in serum creatinine, uric acid, and hepatic-enzyme levels. CONCLUSIONS: Among statin-intolerant patients, treatment with bempedoic acid was associated with a lower risk of major adverse cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization). (Funded by Esperion Therapeutics; CLEAR Outcomes ClinicalTrials.gov number, NCT02993406.).

MYC expression and fatty acid oxidation in EGFR-TKI acquired resistance.

This report expands on our previous research, highlighting a unique inverse correlation between MYC expression in tumor cells and immune cells during the development of EGFR-TKI resistance. It is observed that MYC expression and fatty acid oxidation (FAO) metabolism in tissue-resident memory (TRM) CD8 + T cells are significantly impaired. These findings offer new insights into the mechanisms of TKI resistance. Although the study is preliminary, it suggests caution when interpreting the effectiveness of MYC inhibitors in reversing TKI resistance, especially when immune factors are not considered.

Bempedoic acid: new evidence and recommendations on use.

PURPOSES OF REVIEW: Cardiovascular diseases (CVDs) are the leading cause of mortality and morbidity worldwide. Recognizing the importance of dyslipidemia treatment in the prevention of cardiovascular events has become a part of standard clinical practice. Desired values of LDL cholesterol (LDL-C) have become lower and lower in the last few decades, as evidenced by the most recent guidelines. Therefore, efforts to lower LDL cholesterol concentrations with conventional therapies and combinations of lipid-lowering therapy may not be successful in a high proportion of patients. RECENT FINDINGS: Bempedoic acid is a novel agent, first in-class ATP Citrate Lyase (ACL) inhibitor, which targets biosynthesis of the cholesterol in the liver. Considering the results of phase 3 studies, it has been approved for sole use for dyslipidemia treatment for patients who are statin-intolerant or in combination with statin-ezetimibe for those suffering from familial hypercholesterolemia or ASCVD and unable to reach targeted LDL-C values. SUMMARY: Bempedoic acid has proven beneficial for further reduction of LDL cholesterol for targeted groups of patients. It is not only efficient but also a well tolerated, affordable, and available agent whose place in lipid-lowering management is yet to be fully understood with new data collected from ongoing clinical research. In this review we suggest the place of bempedoic acid in lipid-lowering management.

Effects of bempedoic acid on markers of inflammation and Lp(a).

PURPOSE OF REVIEW: To study the effect of bempedoic acid on markers of inflammation and lipoprotein (a) to help determine if the drug would be useful to treat patients with elevated cardiovascular risks and residual cardiovascular risk despite optimal low-density lipoprotein cholesterol (LDL-C) levels. RECENT FINDINGS: Bempedoic acid is found to cause significant reduction in LDL-C and high-sensitivity C-reactive protein (hs-CRP) in various randomized clinical trials. Multiple meta-analyses have also found that bempedoic acid therapy leads to reduction in non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC) and apolipoprotein B (ApoB) levels. However, it has minimal effect on lipoprotein (a) (Lp(a)) level. SUMMARY: Bempedoic acid is a new lipid-lowering agent that inhibits enzyme ATP-citrate lyase in the cholesterol biosynthesis pathway. Major risk of cardiovascular events and its associated morbidity and mortality are proportional to LDL-C and inflammatory markers levels. It was found that bempedoic acid significantly lowers LDL-C, hs-CRP and other inflammatory markers levels. This drug could potentially be used in patients with elevated cardiovascular risk, in patients with residual cardiovascular risk despite attaining LDL-C goal and in statin intolerant patients.

How Will Our Practice Change After the CLEAR Outcomes Trial?

