Regulation Of Cholesterol Levels Research Articles

The relationship between gallstone disease and the genetic variants of the sterol transporter adenosine triphosphate–binding cassette G8 and G5 in Egyptians

BackgroundGallstones are abnormal lumps in the gallbladder or biliary tract due impaired cholesterol, bilirubin, or bile salt metabolism. The Adenosine triphosphate binding cassette transporter genes G5 and G8 (ABCG5, ABCG8) are two half transporters which work together as a heterodimer to regulate cholesterol levels in bile, and any alterations in their function can contribute to gallstone formation. The primary objective of this study was to evaluate the association between three specific polymorphisms—ABCG5 i7892T > C, ABCG5 Q604E, and ABCG8 D19H—and the risk of gallstone disease (GSD) in Egyptian females. These polymorphisms result from nucleotide substitutions in the gene sequences, which affect the transporter’s ability to efficiently regulate cholesterol secretion into the bile. This alteration can lead to cholesterol supersaturation in the bile, a key factor in the development of cholesterol gallstones. Additionally, the study aimed to examine the impact of these genetic variations on serum lipid profile to understand their role in modulating biochemical markers associated with GSD. Furthermore, the study sought to investigate haplotype patterns and explore their combined effects on disease susceptibility, providing deeper insight into the genetic factors that contribute to the development of GSD.MethodsThe study included 100 female patients diagnosed with gallstones and 100 healthy controls. Genotyping of single nucleotide polymorphisms (SNPs) was performed using allelic discrimination pre-designed TaqMan polymerase chain reaction method. Various laboratory investigations were measured using enzymatic colorimetric methods, and hematology analyzer was used for the whole blood count test.ResultsBetween patients with gallstone disease and healthy controls, there were statistically significant differences in the distribution of these genes polymorphisms. Q604E CC genotype (OR = 15.2; P = 0.004) and C allele (OR = 2; P = 0.007) in ABCG5 (rs6720173) as well as D19H GC genotype (OR = 2.9; P = 0.002) and C allele (OR = 2; P = 0.004) in ABCG8 (rs11887534) were significantly more frequent in gallstone patients. The CCC haplotype is a statistically significant predictor of GSD.ConclusionsThis study suggests that ABCG8 D19H (G/C) and ABCG5 Q604E (C/C) genotypes may play a significant role in GSD susceptibility among Egyptian females.Graphical abstract

Submicron Dispersions of Phytosterols Reverse Liver Steatosis with Higher Efficacy than Phytosterol Esters in a Diet Induced-Fatty Liver Murine Model.

Consumption of phytosterols is a nutritional strategy employed to reduce cholesterol absorption, but recent research shows that their biological activity might go beyond cholesterol reduction for the treatment of metabolic dysfunction-associated fatty liver disease (MAFLD), and novel phytosterol formulations, such as submicron dispersions, could improve these effects. We explored the therapeutic activity of phytosterols, either formulated as submicron dispersions of phytosterols (SDPs) or conventional phytosterol esters (PEs), in a mouse model of MAFLD. MAFLD was induced in mice by atherogenic diet (AD) feeding. The reversion of distorted serum and liver parameter values after a period of AD feeding was investigated after supplementation of the AD with SDPs, PEs, or a placebo (PT). Additionally, the metabolic parameters of fatty acid synthesis, fatty acid oxidation, and inflammation were studied to understand the mechanism of action of phytosterols. AD supplementation with SDPs was shown to reduce liver fat, along with showing a significant improvement in liver triglycerides (TGs), free fatty acids (FFAs), and liver cholesterol levels. These results were reinforced by the analyses of the liver steatosis scores, and liver histologies, where SDP intervention showed a consistent improvement. Treatment with PEs showed slighter effects in the same analyses, and no effects were observed with the PT treatment. Additionally, SDP intervention reversed, with a higher efficacy than PEs, the effect of AD on the serum levels of TGs, total- and LDL-cholesterol levels, and glucose levels. And, exceptionally, while SDP improved HDL-cholesterol serum levels, PEs did not show any effect on this parameter. We provide evidence for the therapeutical activity of phytosterols in MAFLD beyond the regulation of cholesterol levels, which is increased when the phytosterols are formulated as submicron dispersions compared to ester formulations.

Effect of bioactive extracts from Eucalyptus globulus leaves in experimental models of Alzheimer's disease.

