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3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is an endoplasmic reticulum (ER)-localized integral membrane protein that catalyzes the rate-limiting step in the synthesis of cholesterol and many nonsterol isoprenoids including geranylgeranyl pyrophosphate (GGpp). HMGCR is subjected to strict feedback control through multiple mechanisms to ensure cells constantly produce essential nonsterol isoprenoids, but do not overaccumulate cholesterol. Here, we focus on the mechanism of feedback control of HMGCR that involves its sterol-induced ubiquitination and ER-associated degradation (ERAD) that is augmented by GGpp. We will also discuss the how GGpp-regulated intracellular trafficking of the vitamin K2 synthetic enzyme UbiA prenyltransferase domain-containing protein-1 (UBIAD1) inhibits HMGCR ERAD to balance the synthesis of sterol and nonsterol isoprenoids. Finally, we will summarize various mouse models, the characterization of which establish that sterol-accelerated, UBIAD1-modulated ERAD plays a major role in regulation of HMGCR and cholesterol metabolism in vivo.

Diabetes mellitus (DM), an endocrine syndrome characterized by high blood glucose levels due to abrogated insulin activity. The existing treatments for DM have side effects and varying degrees of efficacy. Therefore, it is paramount that novel approaches be developed to enhance the management of DM. Therapeutic plants have been accredited as having comparatively high efficacy with fewer adverse effects. The current study aims to elucidate the phytochemical profile, anti-hyperlipidemic, and anti-diabetic effects of methanolic extract D. salicifolia (leaves) in Alloxan-induced diabetic mice. Alloxan was injected intraperitoneally (150 mg kg-1, b.w), to induced diabetes in mice. The mice were divided into three groups (n=10). Group 1 (normal control) received normal food and purified water, Group II (diabetic control) received regular feed and clean water and group III (diabetic treated) received a methanolic extract of the plant (300 mg kg-1) for 28 days with a typical diet and clean water throughout the experiment. Blood samples were collected to checked serum glucose and concentration of LDL, TC, TG. The extract demonstrated significant antihyperglycemic activity (P

BACKGROUND Environmental and genetic factors are suggested to exhibit factor-based association with HDL-cholesterol (HDL-C) levels. However, the population-based effects of environmental and genetic factors have not been compared clearly. We conducted a cross-sectional study using data from the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study to evaluate the population-based impact of smoking, drinking, and genetic factors on low HDL-C. METHODS Data from 11,498 men and women aged 35-69 years were collected for a genome-wide association study (GWAS). Sixty-five HDL-C-related SNPs with genome-wide significance (P < 5 × 10-8) were selected from the GWAS catalog, and seven representative SNPs were defined, and the population-based impact was estimated using population attributable fraction (PAF). RESULTS We found that smoking, drinking, daily activity, habitual exercise, egg intake, BMI, age, sex and the SNPs CETP rs3764261, APOA5 rs662799, LIPC rs1800588, LPL rs328, ABCA1 rs2575876, LIPG rs3786247, and APOE rs429358 were associated with HDL-C levels. The gene-environmental interactions on smoking and drinking were not statistically significant. The PAF for low HDL-C was the highest in men (63.2%) and in rs3764261 (31.5%) of the genetic factors, and the PAFs of smoking and drinking were 23.1% and 41.8%, respectively. CONCLUSIONS The present study showed that the population-based impact of genomic factor CETP rs3764261 for low HDL-C was higher than that of smoking and lower than that of drinking.

Lysosomal acid lipase (LAL) deficiency is a rare, autosomal recessive disease caused by mutations in the LIPA gene, which produces cholesteryl ester and triglyceride accumulation predominantly in hepatocytes, adrenal glands, and gastrointestinal tract. We describe two new cases occurring in siblings, aged 5 and 7 years, who presented with hepatomegaly, dyslipidemia, and abnormal liver function. Percutaneous liver biopsy revealed portal inflammation, hypertrophic Kupffer cells with a foamy appearance and microvesicular steatosis with fibrosis. Immunostaining for lysosomal markers, cathepsin D and LAMP1 reflected the lysosomal nature of the lipid vacuoles. After enzymatic confirmation, enzyme replacement therapy was initiated for both siblings. Follow-up transaminase levels and lipid profiles showed a notable decrease in AST and ALT and a slight increase in HDL cholesterol. It is crucial to increase awareness of this rare condition among clinicians and pathologists. The expression of lysosomal markers around the lipid vacuoles might help diagnose LAL deficiency in pediatric patients.

Studies on normal concentration of blood constituents of free-living birds are not very common. An adequate knowledge of blood chemistry is greatly recommended for those projects involving research and management of populations as far as they can be valuable for the assessment of the nutritional levels and health status of species. No previous published reports on these parameters from this species are available. The aim of this study was to obtain representative reference measures for hematologic and biochemical values in free-living clinically healthy wild White-tailed Sea Eagle nestlings (Haliaeetus albicilla). In addition, we investigated potential relationships between blood parameters, sex, age and hatching dates. Blood samples were obtained as part of routine monitoring and management when wild chicks were removed from their nest as part of a reintroduction program prerelease health check. A total of 83 nestlings, 43 males and 40 females, between 41 and 66 days of age (mean = 54.22, SD = 5.7), were sampled. Significant differences between sexes were found. Among hematological parameters, MCH, lymphocytes P and thrombocytes showed significant differences between males and females. In biochemical parameters, significant differences were found only in calcium, CK and LDH between sexes. No effect was found of age of the nestling when the sample was taken in any of the analyzed hematological parameters. No other significant relationships were found between biochemical parameters and other considered explanatory variables. Hatching date showed no relationship with blood parameters excepting urea. Urea was the only variable showing a strong relationship with hatching date, with those nestlings hatching later in the season showing higher urea concentration.

Aims/Hypothesis: Optimal diabetes care and risk factor management are important to delay micro- and macrovascular complications in individuals with type 1 diabetes (T1D). Ongoing improvement of management strategies requires the evaluation of target achievement and identification of risk factors in individuals who do (or do not) achieve these targets. Methods: Cross-sectional data were collected from adults with T1D visiting six diabetes centers in the Netherlands in 2018. Targets were defined as glycated hemoglobin (HbA1c)

Aims/Hypothesis: Optimal diabetes care and risk factor management are important to delay micro- and macrovascular complications in individuals with type 1 diabetes (T1D). Ongoing improvement of management strategies requires the evaluation of target achievement and identification of risk factors in individuals who do (or do not) achieve these targets. Methods: Cross-sectional data were collected from adults with T1D visiting six diabetes centers in the Netherlands in 2018. Targets were defined as glycated hemoglobin (HbA1c)

The aim of this study was to compare the effect of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) with equal energy expenditure on glycaemic and cardiometabolic risk factors in people with Type 2 Diabetes Mellitus (T2DM) when compared to the control. Sixty-three people with T2DM were randomly assigned to HIIT, MICT, or non-exercising controls. Individuals were trained with HIIT at 90 and 30% of their VO(2)peak (1:2 min ratio) starting from 8 up to 16 intervals and MICT at 50% of VO(2)peak, on a cycle ergometer, 3 times/week for 12 weeks under supervision. The primary outcome measure was the change in HbA1c. Aerobic capacity, cardiovascular responses, anthropometric measures, body composition, glycaemic, and cardiometabolic risk factors were measured at the beginning and the end of the 12-week training period. There was no significant difference between HIIT and MICT or when compared to the control for HbA1c, glucose, insulin resistance, blood lipids, cardiovascular responses, anthropometric measures, body composition, and abdominal and visceral fat (p(adj )> 0.05). HIIT and MICT increased VO(2)peak significantly compared to controls (p < 0.05) but not to each other (p > 0.05). Both HIIT and MICT improved VO(2)peak and HbA1c after 12 weeks of training compared to their baseline, furthermore, only MICT caused additional improvements in cardiovascular responses, anthropometric measures, and abdominal fat compared to baseline (p < 0.05). As a conclusion, isoenergetic HIIT or MICT did not improve HbA1c. The two protocols were equally efficient for improvement in aerobic capacity but had little effect on other cardiometabolic factors.

