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Introduction: Atrial fibrillation (AF) is a prevalent cardiac arrhythmia with significant clinical implications. The potential influence of lipid-lowering therapies, specifically PCSK9 inhibitors (PCSK9i) and HMG-CoA reductase inhibitors (statins), on AF risk remains a topic of interest. This mendelian randomization (MR) study aimed to elucidate the causal relationship between genetically predicted inhibition of PCSK9 and HMG-CoA reductase and the risk of AF. Methods: Utilizing publicly available, summary-level genome-wide association study data, we employed single-nucleotide polymorphisms associated with lower LDL-C levels as instruments for gene-simulated inhibition of PCSK9 and HMG-CoA reductase. Multiple MR techniques were applied to estimate the causal effects, and sensitivity analyses were conducted to validate the results. Results: Genetically predicted inhibition of PCSK9 demonstrated a reduced risk of AF, with an odds ratio (OR) of 0.92 (95% CI: 0.85–0.99, p = 0.01) using the inverse variance-weighted (IVW) method. In contrast, the inhibition of HMG-CoA reductase did not exhibit a statistically significant association with AF risk (IVW: OR = 1.11, 95% CI: 1.00–1.22, p = 0.05). Conclusion: Our MR study suggests that genetically predicted inhibition of PCSK9, but not HMG-CoA reductase, is associated with a lower risk of AF. These findings provide evidence for a causal protective effect of PCSK9i on AF and support the use of PCSK9i for AF prevention in patients with dyslipidemia. Further studies are needed to elucidate the mechanisms underlying the differential effects of PCSK9i and statins on AF and to confirm the clinical implications of our findings. [ABSTRACT FROM AUTHOR]

The study aimed to assess the effect of high‐intensity statin therapy on testicular and adrenal steroids and vitamin D levels in type 2 diabetic men. A prospective study, conducted between March 2021 and July 2022, including 60 men with type 2 diabetes, aged 40–65 years, statin‐free, and in whom treatment with high‐intensity statin was indicated. The patients had two visits, before and 6 months after a daily intake of 40 mg of atorvastatin. During each visit, they underwent a clinical examination, and a fasting blood sample was collected for biological and hormonal measurements. There was a significant increase in the prevalence of decreased libido (from 22% to 47%, p = 0.001) and a significant decrease in the frequency of sexual intercourse (from 4 [1–8] to 3 [0–4] per month, p = 0.005). The median ADAM's score significantly increased (from 4 [2–7] to 6 [3–8], p = 0.000). Twenty‐two percent of the patients developed gynecomastia. The median total, bioavailable and free testosterone significantly decreased from 15.1 (11.4–17.4), 6.3 (5.0–7.8), and 0.27 (0.22–0.33) nmol/L to 12.7 (10.7–15.9), 5.7 (4.4–7.0), and 0.24 (0.19–0.30) nmol/L, respectively, with no change in FSH and LH levels. Three patients (5%) developed hypogonadism (testosterone <8 nmol/L). There was a significant decrease in DHEAS from 4.5 (2.8–6.1) to 3.8 μmol/L (2.6–5.6) and no change in cortisol and vitamin D levels. High‐intensity statin therapy decreased androgen levels in type 2 diabetic men with significant clinical impact. [ABSTRACT FROM AUTHOR]

Altered cholesterol metabolism is implicated in brain ageing and Alzheimer’s disease. We examined whether key genes regulating cholesterol metabolism and levels of brain cholesterol are altered in dementia and Alzheimer’s disease neuropathological change (ADNC). Temporal cortex (n = 99) was obtained from the Cognitive Function and Ageing Study. Expression of the cholesterol biosynthesis rate-limiting enzyme HMG-CoA reductase (HMGCR) and its regulator, SREBP2, were detected using immunohistochemistry. Expression of HMGCR, SREBP2, CYP46A1 and ABCA1 were quantified by qPCR in samples enriched for astrocyte and neuronal RNA following laser-capture microdissection. Total cortical cholesterol was measured using the Amplex Red assay. HMGCR and SREBP2 proteins were predominantly expressed in pyramidal neurones, and in glia. Neuronal HMGCR did not vary with ADNC, oxidative stress, neuroinflammation or dementia status. Expression of HMGCR neuronal mRNA decreased with ADNC (p = 0.022) and increased with neuronal DNA damage (p = 0.049), whilst SREBP2 increased with ADNC (p = 0.005). High or moderate tertiles for cholesterol levels were associated with increased dementia risk (OR 1.44, 1.58). APOE ε4 allele was not associated with cortical cholesterol levels. ADNC is associated with gene expression changes that may impair cholesterol biosynthesis in neurones but not astrocytes, whilst levels of cortical cholesterol show a weak relationship to dementia status.

Background and Purpose: Statins are competitive inhibitors of 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase (HMGCR), and exert adverse effects on mitochondrial function, although the mechanisms underlying these effects remain unclear. We used a tamoxifen‐induced Hmgcr‐knockout (KO) mouse model, a multi‐omics approach and mitochondrial function assessments to investigate whether decreased HMGCR activity impacts key liver energy metabolism pathways. Experimental Approach: We established a new mouse strain using the Cre/loxP system, which enabled whole‐body deletion of Hmgcr expression. These mice were crossed with Rosa26Cre mice and treated with tamoxifen to delete Hmgcr in all cells. We performed transcriptomic and metabolomic analyses and thus evaluated time‐dependent changes in metabolic functions to identify the pathways leading to cell death in Hmgcr‐KO mice. Key Results: Lack of Hmgcr expression resulted in lethality, due to acute liver damage caused by rapid disruption of mitochondrial fatty acid β‐oxidation and very high accumulation of long‐chain (LC) acylcarnitines in both male and female mice. Gene expression and KO‐related phenotype changes were not observed in other tissues. The progression to liver failure was driven by diminished peroxisome formation, which resulted in impaired mitochondrial and peroxisomal fatty acid metabolism, enhanced glucose utilization and whole‐body hypoglycaemia. Conclusion and Implications: Our findings suggest that HMGCR is crucial for maintaining energy metabolism balance, and its activity is necessary for functional mitochondrial β‐oxidation. Moreover, statin‐induced adverse reactions might be rescued by the prevention of LC acylcarnitine accumulation. [ABSTRACT FROM AUTHOR]

The article presents a case study of an 81-year-old woman successfully treated with reduced oral steroid dosage for statin-induced anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) immune-mediated necrotizing myopathy. Topics discussed include the management strategies, clinical outcomes, and therapeutic adjustments in elderly patients experiencing rare immune-mediated muscle disorders associated with statin use.

Altered cholesterol metabolism is implicated in brain ageing and Alzheimer's disease. We examined whether key genes regulating cholesterol metabolism and levels of brain cholesterol are altered in dementia and Alzheimer's disease neuropathological change (ADNC). Temporal cortex (n = 99) was obtained from the Cognitive Function and Ageing Study. Expression of the cholesterol biosynthesis rate-limiting enzyme HMG-CoA reductase (HMGCR) and its regulator, SREBP2, were detected using immunohistochemistry. Expression of HMGCR , SREBP2 , CYP46A1 and ABCA1 were quantified by qPCR in samples enriched for astrocyte and neuronal RNA following laser-capture microdissection. Total cortical cholesterol was measured using the Amplex Red assay. HMGCR and SREBP2 proteins were predominantly expressed in pyramidal neurones, and in glia. Neuronal HMGCR did not vary with ADNC, oxidative stress, neuroinflammation or dementia status. Expression of HMGCR neuronal mRNA decreased with ADNC (p = 0.022) and increased with neuronal DNA damage (p = 0.049), whilst SREBP2 increased with ADNC (p = 0.005). High or moderate tertiles for cholesterol levels were associated with increased dementia risk (OR 1.44, 1.58). APOE ε4 allele was not associated with cortical cholesterol levels. ADNC is associated with gene expression changes that may impair cholesterol biosynthesis in neurones but not astrocytes, whilst levels of cortical cholesterol show a weak relationship to dementia status. • Cholesterol and its enzymes assessed in the CFAS neuropathology cohort. • HMGCR protein is detected in cortical pyramidal neurones. • HMGCR and SREBP2 mRNA expression alter with Alzheimer's pathology. • Higher levels of cortical cholesterol show a weak relationship to dementia status. • Possession of APOE ε4 allele does not affect cholesterol levels. [ABSTRACT FROM AUTHOR]