Current therapies for Alzheimer's disease (AD) do not delay its progression, therefore, novel disease-modifying strategies are urgently needed. Recently, an increasing number of compounds from natural origin with protective properties against AD have been identified. Mixtures or extracts obtained from natural products containing several bioactive compounds have multifunctional properties and have drawn the attention because multiple AD pathways can be simultaneously modulated. This study evaluated the in vitro and in vivo effect of the essential oil (EO) obtained from the hydrodistillation of Eucalyptus globulus leaves, and an extract obtained from the hydrodistillation residual water (HRW). It was observed that EO and HRW have anti-inflammatory effect in brain immune cells modeling AD, namely lipopolysaccharide (LPS)- and amyloid-beta (Aβ)-stimulated microglia. In cell models that mimic AD-related neuronal dysfunction, HRW attenuated Aβ secretion and Aβ-induced mitochondrial dysfunction. Since the HRW's major components did not cross the blood-brain barrier, both EO and HRW were administered to the APP/PS1 transgenic AD mouse model by an intranasal route, which reduced cortical and hippocampal Aβ levels, and to rescue memory deficits and anxiety-like behaviors. Finally, HRW and EO were found to regulate cholesterol levels in aged mice after intranasal administration, suggesting that these extracts can reduce hypercholesterolemia and avoid risk for AD development. Overall, findings support a protective role of E. globulus extracts against AD‑like pathology and cognitive impairment highlighting the underlying mechanisms. These extracts obtained from underused forest biomass could be useful to develop nutraceutical supplements helpful to avoid AD risk and to prevent its progression.

Glutamine sensing licenses cholesterol synthesis

The mevalonate pathway produces essential lipid metabolites such as cholesterol. Although this pathway is negatively regulated by metabolic intermediates, little is known of the metabolites that positively regulate its activity. We found that the amino acid glutamine is required to activate the mevalonate pathway. Glutamine starvation inhibited cholesterol synthesis and blocked transcription of the mevalonate pathway—even in the presence of glutamine derivatives such as ammonia and α-ketoglutarate. We pinpointed this glutamine-dependent effect to a loss in the ER-to-Golgi trafficking of SCAP that licenses the activation of SREBP2, the major transcriptional regulator of cholesterol synthesis. Both enforced Golgi-to-ER retro-translocation and the expression of a nuclear SREBP2 rescued mevalonate pathway activity during glutamine starvation. In a cell model of impaired mitochondrial respiration in which glutamine uptake is enhanced, SREBP2 activation and cellular cholesterol were increased. Thus, the mevalonate pathway senses and is activated by glutamine at a previously uncharacterized step, and the modulation of glutamine synthesis may be a strategy to regulate cholesterol levels in pathophysiological conditions.

Targeting Oxidative Stress in Neurodegenerative Disorders: A Novel Role for PCSK9 Inhibition?

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein that regulates cholesterol levels by lysosomal low-density lipoprotein receptor (LDLR) degradation and has recently been associated with the production of neuronal oxidative stress and age-associated cardiovascular dysfunction. Since increased oxidative stress and vascular dysfunction are implicated in the pathology of aging and various neurodegenerative disorders, targeting PCSK9 may offer a promising therapeutic avenue for addressing these conditions. While the precise mechanisms through which PCSK9 contributes to vascular and neuronal oxidative stress in the brain remain elusive, preclinical studies have highlighted a neuroprotective effect linked to PCSK9 inhibition. This inhibition has shown promise in reducing oxidative stress, mitigating neuroinflammation, and alleviating neuropathological changes, thus underscoring the therapeutic potential of this approach in addressing neurodegenerative conditions.

Chitosan oligosaccharides as dietary antioxidants in nutrition of broiler chickens