Objective: The aim of this study was an assessment of post hoc associations among circadian rhythm parameters, physical activity (PA), and cardiometabolic risk factors in adults with obesity and prediabetes after 3 years of weight loss maintenance.Methods: Circadian rhythm parameters (continuous wrist-temperature measurements), PA, systolic and diastolic blood pressure (SBP, DBP), heart rate (HR), plasma high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, remnant cholesterol, triacylglycerol, and C-reactive protein (CRP) concentrations were determined in 91 free-living participants (mean [SD], age = 56.6 [10] years; BMI = 28.2 [4.0]; homeostatic model assessment of insulin resistance [HOMA-IR] = 3.2 [3.1]) and in 38 participants in sedentary respiration chamber conditions (age = 56.6 [10] years; BMI = 28.5 [4.0]; HOMA-IR = 3.3 [1.4]). Associations of circadian rhythm parameters and PA with cardiometabolic risk factors were determined using factor analyses followed by Pearson correlations.Results: Values of cardiometabolic risk factors were similar, whereas circadian rhythm parameters and PA differed significantly (p Conclusions: In adults with obesity and prediabetes, parameters indicating a robust circadian rhythm were, independently of PA, associated with lower cardiometabolic risk and CRP. Only in free-living conditions, PA mediated the association of higher circadian stability with lower SBP.

Quatsome nanovesicles, formed through the self-assembly of cholesterol (CHOL) and cetyltrimethylammonium bromide (CTAB) in water, have shown long-term stability in terms of size and morphology, while at the same time exhibiting high CHOL-CTAB intermolecular binding energies. We hypothesize that CHOL/CTAB quatsomes are indeed thermodynamically stable nanovesicles, and investigate the mechanism underlying their formation., This work was supported by funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 712949 (TECNIOspring PLUS) and from the Agency for Business Competitiveness of the Government of Catalonia. The production of quatsomes and part of their characterization has been performed by the ICTS “NANBIOSIS”, more specifically by the Biomaterial Processing and Nanostructuring Unit (U6), Unit of the CIBER in Bioengineering, Biomaterials & Nanomedicine (CIBER-BBN) located at the Institute of Materials Science of Barcelona (ICMAB-CSIC). ICMAB-CSIC acknowledges support from the MINECO through the Severo Ochoa Programme for Centres of Excellence in R&D (SEV-2015-0496 and CEX2019-000917-S). Authors acknowledge financial support from the Spanish Ministry of Science and Innovation through grants “MOL4BIO” (PID2019-105622RB-I00), “SimBioSoft” (PID2021-124297NB-C33) and the FUNFUTURE-FIP-2020 Severo Ochoa project, from Generalitat de Catalunya through grant 2017-SGR-918, from CSIC through grant 2019AEP133, and from the European Commission through the H2020 PHOENIX project (contract no. 953110). We acknowledge the support of the Israel scienceIsrael science Foundation, grant 1117/2016, and thank Dr. Inbal Ionita for her professional assistance in the cryo-TEM analysis. We thank Jannik Nedergaard Pedersen and Beatrice Plazzotta for help with the SAXS measurements. The simulations reported here were performed using the Cori Supercomputing facility of the National Energy Research Scientific Computing Center (NERSC), a U.S. Department of Energy Office of Science User Facility operated under Contract No. DE-AC02-05CH11231., With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000917-S).

The ATP binding cassette (ABC) transporter molecule ABCA1 participates in the cholesterol transport within and through cell membranes. We recently demonstrated that in dog spermatozoa, capacitation could be decreased with probucol (PRO), an ABCA1 specific antagonist. In this study, a dose-effect relationship of PRO on dog sperm capacitation, tyrosine phosphorylation and cholesterol efflux from the sperm plasma membrane was investigated. A total of 16 ejaculates from dogs of different breeds, aged 2-4 years were used. Sperm motility and membrane integrity in the main fraction was determined by CASA. Samples were stained with a boron dipyrromethene difluoride (BODIPY) fluorophore (P9672, Sigma- Aldrich, A) diluted in DMSO at a final concentration of 0.4 μM. All samples were divided into 5 aliquots, with 0, 100, 250, 500 and 1000 μM of PRO. After incubation at 37 °C for 2 h, PI was added and flow cytometry performed. All aliquots were examined for capacitation and acrosome reaction by using the CTC assay and tyrosine phosphorylation (TP). Membrane integrity was measured in all aliquots to investigate the effect of PRO on cell membranes. Membrane integrity did not differ between controls (0 μM), and 100, 250 and 500 μM PRO, but decreased with 1000 μM PRO (p 0.05). Increasing PRO concentration decreased the percentage alive cells with cholesterol efflux per PRO group (0 μM: 77.8 ± 10.6%, 100 μM: 63.7 ± 11.7%, 250 μM: 52.1 ± 12.9%, 500 μM: 37.7 ± 11.6%, 1000 μM: 33.1 ± 14.4%; p 0.05), decreased head and entire tail phosphorylated cells (0 μM: 34.6%, 1000 μM: 5.1% p 0.05); and decreased the percentage capacitated cells (maximum with PRO 500 μM: capacitated vs. control: 54.2 ± 17% vs 25 ± 7.7%, p 0.05). Conclusion: PRO decreased the cholesterol efflux, and decreased tyrosine phosphorylation and capacitation in a dose-dependent manner. This suggests a strong involvement of the ABCA1 transporter in different functional aspects of sperm capacitation in dogs.

Fragile X syndrome (FXS), the most prevalent heritable form of intellectual disability, is caused by the transcriptional silencing of the FMR1 gene. While neuronal contribution to FXS has been extensively studied in both animal and human-based models of FXS, the roles of astrocytes, a type of glial cells in the brain, are largely unknown. Here, we generated a human-based FXS model via differentiation of astrocytes from human-induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs) and characterized their development, function, and proteomic profiles. We identified shortened cell cycle, enhanced Ca(2+) signaling, impaired sterol biosynthesis and pervasive alterations in the proteome of FXS astrocytes. Our work identified astrocytic impairments that could contribute to the pathogenesis of FXS and highlight astrocytes as a novel therapeutic target for FXS treatment.

This study aimed to determine whether sleep disturbance, defined as the wakeup frequency at night, is associated with atherogenic dyslipidemia and to explore possible sex differences.A total of 1,368 adults aged 19-70 years were included in the study of lifestyles and atherogenic dyslipidemia at the National Taiwan University Hospital in the period of 2008-2012. They completed a questionnaire regarding lifestyle information and sleep quality, including sleep hour duration, use of sleeping pills, and wakeup frequency during nighttime sleep. The measured lipid profiles included total cholesterol, triglycerides, low- and high-density lipoprotein cholesterol (LDL-C and HDL-C, respectively), non-HDL-C, and small dense LDL-C (sdLDL-C). Multivariate logistic regression was performed to determine habitual interrupted sleep and the odds ratio of atherogenic dyslipidemia following adjustment for conventional risk factors and for sex-based subgroup analysis.A wakeup frequency ≥ 3 times per night was independently associated with an increased risk [odds ratio (95% confidence interval)] of dyslipidemia was 1.96 (1.17-3.28), and non-HDL-C ≥ 160 mg/dL was 1.78 (1.09-2.89). A higher wakeup frequency was associated with increased atherogenic dyslipidemia in women than in men. The multivariate adjusted relative risks for non-HDL ≥ 160 mg/dL and cholesterol ≥ 200 mg/dL were 3.05 (1.27-7.34) and 4.01(1.29-12.45) for female individuals with insomnia and those with a wakeup frequency ≥ 2 times per night, respectively.A higher wakeup frequency was associated with atherogenic dyslipidemia in Taiwanese adults, particularly in women. This study also provided another evidence of increasing cardiovascular diseases in subjects with habitual interrupted sleep.

