HSDL2 links nutritional cues to bile acid and cholesterol homeostasis.

In response to energy and nutrient shortage, the liver triggers several catabolic processes to promote survival. Despite recent progress, the precise molecular mechanisms regulating the hepatic adaptation to fasting remain incompletely characterized. Here, we report the identification of hydroxysteroid dehydrogenase-like 2 (HSDL2) as a mitochondrial protein highly induced by fasting. We show that the activation of PGC1α-PPARα and the inhibition of the PI3K-mTORC1 axis stimulate HSDL2 expression in hepatocytes. We found that HSDL2 depletion decreases cholesterol conversion to bile acids (BAs) and impairs FXR activity. HSDL2 knockdown also reduces mitochondrial respiration, fatty acid oxidation, and TCA cycle activity. Bioinformatics analyses revealed that hepatic Hsdl2 expression positively associates with the postprandial excursion of various BA species in mice. We show that liver-specific HSDL2 depletion affects BA metabolism and decreases circulating cholesterol levels upon refeeding. Overall, our report identifies HSDL2 as a fasting-induced mitochondrial protein that links nutritional signals to BAs and cholesterol homeostasis.

Blockade of STARD3-mediated cholesterol transport alleviates diabetes-induced podocyte injury by reducing mitochondrial cholesterol accumulation.

AIMS: Steroidogenic acute regulatory (StAR)-related lipid transfer domain-3 (STARD3) is a sterol-binding protein that facilitates cholesterol transport between cellular organelles. Cholesterol accumulation in podocytes directly contributes to the pathogenesis of albuminuria and renal injury under the condition of diabetic kidney disease (DKD). The aim of this study is to determine the role of STARD3 on the intracellular distribution of cholesterol within podocytes. METHODS: In vivo and in vitro models of diabetes were performed. The protein levels of STARD3, Niemann-Pick disease type C1 (NPC1), and Niemann-Pick disease type C2 (NPC2) were respectively detected by western blot analysis, immunohistochemistry, and immunofluorescence. Filipin staining was used to evaluate the subcellular localization of cholesterol in podocytes. Mitochondrial damage was evaluated using JC-1 (CBIC2) and ROS (reactive oxygen species) assays. KEY FINDINGS: Upregulation of STARD3 under diabetes and hyperglycemia increases cholesterol transport from the late endosomal/lysosomal (LE/LY) to mitochondria, leading to mitochondrial cholesterol accumulation and cell injury in podocytes. Conversely, downregulating STARD3 expression attenuated mitochondrial cholesterol accumulation, and improved mitochondrial homeostasis. SIGNIFICANCE: STARD3 may govern intracellular cholesterol transport in podocytes, subsequently leading to regulation of mitochondrial metabolism. Therefore, targeting STARD3 emerges as a potential therapeutic strategy to mitigate diabetes-induced mitochondrial cholesterol accumulation and associated injury in podocytes.

Effects of Nigella sativa supplementation on lipid profiles in adults: An updated systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND AIM: Several experiments have suggested that Nigella sativa (N. sativa) supplementation may have a beneficial effect on the lipid profile. However, the results from these trials have been inconclusive. Therefore, this study aimed to explore the impact of N. sativa supplementation on the lipid profile of adult participants. METHODS: We searched Scopus, Web of Science, PubMed, Cochrane, and Web of Science databases until December 2022. Random effects models were used, and pooled data were determined as standardized mean differences with a 95% confidence interval. RESULTS: The findings of 34 studies with 2278 participants revealed that N. sativa supplementation significantly reduced total cholesterol (TC) (SMD: -1.78; 95% CI: -2.20, -1.37, p < 0.001), triglycerides (TG) (SMD: -1.2725; 95% CI: -1.67, -0.83, p < 0.001), and low-density lipoprotein cholesterol (LDL-C) (SMD: -2.45; 95% CI: -3.06, -1.85; p < 0.001) compared to control groups. However, a significant increase was found in high-density lipoprotein cholesterol (HDL-C) (SMD: 0.79; 95% CI: 0.38, 1.20, p < 0.001). CONCLUSION: N. sativa has improved effects on TG, LDL-C, TC, and HDL-C levels. Overall, N. sativa may be suggested as an adjuvant anti-hyperlipidemic agent.

Interplay of hormones and metabolite excretion with fern pattern prove saliva as a potent indicator of male reproductive status in Kangayam breed cattle.

Kangayam cattle are one of the drought breeds in India with distinct attributes. Agricultural transformation has led to a decline in many pure-breed indigenous cattle, including the Kangayam breed. Hence, a study on the reproductive physiology of male Kangayam breed cattle is necessary to disentangle problems in the area of livestock improvement. In this study, we investigated the relationship between serum hormones and bio-constituents and ascertained the potential of saliva as an indicator of the reproductive status of Kangayam cattle (Bos indicus). The present study confirms that cholesterol was higher in intact males and lower in prepubertal and castrated males. Testosterone levels were also higher in intact males than in castrated or prepubertal males. Hence, it can be inferred that high cholesterol levels contribute to active derivatization of testosterone in intact males. In contrast, reduced cholesterol availability leads to decreased testosterone synthesis in castrated and prepubertal males. Furthermore, it is reasonable to speculate that testosterone could have influenced salivary fern patterns in intact males, and thus, fern-like crystallization in the saliva was apparent. The unique salivary compounds identified through GC-MS across various reproductive statuses of Kangayam males may advertise their physiological status to conspecifics. In addition, the presence of odorant-binding protein (OBP) in saliva further supports its role in olfactory communication. This study attested to a posssible interlink between gonadal status and serum biochemical profiles. The salivary fern pattern revealed in this study can be used as a predictive tool, and the presence of putative volatiles and OBP adds evidence to the role of saliva in chemical communication.

