Reduced Cholesterol Concentrations Research Articles

Zwitterionic Polymer-Functionalized Lipid Nanoparticles for the Nebulized Delivery of mRNA.

Lipid nanoparticles (LNPs) have great potential to enable inhaled delivery of mRNA to treat pulmonary diseases. However, this potential has been limited by the challenge of nebulizing the LNPs. Nebulization of LNPs can cause LNPs to aggregate and release encapsulated mRNA, limiting their delivery efficacy. To overcome this challenge, LNPs are developed whereby the PEG-lipid is fully replaced with a zwitterionic polymer (ZIP)-lipid conjugate to greatly enhance the nebulizer stability. LNPs formulated with ZIP-lipids (ZIP-LNPs) were stable to nebulization across a wide range of formulation parameters. The optimized ZIP-LNP formulation, containing reduced cholesterol content relative to traditional PEG-lipid LNPs, demonstrated improved inhaled mRNA delivery in both healthy and mucoobstructed mouse lungs. Repeat administration of the optimized ZIP-LNP formulation was well tolerated and did not result in pulmonary inflammation. This study demonstrates the potential of zwitterionic polymer-lipid conjugates for improving the performance of inhaled mRNA-LNP formulations.

Exposure to lipid mixture induces intracellular lipid droplet formation and impairs mitochondrial functions in astrocytes

Astrocytes, the predominant glial cells in the central nervous system (CNS), play diverse roles including metabolic support for neurons, provision of neurotrophic factors, facilitation of synaptic neurotransmitter uptake, regulation of ion balance, and involvement in synaptic formation. The accumulation of lipids has been noted in various neurological conditions, yet the response of astrocytes to lipid-rich environments remains unclear. In this study, primary astrocytes isolated from the neonatal rat cortex were exposed to a lipid mixture (LM) comprising cholesterol and various fatty acids to explore their reaction. Our results showed that astrocyte viability remained unchanged following 24 h of 5% or 10% LM treatment. However, exposure to LM for 96 h resulted in reduced cell viability. In addition, LM treatment led to the accumulation of lipid droplets (LDs) in astrocytes, with LD size increasing over prolonged exposure periods. Following 24 h of LM treatment and then 48 h in fresh medium, a significant reduction in intracellular LD size was observed in cultures treated with 5% LM, while no change occurred in cultures exposed to 10% LM. Yet, exposure to 10% LM for 24 h significantly increased the expression of the cholesterol efflux regulatory protein/ATP-binding cassette transporter (ABCA1) gene, responsible for intracellular cholesterol efflux, resulting in reduced cholesterol content within astrocytes. Moreover, LM exposure led to decreased mitochondrial membrane potential (MMP) and increased levels of mature apoptosis-inducing factor (AIF). The smaller LDs were observed to co-localize with microtubule-associated protein 1A/1 B light chain 3 B (LC3) and lysosomal-associated membrane protein-1 (LAMP-1) in LM-treated astrocytes, coinciding with lysosomal acidification. These results indicate that the continuous buildup of LDs in astrocytes residing in lipid-enriched environments may be attributed to disruptions caused by LM in mitochondrial and lysosomal functions. Such disruptions could potentially impede the supportive role of astrocytes in neuronal function.

The Impact of Pediococcus acidilactici BK01 Supplementation on Production Performance and Quality of Japanese Quail Eggs

Probiotic supplementation in feed is currently under extensive research and development, particularly to improve egg production performance and enhance the quality of quail eggs. This study aimed to determine the effects of Pediococcus acidilactici BK01 supplementation on production performance, weight, fat, and cholesterol content of Japanese quail (Coturnix japonica) eggs. This study used four treatments and probiotic supplementation was performed using drinking water at four different concentrations (0, 1, 2, 3%). The supplementation of Pediococcus acidilactici BK01 demonstrated a significant difference (P<0.05) in both egg production and cholesterol content, yet did not yield a significant difference (P>0.05) in egg weight and lipid content. Pediococcus acidilactici BK01 supplementation at concentrations of 2% and 3% resulted in an increase in egg production from 60.85% to 84.52% and led to a reduction in cholesterol content by more than 50% (from 215.43 to 98.57 mg/dL) compared to the control group. Consequently, the administration of the probiotic Pediococcus acidilactici BK01 up to a concentration of 3% influenced on egg production and egg cholesterol content in Japanese quail.