Statins are cholesterol-lowering drugs with a mechanism of inhibiting 3-hydroxy-3- methylglutaryl-CoA reductase, but long-term use can cause side effects. An example of a plant capable of reducing cholesterol levels is Angelica keiskei (ashitaba). Therefore, this study aimed to obtain suitable compounds with inhibitory activity against the HMG-CoA reductase enzyme from ashitaba through in silico tests. The experiment began with screening and pharmacophore modeling, followed by molecular docking on ashitaba’s compounds, statins groups, and the native ligand was (3R,5R)-7-[4-(benzyl carbamoyl)-2-(4-fluorophenyl)-5-(1-methylethyl)-1H-imidazole1-yl]-3,5-dihydroxyheptanoic acid (4HI). Based on the results of the molecular docking simulations, 15 hit compounds had a small binding energy (∆G). Pitavastatin, as the comparator drug (∆G = −8.24 kcal/mol; Ki = 2.11 µM), had a lower ∆G and inhibition constant (Ki) than the native ligand 4HI (∆G = −7.84 kcal/mol; Ki = 7.96µM). From ashitaba’s compounds, it was found that 4′ -O-geranylnaringenin, luteolin, isobavachalcone, dorsmannin A, and 3′ -carboxymethyl-4,2′ - dihydroxy-4′ -methoxychalcone have low ∆G of below −6 kcal/mol. The lowest ∆G value was found in 3′ -carboxymethyl-4,2′ -dihydroxy-4′ -methoxy chalcone with a ∆G of −6.67 kcal/mol and Ki value of 16.66 µM, which was lower than the ∆G value of the other comparator drugs, atorvastatin (∆G = −5.49 kcal/mol; Ki = 1148.17 µM) and simvastatin (∆G = −6.50 kcal/mol; Ki = 22.34 µM). This compound also binds to the important amino acid residues, including ASN755D, ASP690C, GLU559D, LYS735D, LYS691C, and SER684C, through hydrogen bonds. Based on the results, the compound effectively binds to six important amino acids with good binding affinity and only requires a small concentration to reduce half of the enzyme activity [ABSTRACT FROM AUTHOR]

Objective: Cholesterol is crucial compound that plays pivotal role in cellular function in living organisms. Its excess or deficiency in plasma can lead to destruction and disintegration of cell membrane structure. Maintaining balanced intake of cholesterol in diet and seeking medical treatment, if necessary, can help prevent these negative effects. Furthermore, people often resort to natural and herbal remedies, such as walnut septum. Due to dearth of scientific data regarding effects of walnut septum on cholesterol metabolism, this research was undertaken to explore its potential effects. Methods: Analysis was begun by extracting septum using various solvents. Resulting extracts were then analyzed using GC-MS, and compounds were identified by using an integrated library database. To detect effects of extracts on cholesterol esterase and HMG-CoA reductase, a colorimetric method was employed. Results: Monophenol, 2,4-Di-tert-butylphenol, 2,6-Di-tert-butylphenol, ethyl linoleate, and butyl linoleate were some of compounds detected by GC-MS scanning. The highest inhibitions were observed in the enzymatic analysis, with a rate of 3.2% (acetone) in the HMG-CoA reductase analysis and 13.6% (water) in the cholesterol esterase analysis. Conclusions: Although the walnut septum extract contains various chemical compounds, our in vitro analysis data suggest that there is no inhibitory effect at therapeutic level on enzyme pathways that regulate plasma cholesterol levels, namely HMG-CoA reductase and cholesterol esterase. We believe that further research is necessary to comprehensively evaluate its effects on other pathways. [ABSTRACT FROM AUTHOR]

IntroductionLiver fibrosis is a significant global health burden that lacks effective therapies. It can progress to cirrhosis and hepatocellular carcinoma (HCC). Aberrant hedgehog pathway activation is a key driver of fibrogenesis and cancer, making hedgehog inhibitors potential antifibrotic and anticancer agents.MethodsWe evaluated simvastatin and STA-9090, alone and combined, in rats fed a high-fat diet (HFD) and exposed to diethylnitrosamine and thioacetamide (DENA/TAA). Simvastatin inhibits HMG-CoA reductase, depleting cellular cholesterol required for Sonic hedgehog (Shh) modification and signaling. STA-9090 directly inhibits HSP90 chaperone interactions essential for Shh function. We hypothesized combining these drugs may provide liver protective effects through complementary targeting of the hedgehog pathway. Endpoints assessed included liver function tests, oxidative stress markers, histopathology, extracellular matrix proteins, inflammatory cytokines, and hedgehog signaling components.ResultsHFD and DENA/TAA caused aberrant hedgehog activation, contributing to fibrotic alterations with elevated liver enzymes, oxidative stress, dyslipidemia, inflammation, and collagen deposition. Monotherapies with simvastatin or STA-9090 improved these parameters, while the combination treatment provided further enhancements, including improved survival, near-normal liver histology, and compelling hedgehog pathway suppression.DiscussionOur findings demonstrate the enhanced protective potential of combined HMG CoA reductase and HSP90 inhibition in rats fed a HFD and exposed to DENA and TAA. This preclinical study could help translate hedgehog-targeted therapies to clinical evaluation for treating this major unmet need.

Abstract Statins are thought to have positive effects on migraine but existing data are inconclusive. We aimed to evaluate the causal effect of such drugs on migraines using Mendelian randomization. We used four types of genetic instruments as proxies for HMG-CoA reductase inhibition. We included the expression quantitative trait loci of the HMG-CoA reductase gene and genetic variation within or near the HMG-CoA reductase gene region. Variants were associated with low-density lipoprotein cholesterol, apolipoprotein B, and total cholesterol. Genome-wide association study summary data for the three lipids were obtained from the UK Biobank. Comparable data for migraine were obtained from the International Headache Genetic Consortium and the FinnGen Consortium. Inverse variance weighting method was used for the primary analysis. Additional analyses included pleiotropic robust methods, colocalization, and meta-analysis. Genetically determined high expression of HMG-CoA reductase was associated with an increased risk of migraines (OR = 1.55, 95% CI 1.30–1.84, P = 6.87 × 10−7). Similarly, three genetically determined HMG-CoA reductase-mediated lipids were associated with an increased risk of migraine. These conclusions were consistent across meta-analyses. We found no evidence of bias caused by pleiotropy or genetic confounding factors. These findings support the hypothesis that statins can be used to treat migraine.

Statins are thought to have positive effects on migraine but existing data are inconclusive. We aimed to evaluate the causal effect of such drugs on migraines using Mendelian randomization. We used four types of genetic instruments as proxies for HMG-CoA reductase inhibition. We included the expression quantitative trait loci of the HMG-CoA reductase gene and genetic variation within or near the HMG-CoA reductase gene region. Variants were associated with low-density lipoprotein cholesterol, apolipoprotein B, and total cholesterol. Genome-wide association study summary data for the three lipids were obtained from the UK Biobank. Comparable data for migraine were obtained from the International Headache Genetic Consortium and the FinnGen Consortium. Inverse variance weighting method was used for the primary analysis. Additional analyses included pleiotropic robust methods, colocalization, and meta-analysis. Genetically determined high expression of HMG-CoA reductase was associated with an increased risk of migraines (OR = 1.55, 95% CI 1.30–1.84, P = 6.87 × 10−7). Similarly, three genetically determined HMG-CoA reductase-mediated lipids were associated with an increased risk of migraine. These conclusions were consistent across meta-analyses. We found no evidence of bias caused by pleiotropy or genetic confounding factors. These findings support the hypothesis that statins can be used to treat migraine. [ABSTRACT FROM AUTHOR]