PURPOSE OF REVIEW: Bempedoic acid is a novel therapeutic agent that is designed to reduce levels of low-density lipoprotein cholesterol (LDL-C). The purpose of this review is to provide the background for development of bempedoic acid, findings from clinical trials and to discuss clinical implications. RECENT FINDINGS: Bempedoic acid inhibits ATP citrate lyase within the liver and reduces cholesterol synthesis, with the potential to avoid muscle symptoms experienced by patients treated with statins. Early clinical studies demonstrated that administration of bempedoic acid resulted in lowering of LDL-C by 20-30% as monotherapy and by 40-50% when combined with ezetimibe, in addition to lowering of high sensitivity C-reactive protein by 20-30%. The CLEAR Outcomes trial of high cardiovascular risk patients, with elevated LDL-C levels and either unable or unwilling to take statins demonstrated that bempedoic acid reduced the rate of major adverse cardiovascular events. A greater incidence of elevation of hepatic transaminase and creatinine, gout, and cholelithiasis were consistently observed in bempedoic acid-treated patients. Bempedoic acid presents an additional therapeutic option to achieve more effective lowering of LDL-C levels and reduction in cardiovascular risk.

Bempedoic Acid: How Will It Shape the Future Lipid-Lowering Landscape? Mode of Action, Evidence, and Clinical Use.

BACKGROUND: Low-density lipoproteins are now proven to be causal for atherosclerosis. Pharmacological treatment focuses on an increase of low-density lipoprotein (LDL) receptors, particularly in the hepatocyte, which leads to uptake of LDL from blood, thereby reducing the burden to the arterial wall. This mechanism has first been proven by statins to be effective to reduce cardiovascular morbidity and mortality. The concept of "the lower, the better" was shown by high-intensity statins and new compounds like ezetimibe, PCSK9 antibodies, inclisiran, and ultimately bempedoic acid. SUMMARY: Although first considered only a relatively weak LDL-C lowering drug, bempedoic acid proved to be very effective, for example, in statin-intolerant patients to reduce cardiovascular events in the CLEAR-Outcomes study. In the era of personalized medicine, it should not be forgotten that the individual response to a LDL-C lowering drug can vary considerably. Bempedoic acid has a favorable safety profile, particularly it does not induce muscle problems because its precursor is not metabolized to the active drug in the muscle, and it does not induce hyperglycemia. Bempedoic acid probably is best used in combination with ezetimibe, which leads to LDL-C reductions in the range of moderately intensive statins; in an oral triple combination with a high-intensity statin, LDL-C reductions in the range of two-thirds can be achieved. KEY MESSAGES: Bempedoic acid is a further weapon against the atherogenic effect of LDL cholesterol - in both primary and secondary prevention.

Overexpression of the key metabolic protein CPT1A defines mantle cell lymphoma patients with poor response to standard high-dose chemotherapy independent of MIPI and complement established highrisk factors.

The variable outcome to standard immunochemotherapy for mantle cell lymphoma (MCL) patients is a clinical challenge. Established risk factors, including high MCL International Prognostic Index (MIPI), high proliferation (Ki-67), non-classic (blastoid/pleomorphic) morphology, and mutated TP53, only partly identify patients in need of alternative treatment. Deepened understanding of biological factors that influence time to progression and relapse would allow for an improved stratification, and identification of novel targets for high-risk patients. We performed gene expression analyses to identify pathways and genes associated with outcome in a cohort of homogeneously treated patients. In addition to deregulated proliferation, we show that thermogenesis, fatty acid degradation and oxidative phosphorylation are altered in patients with poor survival, and that high expression of carnitine palmitoyltransferase 1A (CPT1A), an enzyme involved in fatty acid degradation, can specifically identify high-risk patients independent of the established high-risk factors. We suggest that complementary investigations of metabolism may increase the accuracy of patient stratification and that immunohistochemistry- based assessment of CPT1A can contribute to defining high-risk MCL.

Simultaneous inhibition of Sirtuin 3 and cholesterol homeostasis targets acute myeloid leukemia stem cells by perturbing fatty acid ß-oxidation and inducing lipotoxicity.