Chitosan oligosaccharides (COS) have attracted considerable attention in poultry research due to their diverse biological activities and possible effects on the welfare and productivity of broiler chickens. A thorough examination of many studies indicates that the influence of COS on indices such as antioxidative functions, growth performance, immunological responses, and metabolic implications in broilers is significant. For example, specific dosage levels of COS have significantly enhanced antioxidant activity, regulation of cholesterol levels, and improved growth performance. The research findings have provided evidence for COS's antioxidative and anti-inflammatory properties and its capacity to mitigate the effects caused by stress. Nevertheless, the effectiveness of reactions might be influenced by the dosage and may demonstrate variances. Broiler chickens are suggested to consume dietary COS levels between 350 mg/kg and 500 mg/kg feed to obtain antioxidant and immunological advantages. Nevertheless, the most favorable results regarding growth and the ability to absorb nutrients are typically found when the intake ranges from 0.5 g/kg to 1.0 g/kg feed. For yellow-feather broilers experiencing heat stress, it is advisable to administer a dosage of 200 mg/kg feed of COS. However, it is essential to closely observe dosages exceeding 2.5 g/kg since they may significantly impair growth performance. The diverse research on using COS in broiler management has provided valuable insights into its intricate nature. This review has highlighted the potential benefits of COS in enhancing chicken health and nutrition. However, it has also underscored the need for additional research to optimize its effectiveness in broiler production fully. It can be concluded that dietary COS in broiler chickens in doses ranging from 200 mg to 1000 mg/kg feed has a positive effect on growth performance, antioxidative properties, regulation of lipid metabolism, ability to mitigate stress, impact on meat quality, and carcass traits, but exceeding 2.5 g/kg feed may significantly impair in growth performance in the broiler.

Doa10/MARCH6 architecture interconnects E3 ligase activity with lipid-binding transmembrane channel to regulate SQLE

Transmembrane E3 ligases play crucial roles in homeostasis. Much protein and organelle quality control, and metabolic regulation, are determined by ER-resident MARCH6 E3 ligases, including Doa10 in yeast. Here, we present Doa10/MARCH6 structural analysis by cryo-EM and AlphaFold predictions, and a structure-based mutagenesis campaign. The majority of Doa10/MARCH6 adopts a unique circular structure within the membrane. This channel is established by a lipid-binding scaffold, and gated by a flexible helical bundle. The ubiquitylation active site is positioned over the channel by connections between the cytosolic E3 ligase RING domain and the membrane-spanning scaffold and gate. Here, by assaying 95 MARCH6 variants for effects on stability of the well-characterized substrate SQLE, which regulates cholesterol levels, we reveal crucial roles of the gated channel and RING domain consistent with AlphaFold-models of substrate-engaged and ubiquitylation complexes. SQLE degradation further depends on connections between the channel and RING domain, and lipid binding sites, revealing how interconnected Doa10/MARCH6 elements could orchestrate metabolic signals, substrate binding, and E3 ligase activity.

Current Understanding of PCSK9 and Its Relevance to Cancer Prognosis and Immune Therapy: A Review.

The effectiveness of immunotherapy for most cancer patients remains low, with approximately 10-30% of those treated surviving. Thus, much effort is being put into finding new ways to improve immune checkpoint therapy. Our review concludes that inhibition of proprotein convertase subtilisin/Kexin type 9 (PCSK9), which plays a critical role in regulating cholesterol metabolism, can cause movement of T cells toward tumors, with increased sensitivity to immune checkpoint therapies. We searched PubMed, NCBI, Scopus, and Google Scholar for the published articles without limitations on publication dates. We used the following terms: "PCSK9", "Cancer", "Immune Checkpoint", and "Cancer Prognosis" in the title and/or abstract. Our search initially revealed 600 records on the subject and stored them in the used databases under EndNote X8 management software. A total of 161 articles were selected and through a careful review, 76 were included in our research. We concluded that PCSK9 reduces the number of LDL receptors (LDL-R) on the cell surface, which is linked to its ability to regulate cholesterol levels in the body. Also, we discuss how suppressing PCSK9 leads to the MHC-1 accumulation on the surface of cancer cells, which results in T lymphocyte invasion. Finally, we believe that inhibiting PCSK9 may be an effective strategy for improving cancer immunotherapy.

Implications for High-intensity Aerobic Exercises on Omani Cardiorespiratory Endurance and Blood Lipids and Lipoproteins