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Hypercholesterolemia is characterized by elevated blood cholesterol levels, exceeding the normal limit of 200 mg/mL. One effective approach to lower the levels is by inhibiting the HMG-CoA reductase enzyme. Therefore, this study aimed to examine HMG-CoA reductase inhibition activity, phytochemical screening, total phenolic content(TPC), and total flavonoid content(TFC) using natural materials such as P.tectorius leaves. The methods used included simplicia standardization. The samples were gradually macerated using n-hexane, ethyl acetate, and methanol. The results of the maceration obtained PH(Pandanus Hexane), PE(Pandanus Ethyl acetate), and PM(Pandanus Methanol) extracts. The PE was fractionated using vacuum liquid chromatography(VLC), the results are PEF1, PEF2, PEF3, PEF4, and PEF5. The antihypercholesterol test was conducted on HMG-CoA reductase enzyme inhibition activity, while TPC and TFC were assessed using the Folin-Ciocalteu and the colorimetric methods. The results of the water, total ash, acid-insoluble ash content, water-soluble, and ethanol-soluble extractive values of simplicia were (6.7, 8.8, 0.76, 6.6, and 5.9)%, respectively. The phytochemical screening of simplicia, extracts, and fractions indicated the presence of flavonoids, saponins, terpenoids, tannins, phenolics, and quinones. The extract that showed the highest value of TPC and TFC was PE(32.65 mg GAE/g dry extract and 5.59 QE/g dry extract, respectively), while the fraction that showed the highest value of TPC and TFC was PEF3(24.95 mg GAE/g dry extract and 4.84 QE/g dry extract, respectively). So, the research results showed that PE (IC50=42.61 ppm) and PEF3 (IC50=95.22 ppm) showed the highest inhibitory activity of HMG-CoA reductase compared to other extracts and suspected as potential anti-hypercholesterol agents. [ABSTRACT FROM AUTHOR]

Obesity became a serious public health problem with enormous socioeconomic implications among the Egyptian population. The present investigation aimed to explore the efficacy of Zingiber officinale extract as a hypolipidemic agent combined with the commercially well‐known anti‐obesity drug simvastatin in obese rats. Thirty‐five male Wister rats were randomly divided into five groups as follows: group I received a standard balanced diet for ten weeks; high‐fat diet was orally administered to rats in groups II–V for ten weeks. From the fifth week to the tenth week, group III orally received simvastatin (40 mg/kg B.W.), group IV orally received Z. officinale root extract (400 mg/kg B.W.), and group V orally received simvastatin (20 mg/kg B.W.) plus Z. officinale extract (200 mg/kg B.W.) separately. Liver and kidney function tests, lipid profiles, serum glucose, insulin, and leptin were determined. Quantitative RT‐PCR analysis of PPAR‐γ, iNOS, HMG‐CoA reductase, and GLUT‐4 genes was carried out. Caspase 3 was estimated in liver and kidney tissues immunohistochemically. Liver and kidney tissues were examined histologically. The administration of Z. officinale extract plus simvastatin to high‐fat diet‐fed rats caused a significant reduction in the expression of HMG‐coA reductase and iNOS by 41.81% and 88.05%, respectively, compared to highfat diet (HFD)‐fed rats that received simvastatin only. Otherwise, a significant increase was noticed in the expression of PPAR‐γ and GLUT‐4 by 33.3% and 138.81%, respectively, compared to those that received simvastatin only. Immunohistochemistry emphasized that a combination of Z. officinale extract plus simvastatin significantly suppressed caspase 3 in the hepatic tissue of high‐fat diet‐fed rats. Moreover, the best results of lipid profile indices and hormonal indicators were obtained when rats received Z. officinale extract plus simvastatin. Z. officinale extract enhanced the efficiency of simvastatin as a hypolipidemic drug in obese rats due to the high contents of flavonoid and phenolic ingredients. [ABSTRACT FROM AUTHOR]

Metastatic melanoma has a very poor prognosis. Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) inhibitors, are cholesterol-lowering agents with a potential for cancer treatment. The inhibition of HMGCR by statins, however, induces feedback, which paradoxically upregulates HMGCR expression via sterol regulatory element-binding protein-2 (SREBP2). Dipyridamole, an antiplatelet agent, is known to inhibit SREBP2 upregulation. We aimed to demonstrate the efficacy of statin–dipyridamole combination treatment in both human and spontaneously occurring canine melanoma cell lines. The half maximal inhibitory concentration (IC50) of atorvastatin showed a 68–92% reduction when combined with dipyridamole, compared with that of atorvastatin alone. In some melanoma cell lines, cell proliferation was suppressed to almost zero by the combination treatment (≥3 μM atorvastatin). Finally, the BRAF inhibitor, vemurafenib, further potentiated the effects of the combined statin–dipyridamole treatment in BRAF V600E mutation-bearing human melanoma cell lines. In conclusion, the inexpensive and frequently prescribed statin–dipyridamole combination therapy may lead to new developments in the treatment of melanoma and may potentiate the effects of vemurafenib for the targeted therapy of BRAF V600E-mutation bearing melanoma patients. The concordance between the data from canine and human melanoma cell lines reinforces this possibility. [ABSTRACT FROM AUTHOR]

Objective: The present investigation aimed to analyze the in vivo study in support with in silico molecular docking mechanism of natural phenolic compounds Syringic acid (SA), Resveratrol (RV), Gallic acid (GA) and combination (COMB) with SA + RV against Isoproterenol (ISO) in myocardial necrotic rats. Methods: The compounds were tested for in vivo and in silico lipid metabolism enzymes HMG-CoA reductase and lipoprotein lipase (LPL) regulatory activities. Rats were orally pretreated with 50 mg/ kg of each compounds SA, RV, GA and COMB (SA 25 mg/ kg + RV 25 mg/ kg) for 30 days. GA has taken as positive control. After the treatment period, ISO (50 mg/ kg) in sub-cutaneous route was administered to the rats for two consecutive days. Then the rats sacrificed and the cardiac tissues were used for enzyme inhibitory analysis. Results: SA, RV, GA and COMB exhibited HMG-CoA reductase enzyme inhibitory activity. Also, the compounds augmented the LPL enzyme activity in the rats administered with ISO. Furthermore, in silico molecular docking reports also supported to the activity of SA, RV, GA and COMB compounds towards the enzymes HMG-CoA reductase and LPL. Conclusion: This report for the first time indicates the potential of phenolic compounds SA, RV, GA and COMB as excellent natural compounds in the therapeutic treatment of lipid metabolism disorders.

Preliminary assessment for anti-inflammatory and anti-lipidemic properties was done with different solvent extracts derived from Urtica urens and Polygonum chinense leaves through in vitro experimentation. To evaluate anti-inflammatory properties, the stability of human red blood cells membranes and the denaturation activity of proteins were assessed. For anti-lipidemic effects, an assay was conducted to measure the inhibition of HMG-CoA reductase. The results of membrane stabilization showed IC50 values of 480.96 ± 0.02 and 319.41 ± 0.19 µg/mL for ethyl acetate extract of U. urens and P. chinense, respectively. The standard drug Diclofenac sodium exhibited IC50 value of 240.37 ± 0.04 µg/mL. For protein denaturation, IC50 values were determined as 221.75 ± 0.2 and 315.76 ± 0.19 µg/mL for U. urens and P. chinense, respectively. The IC50 value of the standard drug was calculated as 126.7 ± 0.34. The IC50 values towards HMG-CoA reductase inhibition were subsequently determined as 29.84 ± 0.35 µg/mL for U. urens and 24.34 ± 0.04 µg/mL for P. chinense against the standard drug Diclofenac sodium (7.52 ± 0.43 µg/mL). GC-MS chromatograms revealed the presence of bioactive compounds in ethyl acetate extract of P. chinense leaves. This work is substantiation for the traditional therapeutic utilization of these extracts. [ABSTRACT FROM AUTHOR]