Outcomes for patients with acute myeloid leukemia (AML) remain poor due to the inability of current therapeutic regimens to fully eradicate disease-initiating leukemia stem cells (LSC). Previous studies have demonstrated that oxidative phosphorylation (OXPHOS) is an essential process that is targetable in LSC. Sirtuin 3 (SIRT3), a mitochondrial deacetylase with a multi-faceted role in metabolic regulation, has been shown to regulate OXPHOS in cancer models; however, it has not yet been studied in the context of LSC. Thus, we sought to identify if SIRT3 is important for LSC function. Using RNAi and a SIRT3 inhibitor (YC8-02), we demonstrate that SIRT3 is a critical target for the survival of primary human LSC but is not essential for normal human hematopoietic stem and progenitor cell function. In order to elucidate the molecular mechanisms by which SIRT3 is essential in LSC we combined transcriptomic, proteomic, and lipidomic approaches, showing that SIRT3 is important for LSC function through the regulation of fatty acid oxidation (FAO) which is required to support OXPHOS and ATP production in human LSC. Further, we discovered two approaches to further sensitize LSC to SIRT3 inhibition. First, we found that LSC tolerate the toxic effects of fatty acid accumulation induced by SIRT3 inhibition by upregulating cholesterol esterification. Disruption of cholesterol homeostasis sensitizes LSC to YC8-02 and potentiates LSC death. Second, SIRT3 inhibition sensitizes LSC to the BCL-2 inhibitor venetoclax. Together, these findings establish SIRT3 as a regulator of lipid metabolism and potential therapeutic target in primitive AML cells.

Amelioration of Osteoarthritis Development by Daily Oral Supplementation of Royal Jelly.

Royal jelly (RJ), an essential food for the queen honeybee, has a variety of biological activities. Although RJ exerts preventive effects on various lifestyle-related diseases, such as osteoporosis and obesity, no study evaluated the effect of RJ on the development of osteoarthritis (OA), the most common degenerative joint disease. Here, we showed that daily oral administration of raw RJ significantly prevented OA development in vivo following surgically-induced knee joint instability in mice. Furthermore, in vitro experiments using chondrocytes, revealed that raw RJ significantly reduced the expression of inflammatory cytokines and enzymes critical for the degradation of the extracellular matrix (ECM). Similar results were observed after treatment with 10-hydroxy-2-decenoic acid, the most abundant and unique fatty acid in raw RJ. Our results suggest that oral supplementation with RJ would benefit the maintenance of joint health and prophylaxis against OA, possibly by suppressing the activity of inflammatory cytokines and ECM-degrading enzymes.

1-O-alkyl-glycerols from Squid Berryteuthis magister Reduce Inflammation and Modify Fatty Acid and Plasmalogen Metabolism in Asthma Associated with Obesity.

Asthma associated with obesity is considered the most severe phenotype and can be challenging to manage with standard medications. Marine-derived 1-O-alkyl-glycerols (AGs), as precursors for plasmalogen synthesis, have high biological activity, making them a promising substance for pharmacology. This study aimed to investigate the effect of AGs from squid Berryteuthis magister on lung function, fatty acid and plasmalogen levels, and cytokine and adipokine production in obese patients with asthma. The investigational trial included 19 patients with mild asthma associated with obesity who received 0.4 g of AGs daily for three months in addition to their standard treatment. The effects of AGs were evaluated at one and three months of treatment. The results of the study demonstrated that intake of AGs increased the FEV1 and FEV1/VC ratios, and significantly decreased the ACQ score in 17 of the 19 patients after three months of treatment. The intake of AGs increased concentration of plasmalogen and n-3 PUFA in plasma, and modified leptin/adiponectin production by adipose tissue. The supplementation of AGs decreased the plasma levels of inflammatory cytokines (TNF-α, IL-4, and IL-17a), and oxylipins (TXB2 and LTB4), suggesting an anti-inflammatory property of AGs. In conclusion, 1-O-alkyl-glycerols could be a promising dietary supplement for improving pulmonary function and reducing inflammation in obese asthma patients, and a natural source for plasmalogen synthesis. The study highlighted that the beneficial effects of AG consumption can be observed after one month of treatment, with gradual improvement after three months of supplementation.

Discovery and Anti-Inflammatory Activity of a Cyanobacterial Fatty Acid Targeting the Keap1/Nrf2 Pathway.