β-sitosterol alleviates high fatty acid-induced lipid accumulation in calf hepatocytes by regulating cholesterol metabolism

A significant reduction in plasma concentration of cholesterol during early lactation is a common occurrence in high-yielding dairy cows. An insufficient synthesis of cholesterol in the liver has been linked to lipid accumulation caused by high concentrations of fatty acids during negative energy balance (NEB). As ruminant diets do not provide quantitative amounts of cholesterol for absorption, phytosterols such as β-sitosterol may serve to mitigate the shortfall in cholesterol within the liver during NEB. To gain mechanistic insights, primary hepatocytes were isolated from healthy female 1-day old calves for in vitro studies with or without 1.2 mM fatty acids (FA) to induce metabolic stress. Furthermore, hepatocytes were treated with 50 μM β-sitosterol with or without FA. Data were analyzed by one-way ANOVA with subsequent Bonferroni correction. Results revealed that calf hepatocytes treated with FA had greater content of non-esterified fatty acids (NEFA) and triacylglycerol (TAG), and greater mRNA and protein abundance of the lipid synthesis-related SREBF1 and FASN. In contrast, mRNA and protein of CPT1A (fatty acid oxidation) and the cholesterol metabolism-related targets SREBF2, HMGCR, ACAT2, APOA1, ABCA1 and ABCG5 was lower. Content of the antioxidant-related glutathione (GSH) and activities of superoxide dismutase (SOD) also was lower. Compared with FA challenge alone, 50 μM β-sitosterol led to greater mRNA and protein abundance of SREBF2, HMGCR, ACAT2 and ABCG5, and greater content of GSH and activity of SOD. In contrast, compared with the FA group, the mRNA and protein abundance of SREBF1 and ACC1 and the content of TAG and NEFA in the β-sitosterol + FA group were lower. Overall, β-sitosterol can promote cholesterol metabolism and reduce oxidative stress while reducing lipid accumulation in hepatocytes challenged with high concentrations of fatty acids.

Abstract 2004: Sex Differences In Bile Acid Metabolism Impact Cholesterol Homeostasis And Cardiovascular Disease

Cardiovascular disease (CVD) remains the leading cause of death in the United States for both men and women, despite cholesterol-lowering drugs such as statins. Diets rich in cholesterol are well-known to contribute to disease progression. The absorption of dietary cholesterol is facilitated by liver-synthesized detergents called bile acids. We hypothesized that manipulating bile acid metabolism to reduce cholesterol absorption would result in decreased plasma cholesterol levels and protect from atherosclerosis. To alter the bile acid pool, we used liver-directed AAV-CRISPR to disrupt Cyp7a1, which catalyzes the rate-limiting step of bile acid synthesis. Consequently, we show that loss of CYP7A1 in adult male mice reduces the size of the bile acid pool. To study atherosclerosis, we co-disrupted Cyp7a1 concurrently with Low Density Lipoprotein Receptor ( Ldlr ) to induce hypercholesterolemia on a Western diet for 20 weeks. Loss of hepatic CYP7A1 in males reduced atherosclerosis and reduced cholesterol absorption. In stark contrast to what we observed in male mice, the absence of this rate limiting enzyme in female mice resulted in only a modest reduction in the bile acid pool. This blunted reduction in bile acids in female Cyp7a1 CRISPR mice was not sufficient to decrease cholesterol absorption, resulting in accumulation of cholesterol, and consequently increasing cardiovascular risk. We hypothesize that there is a female-specific mechanism to preserve bile acid production that operates in the absence of CYP7A1. We are currently in the process of testing candidate female-specific enzymes for bile acid production. These studies indicate new avenues by which female bile acid and cholesterol metabolism regulation differs from than that of males. The resulting differences in cardiovascular risk highlight the essential need for male- and female-specific personalized medicine approaches for cardiovascular disease prevention.