Introduction: Atherosclerosis is common CHD caused by accumulation of oxidized LDL-c forming foam cell with macrophage that narrowing blood vessels. It increased risk of CVD. Green vegetables rich with PUFA is important to maintain healthy status. This study investigated the mechanistic pathway mediate combination of Decosapentanoic acid (DPA) and linoleic acid (LA) as anti-atherothengic effect in rats fed high fat diet. Materials and Methods: Seventy-five male albino rats were divided into five groups (15 rats each) were fed high fat diet (40% Saturated fat) for 3 months: Group (I): Rats given 10 % DPA. Group (II): Rats given 10 % LA. Group (III): Rats given 10 % DPA+10% LA. Group (IV): Rats treated with atorvastatin (10 mg/kg BW) and Group (v) Untreated. In addition, Group (VI): 15 rats fed normal diet. Results: Data obtained showed that, plasma cholesterol and LDL-c levels were highly significant reduced in group III (p < 0.001) versus other groups compared with untreated. Level of triglycerides was reduced but still high than normal (p=0.05) and atherogenic index. The activity of HMG-CoA reductase was reduced while apo-A, apo-c elevated, JAK was upregulated in combination therapy (p< 0.001). The elevated Apo-A, apo-c activate clearing factor and decreased triglycerides. Conclusion: It was concluded that, upregulated of JAK by combination therapy mediate inhibition of HMG-CoA reductase that decreased endogenous synthesis of cholesterol and reduced its level in circulation. [ABSTRACT FROM AUTHOR]

Statins have been used in the treatment of hyperlipidemia, both as monotherapy and in combination therapy. Natural fermentation processes of fungi such as Monascus spp., Penicillium spp., Aspergillus terreus, and Pleurotus ostreatus have given rise to natural statins. Compactin (mevastatin), the original naturally occurring statin, is the primary biotransformation substrate in the manufacturing process of marketed drugs. Statins are classified into natural, semi-synthetic derivatives of natural statins, and synthetic ones. Synthetic statins differ from natural statins in their structural composition, with the only common feature being the HMG-CoA-like moiety responsible for suppressing HMG-CoA reductase. Statins do not differ significantly regarding their pleiotropic and adverse effects, but their characteristics depend on their pharmacokinetic parameters and chemical properties. This paper focuses on describing the processes of obtaining natural statins, detailing the pharmacokinetics of available statins, divided into natural and synthetic, and indicating their pleiotropic effects. [ABSTRACT FROM AUTHOR]

• Hyperlipidemia is a global concern associated with life-threatening diseases. • Discovery of naturally-derived candidates for the management of hyperlipidemia is of special interest. • Numerous natural anti-hyperlipidemic derived from terrestrial plants and their associated endophytes are reviewed. • Previous reports have revealed that natural metabolites exhibited different mechanisms of action. • Hyperlipidemia network design studies showed that epigallocatechin-3- O -gallate (EGCG), quercetin, and monacolin k have the highest connectivity with the putative target proteins. Natural products continue to provide potential pharmacological activities treating life-threatening illnesses. Among them is hyperlipidemia, which is a critical issue affecting approx. one-third of the world population and considered a risk factor for numerous life-threatening diseases, including myocardial infarction and stroke. The current review article highlighted the pathogenesis and pathways involved in the biosynthesis of lipid components revealing the possible targets for treatments of hyperlipidemia. Different phytochemical classes derived from terrestrial plants and their endophytes are discussed with their mechanism of action in the light of previous in vivo studies. Since high levels of triglyceride and cholesterol (> 200 mg/dL) are the most prominent disorders in blood investigational analysis in hyperlipidemic patients, natural medicines acting on inhibition of cholesterol inhibition, such as 3‑hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA) and acetyl-CoA synthetase, are considered potential anti-hyperlipidemic candidates. Different organosulfides derived from garlic and onion, in addition to proanthocyanidins and catechins showed pronounced anti-hyperlipidemic activity in investigational studies. Interestingly, network design-based studies were performed and revealed that epigallocatechin-3- O -gallate (EGCG), quercetin, and monacolin k showed the highest connectivity with the putative proteins involved in the antihyperlipidemic activity. Moreover, they bind effectively to each target with binding energies of less than -5.0 kcal/mol. In addition, EGCG, quercetin, and monacolin k bind to AKT1 (AKT Serine/Threonine Kinase 1) with docking scores of -9.33, -8.37, -7.37 kcal/mol, respectively. Therefore, the current review help discovery of candidate drugs for treatment of hyperlipidemia and associated serious diseases. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to investigate the association between hydroxymethylglutaryl coenzyme A reductase (HMGCR) inhibition and rheumatoid arthritis (RA) using drug-target Mendelian randomization (MR) and genetic colocalization analyses. Methods: Two sets of genetic instruments were employed to proxy HMGCR inhibitors: expression quantitative trait loci (eQTLs) of target genes from the eQTLGen Consortium and genetic variants associated with low-density lipoprotein cholesterol (LDL-C) levels with HMGCR locus from open genomewide association studies (GWAS). Positive control analyses were conducted on type 2 diabetes and coronary heart disease, and multiple sensitivity analyses were performed. Results: Genetically proxied expression of eQTL was associated with a lower risk of RA (OR=0.996, 95% CI =0.992-0.999, p= 0.032). Similarly, hydroxymethylglutaryl coenzyme A reductase (HMGCR)-mediated low-density lipoprotein cholesterol was negatively associated with risk of RA (OR=0.995, 95% CI =0.991-0.998, p= 0.007) in the inverse variance weighted (IVW) method. Colocalization analysis suggested a 74.6% posterior probability of sharing a causal variant within the SNPs locus (PH4 = 74.6%). A causal relationship also existed between HMGCR-mediated LDL and RA risk factors. The results were also confirmed by multiple sensitivity analyses. The results in positive control were consistent with the previous study. Conclusion: Our study suggested that HMGCR inhibition was associated with an increased risk of RA while also highlighting an increased risk of current smoking and obesity. These findings contribute to a growing body of evidence regarding the adverse effects of HMGCR inhibition on RA risk, calling for further research on alternative approaches using HMGCR inhibitors in RA management. [ABSTRACT FROM AUTHOR]

Lemongrass (Cymbopogon citratus Stapf.) has been used in the Philippines for cooking and as an herb to treat a variety of ailments including hypertension and related cardiovascular diseases (CVDs). This study determined the potential of peptides obtained from the hydrolysis of lemongrass proteins to lower cholesterol in vitro and in an animal model. Proteins were extracted and digested in vitro simulating gastrointestinal conditions. Protein hydrolysates were collected and fractionated using RP-SPE column, and assayed for HMG-CoA reductase inhibitory activity against pravastatin as a control drug. Tannin-free protein extract (TFPE) and total protein hydrolysates (TPC) were administered for two weeks to Sprague-Dawley rats maintained on a high-fat high-cholesterol diet. TFPE yield was 0.03%. Simulated gastrointestinal digestion of the TFPE resulted in 74% yield of protein hydrolysates. Three fractions were obtained from RP-SPE elution of the protein hydrolysates, each with potent HMG-CoA inhibitory activity. The F3 fraction had the highest inhibition of HMG-CoA reductase (IC50 = 0.76 ppm, comparable to pravastatin (IC50 = 0.25 ppm). The inhibitory activity of the fractions was further confirmed through significant serum cholesterol reduction (p < 0.05) in Sprague-Dawley rats. Thus, protein hydrolysates from lemongrass have potential cholesterol-lowering effects in vitro through HMG-CoA reductase inhibition and in vivo through significant reduction of cholesterol levels in an animal model. Protein hydrolysates from lemongrass dietary proteins may serve as promising functional foods for the prevention of CVD risk. [ABSTRACT FROM AUTHOR]