Background: Regular exercise provides benefits that are beyond dispute, and promoting physical activity levels ought to be a primary focus at all levels of healthcare. Chronic exercise causes a variety of cellular and organismal changes that modify how the body processes all macronutrients, including lipids. Purpose: The study investigates different types of aerobic exercise and their impact on both types of cholesterols—low-density-lipoprotein and high-density-lipoprotein cholesterol and recommends the best protocol for regulating cholesterol levels. Design/Methodology/Approach: This mixed-method study analyzes survey questionnaires distributed among physicians from two different sites in Oman. A total of 60 randomly selected and complete samples were used for the analysis using the Chi-square test. The survey consists of demographic information and questions about the types of cholesterol and types of aerobic exercise and the effect of different kinds of aerobic exercise on cholesterol levels. Finding: The study’s findings demonstrate a statistically significant reduction of cholesterol levels through 20-30 minutes of aerobic exercise (walking, swimming, and running). The relationship between aerobic exercise and cholesterol levels vis-a-vis age and gender is not statistically significant. Furthermore, this study recommends the best protocol for regulating cholesterol levels. Research implications: The study has wider implications for future studies in wellness rhetoric in the Arab Gulf States. The outcome is on the wellness discourse which has mass level impact. The rhetoric of wellness programs has a buy-in potential for the Arab Gulf States sitting on the cusp of lifestyle-based diseases, including blood pressure and diabetes. Originality/value: With hardly any extant research in this field in Oman and some sporadic studies in Arab Gulf states, this study establishes its originality, exigency, and value addition in the repertoire of wellness programs in Oman and the Arab Gulf States.

Cholesterol is required for activity-dependent synaptic growth.

Changes in cholesterol content of neuronal membranes occur during development and brain aging. Little is known about whether synaptic activity regulates cholesterol levels in neuronal membranes and whether these changes affect neuronal development and function. We generated transgenic flies that express the cholesterol-binding D4H domain of perfringolysin O toxin and found increased levels of cholesterol in presynaptic terminals of Drosophila larval neuromuscular junctions following increased synaptic activity. Reduced cholesterol impaired synaptic growth and largely prevented activity-dependent synaptic growth. Presynaptic knockdown of adenylyl cyclase phenocopied the impaired synaptic growth caused by reducing cholesterol. Furthermore, the effects of knocking down adenylyl cyclase and reducing cholesterol were not additive, suggesting that they function in the same pathway. Increasing cAMP levels using a dunce mutant with reduced phosphodiesterase activity failed to rescue this impaired synaptic growth, suggesting that cholesterol functions downstream of cAMP. We used a protein kinase A (PKA) sensor to show that reducing cholesterol levels reduced presynaptic PKA activity. Collectively, our results demonstrate that enhanced synaptic activity increased cholesterol levels in presynaptic terminals and that these changes likely activate the cAMP-PKA pathway during activity-dependent growth.

Carbon dioxide regulates cholesterol levels through SREBP2.

In mammals, O2 and CO2 levels are tightly regulated and are altered under various pathological conditions. While the molecular mechanisms that participate in O2 sensing are well characterized, little is known regarding the signaling pathways that participate in CO2 signaling and adaptation. Here, we show that CO2 levels control a distinct cellular transcriptional response that differs from mere pH changes. Unexpectedly, we discovered that CO2 regulates the expression of cholesterogenic genes in a SREBP2-dependent manner and modulates cellular cholesterol accumulation. Molecular dissection of the underlying mechanism suggests that CO2 triggers SREBP2 activation through changes in endoplasmic reticulum (ER) membrane cholesterol levels. Collectively, we propose that SREBP2 participates in CO2 signaling and that cellular cholesterol levels can be modulated by CO2 through SREBP2.

Systematic Evaluation of the Impact of Moringa oleifera on the Health Status of HIV-Infected Individuals

The Human Immunodeficiency Virus (HIV), if left untreated, poses a significant threat to health, resulting in morbidity and mortality rates up to 14 times higher than those observed in individuals free from HIV/AIDS. Currently, the use of antiretroviral therapy (ART) has substantially increased the life expectancy of people living with HIV (PLWHIV). In many developing nations, PLWHIV often complements their treatment with traditional medicines, such as Moringa oleifera, alongside ART. However, the utilization of Moringa in this context is primarily advocated for by non-professionals due to the lack of consensus regarding its impact on the health status of PLWHIV. Consequently, the objective of this review was to systematically investigate the influence of Moringa oleifera on the health status of PLWHIV. A meticulous search was conducted in three scientific databases between July 1st and August 31st, 2022, using “Moringa oleifera” and “HIV” as keywords. Only articles published in peer-reviewed journals were considered for inclusion in this study. Out of the 20 articles retrieved, 11 were excluded as they did not employ a randomized control study design or were review articles. The remaining 9 articles were meticulously examined and synthesized to assess the impact of Moringa oleifera on various health parameters among PLWHIV. The findings extracted from these articles collectively indicate that Moringa supplementation offers several notable benefits to PLWHIV. These benefits encompass an increase in CD+4 cell counts, improvements in Body Mass Index (BMI), enhanced psychological well-being, effective management of depression and anxiety, improved functioning of vital body organs, and regulation of cholesterol levels. In light of these findings, it is concluded that Moringa oleifera supplementation contributes significantly to the enhanced health status of PLWHIV. These results advocate for the consideration of Moringa oleifera as a valuable adjunctive therapy alongside ART, thereby potentially augmenting the overall treatment outcomes for individuals living with HIV. Keywords: HIV, AIDs, Moringa oleifera