The monounsaturated fatty acid 7(E)-9-keto-hexadec-7-enoic acid (1) and three structurally related analogues with different oxidation states and degrees of unsaturation (2-4) were discovered from a marine benthic cyanobacterial mat collected from Delta Shoal, Florida Keys. Their structures were elucidated using NMR spectroscopy and mass spectrometry. The structure of 1 contained an α,ß-unsaturated carbonyl system, a key motif required for the activation of the Keap1/Nrf2-ARE pathway that is involved in the activation of antioxidant and phase II detoxification enzymes. Compounds 1-4 were screened in ARE-luciferase reporter gene assay using stably transfected HEK293 cells, and only 1 significantly induced Nrf2 activity at 32 and 10 µM, whereas 2-4 were inactive. As there is crosstalk between inflammation and oxidative stress, subsequent biological studies were focused on 1 to investigate its anti-inflammatory potential. Compound 1 induced Nqo1, a well-known target gene of Nrf2, and suppressed iNos transcript levels, which translated into reduced levels of nitric oxide in LPS-activated mouse macrophage RAW264.7 cells, a more relevant model for inflammation. RNA sequencing was performed to capture the effects of 1 on a global level and identified additional canonical pathways and upstream regulators involved in inflammation and immune response, particularly those related to multiple sclerosis. A targeted survey of marine cyanobacterial samples from other geographic locations, including Guam, suggested the widespread occurrence of 1. Furthermore, the previous isolation of 1 from marine diatoms and green algae implied a potentially important ecological role across marine algal eukaryotes and prokaryotes. The previous isolation from sea lettuce raises the possibility of dietary intervention to attenuate inflammation and related disease progression.

The effect of fatty acids, vitamins, and minerals on pediatric atopic dermatitis: A systematic review.

BACKGROUND: A body of research has examined the role of fatty acid (FA), vitamin, and mineral supplementation as adjunctive treatment for atopic dermatitis (AD); however, results are conflicting and concrete recommendations are lacking. The objective of this study is to highlight the role of these nutrients in alleviating AD severity and provide the clinician with consolidated information that can be used to make recommendations to the pediatric patient and caretaker, where this topic is of high interest. METHODS: A review of the PubMed and Embase databases was conducted to identify and qualitatively analyze all randomized controlled trials, systematic reviews, and meta-analyses conducted within the last 21 years regarding use of these nutrients to alleviate symptoms of AD. Inclusion criteria include AD diagnosis, non-infant age groups, and AD severity outcomes; exclusion criteria include preventative studies, predominantly maternal or infant demographics, or nonclinical outcomes. RESULTS: Sixty-nine studies were included. Evidence regarding FA supplementation is inconclusive; however, targeting an ideal omega-3:omega-6 FA ratio may play a small role in alleviating AD symptoms. Studies results regarding vitamin/mineral supplementation are inconsistent and supplementation should not be advised unless the patient has a documented deficiency. CONCLUSION: Pediatric AD patients should lead a healthy lifestyle with an emphasis on consumption of wholesome foods. Nutritional supplementation can play a role in improving AD symptoms; however, this should be evaluated on a case-by-case basis. Limitations include heterogeneity of studies.

Medium-chain fatty acids as an alternative treatment for denture stomatitis in older people.

OBJECTIVE: To determine the effect of medium-chain fatty acids (MCFA) on the severity of denture stomatitis (DS) and the counts of Candida spp. in older people (OP) wearing removable prostheses (RP). MATERIALS AND METHODS: This randomized, controlled and triple-blind study included forty-three OP presenting DS. The control group was treated with 0.12% chlorhexidine (CHX) and the experimental group with MCFA, 2 × /day for 15 days. Intraoral examination and counts of Candida spp. were performed at 0, 7, and 15 days. The differences between both groups in the decrease of the severity of DS and the viability of Candida spp. were determined clinically and microbiologically, respectively. RESULTS: OP carriers of RP treated with MCFA presented remission of the clinical signs of DS, but the Candida spp. counts only decreased significantly in the CHX-treated group at 7 days of treatment (p < 0.05). Besides, MCFA was shown to reduce the clinical signs of DS after the first week of application, while CHX after the second week. CONCLUSIONS: The MCFA is effective in reducing the clinical signs of DS associated with oral candidiasis in subjects with RP. Both treatments showed a significant decrease in severity, for MCFA after the first week and for CHX two weeks after starting the corresponding treatment. CLINICAL RELEVANCE: The MCFA is an effective, harmless, and accessible treatment alternative against DS, since it manages to reduce the severity of the lesion in the milder cases of DS in the oral mucosa of OP carriers of RP.