N-terminal residues (770-788) of the S2 glycoprotein of severe acute respiratory syndrome coronavirus (SARS-CoV) have been recognized as a potential fusion peptide that can be involved in the entry of the virus into the host cell. Membrane composition plays an important role in lipid-peptide interaction and the oligomeric status of the peptide. SARS-CoV fusion peptide (S2 fusion peptide) is known to undergo cholesterol-dependent oligomerization in the membrane; however, its significance in membrane fusion is still speculative. This study aimed to investigate the oligomerization of SARS-CoV fusion peptide in a membrane containing phosphatidylcholine, phosphatidylethanolamine, and phosphatidylglycerol, with varying concentrations of cholesterol, and to evaluate peptide-induced membrane fusion to correlate the importance of peptide oligomerization with membrane fusion. Peptide-induced modulation of membrane organization and dynamics was explored by steady-state and time-resolved fluorescence spectroscopic measurements using depth-dependent probes. The results clearly demonstrated the induction of S2 fusion peptide oligomerization by membrane cholesterol and the higher efficiency of the oligomer in promoting membrane fusion compared to its monomeric counterpart. Cholesterol-dependent peptide oligomerization and membrane fusion are important aspects of viral infection since the cholesterol level can change with age as well as with the onset of various pathophysiological conditions. Ministry of Education (MOE) Submitted/Accepted version This work was supported by the Core Research Grant (CRG/ 2021/001515) of Science and Engineering Research Board (SERB), and SERB-Science and Technology Award for Research (STR/2021/000029), Department of Science and Technology (DST), New Delhi to HC, and Ministry of Education (MOE), Singapore to SB.

Oxidative stress is vital for pathophysiology of atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Monoamine oxidase (MAO) is an important source of oxidative stress in the vascular system and liver. However, the effect of MAO inhibition on atherosclerosis and NAFLD has not been explored. In the present study, MAO A and B expressions were increased in atherosclerotic plaques in human and apolipoprotein E (ApoE)-deficient mice. Inhibition of MAO B (by deprenyl), but not MAO A (by clorgyline), reduced the atheroma area in the thoracic aorta and aortic sinus in ApoE-deficient mice fed the cholesterol-enriched diet for 15 weeks. MAO B inhibition attenuated oxidative stress, expression of adhesion molecules, production of inflammatory cytokines, and macrophage infiltration in atherosclerotic plaques and decreased plasma triglyceride and low-density lipoprotein (LDL) cholesterol concentrations. MAO B inhibition had no therapeutic effect on restenosis in the femoral artery wire-induced injury model in C57BL/6 mice. In the NAFLD mouse model, MAO B inhibition reduced lipid droplet deposition in the liver and hepatic total cholesterol and triglyceride levels in C57BL/6 mice fed high-fat diets for 10 weeks. Key enzymes for triglyceride and cholesterol biosynthesis (fatty acid synthase and 3-hydroxy-3-methylglutaryl-CoA reductase, HMGCR) and inflammatory markers were inhibited, and cholesterol clearance was up-regulated (increased LDL receptor expression and reduced proprotein convertase subtilisin/kexin type 9, PCSK9, expression) by MAO B inhibition in the liver. These results were also demonstrated in the HepG2 liver cell model. Our data suggest that MAO B inhibition is a potential and novel treatment for atherosclerosis and NAFLD.

Synaptic dysfunction is a hallmark of aging and is found in several neurological disorders such as Alzheimer's disease. A common mechanism related to synaptic dysfunction is dysregulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which mediate excitatory neurotransmission and synaptic plasticity. Accumulating evidence suggests that tocotrienols, vitamin E molecules that contain an isoprenoid side chain, may promote cognitive improvement in hippocampal-dependent learning tasks. Tocotrienols have also been shown to reduce the secretion of β-amyloid (Aβ) and cholesterol biosynthesis in part by downregulating 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme that controls flux of the mevalonate pathway and cholesterol biosynthesis. We hypothesized that tocotrienols might promote cognitive improvement by increasing AMPA receptor-mediated synaptic transmission. Here, we found that δ-tocotrienol increased surface levels of GluA1 but not the GluA2 AMPA receptor subunit in primary hippocampal neurons. Unexpectedly, δ-tocotrienol treatment caused a decrease in the phosphorylation of GluA1 at Serine 845 with no significant changes in GluA1 at Serine 831. Moreover, δ-tocotrienol increased spontaneous excitatory postsynaptic current (sEPSC) amplitude and reduced the secretion of Aβ

Remnant cholesterol (RC) and non-high-density lipoprotein cholesterol (non-HDL-C) may contribute to the residual risk for atherosclerotic cardiovascular disease. High cardiorespiratory fitness (CRF) is associated with favorable traditional lipid profiles, but its relation with RC and non-HDL-C remains unclear. We analyzed cross-sectional data on 4,613 healthy men (mean age 49 years). CRF was measured using peak oxygen uptake during incremental exercise testing and categorized into quartiles. RC was estimated as total cholesterol minus HDL-C and low-density lipoprotein cholesterol, and elevated RC was defined as ≥38 mg/100 ml (90 percentile). Non-HDL-C was calculated as total cholesterol minus HDL-C, and high non-HLD-C was defined as ≥190 mg/100 ml. CRF was inversely associated with RC (β -0.31, 95% confidence interval [CI] -0.39 to -0.24) and non-HDL-C (β -0.34, 95% CI -0.57 to -0.11) after adjustment for several risk factors. Each metabolic equivalent increment in CRF was associated with lower odds of having elevated RC (odds ratio [OR] 0.85, 95% CI 0.77 to 0.93) and non-HDL-C (OR 0.93, 95% CI 0.85 to 1.00) in multivariable analysis. Compared with the bottom quartile, the top quartile of CRF had significantly lower odds of elevated RC (OR 0.63, 95% CI 0.45 to 0.88) and non-HDL-C (OR 0.68, 95% CI 0.51 to 0.91). In conclusion, higher CRF was independently associated with lower levels of RC and non-HDL-C and lower odds of the prevalence of elevated RC and non-HDL-C in healthy men.

Preclinical and human studies on the relationship between obesity/metabolic syndrome (MetS) and lower urinary tract dysfunction (LUTD) are inconsistent. We compared the temporal effects of feeding four different diets used to induce obesity/MetS, including 60% fructose, 2% cholesterol +10% lard, 30% fructose + 20% lard, or 32.5% lard diet, up to 42 wk, on metabolic parameters and bladder function in male Sprague-Dawley rats. Rats fed a 30% fructose + 20% lard or 32.5% lard diet consumed less food (grams), but only the 32.5% lard diet group took in more calories. Feeding rats a 60% fructose or 30% fructose + 20% lard diet led to glucose intolerance and increased blood pressure. Higher body weight and increased cholesterol levels were observed in the rats maintained on a 2% cholesterol +10% lard diet, whereas exposure to a 32.5% lard diet affected most of the above parameters. Voiding behavior measurement showed that voiding frequency and the total voided volume were lower in the experimental diet groups except for the 30% fructose + 20% lard group. The mean voided volume was lower in the 30% fructose + 20% lard and 32.5% lard groups compared with the control group. Cystometric analysis revealed a decreased bladder capacity, mean voided volume, intermicturition interval, and compliance in the 32.5% lard diet group. In conclusion, experimental diets including 60% fructose, 30% fructose + 20% lard, or 2% cholesterol + 10% lard diet differently affected physiological and metabolic parameters and bladder function to a limited extent, while exposure to a 32.5% lard diet had a greater impact.