Analysis of multi-disease targeting effect of phytochemicals by AMPK stimulation– diabetes: A computational approach

Diabetes is a silent killer and a metabolic syndrome characterized by hyperglycemia that has been exponentially increasing in recent years. There is a need to develop therapeutic agents to control hyperglycemia and its secondary complications as well as protect and revive beta cells in diabetic patients. The target for first-line diabetes treatment is the adenosine monophosphate protein kinase (AMPK), which participates in cellular energy metabolism through phosphorylation of metabolic enzymes and transcription regulators. This study examined the drug-related properties as well as lead preparation of Catharanthus roseus alkaloids and testing molecular interaction at the AMPK targets to confirm their anti-diabetic effect. A control drug metformin and a library of 85 molecules of C. roseus alkaloids were crossed with the ADMET test, followed by the investigation of molecular interaction tested on AMPK1 and AMPK2 targets through an in silico docking process. Vindolinine (CID: 24148538), vindoline (CID: 425978), (+)-vindorosine (CID: 261578), Cr-1 (CID: 5315746), and Cr-2 (CID: 59908094) had passed the ADMET test. Molecular interaction of the tested C. roseus alkaloids on AMPK1 and AMPK2 targets had potential energy that varied from −7.4 to −5.3 kcal/mol, whereas binding energies of −4.0 kcal/mol for AMPK1-metformin interaction and −4.2 kcal/mol for AMPK2-metformin interaction were observed. The tested C. roseus alkaloids were shown to be more potent activators of AMPK than the control drug. All five biomolecules of C. roseus acted as modulators that have the potential to stimulate AMPK, reduce glucose production, and increase glucose utilization in hepatocytes. In addition, they diminished insulin resistance and secondary complications of diabetes by inhibiting acetyl-CoA carboxylase, regulating cholesterol levels and macrophage, and reviving beta cells in Type 2 diabetes. These results provided the foundation for developing new multi-disease-targeting drugs that can treat diabetes, obesity, cardiovascular disease, cancer, and other diseases by the stimulation of AMPK1 and AMPK2 targets.

Protective Effects of Melatonin in High-Fat Diet-Induced Hepatic Steatosis via Decreased Intestinal Lipid Absorption and Hepatic Cholesterol Synthesis.

The preventative effect of melatonin on the development of obesity and the progression of fatty liver under a high-fat diet (HFD) has been well elucidated through previous studies. We investigated the mechanism behind this effect regarding cholesterol biosynthesis and regulation of cholesterol levels. Mice were divided into three groups: normal chow diet (NCD); HFD; and HFD and melatonin administration group (HFD+M). We assessed the serum lipid profile, mRNA expression levels of proteins involved in cholesterol synthesis and reabsorption in the liver and nutrient transporters in the intestines, and cytokine levels. Additionally, an in vitro experiment using HepG2 cells was performed. Expression of hepatic sterol regulatory element-binding protein 2 (SREBP-2), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), and low-density lipoprotein receptor (LDLR) demonstrated that melatonin administration significantly reduces hepatic cholesterol synthesis in mice fed an HFD. Expression of intestinal sodium-glucose transporter 1 (SGLT1), glucose transporter 2 (GLUT2), GLUT5, and Niemann-pick C1-like 1 (NPC1L1) demonstrated that melatonin administration significantly reduces intestinal carbohydrate and lipid absorption in mice fed an HFD. There were no differences in local and circulatory inflammatory cytokine levels among the NCD, HFD, and HFD+M group. HepG2 cells stimulated with palmitate showed reduced levels of SREBP, LDLR, and HMGCR indicating these results are due to the direct mechanistic effect of melatonin on hepatocytes. Collectively, these data indicate the mechanism behind the protective effects of melatonin from weight gain and liver steatosis under HFD is through a reduction in intestinal caloric absorption and hepatic cholesterol synthesis highlighting its potential in the treatment of obesity and fatty liver disease.