Anti-Inflammatory Activity of Black Soldier Fly Oil Associated with Modulation of TLR Signaling: A Metabolomic Approach.

Dietary intervention in the treatment of ulcerative colitis involves, among other things, modifications in fatty acid content and/or profile. For example, replacing saturated long chain fatty acids with medium chain fatty acids (MCFAs) has been reported to ameliorate inflammation. The Black Soldier Fly Larvae's (BSFL) oil is considered a sustainable dietary ingredient rich in the MCFA C12:0; however, its effect on inflammatory-related conditions has not been studied until now. Thus, the present study aimed to investigate the anti-inflammatory activity of BSFL oil in comparison to C12:0 using TLR4- or TLR2-activated THP-1 and J774A.1 cell lines and to assess its putative protective effect against dextran sulfate sodium (DSS)-induced acute colitis in mice. BSFL oil and C12:0 suppressed proinflammatory cytokines release in LPS-stimulated macrophages; however, only BSFL oil exerted anti-inflammatory activity in Pam3CSK4-stimulated macrophages. Transcriptome analysis provided insight into the possible role of BSFL oil in immunometabolism switch, involving mTOR signaling and an increase in PPAR target genes promoting fatty acid oxidation, exhibiting a discrepant mode of action compared to C12:0 treatment, which mainly affected cholesterol biosynthesis pathways. Additionally, we identified anti-inflammatory eicosanoids, oxylipins, and isoprenoids in the BSFL oil that may contribute to an orchestrated anti-inflammatory response. In vivo, a BSFL oil-enriched diet (20%) ameliorated the clinical signs of colitis, as indicated by improved body weight recovery, reduced colon shortening, reduced splenomegaly, and an earlier phase of secretory IgA response. These results indicate the novel beneficial use of BSFL oil as a modulator of inflammation.

The effect of oral treatment of royal jelly on the expression of the PDGF-ß gene in the skin wound of male mice.

AIMS OF THE STUDY: Royal jelly (RJ) is one of the most widely used drugs in traditional medicine. One of its important applications is the repair of skin damage, although the path of its mechanism is still unknown. Platelet-derived growth factor-beta (PDGF-beta) is one of the important factors in wound healing and it has been observed that PDGF-ß expression decreases with increasing age. In this study, for the first time, the effect of RJ on skin wounds has been investigated through the expression of PDGF-ß and tissue studies. MATERIALS AND METHODS: 25 small laboratory male BALB/c mice were selected randomly and after creating a 5 mm wound on the back of their neck, they were treated with doses of 2.5, 10, and 40 mg/kg body weight, After sampling from the healed wound in 9th day, histopathological studies and the expression of PDGF-ß gene were performed by Real-time PCR method. RESULTS: The findings of the present study showed that royal jelly caused a significant increase in PDGF-ß (10.99 times) compared to the healthy group. Also, royal jelly increased the formation of covering tissue or epithelium, the synthesis of collagen, the presence of inflammatory cells, and the formation of new blood vessels. CONCLUSION: The oral treatment of royal jelly is probably effective in skin wound healing by changing the expression of PDGF-ß.

Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol.