Development of flour-based confectionery products with increased nutritional value based on triticale flour

The relevance of the research is in the potential use of triticale with increased protein and mineral content to expand the ingredient base of flour confectionery products technology. The aim of the study was to investigate the quality indicators of flour confectionery products, specifically sponge cakes, in recipes of which wheat flour was replaced with triticale flour and whole milk powder as a protein enricher. Using statistical methods to analyse experimental data, samples of each type of product with different concentrations of whole milk powder (ranging from 5 to 25%) were examined. It was concluded that the developed sponge cake recipes provide a degree of satisfaction for the average daily intake of iron – 29.21%, calcium – 95%, potassium – 40%, magnesium – 50%, phosphorus – 100%, and more; B-group vitamins – 18-80%. Compared to the control sample, the biological value is increased to 71%; the energy value is reduced by 426 kJ. The absence of egg melange in the developed product recipes allows for a 97% reduction in cholesterol content, categorising these products as dietary. The best samples and optimal dosages of whole milk powder were determined: 15% by the weight of flour during sponge cake production. The functional purpose of triticale flour was theoretically and practically confirmed, yielding new results on the dependence of dough structure formation process on technological production parameters and recipe components. A recipe for sponge cakes of increased nutritional and biological value based on triticale flour has been developed, involving the addition of enrichers such as whole milk powder and the exclusion of egg melange from the recipe. The obtained results can be utilised in the confectionery industry to create new products that meet modern trends in nutrition and cater to consumers who value higher nutritional content and healthy food composition

Beneficial effects of sour pork fermented with a Lactobacillus plantarum strain on lowering blood lipids in mice

As a type of main meat food, pork is widely accepted, and has been used over a long time by residents in China. However, its high cholesterol is the primary unfavourable factor that influences human health. The reduction of cholesterol content in pork through fermentation using probiotics may be a promising candidate approach. In the present work, the probiotic strains were obtained from traditional naturally fermented foods, and identified via monoclonal culture, morphological observation, biochemical detection, and 16S rRNA sequencing. The dominant strain was used to produce sour pork, which was applied to regulate lipid metabolism in mice. Results showed that a total of 31 strains were identified from the traditional naturally fermented foods, of which four strains had similar characteristics to Lactobacillus plantarum, and displayed good capacity for cholesterol degradation with metabolism efficiencies of 75.31% (DC2 strain), 68.01% (PC1 strain), 60.49% (SC1 strain), and 58.02% (DC1 strain). The dominant strain DC2 had 99.93% homology with L. plantarum. Following fermentation with DC2 strain (4 × 106 CFU/g inoculum size, 20-day incubation), the cholesterol in sour pork was significantly reduced with 77.2% efficiency. The serum lipids in mice that were fed with sour pork were significantly lower than those in mice that were fed with normal pork. In summary, a L. plantarum strain with good capacity for cholesterol degradation was obtained (CCTCC NO: M 2019121). The strain can be used to produce fermented sour pork. Dietary sour pork may be beneficial for lowering blood lipid levels.

The Antiobesity Effects and Potential Mechanisms of Theaflavins.

Theaflavins are the characteristic polyphenols in black tea which can be enzymatically synthesized. In this review, the effects and molecular mechanisms of theaflavins on obesity and its comorbidities, including dyslipidemia, insulin resistance, hepatic steatosis, and atherosclerosis, were summarized. Theaflavins ameliorate obesity potentially via reducing food intake, inhibiting pancreatic lipase to reduce lipid absorption, activating the adenosine monophosphate-activated protein kinase (AMPK), and regulating the gut microbiota. As to the comorbidities, theaflavins ameliorate hypercholesterolemia by inhibiting micelle formation to reduce cholesterol absorption. Theaflavins improve insulin sensitivity by increasing the signaling of protein kinase B, eliminating glucose toxicity, and inhibiting inflammation. Theaflavins ameliorate hepatic steatosis via activating AMPK. Theaflavins reduce atherosclerosis by upregulating nuclear factor erythropoietin-2-related factor 2 signaling and inhibiting plasminogen activator inhibitor 1. In randomized controlled trails, black tea extracts containing theaflavins reduced body weight in overweight people and improved glucose tolerance in healthy adults. The amelioration on the hyperlipidemia and the prevention of coronary artery disease by black tea extracts were supported by meta-analysis.