International audience; The increasing frequency and intensity of summer heatwaves are pushing freshwater zooplankton towards their upper thermal tolerance limits. At the same time, higher temperatures and prolonged water column stratification can favour the dominance of cyanobacteria in phytoplankton. Even when not toxic or grazing resistant, these prokaryotes lack phytosterols as essential precursors for cholesterol, the main sterol in animal tissues. Cholesterol plays a crucial role in the physiological adaptation of ectotherms to high temperature. Therefore, the shift to cyanobacteria-dominated systems may increase the vulnerability of zooplankton to heatwaves by intensifying cholesterol limitation.Here, we used death time curves that take into consideration the intensity and duration of a thermal challenge and a dynamic model to study the effects of cholesterol limitation on the heat tolerance of the keystone species Daphnia magna and to simulate the cumulative mortality that could occur in a fluctuating environment over several days of heatwave.We show that increasing cholesterol limitation does not affect the slope between time-to-immobilisation and temperature, but does decrease the maximal temperature that Daphnia can withstand by up to 0.74°C. This seemingly small difference is sufficient to halve the time individuals can survive heat stress.Our simulations predicted that, when facing heatwaves over several days, the differences in survival caused by cholesterol limitation build up rapidly. Considering the anticipated intensity and duration of future (2070–2099) heatwaves, cholesterol limitation could increase mortality by up to 45% and 72% under low and medium greenhouse gas emission scenarios, respectively.These results suggest that the increasing risk of cholesterol limitation due to more frequent cyanobacterial blooms could compromise the resistance of zooplankton populations to future heatwaves. More generally, this study shows the importance of considering the nutritional context in any attempt to predict ectotherm mortality with increasing temperatures in the field.

Objectives: Various vascular grafts are used in coronary artery bypass graft (CABG) surgeries, however, the most commonly used one is the saphenous vein graft (SVG). Various studies conducted on this topic have found a relationship between uric acid to HDL-C (UHR) and cardiovascular diseases. In this current study, we aimed to investigate the predictive importance of UHR value in predicting long-term SVG disease in patients who underwent CABG surgery. Methods: Patients who had a history of CABG surgery at least one year prior, had stable angina pectoris, and underwent coronary angiography between January 01, 2016 and January 01, 2020, were included in the study retrospectively. Patients with open saphenous veins were defined as Group 1, and patients who had 50% or more stenosis in at least one SVG after coronary angiography, were defined as Group 2. Results: The median age of the 204 patients included in Group 1 and 292 patients in Group 2 were 65 (38-77) years and 66 (45-79) years, respectively (p = 0.251). The two groups were similar in terms of gender, hypertension, chronic obstructive pulmonary disease rates, history of cerebrovascular events, ejection fraction, body mass index, and current medical treatments. In univariate analysis, SVG disease was found to significantly correlate with diabeter mellitus (odds ratio [OR]: 1.644, 95% confidence interval [CI]: 1.190-1.985, p = 0.008), current smoking (OR: 0.875, 95% CI: 0.669-0.940, p = 0.030), number of patients with target artery diameter < 1.5 mm (OR: 1.945, 95% CI: 1.221-2.398, p < 0.001), age of SVG (OR: 2.960, 95% CI: 1.980-4.168, p < 0.001), uric acid (OR: 1.241, 95% CI: 1.078-1.592, p = 0.004), triglyceride (OR: 0.780, 95% CI: 0.569-0.935, p = 0.044) and UHR (OR: 1.894, 95% CI: 1.384-2.896, p < 0.001). Conclusions: In this study, we showed that we can predict saphenous vein graft occlusion with serum UHR value.

Porcine epidemic diarrhea virus (PEDV) is deadly for suckling piglets and is a significant threat to most pig farms. Alpiniae oxyphyllae fructus polysaccharide 3 (AOFP3) shows antiviral activity against PEDV. However, the anti-PEDV mechanism of AOFP3 is unknown. Entering the host cell is important for viral infection, and many drugs play antiviral roles by inhibiting this process. To understand the antiviral mechanism of AOFP3 against PEDV, the effect of AOFP3 on PEDV entering IPEC-J2 cells was investigated in the present study. Real-time PCR and immunofluorescence were used to study the effect of AOFP3 on PEDV binding and penetrating IPEC-J2 cells. The effect of PEDV on AOFP3 attachment to IPEC-J2 cells was also investigated. Afterward, the effect of AOFP3 on PEDV spike (S) protein binding to porcine aminopeptidase was tested by using coimmunoprecipitation, and the effect of AOFP3 on the cholesterol level of IPEC-J2 cells was detected. The results showed that AOFP3 competitively inhibited PEDV adsorption on IPEC-J2 cells by blocking PEDV S protein binding to porcine aminopeptidase in IPEC-J2 cells. Furthermore, AOFP3 decreased PEDV penetration into host cells by decreasing the cholesterol level in IPEC-J2 cells.

The term extracellular vesicles (EVs) has been recommended to describe various membrane-bound vesicles secreted by most living cells and found in various biological fluids. They gained growing interest as mediators of cell-cell communication and for their roles in different patho-physiological processes. In addition, they were recently considered as disease biomarkers and new drug delivery systems. However, it is still difficult to link a biological function to a specific EV population among the heterogenous EV mixture secreted in the extracellular space due to limitations of optimal isolation methods. EV classification according to their size as small (\textless200 nm) and large (\textgreater200 nm) vesicles is also completed by the identification of selected proteins, nucleic acids and lipids. In this review, we summarized briefly knowledge about the composition and role of EV lipids that received less attention compared to their protein and nucleic acid content. Lipids are not only essential structural components of EVs, but can give important information on their biogenesis. Especially, we discussed our recent data showing the utility of bis(monoacylglycero)phosphate (BMP), a specific endolysosomal lipid marker, that could sign the endosomal origin of small EVs, classically named as exosomes.

Coronary artery disease (CAD) due to atherosclerosis is one of the important reasons for death worldwide. Recent evidence has suggested the essential role of inflammation in the progression of atherosclerosis. Interleukin (IL)-37 is a critical anti-inflammatory member of the IL-1 family which regulates the inflammatory processes. The aim of this study was to compare the serum levels of IL-37 in patients with CAD compared with the control group and its correlation with oxidative stress, cholesterol homeostasis, and inflammation in patients with CAD. A total of 42 patients with CAD and 42 sex-matched and age- matched controls who underwent coronary angiography were included in this study. The serum levels of IL-37 were evaluated via ELISA. Serum levels of biochemical risk factors were determined by enzymatic methods. Serum levels of IL-37 in the CAD group subjects were significantly lower than in the control group and IL-37 was significantly increased in men with CAD than in women with CAD. IL-37 significantly had an inverse correlation with IL-6, tumor necrosis factor-α, IL-32, high-sensitivity C reactive protein, oxidized low-density lipoprotein, and malondialdehyde. Also, IL-37 had a significantly positive correlation with ferric-reducing antioxidant power (FRAP) assay. In addition, IL-37 has positively correlated with ATP-binding cassette transporter A1 and G1 gene expression in peripheral blood mononuclear cells and serum levels of the FRAP. A receiver operating characteristic test displayed that IL-37 level ratios were a relatively significant CAD predictor. Our results indicated that decreased serum levels of IL-37 in patients with CAD and its relationship with inflammatory cytokines and reverse cholesterol transport genes are more likely to be associated in the inflammatory process with disease pathology.