Statins are cholesterol-lowering drugs with a mechanism of inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase, but long-term use can cause side effects. An example of a plant capable of reducing cholesterol levels is Angelica keiskei (ashitaba). Therefore, this study aimed to obtain suitable compounds with inhibitory activity against the HMG-CoA reductase enzyme from ashitaba through in silico tests. The experiment began with screening and pharmacophore modeling, followed by molecular docking on ashitaba’s compounds, statins groups, and the native ligand was (3R,5R)-7-[4-(benzyl carbamoyl)-2-(4-fluorophenyl)-5-(1-methylethyl)-1H-imidazole-1-yl]-3,5-dihydroxyheptanoic acid (4HI). Based on the results of the molecular docking simulations, 15 hit compounds had a small binding energy (ΔG). Pitavastatin, as the comparator drug (ΔG = −8.24 kcal/mol; Ki = 2.11 µM), had a lower ΔG and inhibition constant (Ki) than the native ligand 4HI (ΔG = −7.84 kcal/mol; Ki = 7.96µM). From ashitaba’s compounds, it was found that 4′-O-geranylnaringenin, luteolin, isobavachalcone, dorsmannin A, and 3′-carboxymethyl-4,2′-dihydroxy-4′-methoxychalcone have low ΔG of below −6 kcal/mol. The lowest ΔG value was found in 3′-carboxymethyl-4,2′-dihydroxy-4′-methoxy chalcone with a ΔG of −6.67 kcal/mol and Ki value of 16.66 µM, which was lower than the ΔG value of the other comparator drugs, atorvastatin (ΔG = −5.49 kcal/mol; Ki = 1148.17 µM) and simvastatin (ΔG = −6.50 kcal/mol; Ki = 22.34 µM). This compound also binds to the important amino acid residues, including ASN755D, ASP690C, GLU559D, LYS735D, LYS691C, and SER684C, through hydrogen bonds. Based on the results, the compound effectively binds to six important amino acids with good binding affinity and only requires a small concentration to reduce half of the enzyme activity.

Nearly one-third of proteins are initially targeted to the endoplasmic reticulum (ER) membrane, where they are correctly folded and then delivered to their final cellular destinations. To prevent the accumulation of misfolded membrane proteins, ER-associated degradation (ERAD) moves these clients from the ER membrane to the cytosol, a process known as retrotranslocation. Our recent work in Saccharomyces cerevisiae reveals a derlin rhomboid pseudoprotease, Dfm1, is involved in the retrotranslocation of ubiquitinated ERAD membrane substrates. In this study, we identify conserved residues of Dfm1 that are critical for retrotranslocation. We find several retrotranslocation-deficient Loop 1 mutants that display impaired binding to membrane substrates. Furthermore, Dfm1 possesses lipid thinning function to facilitate in the removal of ER membrane substrates, and this feature is conserved in its human homolog, Derlin-1, further implicating that derlin-mediated retrotranslocation is a well-conserved process.

Background and Objectives: Cardiovascular diseases are the main cause of death worldwide. High cholesterol level is a risk factor for coronary artery disease. Cholesterol production is regulated by the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Statins, as the inhibitors of HMG-CoA reductase, are often used as cholesterol-lowering drugs to prevent cardiovascular diseases. This study aims to synthesize novel derivatives of atorvastatin and investigate their effect on liver and kidney serum parameters, function, and histology. Methods: Atorvastatin derivatives named S1, S2, and S3 were synthesized by acylation of the benzene ring of atorvastatin. The effect of compound S3 on serum parameters related to liver and kidney function was evaluated in rabbits with a high-fat diet-induced hypercholesterolemia. SPSS software, version 20 was used to analyze the data using statistical tests. Results: The compound S3 increased high-density lipoprotein cholesterol and reduced total cholesterol, low-density lipoprotein, and triglyceride compared to the standard drug atorvastatin during 30 days of treatment (P

This study investigated the effects of galactose-depleted xyloglucan derived from tamarind seed gum (GXG-TG) on glucose and lipid metabolism in diet-induced obese mice by comparison with intact xyloglucan (TG). Twenty-four male C57BL/6J mice were fed a high-fat diet containing 3 g/100 g of either GXG-TG or TG for 12 weeks. Reduction of postprandial glucose rise was observed in the TG group compared to the control, whereas the GXG-TG group showed intermediate values. Serum cholesterol levels and hepatic mRNA expression of HMG-CoA reductase were significantly lower in the GXG-TG and TG groups compared to the control, while there was no increase in cecal short chain fatty acids in the GXG-TG or TG group. These results indicated that GXG-TG was converted to insoluble dietary fiber and maintained the serum cholesterol-lowering effect, although the blood glucose level-lowering effect was attenuated. TG, although moderately viscous, improved glucose tolerance and lipid metabolism in diet-induced obesity model mice.

Introduction: Isoliquiritigenin, one of the components in the root of Glycyrrhiza glabra L., is a member of the flavonoids, which are known to have anti-tumor activity in vitro and in vivo. HMG-CoA reductase inhibitors, called statins, are used to reduce the risk of heart disease by lowering blood cholesterol levels. Material and methods: HMG-CoA reductase activity was determined according to the method described by Takahashi et al. The structure of human HMG-COA reductase in the resolution of 2.22 Å with the X-ray diffraction method (PDB ID: 1HWK) was obtained from the PDB database. Results: In our study, the inhibitory activity of isoliquiritigenin towards HMG-CoA reductase showed a lower value of IC50 = 193.77 ±14.85 µg/ml. For a better understanding of biological activities and interactions, the molecular docking study was performed. The results of molecular docking revealed that isoliquiritigenin with a docking score of -6.740 has a strong binding affinity to HMG-COA reductase. Therefore, this compound could be considered as a potential inhibitor for the enzyme. Also, the activity of isoliquiritigenin against common human pancreatic acinar cell tumor cell lines, i.e. 266-6, TGP49, and TGP47, was evaluated. Conclusions: The cells treated with isoliquiritigenin were assessed by MTT assay for 48 h as regards the cytotoxicity and anti-human pancreatic acinar cell tumor properties in normal (HUVEC) and human pancreatic acinar cell tumor cell lines, i.e. 266-6, TGP49, and TGP47. The IC50 values of isoliquiritigenin were 262, 389, and 211 µg/ml against 266-6, TGP49, and TGP47 cell lines, respectively. The viability of the human pancreatic acinar cell tumor cell line decreased dose-dependently in the presence of isoliquiritigenin. After clinical study, isoliquiritigenin can be utilized as an efficient drug in the treatment of human pancreatic acinar cell tumor in humans. [ABSTRACT FROM AUTHOR]

Neolamarckia cadamba (Roxb.) Bosser, a member of the Rubiaceae family, is a botanical species with recognized therapeutic properties. It is commonly used in traditional medicine to treat cardiac ailments and other disorders. However, the precise active constituents and the potential mechanisms by which they manage cardiovascular disorders remain unclear. Therefore, this study aimed to ascertain the bioactive components and investigate their underlying mechanisms of action. N. cadamba is used to treat cardiovascular disorders using the integrated metabolomic methodology. An HPLC-QTOF-MS/MS analysis determined the potential chemicals in the N. cadamba leaf ethanol extract (NCEE). A thorough investigation of the NCEE samples used in this study led to the identification of 32 phytoconstituents. Of the 32 compounds, 19 obeyed Lipinski's rule of five (RO5). A molecular docking study directed towards HMG-CoA reductase used 19 molecules. The reference drug atorvastatin indicated a binding energy of −3.9 kcal/mol, while the other substances, Cinchonain Ib and Dukunolide B, revealed binding energies of −5.7 and −5.3 kcal/mol, respectively. Both phytocompounds showed no toxicity and exhibited favorable pharmacokinetic properties. In vivo study results concluded that treatment with NCEE significantly reduced the cardiac myocardial infarction (MI) marker CK-MB and atherogenic risk indices, such as the atherogenic index plasma (AIP), cardiac risk ratio (CRR), and atherogenic coefficient (AC) in isoproterenol-induced MI rats. In MI rats, NCEE therapy significantly improved the antioxidant system of the heart tissue, as evidenced by the increased levels of GSH and SOD, lower levels of the oxidative stress marker MDA, and significantly decreased HMG-CoA activity. Additionally, electrocardiogram (ECG) signals from rats treated with NCEE resembled those treated with traditional atorvastatin to treat myocardial infarction. This study used H&E staining to show that administering NCEE before treatment reduced cardiac myocyte degeneration in rats with myocardial infarction, increased the presence of intact nuclei, and increased myocardial fiber strength. The potential cardioprotective effect observed in myocardial infarction (MI) rats treated with NCEE can be extrapolated from computational data to be caused by Cinchonain Ib. [ABSTRACT FROM AUTHOR]