Cinobufacini injection delays hepatocellular carcinoma progression by regulating lipid metabolism via SREBP1 signaling pathway and affecting macrophage polarization

Ethnopharmacological relevanceCinobufacini injection, an aqueous extract of the toad, is a commonly used anti-tumor animal herbal medicine in clinical practice. It has the effects of detoxifying, reducing swelling, and relieving pain. Aims of the studyTo investigate the effects of Cinobufacini injection on hepatocellular carcinoma progression by regulating lipid metabolism and macrophage polarization in the tumor microenvironment and to identify the potential molecular mechanisms. Materials and methodsTo establish the axillary transplantation tumor model of hepatocellular carcinoma Hepa1-6 in C57BL/6 mice, and to evaluate the inhibitory effect of Cinobufacini injection on hepatocellular carcinoma in vivo as well as drug delivery security. Combined metabolomics and transcriptomics analysis of the effect of Cinobufagin Injection on tumor microenvironment. An in vitro mouse co-culture model of peritoneal macrophages and Hepa1-6 cells was established to research the effects of Cinobufacini injection on macrophage polarization, hepatocellular carcinoma cell growth, migration, and changes in lipid metabolism. Cinobufacini injection inhibition of the AMPK/SREBP1/FASN signaling pathway regulating cholesterol metabolism and affecting macrophage polarization was examined using qRT-PCR, lentiviral transfection, immunofluorescence, and Western blot. ResultIn vivo experiments demonstrated that Cinobufacini injection treatment significantly inhibited the growth of Hepa1-6 hepatomas, along with a reduction in cholesterol content and a decrease in the percentage of M2 macrophages in tumor tissue. In vitro, we found that Cinobufacini injection inhibits IL-4-induced M2 macrophage polarization, reduces the cholesterol content of Hepa1-6 cells in a co-culture system, and inhibits the promotion of hepatocellular carcinoma cells by M2 macrophages. In addition, successful overexpression of SREBP1 in Hepa1-6 cells showed more pronounced cellular activity whereas Cinobufacini injection inhibited this change and reduced intracellular lipid levels. ConclusionCinobufacini injection inhibits cholesterol synthesis within the tumor microenvironment via the AMPK/SERBP1/FASN signaling pathway, which in turn blocks the M2 polarization of macrophages, leading to the weakening of hepatocellular carcinoma growth and migration, and the promotion of its apoptosis. Our findings provide an important Introduction to understanding the molecular mechanism of Cinobufacini injection's anticancer activity and provide reliable theoretical and experimental support for its clinical application.

The effect of proprotein convertase subtilisin/kexin type 9 inhibition on the plasma proteome: a SPIRE sub-study

Abstract Background The plasma proteome is an intermediate phenotype for disease and is a tool to inform on pharmacological mechanisms of effect. For selective low-density lipoprotein cholesterol (LDL-C) lowering by proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition, multiple studies have demonstrated that its potent LDL-C lowering effect coincides with marked reductions in both cellular and arterial plaque inflammation, despite unaltered high-sensitivity C-reactive protein (hs-CRP) levels. Purpose In the present study, we set out to investigate potential anti-inflammatory effects of PCSK9 inhibition using plasma proteomics. Methods In 190 patients participating in the SPIRE-1/2 trials, 184 targeted proteins were measured at baseline and after 12 months of bococizumab treatment using the Cardiovascular II and III panels (Sweden). Of the included patients, 96 patients received placebo and 94 received 150mg of bococizumab, once every two weeks. Considering the development of auto-antibodies in some patients, patients with LDL-C reduction below 15% were excluded. The primary outcome was the fold change in protein levels after 12 months compared to baseline. The Benjamini-Hochberg method was used to adjust for multiple comparisons with a false discovery rate (FDR) of 5%. The findings were compared to the LoDoCo2 sub-study which used the same proteomic panels. Results In the placebo group, there was no significant change in any of the proteins. In the bococizumab group (n=77, mean age 62.2±9.7 years and 70 [91%] male), LDL-C levels were reduced from 114±41 mg/dL to 47±34 mg/dL (mean reduction 66±29 mg/dL) on top of statin therapy while there was a neutral effect on hs-CRP (median change 0.0 mg/L IQR [-0.8,1.1]). PCSK9 was the only protein with change upon treatment with bococizumab (24.4±11.0 vs. 15.0±10.7; PFDR=0.033; Figure 1A). In comparison, treatment of colchicine in the LoDoCo2 sub-study was associated with a significant change in 60 proteins (Figure 1B). Conclusion Here, we show that PCSK9 inhibition with bococizumab resulted in a highly selective reduction of PCSK9 plasma levels without robustly affecting other circulating proteins in the measured panels, implying PCSK9 inhibition lowers ASCVD risk via pure lipid lowering pathways. Our study reinforces the neutral systemic inflammatory effect of PCSK9 inhibition on top of statin therapy. The local effects on cellular and vascular inflammation by PCSK9 inhibition observed in earlier studies most likely reflect a direct consequence of a reduced cholesterol content in inflammatory cells and plaques, subsequently leading to a local anti-inflammatory effect. These findings support the combination of targeted anti-inflammatory therapies on top of potent LDL-C lowering in order to further reduce the residual inflammatory risk.