Metabolomics Analysis Reveals Molecular Signatures of Metabolic Complexity in Children with Hypercholesterolemia

Despite the importance of hypercholesterolemia in children, it is overlooked, and there are currently few metabolomics-based approaches available to understand its molecular mechanisms. Children from a birth cohort had their cholesterol levels measured with the aim of identifying the metabolites for the molecular biological pathways of childhood hypercholesterolemia. One hundred and twenty-five children were enrolled and stratified into three groups according to cholesterol levels (acceptable, <170 mg/dL, n = 42; borderline, 170-200 mg/dL, n = 52; and high, >200 mg/dL, n = 31). Plasma metabolomic profiles were obtained by using 1H-nuclear magnetic resonance (NMR) spectroscopy, and partial least squares-discriminant analysis (PLS-DA) was applied using the MetaboAnalyst 5.0 platform. Metabolites significantly associated with different cholesterol statuses were identified, and random forest classifier models were used to rank the importance of these metabolites. Their associations with serum lipid profile and functional metabolic pathways related to hypercholesterolemia were also assessed. Cholesterol level was significantly positively correlated with LDL-C and Apo-B level, as well as HDL-C and Apo-A1 level separately, whereas HDL-C was negatively correlated with triglyceride level (p < 0.01). Eight metabolites including tyrosine, glutamic acid, ornithine, lysine, alanine, creatinine, oxoglutaric acid, and creatine were significantly associated with the different statuses of cholesterol level. Among them, glutamic acid and tyrosine had the highest importance for different cholesterol statuses using random forest regression models. Carbohydrate and amino acid metabolisms were significantly associated with different cholesterol statuses, with glutamic acid being involved in all amino acid metabolic pathways (FDR-adjusted p < 0.01). Hypercholesterolemia is a significant health concern among children, with up to 25% having high cholesterol levels. Glutamic acid and tyrosine are crucial amino acids in lipid metabolism, with glutamic-acid-related amino acid metabolism playing a significant role in regulating cholesterol levels.

Cardiomyocyte-specific PCSK9 deficiency compromises mitochondrial bioenergetics and heart function.

Pro-protein convertase subtilisin-kexin type 9 (PCSK9), which is expressed mainly in the liver and at low levels in the heart, regulates cholesterol levels by directing low-density lipoprotein receptors to degradation. Studies to determine the role of PCSK9 in the heart are complicated by the close link between cardiac function and systemic lipid metabolism. Here, we sought to elucidate the function of PCSK9 specifically in the heart by generating and analysing mice with cardiomyocyte-specific Pcsk9 deficiency (CM-Pcsk9-/- mice) and by silencing Pcsk9 acutely in a cell culture model of adult cardiomyocyte-like cells. Mice with cardiomyocyte-specific deletion of Pcsk9 had reduced contractile capacity, impaired cardiac function, and left ventricular dilatation at 28 weeks of age and died prematurely. Transcriptomic analyses revealed alterations of signalling pathways linked to cardiomyopathy and energy metabolism in hearts from CM-Pcsk9-/- mice vs. wild-type littermates. In agreement, levels of genes and proteins involved in mitochondrial metabolism were reduced in CM-Pcsk9-/- hearts. By using a Seahorse flux analyser, we showed that mitochondrial but not glycolytic function was impaired in cardiomyocytes from CM-Pcsk9-/- mice. We further showed that assembly and activity of electron transport chain (ETC) complexes were altered in isolated mitochondria from CM-Pcsk9-/- mice. Circulating lipid levels were unchanged in CM-Pcsk9-/- mice, but the lipid composition of mitochondrial membranes was altered. In addition, cardiomyocytes from CM-Pcsk9-/- mice had an increased number of mitochondria-endoplasmic reticulum contacts and alterations in the morphology of cristae, the physical location of the ETC complexes. We also showed that acute Pcsk9 silencing in adult cardiomyocyte-like cells reduced the activity of ETC complexes and impaired mitochondrial metabolism. PCSK9, despite its low expression in cardiomyocytes, contributes to cardiac metabolic function, and PCSK9 deficiency in cardiomyocytes is linked to cardiomyopathy, impaired heart function, and compromised energy production.