Human, rat, and mouse C-reactive protein (CRP) possess distinct expression patterns, but have similar conformations and conserved in vivo functions. We have previously demonstrated that this level-function mismatch is delicately tuned by the hidden activities of unfolded CRP. The cholesterol-binding sequence (CBS; a.a. 35-47) is a major functional motif exposed on monomeric CRP, which is the unfolded and activated conformation of CRP. We replaced the CBS of rat CRP with that of either mouse or human CRP, yielding two grafting mutants with unaffected pentameric assembly. However, these mutants exhibited altered cellular foldability and conformational activation efficiency that matched those of the CRP that provided the grafted CBS. These results indicate that CBS is a critical regulatory motif, whose variation maintains the pentameric assembly of CRP but derives distinct cellular foldabilities and conformational activation efficiencies, therefore helping to ensure that CRPs with various expression patterns exhibit overall conserved functions.

The number of patients with heart failure and related deaths is rapidly increasing worldwide, making it a major problem. Cardiac hypertrophy is a crucial preliminary step in heart failure, but its treatment has not yet been fully successful. In this study, we established a system to evaluate cardiomyocyte hypertrophy using a deep learning-based high-throughput screening system and identified drugs that inhibit it. First, primary cultured cardiomyocytes from neonatal rats were stimulated by both angiotensin II and endothelin-1, and cellular images were captured using a phase-contrast microscope. Subsequently, we used a deep learning model for instance segmentation and established a system to automatically and unbiasedly evaluate the cardiomyocyte size and perimeter. Using this system, we screened 100 FDA-approved drugs library and identified 12 drugs that inhibited cardiomyocyte hypertrophy. We focused on ezetimibe, a cholesterol absorption inhibitor, that inhibited cardiomyocyte hypertrophy in a dose-dependent manner in vitro. Additionally, ezetimibe improved the cardiac dysfunction induced by pressure overload in mice. These results suggest that the deep learning-based system is useful for the evaluation of cardiomyocyte hypertrophy and drug screening, leading to the development of new treatments for heart failure.

Intestinal transplantation from deceased donors is the established procedure for patients with irreversible intestinal failure. However, a living-donor intestinal transplant has not been routinely performed yet because of undefined surgical risks to the donor. In this report, we reviewed our experience with living-donor ileal resection from May 1999 to December 2021. A total of 40 living-donor ileal resections were performed for 40 intestinal transplant recipients. Clinical data were prospectively collected and analyzed for postoperative complications after ileal procurement. None of the donors experienced life-threatening complications or mortality. Six (15%) of 40 donors experienced minor operative complications. Transit intestinal graft inadequacy including weight loss, diarrhea, and vitamin B12 deficiency was common early following surgery, but was manageable and disappeared in most cases within a year. All donors had significant reductions in total plasma cholesterol and low-density lipoprotein cholesterol concentrations after donation as compared with the baseline levels. With an average follow-up of 67.8 months, bilateral kidney stones occurred in one donor and gallstones in the other. All the donors have regained their normal capacity for work. Living-donor ileal resection is associated with minimal short- and long-term morbidity and remains an attractive alternative for potential recipients when suitable deceased donors are unavailable.

Serum lipids, glucose and uric acid are well-known risk factors for metabolic syndrome and cardiovascular diseases; however, how serum uric acid levels are associated with fasting glucose and lipid levels remains to be evaluated.A cross-sectional study was performed in 104,328 males and 74,916 females. Quantile regression analyses were adopted to optimally fit the associations between levels of uric acid, lipids and glucose. Fasting high-density lipoprotein cholesterol (HDL-C) levels were negatively associated with serum uric acid levels; the associations remained stable in males but strengthened in females with increasing uric acid concentrations. Non-HDL-C and triglyceride (TG) levels were positively associated with serum uric acid levels; the associations also strengthened across deciles of uric acid levels from low to high. Fasting glucose levels were positively associated with uric acid levels in both sexes except in males in the 1st and 2nd deciles of uric acid concentrations; the association coefficients for females were higher than coefficients in males in each decile of uric acid levels. All associations had distinguishable patterns by sex except non-HDL-C, which was associated with uric acid levels with relatively similar trends between sexes. Adjustment for known confounding factors only slightly altered the above associations.Fasting serum uric acid levels are associated with fasting levels of HDL-C, non-HDL-C, TG and glucose; the associations strengthened with the deciles of uric acid increase and displayed non-negligible sex differences.

Background: Abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disease characterized by dilated abdominal aorta. Immune cells have been shown to contribute to the development of AAA, and that the gut microbiota is associated with numerous diseases, including cardiovascular diseases, by regulating immune systems or metabolic pathways of the host. However, the interaction between the gut microbiota and AAA remains unknown. Methods: Apolipoprotein E–deficient male mice were fed a high-cholesterol diet and divided into three groups: the control group was maintained under normal water (control group), the oral AVNM group was maintained under drinking water supplemented with ampicillin, vancomycin, neomycin, and metronidazole, and the i.p. AVNM group was injected AVNM intraperitoneally. After 1 week of pretreatment with antibiotics, these mice were administrated Ang II via subcutaneous osmotic pumps for 4 weeks and euthanized to evaluate AAA formation. Results: Depletion of gut microbiota by oral AVNM ameliorated the incidence of AAAs (control group: 58.9% versus oral AVNM group: 28.6% versus i.p. AVNM group: 75.0%, P = 0.0005) and prevented death due to ruptured aneurysms (control group: 11% versus oral AVNM group: 0% versus i.p. AVNM group: 15%). Oral AVNM suppressed monocyte storage in the spleen, but not in other organs. Despite possessing a higher level of cholesterol, recruitment of monocytes into the suprarenal aorta was suppressed in the oral AVNM group. In AVNM drinking mice, NOD1 ligand, a kind of PRR ligands, increased the development of AAAs and accumulation of macrophages in the aortae. Conclusions: The gut microbiota plays a critical role in AAA formation. Therefore, regulation of the microbiota or the immune system can be a therapeutic approach for AAA.

In this study, we aim to investigate the effect of metformin on cholesterol synthesis and efflux-related genes in chondrocytes during osteoarthritis (OA) and explore the underlying mechanisms. Primary chondrocytes were harvested from Wistar rat cartilage and divided into control and treatment groups. Chondrocytes in the treatment group were treated with interleukin-1β (IL-1β) mimicking the inflammatory environment of osteoarthritis. Subsequently, RT-qPCR, Western blotting, immunofluorescence staining, and Cell Counting Kit-8 (CCK-8) were conducted. Significant reductions in phosphorylated AMP-activated protein kinase (p-AMPK) and silent information regulator 1 (SIRT1) protein expression were observed in both human OA chondrocytes and cultured primary murine chondrocytes treated with IL-1β, while AMP-activated protein kinase (AMPK) was not inhibited. Moreover, in the presence of IL-1β, metformin significantly increased the expression of p-AMPK and SIRT1 at the protein and mRNA level. Meanwhile, metformin could reverse IL-1β-induced cartilage extracellular matrix degradation in chondrocytes from the rat model of OA (treated by IL-β) by activating the AMPK/SIRT1 pathway. Moreover, metformin activated AMPK and SIRT1, mediated by the activation of SREBP-2 and HMGCR in OA chondrocytes. Inhibiting AMPK/SIRT1 activity by its specific inhibitor could suppress IL-1β-induced expression of LXRα, ABCA1 and ApoA1 and cholesterol efflux. Thus, metformin inhibits cholesterol synthesis and promotes cholesterol efflux by activating the AMPK/SIRT1 pathway in OA chondrocytes. This study improves our understanding of the effect of metformin on cholesterol accumulation in OA chondrocytes.