Regulation of cholesterol metabolism: New players for an old physiological process.

Identified more than two centuries ago, cholesterol plays a pivotal role in human physiology. Since cholesterol metabolism is a physiologically significant process, it is not surprising that its alterations are associated with several pathologies. The discovery of new molecular targets or compounds able to modulate this sophisticated metabolism has been capturing the attention of research groups worldwide since many years. Endogenous and exogenous compounds are known to regulate cellular cholesterol synthesis and uptake, or reduce cholesterol absorption at the intestinal level, thereby regulating cholesterol homeostasis. However, there is a great need of new modulators and diverse new pathways have been uncovered. Here, after illustrating cholesterol metabolism and its well-known regulators, some new players of this important physiological process are also described.

Self-assembled condensed tannins supramolecular system can adsorb cholesterol micelles to promote cholesterol excretion

In this study, the cholesterol (CH)-lowering behavioral mechanisms and drivers of condensed tannins (CTs) were revealed using a molecular aggregation theoretical model combined with in vitro experiments, as well as the CH-lowering effects of CTs validated based on animal experiments. Theoretical model results indicated that CTs can spontaneously aggregate to form supramolecular systems, can break CH micelles and form larger aggregates, a behavior driven by van der Waals forces and hydrogen bonds; DLS and TEM results confirmed that the presence of CH leads to a larger particle size of CTs and the formation of large aggregates; thermodynamic analysis and ITC revealed that the adsorption of CH by CTs is a spontaneous reaction driven by hydrogen bonds and hydrophobic forces; Animal experiments and fecal biochemical parameters further confirmed that the intake of CTs can reduce CH absorption and promotes CH excretion. Overall, this study reveals the CH-lowering behavioral mechanism of CTs from the perspective of molecular aggregation behavior.

Dietary Morus alba L. leaf supplementation improves hepatic lipid accumulation of laying hens via downregulating CircACACA

Fatty liver hemorrhagic syndrome (FLHS) is the most common metabolic disease in laying hens. Morus alba L. (mulberry) leaf has the effect of regulating lipid metabolism. We evaluated the effects of dietary 3% mulberry leaf (MUL) supplementation in production performance, egg quality, and liver lipid deposition in laying hens. Differentially expressed genes and circRNAs in the liver were identified using whole-transcriptome sequencing. We also evaluated the effects of the MUL extract using an in vitro model of primary hepatocytes induced by free fatty acids and explored the role of key circRNAs in this process. Dietary supplementation with 3% MUL alleviated liver steatosis in laying hens, as shown by decreased fatty liver color score, relative liver weight (P < 0.01), and triglyceride levels (P < 0.05), and showed a tendency to reduce the mortality rate of laying hens (P=0.09). In addition, mulberry leaf supplementation significantly reduced cholesterol content in egg yolk (P < 0.01). Dietary mulberry leaf supplementation downregulated the expression of genes involved in fatty acid and cholesterol biosynthesis, and upregulated the expression of fatty acid oxidation-related genes in the liver. CircACACA, which is derived from exons 2 and 3 of the acetyl-CoA carboxylase alpha (ACACA) pre-mRNA, was significantly reduced in the MUL group (P < 0.01). Upregulation of circACACA expression reversed the lipid-lowering effect of mulberry leaf extract by upregulating sterol regulatory element-binding proteins 1 c (SREBP-1c) and fatty acid synthase (FASN) (P < 0.05). Overall, mulberry leaf is an effective therapeutic strategy for FLHS in hens and can improve liver lipid metabolism by downregulating circACACA.