The antioxidant activity capacities of some plants, and their inhibitory effects on the HMG-CoA reductase enzyme, the rate-determining enzyme of cholesterol synthesis, were investigated in our study. Antioxidant activity capacity and inhibitory effect of the HMG-CoA reductase enzyme were detected in all plant extracts used in our research. From the results obtained, it was determined that both antioxidant activity and % inhibition values of HMG-CoA reductase enzyme increased as the plant extracts concentration increased. The strongest ABTS and DPPH radical scavenging activities were exhibited by pomegranate fruit extract (IC50= 1.07 ±0.04 mg/mL and IC50= 0.39 ±0.01 mg/mL, respectively). At the same time, lemon had the strongest DMPD radical scavenging activity (IC50= 9×10-4 ±6×10-5 mg/mL). The best HMG-CoA reductase inhibitory activity was observed in persimmon fruit extract (IC50= 0.71 ±0.18 μg/mL). The inhibitory power of this extract was much higher than that of the enzyme’s standard inhibitor, Atorvastatin (IC50= 1.76 ±0.12 μg/mL). The extracts' potent antioxidant and inhibitory properties can be attributed to the rich phytochemical composition of plant extracts. Thus, it may be a potential source of new bioactive compounds effective against oxidative stress, hypercholesterolemia and cardiovascular complications. [ABSTRACT FROM AUTHOR]

Mikania micrantha Kunth (Asteraceae) is a plant traditionally used to reduce the risk of hyperlipidemia and hypertension. There is limited information on the anti-hyperlipidemic and anti-hypertensive effects of the various M. micrantha leaves and stem extracts. This study aimed to examine the in vitro potential of different parts of M. micrantha (leaves and stem) extracts in inhibiting hyperlipidemia-related enzymes, i.e., pancreatic lipase (PL), lipoprotein lipase (LPL) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR), in addition to the hypertension-related, i.e., angiotensin-I converting enzyme (ACE). This study spectrophotometrically determined the inhibitory activities of hot water, cold water, 70% ethanol, and ethyl acetate M. micrantha leaves and stem extracts against the above-said enzymes using PL, LPL, HMGR, and ACE inhibition assays. The study found that the ethanol stem (ETS) extract exhibited the highest PL inhibitory activity (IC50=4.49±2.50 μg/mL), albeit the difference was insignificant (p > 0.05) compared to orlistat (IC50=0.31±0.01 μg/mL). Meanwhile, the ethanol leaves (ETL) extract yielded the highest LPL (IC50=1.42±0.48 μg/mL) and HMGR inhibitory activity (50.12±3.44%), although the greatest ACE inhibition was observed for the hot water stem (HWS) extract (97.47±1.19%). However, the result was insignificant (p > 0.05) compared to other extracts and captopril (98.42±0.93%). In brief, the extracts generally exhibited remarkable inhibitory activity against PL, LPL, HMGR, and ACE, thus conveying the M. micrantha extracts' anti-hyperlipidemic and anti-hypertensive potentials.

HMG-CoA reductase (HMGR) undergoes feedback-regulated degradation as part of sterol pathway control. Degradation of the yeast HMGR isozyme Hmg2 is controlled by the sterol pathway intermediate GGPP, which causes misfolding of Hmg2, leading to degradation by the HRD pathway; we call this process mallostery. We evaluated the role of the Hmg2 sterol sensing domain (SSD) in mallostery, as well as the involvement of the highly conserved INSIG proteins. We show that the Hmg2 SSD is critical for regulated degradation of Hmg2 and required for mallosteric misfolding of GGPP as studied by in vitro limited proteolysis. The Hmg2 SSD functions independently of conserved yeast INSIG proteins, but its function was modulated by INSIG, thus imposing a second layer of control on Hmg2 regulation. Mutant analyses indicated that SSD-mediated mallostery occurred prior to and independent of HRD-dependent ubiquitination. GGPP-dependent misfolding was still extant but occurred at a much slower rate in the absence of a functional SSD, indicating that the SSD facilitates a physiologically useful rate of GGPP response and implying that the SSD is not a binding site for GGPP. Nonfunctional SSD mutants allowed us to test the importance of Hmg2 quaternary structure in mallostery: a nonresponsive Hmg2 SSD mutant strongly suppressed regulation of a coexpressed, normal Hmg2. Finally, we have found that GGPP-regulated misfolding occurred in detergent-solubilized Hmg2, a feature that will allow next-level analysis of the mechanism of this novel tactic of ligand-regulated misfolding.

Metastatic melanoma has a very poor prognosis. Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) inhibitors, are cholesterol-lowering agents with a potential for cancer treatment. The inhibition of HMGCR by statins, however, induces feedback, which paradoxically upregulates HMGCR expression via sterol regulatory element-binding protein-2 (SREBP2). Dipyridamole, an antiplatelet agent, is known to inhibit SREBP2 upregulation. We aimed to demonstrate the efficacy of statin–dipyridamole combination treatment in both human and spontaneously occurring canine melanoma cell lines. The half maximal inhibitory concentration (IC50) of atorvastatin showed a 68–92% reduction when combined with dipyridamole, compared with that of atorvastatin alone. In some melanoma cell lines, cell proliferation was suppressed to almost zero by the combination treatment (≥3 μM atorvastatin). Finally, the BRAF inhibitor, vemurafenib, further potentiated the effects of the combined statin–dipyridamole treatment in BRAF V600E mutation-bearing human melanoma cell lines. In conclusion, the inexpensive and frequently prescribed statin–dipyridamole combination therapy may lead to new developments in the treatment of melanoma and may potentiate the effects of vemurafenib for the targeted therapy of BRAF V600E-mutation bearing melanoma patients. The concordance between the data from canine and human melanoma cell lines reinforces this possibility.

In this study, we evaluated the effects of Lactobacillus reuteri NCIMB (LRC™) supplementation on hypercholesterolemia by researching its effects on cellular cholesterol metabolism in hypercholesterolemic rats (KHGASP-22-170) and HepG2 cell line. Rats were separated into six groups after adaptation and were then fed a normal control (NC), a high-cholesterol diet (HC), or a HC supplemented with simvastatin 15 mg/kg body weight (positive control [PC]), LRC 1 × 109 colony-forming units (CFU)/rat/day, LRC 4 × 109 CFU/rat/day, or LRC 1 × 1010 CFU/rat/day (1 × 109, 4 × 109, or 1 × 1010). The rats were dissected to study the effects of LRC on cholesterol metabolism and intestinal excretion at the end of experimental period. We discovered that LRC mainly participated in the restraint of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the uptake of low-density lipoprotein (LDL) cholesterol into tissues, partially in the transport of cholesteryl esters into high density lipoprotein for maturation, and intestinal excretion of cholesterol. These results are supported by the expression of transcription factors and enzymes such as HMG-CoA reductase, SREBP2, CYP7A1, CETP, and LCAT in both messenger RNA (mRNA) and protein levels in serum and hepatic tissue. Furthermore, the LRC treatment in HepG2 significantly reduced the mRNA expression of HMG-CoA reductase, SREBP2, and CEPT and significantly increased the mRNA expression of LDL-receptor, LCAT, and CYP7A1 at all doses. Hence, we suggest that LRC supplementation could alleviate the serum cholesterol level by inhibiting the intracellular cholesterol synthesis, and augmenting excretion of intestinal cholesterol. [ABSTRACT FROM AUTHOR]