BACKGROUND: Short-term studies have shown that bempedoic acid, an inhibitor of ATP citrate lyase, reduces levels of low-density lipoprotein (LDL) cholesterol. Data are limited regarding the safety and efficacy of bempedoic acid treatment in long-term studies involving patients with hypercholesterolemia who are receiving guideline-recommended statin therapy. METHODS: We conducted a randomized, controlled trial involving patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both. Patients had to have an LDL cholesterol level of at least 70 mg per deciliter while they were receiving maximally tolerated statin therapy with or without additional lipid-lowering therapy. (Maximally tolerated statin therapy was defined as the highest intensity statin regimen that a patient was able to maintain, as determined by the investigator.) Patients were randomly assigned in a 2:1 ratio to receive bempedoic acid or placebo. The primary end point was safety, and the principal secondary end point (principal efficacy end point) was the percentage change in the LDL cholesterol level at week 12 of 52 weeks. RESULTS: The trial involved 2230 patients, of whom 1488 were assigned to receive bempedoic acid and 742 to receive placebo. The mean (±SD) LDL cholesterol level at baseline was 103.2±29.4 mg per deciliter. The incidence of adverse events (1167 of 1487 patients [78.5%] in the bempedoic acid group and 584 of 742 [78.7%] in the placebo group) and serious adverse events (216 patients [14.5%] and 104 [14.0%], respectively) did not differ substantially between the two groups during the intervention period, but the incidence of adverse events leading to discontinuation of the regimen was higher in the bempedoic acid group than in the placebo group (162 patients [10.9%] vs. 53 [7.1%]), as was the incidence of gout (18 patients [1.2%] vs. 2 [0.3%]). At week 12, bempedoic acid reduced the mean LDL cholesterol level by 19.2 mg per deciliter, representing a change of -16.5% from baseline (difference vs. placebo in change from baseline, -18.1 percentage points; 95% confidence interval, -20.0 to -16.1; P<0.001). Safety and efficacy findings were consistent, regardless of the intensity of background statin therapy. CONCLUSIONS: In this 52-week trial, bempedoic acid added to maximally tolerated statin therapy did not lead to a higher incidence of overall adverse events than placebo and led to significantly lower LDL cholesterol levels. (Funded by Esperion Therapeutics; CLEAR Harmony ClinicalTrials.gov number, NCT02666664.).

Mendelian Randomization Study of ACLY and Cardiovascular Disease.

BACKGROUND: ATP citrate lyase is an enzyme in the cholesterol-biosynthesis pathway upstream of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the target of statins. Whether the genetic inhibition of ATP citrate lyase is associated with deleterious outcomes and whether it has the same effect, per unit decrease in the low-density lipoprotein (LDL) cholesterol level, as the genetic inhibition of HMGCR is unclear. METHODS: We constructed genetic scores composed of independently inherited variants in the genes encoding ATP citrate lyase (ACLY) and HMGCR to create instruments that mimic the effect of ATP citrate lyase inhibitors and HMGCR inhibitors (statins), respectively. We then compared the associations of these genetic scores with plasma lipid levels, lipoprotein levels, and the risk of cardiovascular events and cancer. RESULTS: A total of 654,783 participants, including 105,429 participants who had major cardiovascular events, were included in the study. The ACLY and HMGCR scores were associated with similar patterns of changes in plasma lipid and lipoprotein levels and with similar effects on the risk of cardiovascular events per decrease of 10 mg per deciliter in the LDL cholesterol level: odds ratio for cardiovascular events, 0.823 (95% confidence interval [CI], 0.78 to 0.87; P = 4.0×10-14) for the ACLY score and 0.836 (95% CI, 0.81 to 0.87; P = 3.9×10-19) for the HMGCR score. Neither lifelong genetic inhibition of ATP citrate lyase nor lifelong genetic inhibition of HMGCR was associated with an increased risk of cancer. CONCLUSIONS: Genetic variants that mimic the effect of ATP citrate lyase inhibitors and statins appeared to lower plasma LDL cholesterol levels by the same mechanism of action and were associated with similar effects on the risk of cardiovascular disease per unit decrease in the LDL cholesterol level. (Funded by Esperion Therapeutics and others.).

The functional mechanisms of synchronizing royal jelly consumption and physical activity on rat with multiple sclerosis-like behaviors hallmarks based on bioinformatics analysis, and experimental survey.