The positive charge on liposome surface is known to promote the crossing of the Blood brain barrier (BBB). However, when diastereomeric cationic gemini amphiphiles are among lipid membrane components, also the stereochemistry may affect the permeability of the vesicle across the BBB.Liposomes featuring cationic diasteromeric gemini amphiphiles were formulated, characterized, and their interaction with cell culture models of BBB investigated.Liposomes featuring the gemini amphiphiles were internalized in a monolayer of brain microvascular endothelial cells derived from human induced pluripotent stem cells (hiPSC) through an energy dependent transport, internalization involving both clathrin- and caveolae-mediated endocytosis. On the same formulations, the permeability was also evaluated across a human derived in vitro BBB transport model. The permeability of liposomes featuring the gemini amphiphiles was significantly higher compared to that of neutral liposomes (DPPC/Cholesterol), that were not able to cross BBB. Most importantly, the permeability was influenced by the stereochemistry of the gemini and pegylation of these formulations did not result in a drastic reduction of the crossing ability. The in vitro iPSC-derived BBB models used in this work represent an important advancement in the drug discovery research of novel brain delivery strategies and therapeutics for central nervous system diseases.

Cholesterol-dependent cytolysin (CDC) is a bacterial toxin that binds to eukaryotic cholesterol-containing membranes, forms oligomeric complexes, and is inserted into the bilayer to create large aqueous pores. Recently, we reported a species-specific duplication of the hemolysin gene in group III Clostridium botulinum. The duplicated genes (bly1 and bly2) encoded two separate CDC proteins (botulinolysins; BLY1 and BLY2). Here, we aimed to investigate whether BLY1 and BLY2 exert differential cytotoxicity. We isolated two bly genes from C. botulinum and evaluated the cytotoxicity of two recombinant BLY proteins (rBLY1 and rBLY2) in HeLa, IEC-6, and NRK cells. rBLYs were cytotoxic to equine erythrocytes. rBLY1 showed higher hemolytic activity than rBLY2. rBLY2 showed no or very weak cytotoxicity to the HeLa, IEC-6, and NRK cells, whereas rBLY1 showed high cytotoxicity to these cells. The comparison of the amino acid sequence of BLYs with those of other CDCs revealed that the already-known amino acid residues involved in cholesterol-containing membrane recognition, oligomerization, and insertion into membranes are well conserved in both BLYs. However, several amino acid substitutions were observed in the conserved regions, particularly in L2 and L3 regions involved in cell binding. These findings suggest that gene duplication in group III C. botulinum evolved distinct functional specializations, and differential cytotoxicity of BLY1 and BLY2 could be due to the amino acid substitution in the conserved regions. However, the structural and functional comparisons of the two BLYs are essential to gain insights into the function of the CDCs.

Background: Intraplaque hemorrhage (IPH) is associated with plaque progression and ischemic events, and plaque lipid content (% lipid core) predicts the residual atherosclerotic cardiovascular disease risk. This study examined the impact of IPH on lipid content change in the setting of intensive lipid-lowering therapy. Methods: In total, 214 AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low High-Density Lipoprotein/High Triglycerides: Impact on Global Health Outcomes) participants with clinically established ASCVD and low high-density lipoprotein cholesterol received cartoid MRI at baseline and 2 years to assess changes in carotid morphology and composition. Patients were randomized to extended-release niacin or placebo, and all received simvastatin with optional ezetimibe as necessary to lower low-density lipoprotein cholesterol to 40 to 80 mg/dL. Changes in lipid content and carotid morphology were tested using the Wilcoxon signed-rank test. Differences between subjects with and without IPH and between subjects assigned extended-release niacin or placebo were tested using the Wilcoxon rank-sum test. Linear regression was used to test the association of IPH and lipid content changes after adjusting for clinical risk factors. Results: Among 156 patients (61±9 years; 81% men) with complete MRI, prior statin use: 5 years, 37%. Triglycerides and ApoB decreased significantly, whereas high-density lipoprotein cholesterol and ApoA1 increased significantly over time. Plaque lipid content was significantly reduced (−0.5±2.4 %/year, P = 0.017) without a significant difference between the 2 treatment groups. However, the lipid content increased in plaques with IPH but regressed in plaques without IPH (1.2±2.5 %/year versus −1.0±2.2, P = 0.006). Additionally, IPH was associated with a decrease in lumen area (−0.4±0.9 mm2/year versus 0.3±1.4, P = 0.033). IPH remained significantly associated with increase in lipid content in multivariable analysis (54.4%, 95% CI: 26.8, 88.0, P < 0.001). Conclusions: Carotid plaques under continued intensive lipid-lowering therapy moved toward stabilization. However, plaques with IPH showed greater increases in lipid content and greater decreases in lumen area than plaques without IPH. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01178320.

Understanding the function and mechanism of pore-forming toxins (PFTs) is challenging because cells resist the membrane damage caused by PFTs. While biophysical approaches help understand pore formation, they often rely on reductionist approaches lacking the full complement of membrane lipids and proteins. Cultured human cells provide an alternative system, but their complexity and redundancies in repair mechanisms make identifying specific mechanisms difficult. In contrast, the human protozoan pathogen responsible for cutaneous leishmaniasis, Leishmania major, offers an optimal balance between complexity and physiologic relevance. L. major is genetically tractable and can be cultured to high density in vitro, and any impact of perturbations on infection can be measured in established murine models. In addition, L. major synthesizes lipids distinct from their mammalian counterparts, which could alter membrane dynamics. These alterations in membrane dynamics can be probed with PFTs from the best-characterized toxin family, cholesterol-dependent cytolysins (CDCs). CDCs bind to ergosterol in the Leishmania membrane and can kill L. major promastigotes, indicating that L. major is a suitable model system for determining the cellular and molecular mechanisms of PFT function. This work describes methods for testing PFT function in L. major promastigotes, including parasite culture, genetic tools for assessing lipid susceptibility, membrane binding assays, and cell death assays. These assays will enable the rapid use of L. major as a powerful model system for understanding PFT function across a range of evolutionarily diverse organisms and commonalities in lipid organization.

Cell-coupled field-effect transistor (FET) biosensors have attracted considerable attention because of their high sensitivity to biomolecules. The use of insect cells (Sf21) as a core sensor element is advantageous due to their stable adhesion to sensors at room temperature. Although visualization of the insect cell-substrate interface leads to logical amplification of signals, the spatiotemporal processes at the interfaces have not yet been elucidated. We quantitatively monitored the adhesion dynamics of Sf21 using interference reflection microscopy (IRM). Specific adhesion signatures with ring-like patches along the cellular periphery were detected. A combination of zeta potential measurements and lectin staining identified specific glycoconjugates with low electrostatic potentials. The ring-like structures were disrupted after cholesterol depletion, suggesting a raft domain along the cell periphery. Our results indicate dynamic and asymmetric cell adhesion is due to low electrostatic repulsion with fluidic sugar rafts. We envision the logical design of cell-sensor interfaces with an electrical model that accounts for actual adhesion interfaces.

Based on decades of both basic science and epidemiologic research, there is overwhelming evidence for the causal relationship between high levels of cholesterol, especially low-density lipoprotein cholesterol and cardiovascular disease. Risk evaluation and monitoring the response to lipid-lowering therapies are heavily dependent on the accurate assessment of plasma lipoproteins in the clinical laboratory. This article provides an update of lipoprotein metabolism as it relates to atherosclerosis and how diagnostic measures of lipids and lipoproteins can serve as markers of cardiovascular risk, with a focus on recent advances in cardiovascular risk marker testing.