Purpose: This study clarifies the reality of persistence and adherence to statins in older Japanese people who initiated statin use and compares it between primary and secondary prevention cohorts. Methods: The nationwide study using the national claims database targeted statin initiators aged ≥55 years from FY2014 to FY2017 in Japan. Persistence and adherence to statins were analyzed overall and according to subgroups based on sex, age stratum, and prevention cohorts. Permissible gap of median days that statins were supplied per prescription to an individual was employed. Persistence rates were estimated as Kaplan–Meier estimates. Poor adherence during persistence was evaluated and defined as <0.8 of the proportion of days covered. Results: Of 3 675 949 initiators, approximately 80% initiated statin use with strong variants. The persistence rate at 1 year was 0.61. Poor adherence to statins during persistence was 8.0% in all patients and this value gradually improved with increasing age. Persistence rate and adherence were lower for the primary prevention cohort than for the secondary prevention cohort, and a notable sex difference was observed for the secondary prevention cohort, which was lower in females but was almost never and slightly observed in the primary prevention cohorts without and with high‐risk factors, respectively. Conclusions: Many statin initiators discontinued statins shortly following statin initiation but adherence while on statin therapy was good. Attentively watching older patients not to discontinue statins and listening to their reasons for discontinuation are required, especially for initiators in primary prevention and females in secondary prevention. [ABSTRACT FROM AUTHOR]

Thymus atlanticus has been reported to have significant hypolipidaemic effect in animal models. However, the mechanism of this hypolipidaemic action still unknown. To determinate the possible mechanism(s) of hypolipidaemic action of a Thymus atlanticus polyphenol-rich extract (PRE). Plasma, faecal, and liver cholesterol, bile acid content in the faeces, and gene expression level of HMG-CoA reductase, CYP7A1, ABCG5 and ABCG8 were analysed after 9 weeks in hamsters feeding normal diet, high-fat diet (HFD) or HFD supplemented with 400 mg/kg body weight/day of PRE. PRE significantly decreased total cholesterol content (p <.05) and HMG-CoA reductase expression (p <.05), but did not affect the faecal cholesterol, bile acid contents and CYP7A1 and ABCG5/G8 expression (p >.05). We can conclude that the T. atlanticus extract is efficient in the alleviation of chronic hyperlipidaemia by acting as cholesterol biosynthesis inhibitor. [ABSTRACT FROM AUTHOR]

Primary amebic meningoencephalitis (PAM), caused by the free-living ameba Naegleria fowleri, has a fatality rate of over 97%. Treatment of PAM relies on amphotericin B in combination with other drugs, but few patients have survived with the existing drug treatment regimens. Therefore, development of effective drugs is a critical unmet need to avert deaths from PAM. Since ergosterol is one of the major sterols in the membrane of N. fowleri, disruption of isoprenoid and sterol biosynthesis by small-molecule inhibitors may be an effective intervention strategy against N. fowleri. The genome of N. fowleri contains a gene encoding HMG-CoA reductase (HMGR); the catalytic domains of human and N. fowleri HMGR share

ObjectiveIncreased de novo fatty acid (FA) synthesis and cholesterol biosynthesis have been independently described in many tumour types, including hepatocellular carcinoma (HCC).DesignWe investigated the functional contribution of fatty acid synthase (Fasn)-mediated de novo FA synthesis in a murine HCC model induced by loss of Pten and overexpression of c-Met (sgPten/c-Met) using liver-specific Fasn knockout mice. Expression arrays and lipidomic analysis were performed to characterise the global gene expression and lipid profiles, respectively, of sgPten/c-Met HCC from wild-type and Fasn knockout mice. Human HCC cell lines were used for in vitro studies.ResultsAblation of Fasn significantly delayed sgPten/c-Met-driven hepatocarcinogenesis in mice. However, eventually, HCC emerged in Fasn knockout mice. Comparative genomic and lipidomic analyses revealed the upregulation of genes involved in cholesterol biosynthesis, as well as decreased triglyceride levels and increased cholesterol esters, in HCC from these mice. Mechanistically, loss of Fasn promoted nuclear localisation and activation of sterol regulatory element binding protein 2 (Srebp2), which triggered cholesterogenesis. Blocking cholesterol synthesis via the dominant negative form of Srebp2 (dnSrebp2) completely prevented sgPten/c-Met-driven hepatocarcinogenesis in Fasn knockout mice. Similarly, silencing of FASN resulted in increased SREBP2 activation and hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase (HMGCR) expression in human HCC cell lines. Concomitant inhibition of FASN-mediated FA synthesis and HMGCR-driven cholesterol production was highly detrimental for HCC cell growth in culture.ConclusionOur study uncovers a novel functional crosstalk between aberrant lipogenesis and cholesterol biosynthesis pathways in hepatocarcinogenesis, whose concomitant inhibition might represent a therapeutic option for HCC.

Highlight Research 1. There were 26 active compounds from water clover leaf extract that were identified using GC-MS 2. In silico approach was used to screen potential anticholesterolemic compounds from water clover leaf extract 3. Anticholesterolemic compounds from water clover leaf extract were interacted with HMG-CoA reductase receptors and compared to native ligand and medicine 4. There were 6 potential anticholesterolemic compounds identified from water clover leaf extract Abstract Water clover (Marsilea crenata C. Presl.) is a widely available plant in Indonesia and often utilized as a traditional food ingredient. This plant is also traditionally believed to contain compounds that can decrease blood cholesterol. This study aimed to determine the compounds in water clover which have the potential to decrease blood cholesterol through inhibition of the HMG-CoA enzyme using in silico approach. This research was done in several steps, i.e., extraction using ethyl acetate solvent, identification of chemical compounds using GC-MS, and screening of compounds with potential to be anticholesterolemic agent through in silico using PyRx 0.8 (AutoDockVina and Open Babel GUI version 2.4.1), Discovery Studio Visualizer 2021, and PyMOLâ„¢ 1.7.4.5 software. Results showed that ethyl acetate extract of water clover contained 26 compounds, 6 of which were potential to be anticholesterolemic agent, i.e., phytol, 1,2-benzenedicarboxylic acid, 2,4-di- tert-butylphenol, diethyl phthalate, 1,2,3,4-tetramethylbenzene, and dipentene. Binding affinity values of those six compounds were lower than the native ligand of the HMG-CoA reductase, although still higher compared to pravastatin. The binding affinity value of pravastatin was -7.13 kcal/mol and the binding affinity value of 3-methyl glutaric acid as a native ligand was -5.33 kcal/mol, meanwhile, the lowest binding affinity value of compounds in water clover was phytol (-6.37 kcal/mol) and the highest was dipentene (-5.40 kcal/mol). Through in silico study, there were six compounds from water clover leaf's ethyl acetate extract that could inhibit the HMG-CoA reductase. Therefore, water clover leaf has the potential to become an anticholesterolemic functional food ingredient.

Leukemia is a type of dangerous cancer in humans. Many efforts have been done to find effective drugs to treat leukemia. One of the suitable options is the antioxidant molecules. Thus, the discovery of novel metabolites against cancer cells is of interest in current biomedicine. HMG-CoA Reductase activity was determined according to the method described by Takahashi S. et al. The MTT protocol was applied to determine the anti-leukemia potentials of 4-Butylresorcinol. Because of the 4-Butylresorcinol study, IC50 of HMG-CoA reductase enzyme: 182.04 micromolar was obtained, for urease IC50 was 91.44 micromolar. Molecular docking calculations were made to learn the theoretical activities of the 4-Butylresorcinol against the 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase reductase (PDB ID: 4I6A) and urease enzyme (PDB ID: 4H9M). Afterward, ADME/T calculations were made so that the molecule could be used as a drug. Additionally, the anticancer effects of molecule samples against the leukemia cells (KASUMI-1, HL-60, THP-1‎, K-562‎, RS4;11‎, and MOLT-4‎) were investigated. The aim of this study is to find a candidate compound for drug design that we recorded 4-Butylresorcinol as a good inhibitor and as an anticancer potential.