BACKGROUND: Natural nutrition and physical training have been defined as non-pharmacochemical complementary and alternative medicines to prevent and treat various pathogenesis. Royal jelly possesses various pharmacological properties and is an effective therapeutic supplement for halting neurodegeneration. Multiple sclerosis is a prevalent neurodegenerative disorder that manifests as a progressive neurological condition. Inflammation, hypoxia, and oxidative stress have been identified as significant hallmarks of multiple sclerosis pathology. RESULTS: In the present study, based on artificial intelligence and bioinformatics algorithms, we marked hub genes, molecular signaling pathways, and molecular regulators such as non-coding RNAs involved in multiple sclerosis. Also, microRNAs as regulators can affect gene expression in many processes. Numerous pathomechanisms, including immunodeficiency, hypoxia, oxidative stress, neuroinflammation, and mitochondrial dysfunction, can play a significant role in the MSc pathogenesis that results in demyelination. Furthermore, we computed the binding affinity of bioactive compounds presented in Royal Jelly on macromolecules surfaces. Also, we predicted the alignment score of bioactive compounds over the pharmacophore model of candidate protein as a novel therapeutic approach. Based on the q-RT-PCR analysis, the expression of the Dnajb1/Dnajb1/Foxp1/Tnfsf14 and Hspa4 networks as well as miR-34a-5p and miR155-3p were regulated by the interaction of exercise training and 100 mg/kg Royal Jelly (ET-100RJ). Interestingly, characteristics, motor function, a proinflammatory cytokine, and demyelination were ameliorated by ET-100RJ. DISCUSSION: Here, we indicated that interaction between exercise training and 100 mg/kg Royal jelly had a more effect on regulating the microRNA profiles and hub genes in rats with Multiple sclerosis.

Response to triheptanoin therapy in critically ill patients with LC-FAOD: Report of patients treated through an expanded access program.

Long-chain fatty acid oxidation disorders (LC-FAOD) are a group of inborn errors of metabolism wherein patients are unable to process long-chain fatty acids into useable energy in the mitochondria. LC-FAOD commonly affects organ systems with high energy demand, manifesting as hypoketotic hypoglycemia, liver dysfunction, cardiomyopathy, rhabdomyolysis, and skeletal myopathy, as well as peripheral neuropathy and retinopathy in some subtypes. Collectively, LC-FAOD have a high mortality rate, especially in cases of early onset disease, and in the presence of cardiomyopathy. Triheptanoin is a synthetic medium-odd chain triglyceride, produced using a GMP-compliant process, which was designed to replenish mitochondrial metabolic deficits and restore energy homeostasis. Prior to its approval, triheptanoin was only available through clinical trials or to seriously ill patients as part of an expanded access program (EAP) following physician request. This retrospective study examined the impact of triheptanoin on cardiovascular parameters, in critically ill patients who participated in the EAP from February 2013 to January 2018. These patients persisted in critical condition despite receiving standard treatment in highly qualified centers by expert metabolic physicians and dietitians. Physician-completed questionnaires and narrative summaries were used to evaluate the disease presentation and management prior to the trigger event leading to triheptanoin request and use, and the response to triheptanoin treatment. Following triheptanoin initiation, most patients survived the initial trigger event (e.g., severe urinary tract infection, pneumonia) and demonstrated improvements in both short-term and long-term LC-FAOD manifestations. In patients with cardiomyopathy, stabilization or improvement from pretreatment levels was reported in left ventricular ejection fraction and left ventricular mass, in particular, all infants with cardiomyopathy showed improvement in cardiac function during triheptanoin therapy. Triheptanoin therapy was generally well tolerated. The study results are consistent with the existing positive benefit/risk profile of triheptanoin and reflect the effect of triheptanoin improving cardiac function in patients experiencing severe episodes of metabolic decompensation despite standard therapy.

Major Concepts in Treatment with Bempedoic Acid and Inclisiran that Clinicians Need To Know.

PURPOSE OF REVIEW: There have been recent developments of novel therapeutic agents for lipid lowering. This article reviews treatment concepts for two of the newest lipid-lowering medications. RECENT FINDINGS: Bempedoic acid inhibits adenosine citrate lyase, decreasing intracellular lipogenesis. This oral medication is a prodrug and requires activation by enzymes present in hepatocytes but absent in the skeletal muscle. Clinical trials demonstrated additive benefit with statin therapy, and it was well tolerated in statin-intolerant populations. Inclisiran uses RNA interference to prevent translation of PCSK9 mRNA. Due to its stability, it can be given as an injection every 6 months and produces consistent, durable, and potent cholesterol lowering. Bempedoic acid and inclisiran represent new avenues of treatment for the prevention and treatment of cardiovascular disease. This will allow for more comprehensive care by addressing challenges with medication adherence, such as adverse effects to prior medications as well as ease of dosing.