The Effects of Statins on Cognitive Performance Are Mediated by Low-Density Lipoprotein, C-Reactive Protein, and Blood Glucose Concentrations.

Statins are widely used for cardiovascular disease prevention but their effects on cognition remain unclear. Statins reduce cholesterol concentration and have been suggested to provide both beneficial and detrimental effects. Our aim was to investigate the cross-sectional and longitudinal association between statin use and cognitive performance, and whether blood low-density lipoprotein, high-density lipoprotein, triglycerides, glucose, C-reactive protein, and vitamin D biomarkers mediated this association. We used participants from the UK biobank aged 40-69 without neurological and psychiatric disorders (n = 147 502 and n = 24 355, respectively). We performed linear regression to evaluate the association between statin use and cognitive performance and, mediation analysis to quantify the total, direct, indirect effects and the proportion meditated by blood biomarkers. Statin use was associated with lower cognitive performance at baseline (β = -0.40 [-0.53, -0.28], p = <.0001), and this association was mediated by low-density lipoprotein (proportion mediated = 51.4%, p = .002), C-reactive protein (proportion mediated = -11%, p = .006) and blood glucose (proportion mediated = 2.6%, p = .018) concentrations. However, statin use was not associated with cognitive performance, measured 8 years later (β = -0.003 [-0.11, 0.10], p = .96). Our findings suggest that statins are associated with lower short-term cognitive performance by lowering low-density lipoprotein and raising blood glucose concentrations, and better performance by lowering C-reactive protein concentrations. In contrast, statins have no effect on long-term cognition and remain beneficial in reducing cardiovascular risk factors.

Growth and blood lipid profile of native chickens given noni juice (Morinda citifolia) via drinking water

The concept of phytogenic feed additives refers to natural medicinal products derived from herbal plants to promote the growth and health of poultry. This study aims to examine the inclusion of Noni fruit juice (NFJ) in drinking water on the growth and blood lipid profile of native chickens. A total of 160 native chickens aged 2 weeks with homogeneous body weight were randomly divided into 4 treatment groups and 4 replications, each repetition with 40 chickens. Chickens were given treatment, namely: chickens were given drinking water without NFJ (A), drinking water with 4% NFJ (B), drinking water with 4.5% NFJ (C), and drinking water with 5% NFJ (D). The results showed that NLJ supplementation in drinking water had no significant effect (P&gt;0.05) on chicken growth and feed efficiency. Blood cholesterol and HDL levels showed significant differences (P&lt;0.05) between treatments. The lowest blood cholesterol levels were found in group C chickens and the highest in group A chickens. On the other hand, the highest HDL levels were found in group C chickens and the lowest in group A chickens. It was concluded that supplementation of 4.5% NFJ in drinking water had no impact on growth, but significantly reduced cholesterol content and increased HDL concentrations in native chicken blood.

MODERN APPROACHES IN THE TREATMENT OF DYSLIPIDEMIA AND FUTURE PERSPECTIVES

Dyslipidemia, defined as an elevated level of total low-density lipoprotein-cholesterol (LDL-C) (&lt;90 percentile), or high-density lipoprotein-cholesterol (HDL-C), occupies one of the main places among metabolic disorders. or reduced levels of apoprotein A-1 (&lt;10 percentile). The reduction of cholesterol and especially its atherogenic fraction DSP is focused on the identification of proteins involved in cholesterol endo and exosynthesis. Aim of the study: to show that, despite the widely studied and widely recognized use of statins in the treatment of dyslipidemia, the "gold standard" is pharmacologically recognized. Materials and Methods: Dyslipidemia has become a major problem in the civilized world. The paper details researches on the possibilities of managing low-density lipoproteins. Since the discovery of compactin, the dominant effectiveness of statins in the treatment of dyslipidemia has been proven. Available, innovative and will be able to reduce cholesterol and especially its atherogenic fraction DSP, focused on the identification of proteins involved in endo and exosynthesis of cholesterol. Conclusion: approaches to the treatment of dyslipidemia have changed significantly. The use of probucol has been practically stopped. Nicotinic acid has been significantly reduced. According to the recommendations of ESC/EAK and AHA/ACC, the first-line drugs for lowering LHL-C levels are statins, and drugs that reduce cholesterol absorption from the intestines - Ezetims are also a priority. Sequestrants of bile acids - cholestyramine and others, and in the case of familial hypercholesterolemia - monoclonal antibodies. When choosing a drug for PCSK-9 (Evolokumab and others), we should take into account the potential cost-benefit of treatment, some groups, for example, statins are cheaper than new drugs. However, new drugs in certain patient populations (as opposed to those with familial hypercholesterolemia) may be more effective in lowering LHL-c levels.