Youth living with perinatally acquired HIV (YLPHIV) have been found to have a range of mental disorders. Some adult HIV studies have linked mental health to adverse metabolic outcomes due to dysregulation of the sympathetic nervous system and hypothalamic-pituitary-adrenal axis, but this association has not previously been explored in YLPHIV.We investigated the association of mental health measures with metabolic outcomes in YLPHIV and HIV-uninfected youth (HIV-U) and linear regression was used to assess the adjusted associations.Overall, 203 YLPHIV (median age = 10.7years; 52% female; mean duration on ART 8 years, 12% CD4 count 50 copies/mL) and 44 HIV-U (median age = 10.3 years; 55% female) were enrolled. YLPHIV had higher median total cholesterol (4.2 vs 3.9 mmol/L, p = 0.049) and triglyceride (0.9 vs 0.7 mmol/L, p < 0.001) compared to HIV-U. We found higher percentage of poor functional competence (40% vs 25%, p = 0.02) and self-concept (23% vs 9%, p = 0.03) and higher depression (6% vs 2%, p < 0.01), anger (6% vs 2%, p = 0.04) and disruptive behaviour (4% vs 0%, p < 0.01) in YLPHIV as compared to HIV-U. Among YLPHIV, higher scores of anger were associated with higher total cholesterol and higher low-density lipoprotein (s = 0.010, p = 0.041 and s = 0.012, p = 0.048 respectively) and disruptive behaviour with higher low-density lipoprotein (s = 0.010, p = 0.043) after adjusting for age, sex and BMIZ.This is the one of first study to investigate the association of mental health with metabolic outcomes among YLPHIV. The association of increased anger and disruptive behaviour with increased lipid concentration is a novel finding. Further longitudinal studies are needed to evaluate the causal relationships between mental health and metabolic outcomes.

Obesity is associated with alterations in cholesterol and bile acid (BA) metabolism. However, the interaction among dietary intake, cholesterol absorption, and BA metabolism in patients with obesity remains unclear. We conducted a 4-wk nutritional intervention nonrandomized clinical trial with three different sequential diets for a week in the following order: regular diet (RD); high calorie, high-fat diet (HCHF), washout period on RD; and low-calorie, low-fat diet (LCLF). We provided participants with meal replacements during HCHF and LCLF diets. A total of 16 participants completed the study [

Atherosclerosis (AS) is a major cause of death and morbidity worldwide. There is an increasing amount of evidence that the gut microbiota plays an important role in disorders associated with lipid metabolism, such as AS, and alterations in the composition of the gut microbiota and its metabolic potential have been identified as contributing factors in the development of AS. Recently, probiotics have attracted great interest for their excellent cholesterol-lowering ability, their capacity to improve vascular endothelial function, and their participation in the remodeling of the intestinal flora to prevent AS. The incidental findings of our other study suggest that probiotic Lactobacillus rhamnosus GG may be associated with slowing the progression of AS. Thus, we delivered strain GG into mice by oral feeding and found that strain GG could effectively inhibit AS plaque generation. We analyzed the differences in gut microbiota composition and the peripheral blood metabolome in mice after oral feeding of strain GG by 16S DNA sequencing and untargeted metabolomics, respectively. The results showed that strain GG changed the composition of the gut microbiota in mice fed a high-fat diet; elevated the abundance of beneficial bacteria, such as Bilophila and Alistipes, and decreased the abundance of harmful bacteria, such as Deltaproteobacteria. The results of enrichment analysis of the gut microbiota and the peripheral blood metabolome both indicated that the antiatherosclerotic effect of strain GG might be associated with the biosynthesis pathway of ketone bodies. In addition, strain GG attenuated endothelial injury and elevated peripheral blood ketone body content in mice but did not significantly affect low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) content. In conclusion, our study provides new evidence that strain GG slows the progression of AS, which may be associated with its improvement of the gut microbiome and peripheral blood metabolome, its ability to increase the abundance of beneficial bacteria, and its participation in unsaturated fatty acid and ketone body synthesis and degradation. KEY POINTS: • L. rhamnosus GG attenuated endothelial injury and atherosclerotic plaque formation • L. rhamnosus GG elevated the abundance of beneficial bacteria • L. rhamnosus GG elevated peripheral blood ketone body content in mice.

Exposure to perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) is associated with blood lipids in adults, but the underlying mechanisms remain unclear. This pilot study aimed to investigate the associations between PFOA or PFOS and epigenome-wide DNA methylation and assess the mediating effect of DNA methylation on the PFOA/PFOS-blood lipid association. We measured plasma PFOA/PFOS and leukocyte DNA methylation in 98 patients enrolled from the hospital between October 2018 and August 2019. The median plasma PFOA/PFOS levels were 0.85 and 2.29 ng/mL. Plasma PFOA and PFOS levels were significantly associated with elevated total cholesterol (TC) and low-density lipoprotein cholesterol (LDL) levels. There were 63/87 CpG positions and 8/11 differentially methylated regions (DMRs) associated with plasma PFOA/PFOS levels, respectively. In addition, 5 CpG positions (annotated to

Background. Roxadustat is a newly listed oral hypoxia-inducible factor-proline enhancing enzyme inhibitor (HIF-PHI) in recent years. There have been some studies that have proved the efficacy of roxadustat on the treatment of renal anemia in patients with chronic kidney disease (CKD), but there are still different conclusions on its safety. Methods. PubMed, Embase, Cochrane, and ClinicalTrials were searched for randomized controlled trials (RCTs) that assess efficacy and safety of roxadustat treatment for anemia in CKD patients. The Cochrane Literature Quality Evaluation Scale was used to evaluate the quality of included literature. We choose fixed-effects model or random effects model for data processing based on heterogeneity. It was considered statistically significant when p value

Objectives Oxysterols, a family of oxidized cholesterol derivates, are of increasing interest due to their role in cancer development and progression. Some oxysterols are estrogen receptor modulators and thus of particular interest in breast cancer research. In human studies, two forms of circulating oxysterols are commonly evaluated: “free” (unesterified) and “total” (esterified and unesterified). However, associations between free and total oxysterols are not well established. We addressed this knowledge gap in a pilot study by evaluating correlations between the free and the total form of each of the circulating oxysterols (free vs. total), and pairwise associations within the panel of total oxysterols (total vs. total) and the panel of free oxysterols (free vs. free). Methods Concentrations of oxysterols and other non-cholesterol sterols were quantified in blood samples of 27 breast cancer patients from the MARIE breast cancer patient cohort using liquid chromatography mass spectrometry. We used Spearman rank correlations to assess associations. Overall, 12 oxysterols (including 27-hydroxycholesterol (HC), 25-HC, 24S-HC, 7a-HC, 5a6a-epoxycholesterol) and five sterols (including lanosterol and desmosterol) were analyzed. Results Strong correlations (r≥0.82) were observed for seven circulating free and total oxysterols/sterols. The free and total form of 27-HC (r=0.63), 25-HC (r=0.54), and two more oxysterols were weaker correlated. Correlation patterns in the panel of total oxysterols/sterols and the panel of free oxysterols/sterols were similar. Conclusions These findings demonstrate that concentrations of most free and total oxysterols/sterols are strongly correlated. We provide further insight into the interrelationships between oxysterols in breast cancer patients.