Mikania micrantha Kunth (Asteraceae) is a plant traditionally used to reduce the risk of hyperlipidemia and hypertension. There is limited information on the anti-hyperlipidemic and anti-hypertensive effects of the various M. micrantha leaves and stem extracts. This study aimed to examine the in vitro potential of different parts of M. micrantha (leaves and stem) extracts in inhibiting hyperlipidemia-related enzymes, i.e., pancreatic lipase (PL), lipoprotein lipase (LPL) and 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMGR), in addition to the hypertension-related, i.e., angiotensin- I converting enzyme (ACE). This study spectrophotometrically determined the inhibitory activities of hot water, cold water, 70% ethanol, and ethyl acetate M. micrantha leaves and stem extracts against the above-said enzymes using PL, LPL, HMGR, and ACE inhibition assays. The study found that the ethanol stem (ETS) extract exhibited the highest PL inhibitory activity (IC50=4.49±2.50 μg/mL), albeit the difference was insignificant (p > 0.05) compared to orlistat (IC50=0.31±0.01 μg/mL). Meanwhile, the ethanol leaves (ETL) extract yielded the highest LPL (IC50=1.42±0.48 μg/mL) and HMGR inhibitory activity (50.12±3.44%), although the greatest ACE inhibition was observed for the hot water stem (HWS) extract (97.47±1.19%). However, the result was insignificant (p > 0.05) compared to other extracts and captopril (98.42±0.93%). In brief, the extracts generally exhibited remarkable inhibitory activity against PL, LPL, HMGR, and ACE, thus conveying the M. micrantha extracts' anti-hyperlipidemic and anti-hypertensive potentials. [ABSTRACT FROM AUTHOR]

Objective: In this study, we report that a novel combination therapy of different statins with Ibrutinib can overcome such resistance. Methods: For this, we generated a cell line model, exhibiting resistance to Ibrutinib, by repeated exposure of mantle cell lymphoma cell line to Ibrutinib. Apoptosis was assessed by the extent of phosphatidylserine externalisation. Results: Our results indicated that resistance to Ibrutinib could be overcome by targeting a key enzyme, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in the cholesterogenesis pathway. Conclusion: Reusing different statins in combination with Ibrutinib could improve therapy and enhance sensitivity to Ibrutinib mediated apoptosis. [ABSTRACT FROM AUTHOR]

Pinus morrisonicola hay (PM) is a pine tree unique to Taiwan, whose needles are used as traditional medicine and as functional drink. PME3-1 was made using supercritical extraction to evaluate the prevention of hyperlipidemia. This study explored the hypolipidemic effect of PME3-1 on hamsters on a high fat and cholesterol (HFC) diet. Three groups of hamsters were fed with PME3-1 (0.2, 1.0, and 5.0 mg/kg bw). After feeding for eight weeks, PME3-1 reduced the serum cholesterol, triglyceride levels, the low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (LDL/HDL) ratio, and the swelling of the liver and kidney significantly (p < 0.05). In addition, feeding the hamsters with 5.0 mg/kg bw of PME3-1 could significantly reduce their total lipid (TL) content, total cholesterol (TC) content, total triglyceride (TG) content, and the HMG-CoA reductase activity in the liver (p < 0.05). Meanwhile, the antioxidant enzymes in the liver, glutathione peroxidase (GPx) and glutathione S-transferase (GST), can also improve, promoting the excretion of triglycerides (TG) and total cholesterol (TC) in the feces (p < 0.05). Therefore, these results confirm that PME3-1 hypolipidemic and antioxidant regulating functions in vivo. [ABSTRACT FROM AUTHOR]

Abstract The aim of this study was to evaluate hypocholesterolemic potential of phytoconstituents of ethanolic seed extract of cumin (Cuminum cyminum L.) by assessments of interaction capabilities with 3‐hydroxy‐3‐methyl‐glutaryl‐coenzyme A reductase (HMG‐CoA) reductase through in vivo and in silico assessments along with screening of phytoconstituents of the test extract. The phytoconstituents of the test extract were identified by Gas chromatography‐mass spectrometry (GC‐MS)/MS examinations. The hypercholesterolemic rabbit animal model was used for in vivo study and further examined the lipid profile and atherogenic indices. The treatments of the test extract and standard drug (atorvastatin) caused significant reductions in dyslipidemia indices, that is, atherogenic index of plasma (AIP), Casteli Risk Index‐I (CRI‐I), CRI‐II and atherogenic coefficient (AC). Accordingly, the molecular docking showed significant interactions between the cuminaldehyde and HMG‐CoA reductase compared to the other phytoconstituents. Further, molecular dynamics (MD) validated the interaction capabilities through assessments of N‐Substance, V‐Volume, T‐Temperature (NVT), N‐Substance, P‐Pressure, T‐Temperature (NPT), Root Mean Score Deviation (RSMD), Root Mean Score Fluctuation (RSMF), radius of gyration, system density, and potential energy along with locality assessment of complex interactions evaluated by angle distribution, average angle interaction, free energy of solvation, and solvent accessible surface area (SASA). Subsequently, the absorption, distribution, metabolism, excretion and toxicity (ADMET) predictions revealed the druggability and bioavailability criteria of the leading identified compounds. On the basis of results obtained, it can be concluded that small phytochemical molecules of test extract of cumin (Cuminum cyminum L.) have capabilities to inhibit the HMG‐CoA reductase and ameliorate the dyslipidemia indices.

Nyctanthes arbor-tristis L. contains various phytochemicals with tremendous potential to fight against different infections. However, the effect of these phytochemicals on Mycobacterium tuberculosis is yet unknown. Treatment of multi-drug resistance (MDR) and extensively drug-resistant (XDR) strains of the tuberculosis bacterium are still challenging. Therefore, there is an urgent need to overcome this problem. The present review focuses on the potential action of the hypolipidemic phytochemicals obtained from N. arbor-tristis on the growth and survival of M. tuberculosis in the human host. The extracts from different parts of this plant are hypolipidemic by various established mechanisms. Phytochemicals like iridoids and flavonoids from plant origin exhibit a high capacity to regulate cholesterol and fatty acid biosynthesis in vivo. The hypolipidemic properties of N. arbor-tristis-derived extracts are probably due to the presence of phytochemicals such as iridoids, flavonoids, etc. It may regulate fatty acid biosynthesis in M. tuberculosis by targeting bacterial fatty acid synthase enzyme. Additionally, these phytochemicals also inhibit cholesterol biosynthesis in the host by interrupting the function of HMG-CoA reductase. M. tuberculosis is an intracellular pathogen. It is also established fact as on date that entry of tuberculosis bacterium in the macrophage is macrophage membrane cholesterol-dependent. Host cholesterol is also otherwise necessary by multiple mechanisms for the pathogenesis of tuberculosis. Based on the above facts, we believe that N. arbor-tristis derived phytochemicals can act both on the tuberculosis bacterium and on the host for prevention and cure of tuberculosis. [ABSTRACT FROM AUTHOR]

Nyctanthes arbor-tristis L. contains various phytochemicals with tremendous potential to fight against different infections. However, the effect of these phytochemicals on Mycobacterium tuberculosis is yet unknown. Treatment of multi-drug resistance (MDR) and extensively drug-resistant (XDR) strains of the tuberculosis bacterium are still challenging. Therefore, there is an urgent need to overcome this problem. The present review focuses on the potential action of the hypolipidemic phytochemicals obtained from N. arbor-tristis on the growth and survival of M. tuberculosis in the human host. The extracts from different parts of this plant are hypolipidemic by various established mechanisms. Phytochemicals like iridoids and flavonoids from plant origin exhibit a high capacity to regulate cholesterol and fatty acid biosynthesis in vivo. The hypolipidemic properties of N. arbor-tristis-derived extracts are probably due to the presence of phytochemicals such as iridoids, flavonoids, etc. It may regulate fatty acid biosynthesis in M. tuberculosis by targeting bacterial fatty acid synthase enzyme. Additionally, these phytochemicals also inhibit cholesterol biosynthesis in the host by interrupting the function of HMG-CoA reductase. M. tuberculosis is an intracellular pathogen. It is also established fact as on date that entry of tuberculosis bacterium in the macrophage is macrophage membrane cholesterol-dependent. Host cholesterol is also otherwise necessary by multiple mechanisms for the pathogenesis of tuberculosis. Based on the above facts, we believe that N. arbor-tristis derived phytochemicals can act both on the tuberculosis bacterium and on the host for prevention and cure of tuberculosis.