Green synthesis and characterization of silver nanoparticles for reducing the damage to sperm parameters in diabetic compared to metformin

The present study used physics to synthesize silver nanoparticles using aqueous extract of fresh garlic as reducing and as a stabilizing agent silver nitrate solution. This method has proven to be environmentally friendly and safe for the synthesis of stable silver nanoparticles. The acquisition of silver nanoparticles was confirmed by optical detection, that is, by changing the color of the liquid to transparent orange and then blackish brown. Then, the characterization was confirmed using other assays. In this study, it was found that the absorption peak of silver nanoparticles was at a wavelength of 420 nm and the particle size ranged between [50–350] nm. The surface roughness of silver oxide/silver nanoparticles was 9.32 nm with an average square roughness of 21.19 nm, and the energy dispersive spectra showed that the absorption peak was in the region of 3 keV, indicating that the nanoparticles contained crystalline silver. In this study, the stability of the silver nanoparticles was good, as ZP reached (− 19.5). The results confirm that the conductivity increases with the increase in frequency due to the high energy of the photons, which causes the electrons to vibrate in the energy levels and thus increase the energy in the mitochondria and increase the movement of sperm in the Diabetic mice treated with doses of silver nanoparticles. The toxic effect of silver nanoparticles has been evaluated in other studies, in addition to evaluating antioxidants, antifungals, treating cancer cells, regulating cholesterol levels, the effect of these nanoparticles on sex cells in pregnant female mice, heart tension, and many other tests. In this study, the activities and efficacy of silver nanoparticles on sperms were determined in male mice with diabetes caused by STZ, and the treatment period was long (35 days) so that the evaluation period was a complete life cycle of male sex cells and within a long period of time and at an average nano size. This has not been studied in other previous studies. The results indicate that the biosynthesis of silver nanoparticles using garlic plant led to positive results on sperm treatments by contributing to an increase in the number of sperm with reactivation and a decrease in abnormalities in addition to a decrease in mortality due to diabetes. This is evidence that the synthesis of silver nanoparticles using garlic plant size (50–350 nm) can treat impotence and be used in the future in the treatment of many diseases without side effects.

Fenofibrate, a drug for COVID-19? All we need to know

Fenofibrate, a cholesterol-lowering medication, also destabilizes the spike protein on SARS-CoV-2 and prevents it from attaching to human cells. It was efficacious even against SARS-CoV-2 variants investigated in vitro by the researchers.1 According to laboratory tests, a low-cost generic medication decreases SARS-CoV-2 contamination in human cells by up to 70%.2 One medicine that individuals used to regulate cholesterol levels might be an effective therapy against COVID-19, according to a multinational initiative comprising scientists from San Raffaele Scientific Institute in Milan, University of Birmingham, and the University of Keele in the United Kingdom. The study's findings will be published in the journal Frontiers in Pharmacology.1,2In the beginning, researchers tested a number of approved medicines on animals. For COVID-19 therapy, they were seeking medicines that disrupted interactions between the viral spike protein and human cell surface. Dr. Alan Richardson, a co-author of the study, told a source that they have evaluated above 100 medicines and discovered that fibric acids had the most potential. Fenofibrate proved to be a better alternative to clofibrate because of its unfavorable side effects.”3 Fenofibrate was developed by scientists in the 1980s, and it was frequently prescribed by Physicians to lower cholesterol levels in patients.2 It was incredibly popular, until statins were discovered, to reduce the risk of heart disease. Statins are currently taken by over 30 million people in the United States and throughout the world. Fenofibrate, on the other hand, is used by patients who cannot tolerate statins.4Currently, the medication is efficacious against the Beta and Alpha strains of SARS-CoV-2, and the team is researching its efficacy against the Delta variant nowadays. “\Resistance will be tougher to develop since the medication hits several targets, not only the spike protein, thus future variations should not be able to escape the effect.2 Fenofibrate was shown to be just as efficient against a live virus as the isolated protein.3 Dr. Farhat Khanim, a co-author of the paper, tested the medication against a live virus. She had high hopes for it. The scientists are cautiously and extremely enthusiastic about the possibilities. They further opined that we must not lose sight of the reality that there are high-risk categories of individuals for whom the vaccination will not function. In order to treat SARS-CoV-2, we must urgently increase our arsenal of medicines.4According to Dr. Khanim: “The medication appears to work, regardless of spike mutations.”4When infected cells were given fenofibrate in vitro, the researchers looked at the amount of virus that was released from them. When compared to untreated cells, they discovered that viral release was reduced by 60%. Statins, for example, did not have the same impact.5 Fascinatingly, fenofibrate can be taken orally and is extremely inexpensive, so if scientists duplicate the findings in clinical trials, it might be helpful for poor and medium-income countries that have struggled with vaccinations in the past. Fenofibrate is readily available, according to the estimates, a course of therapy would cost between £10 and £20.6If this in vitro result translates into a beneficial clinical impact, it may add another medication to our arsenal, according to Dr. Peter English. This is all theoretical at the moment, he says, because the medication hasn't been tested outside of the laboratory yet. The study's authors urge caution in interpreting their conclusions because they are based on laboratory experiments. For COVID-19, they are eager to begin clinical studies with fenofibrate.7As Dr. Khanim told, “I'd want to see clinical studies in high-risk people in the community with symptoms, initiating therapy early to see whether it reduces hospitalization.”2