Cholesterol in the central nervous system has been increasingly found to be closely related to neurodegenerative diseases. Defects in cholesterol metabolism can cause structural and functional disorders of the central nervous system. The detection of abnormal cholesterol is of great significance for the cognition of physiological and pathological states of organisms, and the spatial distribution of cholesterol can also provide more clues for our understanding of the complex mechanism of disease. Here, we developed a novel pyrylium-based derivatization reagent combined with matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to visualize cholesterol in biological tissues. A new class of charged hydroxyl derivatization reagents was designed and synthesized, and finally 1-(carboxymethyl)-2,4,6-trimethylpyridinium (CTMP) was screened for tissue derivatization of cholesterol. Different from the shortcomings of traditional hydroxyl labeling methods such as harsh reaction conditions and long reaction time, in our study, we combined the advantages of CTMP itself and the EDCl/HOBt reaction system to achieve instant labeling of cholesterol on tissues through two-step activation. In addition, we also reported changes in cholesterol content in different stages and different brain regions during disease development in SOD1 mutant mouse model. The cholesterol derivatization method we developed provides an efficient way to explore the distribution and spatial metabolic network of cholesterol in biological tissues.

Nanoparticle drug delivery systems have drawn considerable attention worldwide due to their unique characteristics and advantages in anticancer drug delivery. Herein, the curcumin (Cur) loaded nanomicelles with two-stage drug release behavior were developed. β-Cyclodextrin (β-CD) and cholesterol were conjugated onto both ends of the poly(ethylene glycol) (PEG) chain to obtain an amphiphilic β-CD-PEG-Chol. The Cur was loaded into the cavities of β-CD and nanomicelle when the β-CD-PEG-Chol self-assembled to the Cur@β-CD-PEG-Chol nanomicelles (Cur@CPC NMs). These Cur@CPC NMs are spherical particles with a particle size of 120.9 nm. The Cur drug loading capacity of Cur@CPC NMs are 61.6 ± 6.9 mg/g. The release behavior of Cur from Cur@CPC NMs conformed to a two-stage mode of "burst-release followed by sustained-release". The prepared Cur@CPC NMs possess high storage stability and excellent hemocompatibility. Moreover, these Cur@CPC NMs exhibit satisfactory antioxidant activity and anticancer activity, resulting in significant reduction in intracellular H

SUMMARY OBJECTIVE: In this study, the hormone profile, lipid profile, and inflammatory parameters of patients with polycystic ovary syndrome were compared with those of non-polycystic ovary syndrome patients to determine predictive markers in young polycystic ovary syndrome patients who have not yet had children. METHODS: Patients’ age, height, weight, body mass index, waist circumference, degree of hirsutism, and ultrasound findings were recorded. Hormone profile, lipid levels, ratio of complete blood count parameters, monocyte/high-density lipoprotein ratio, and total cholesterol/high-density lipoprotein ratio were compared between groups. RESULTS: No statistically significant differences were found between groups in terms of age, weight, waist circumference, body mass index, and dysmenorrhea (p>0.05). A significant relationship was found between the height and the degree of hirsutism in the groups (p

The objective of this report was to review the application of the pooled cohort equations in primary prevention and the assessment of cardiovascular health.Literature review was conducted using the PubMed database. In addition, the 2018 Multi-Society Guidelines on Management of Blood Cholesterol and the 2019 American College of Cardiology/American Heart Association Guidelines on the Primary Prevention of Cardiovascular Disease were reviewed.Primary prevention refers to individuals with no history of atherosclerotic cardiovascular disease, severe hypercholesterolemia, or diabetes. For these adults, aged 40-75 yr, who have a low-density lipoprotein-cholesterol of ≥70 mg/dL andlt;190 mg/dL, the pooled cohort equations should be used to provide a quantitative assessment of 10-yr atherosclerotic cardiovascular disease risk. From here, individuals are grouped as low risk (lt;5%), borderline risk (5 tolt;7.5%), intermediate risk (7.5 tolt;20%), or high risk (≥20%). Statin therapy should be strongly advised in those with an atherosclerotic cardiovascular disease risk of ≥20%, while statin therapy can be considered in those with a risk between 5% andlt;20%, especially if risk enhancing factors are present. If uncertainty still exists regarding treatment, a coronary artery calcium score can help further refine risk. All individuals, regardless of atherosclerotic cardiovascular disease risk, should have a cardiovascular health assessment using Life's Essential 8, which includes diet, physical activity, nicotine exposure, body mass index, blood glucose, blood lipids, blood pressure, and sleep.

Atherosclerosis (AS) is the pathological basis of many cardiovascular and cerebrovascular diseases, in which macrophage-derived foam cells are the critical step and a typical pathological feature of early atherosclerosis. We previously confirmed that low-molecular-weight fucoidan (LMWF) had a good anti-AS effect, but the mechanism is still unclear. Here with aim to investigate the inhibitory effect of LMWF on foam cells and its molecular mechanism. Oil red O staining showed that LMWF effectively alleviated lipid accumulation and the formation of foam cells. Flow cytometry detection showed that LMWF promoted foam cells apoptosis. In addition, immunofluorescence showed that LMWF inhibited macrophage scavenger receptor A1 (SR-A1)-mediated lipid uptake and promoted ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol outflow. Western blot showed that LMWF downregulated SR-A1 protein expression and upregulated ABCA1 protein expression by inhibiting p38 mitogen activated protein kinase (p38MAPK) phosphorylation. Moreover, the mRNA transcriptions of Stat1, Elk-1, and Myc were downregulated when treated with LMWF. It concluded that, LMWF achieved bidirectional regulation of SR-A1 and ABCA1, then prevented the formation of foam cells, finally ameliorated the development of AS.

In our study, two high efficiency cellulose degrading strains were screened, isolated and identified as Cochliobolus kusanoi and Aspergillus puulaauensis by 18S rDNA gene sequencing. In addition, the composite microbial system was constructed to develop the synergistic effect among different strains. Under the optimum conditions, the yield of soluble dietary fiber from tea residues by mixed fermentation method (MF-SDF) dramatically increased compared to single strain fermentation. The structural analysis demonstrated that all samples possessed the representative infrared absorption peaks of polysaccharides, whereas MF-SDF revealed more loose structure, lower crystallinity and smaller molecular size. For the adsorption capacities indexes, MF-SDF also owned the highest adsorbing capacity for the water molecule, oil molecule, cholesterol molecule and nitrite ion. Overall, our data showed that mixed fermentation method could be better choices to improve the functional properties of dietary fiber, and screening of cellulose degrading strains could provide new thinkings for the study of dietary fiber modification and realize high-quality utilization of crop residues.

Atherosclerosis (AS) is an inflammatory vascular disease. Branched-chain amino acid transaminase 1 (BCAT1) has been implicated in inflammatory diseases, while its role in AS is unclear yet. In ApoEsup-/-/supmice with a high fat diet (HDF), BCAT1 was highly up-regulated and more pronounced in aged than in young ApoEsup-/-/supmice, which was abundantly expressed in macrophages located in AS lesions. The function of BCAT1 in AS was explored using lentivirus-mediated BCAT1 overexpression. ApoEsup-/-/supmice fed a HFD with BCAT1 overexpression exhibited the worsening lipid deposition and pathological injury of aortic tissues, accompanied by aggravated hyperlipidemia as proved by increased serum triglyceride, total cholesterol, and low-density lipoprotein-cholesterol levels. Immunohistochemical staining of vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1), and CD68 in the aortic root plaque suggested that BCAT1 overexpression could induce monocyte-endothelial cell adhesion and macrophages infiltration, thereby contributing inflammatory response by promoting TNF-α, IL-6, and IL-1β expression. Further, in vivo experiments, lipid accumulation, and inflammatory response induced by oxidized-LDL in RAW267.4 cells were also intensified or alleviated by BCAT1 overexpression or knockdown. Finally, BCAT1 overexpression aggravated AS development. These adverse effects of BCAT1 on hyperlipidemia, lipid accumulation, foaming cell formation, and inflammation suggested that the modulation of BCAT1 might be a potential approach to prevent AS disease.