Anticancer Activity of Methyl Protodioscin against Prostate Cancer by Modulation of Cholesterol-Associated MAPK Signaling Pathway via FOXO1 Induction.

Methyl protodioscin (MPD), a furostanol saponin found in the rhizomes of Dioscoreaceae, has lipid-lowering and broad anticancer properties. However, the efficacy of MPD in treating prostate cancer remains unexplored. Therefore, the present study aimed to evaluate the anticancer activity and action mechanism of MPD in prostate cancer. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), wound healing, transwell, and flow cytometer assays revealed that MPD suppressed proliferation, migration, cell cycle, and invasion and induced apoptosis of DU145 cells. Mechanistically, MPD decreased cholesterol concentration in the cholesterol oxidase, peroxidase and 4-aminoantipyrine phenol (COD-PAP) assay, disrupting the lipid rafts as detected using immunofluorescence and immunoblot analyses after sucrose density gradient centrifugation. Further, it reduced the associated mitogen-activated protein kinase (MAPK) signaling pathway protein P-extracellular regulated protein kinase (ERK), detected using immunoblot analysis. Forkhead box O (FOXO)1, a tumor suppressor and critical factor controlling cholesterol metabolism, was predicted to be a direct target of MPD and induced by MPD. Notably, in vivo studies demonstrated that MPD significantly reduced tumor size, suppressed cholesterol concentration and the MAPK signaling pathway, and induced FOXO1 expression and apoptosis in tumor tissue in a subcutaneous mouse model. These results suggest that MPD displays anti-prostate cancer activity by inducing FOXO1 protein, reducing cholesterol concentration, and disrupting lipid rafts. Consequently, the reduced MAPK signaling pathway suppresses proliferation, migration, invasion, and cell cycle and induces apoptosis of prostate cancer cells.

Optimization and cholesterol-lowering activity of exopolysaccharide from Lactiplantibacillus paraplantarum NCCP 962

Exopolysaccharides (EPSs) are biological polymers with unique structural features have gained particular interest in the fields of food, chemistry and medicine, and food industry. EPS from the food-grade lactic acid bacteria (LAB) can be used as a natural food additives to commercial ones in the processing and development of functional foods and nutraceuticals. The current study was aimed to explore the EPS-producing LAB from the dahi; to optimize the fermentation conditions through Plackett-Burman (PB) and response surface methodology (RSM); and to study its physicochemical, rheological, functional attributes, and cholesterol-lowering activity. Lactiplantibacillus paraplantarum NCCP 962 was isolated among the 08 strains screened at the initial stage. The PB design screened out four independent factors that had a significant positive effect, i.e., lactose, yeast extract, CaCl2, and tryptone, while the remaining seven had a non-significant effect. The RSM exhibited lactose, yeast extract, and CaCl2, significantly contributing to EPS yield. The maximum EPS yield (0.910g/L) was obtained at 6.57% lactose, 0.047% yeast extract, 0.59% CaCl2, and 1.37% tryptone. The R2 value above 97% explains the higher variability and depicts the model's validity. The resulted EPS was a heteropolysaccharide in nature with mannose, glucose, and galactose monosaccharides. FTIR spectrum reflected the presence of functional groups, i.e., O-H, C-H, C = O, C-O-H, and CH2. SEM revealed a porous and rough morphology of EPS, also found to be thermally stable and negligible weight loss, i.e., 14.0% at 257°C and 35.4% at 292.9°C was observed in the 1st and 2nd phases, respectively. Rheological attributes revealed that strain NCCP 962 had high viscosity by increasing the EPS concentration, low pH, and temperature with respectable water holding, oil capacities, foaming abilities, and stability. NCCP 962 EPS possessed up to 46.4% reduction in cholesterol concentration in the supernatant. Conclusively, these results suggested that strain NCCP 962 can be used in food processing applications and other medical fields. KEY POINTS: • The fermentation conditions affect EPS yield from L. paraplantarum and significantly increased yield to 0.910g/L. • The EPS was heteropolysaccharide in nature and thermally stable with amorphous morphology. • Good cholesterol-lowering potential with the best rheological, emulsifying, and foaming capacities.