(BORING SEN) CHERRY LEAF DRIED SPONGE IS BENEFICIAL IN MAINTAINING CHOLESTEROL LEVELS AND HIGH BLOOD PRESSURE

The myocardium is a layer of heart muscle that is responsible for pumping the heart and supplying the entire body with blood. Cherry leaf extract that can be used are: 100 ml of water with a water content of 22.63%; Reducing sugar 3.8173%; 2.43% ash content; Texture (physical) 15.52%; 17.60% brightness; 8.796% protein; Flavor 4.30%; Fragrance 4.15%; Color 4.75%; Texture 4.75%. Cherry leaves have properties to protect liver cells from damage caused by free radicals, the content of sponins, and flavonoids in cherry leaves. The benefits of these leaves provide an innovation for the author in making snacks in the form of dry sponge cakes that can provide benefits in regulating cholesterol levels and high blood pressure. The price of the BORING SEN product for a weight of 250 grams is Rp. 15,000, - and is quite cheap and affordable for the general public. The target of this BORING SEN product is for people who have cholesterol and high blood pressure problems. The flavor variants of this product are: Original, Lime Leaves, Pandanus, and Chocolate.

Dapagliflozin attenuates cholesterol overloading-induced injury in mice hepatocytes with type 2 diabetes mellitus (T2DM) via eliminating oxidative damages

ABSTRACT Cholesterol overloading-induced damages on hepatocytes cause liver dysfunctions, which further damages cholesterol metabolism and results in visceral fat accumulation in patients with type 2 diabetes mellitus (T2DM). The sodium-glucose cotransporter 2 (SGLT2) inhibitor Dapagliflozin has been reported to regulate cholesterol levels in T2DM patients, but the underlying mechanisms have not been studied. In the present study, we initially established in vivo T2DM mice models, and our results showed that both free cholesterol (FC) and cholesteryl ester (CE) were accumulated, while the pro-proliferation associated genes were downregulated in T2DM mice liver tissues, which were reversed by Dapagliflozin co-treatment. Similarly, the mice primary hepatocytes were loaded with cholesterol to establish in vitro models, and we expectedly found that Dapagliflozin attenuated cholesterol-overloading induced cytotoxicity and cellular senescence in the hepatocytes. Then, we noticed that oxidative damages occurred in T2DM mice liver tissues and cholesterol treated hepatocytes, which could be suppressed by Dapagliflozin. Also, elimination of Reactive Oxygen Species (ROS) by N-acetyl-L-cysteine (NAC) recovered cellular functions of hepatocytes in vitro and in vivo. Furthermore, the potential underlying mechanisms were uncovered, and our data suggested that Dapagliflozin activated the anti-oxidant Nrf2/HO-1 pathway in mice hepatocytes, and silencing of Nrf2 abrogated the protective effects of Dapagliflozin on cholesterol-overloaded hepatocytes. Collectively, we concluded that Dapagliflozin recovered cholesterol metabolism functions in T2DM mice liver via activating the anti-oxidant Nrf2/HO-1 pathway, and our data supported that Dapagliflozin was a potential therapeutic drug to eliminate cholesterol-induced cytotoxicity during T2DM pathogenesis.