Curcumin suppresses cell proliferation and reduces cholesterol absorption in Caco-2 cells by activating the TRPA1 channel

BackgroundCurcumin (Cur) is a bioactive dietary polyphenol of turmeric with various biological activities against several cancers. Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths. Intestinal cholesterol homeostasis is associated with CRC. Chemotherapy for CRC is related to varied adverse effects. Therefore, natural products with anti-cancer properties represent a potential strategy for primary prevention of CRC.MethodsThe present study used Cur as a therapeutic approach against CRC using the Caco-2 cell line. The cells were treated with different concentrations of Cur for different duration of time and then the proliferation ability of cells was assessed using Cell Counting Kit-8 and 5-Ethynyl-2′-deoxyuridine assays. Oil red O staining and cholesterol assay kit were used to evaluate cellular lipid content and cholesterol outward transportation. Finally, the protein expressions of cholesterol transport-related protein and signal transduction molecules were assessed using Western blot assay.ResultsCur inhibited cell proliferation in Caco-2 cells in a dose- and time-dependent manner by activating the transient receptor potential cation channel subfamily A member 1 (TRPA1) channel. Activation of the TRPA1 channel led to increased intracellular calcium, peroxisome proliferator-activated receptor gamma (PPARγ) upregulation, and the subsequent downregulation of the specificity protein-1 (SP-1)/sterol regulatory element-binding protein-2 (SREBP-2)/Niemann-Pick C1-like 1 (NPC1L1) signaling pathway-related proteins, and finally reduced cholesterol absorption in Caco-2 cells.ConclusionsCur inhibits cell proliferation and reduces cholesterol absorption in Caco-2 cells through the Ca2+/PPARγ/SP-1/SREBP-2/NPC1L1 signaling by activating the TRPA1 channel, suggesting that Cur can be used as a dietary supplement for the primary prevention of CRC.Graphical In Caco-2 cells, Cur first stimulates calcium influx by activating the TRPA1 channel, further upregulates PPARγ and downregulates SP-1/SREBP-2/NPC1L1 signaling pathway, and finally inhibits the absorption of cholesterol. TRPA1, transient receptor potential cation channel subfamily A member 1; NPC1L1, Niemann-Pick C1-like 1; PPARγ, peroxisome proliferator-activated receptor gamma; SP-1, specificity protein-1; SREBP-2, sterol regulatory element-binding protein-2; Cur, curcumin.

MECHANISM OF CAMEL MILK ON DIABETES COMPLICATIONS AND CARDIOVASCULAR DISORDERS

Diabetes is a common metabolic disease that causes cardiovascular disease. Insulin and oral hypoglycemic drugs are the treatment for diabetes, but high percentage of patients cannot use allopathic drugs and rely on natural alternative healings. Camel milk with therapeutic properties, is a good source of vitamins C, minerals such as Mn, iron, Cu, Zn; and immunoglobulins compared to cow milk. Insulin of camel milk is a great substitute due to no coagulum formation in the stomach. Raw camel milk increases insulin secretion, reduces insulin resistance and affects signaling and glucose transport. It also decreases the complications due to diabetes like cardiovascular disorders, obesity, oxidative stress and promotes wound healing. There is high amount of unsaturated fatty acids in camel milk for heart health. Also, probiotic bacteria and hypocholesterolemia peptides reduce cholesterol absorption and hence better control of its blood level and cardiovascular issues. Therefore, camel milk is effective in preventing complications due to diabetes and cardiovascular disorders.