Comparison of the Friedewald and Vujovic methods with the calculated LDL concentration in a biochemical auto-analyzer.

Objective: To compare the concentration of Low-Density Lipoprotein (LDL-c) obtained using the Friedewald formula with those obtained directly with the RAYTO CHEMRAY 120 autoanalyzer. Methods: Cross-sectional study. We evaluated outpatients with a medical request for a lipid profile study (total cholesterol, triglycerides, LDL, and HDL). The analyses were carried out in a RAYTO CHEMRAY 120 autoanalyzer under the principle of spectrophotometry. We obtained LDL-c using the Friedewald and Vujovic formulas. Results: We evaluated 199 individuals whose direct LDL concentration averages were measured by the RAYTO CHEMRAY 120 equipment. Those calculated by the Friedewald and Vujovic formulas were 129.97 ± 32.66, 119.28 ± 30.44, and 127.01 ± 32.01, respectively, and in all cases, significant differences (P < 0.001) were observed with the RAYTO analyzer. In both cases a low positive bias was found with the RAYTO analyzer.. The Passing-Bablok and Deming's regressions showed a linear correlation between both methods (Friedewald and Vujovic) with the LDL values obtained with the Rayto autoanalyzer. Conclusions: Our study found that the Friedewald and Vujovic methods are good predictors of LDL cholesterol levels and have a low level of bias. Therefore, they could be used as potential predictors.

Objetivo: Comparar las concentraciones de Lipoproteínas de Baja Densidad (LDL-c) obtenidas mediante la fórmula de Friedewald con las obtenidas directamente con el autoanalizador RAYTO CHEMRAY 120. Métodos: Estudio transversal. Se evaluaron pacientes ambulatorios con solicitud médica de perfil lipídico (colesterol total, triglicéridos, LDL y HDL). Los análisis se realizaron con un autoanalizador RAYTO CHEMRAY 120 bajo el principio de espectrofotometría. Obtuvimos el LDL-c usando las fórmulas de Friedewald y Vujovic. Resultados: Se evaluaron 199 individuos cuyos promedios directos de concentración de LDL fueron medidos con el equipo RAYTO CHEMRAY 120. Las concentraciones calculadas por las fórmulas de Friedewald y Vujovic fueron de 129,97 ± 32,66, 119,28 ± 30,44, y de 127,01 ± 32,01, respectivamente, y en todos los casos se observaron diferencias significativas (P < 0,001) con el analizador RAYTO. En ambos casos se encontró un sesgo positivo bajo en el analizador RAYTO. Las regresiones de Passing-Bablok y Deming mostraron una correlación lineal entre ambos métodos (Friedewald y Vujovic) con los valores de LDL obtenidos con el autoanalizador Rayto. Conclusión: Nuestro estudio encontro que los métodos de Friedewald y Vujovic son buenos predictores de los niveles de colesterol LDL y presentan un nivel de sesgo bajo. Por lo que podrían usarse como potenciales predictores.

Effect of feeding sodium butyrate to beef female cows during pre- and post-partum period on concentrations of glucagon-like peptides in plasma and colostrum.

The objective of this study was to evaluate the effect of feeding beef cows with sodium butyrate during the late pregnancy and early post-partum periods on concentrations of glucagon-like peptide (GLP)-1 and 2 in plasma, colostrum, and transition milk. Twelve Japanese Black female cows were fed concentrate feed without (CON; n = 6) or with (BUTY; n = 6) sodium butyrate supplementation at 1.1% of dietary dry matter from -60 d relative to the expected parturition date to 4 d after parturition. Plasma total cholesterol concentration was higher for the BUTY than for the CON (P = 0.04). In addition, plasma GLP-1 concentration was higher for the BUTY than for the CON at 3 d after calving (P < 0.05). This study showed for the first time that GLP-1 is present in the colostrum of Japanese Black cows at higher concentrations as compared to in plasma (P < 0.01). On the other hand, no treatment effect was observed for concentrations of metabolite and hormone in colostrum and transition milk. In summary, feeding beef cows with sodium butyrate during the late gestation and early post-partum period likely increases plasma GLP-1 concentrations post-partum without affecting the components of colostrum and transition milk.

Polysaccharide functionalization reduces lipid vesicle stiffness.

The biophysical properties of lipid vesicles are important for their stability and integrity, key parameters that control the performance when these vesicles are used for drug delivery. The vesicle properties are determined by the composition of lipids used to form the vesicle. However, for a given lipid composition, they can also be tailored by tethering polymers to the membrane. Typically, synthetic polymers like polyethyleneglycol are used to increase vesicle stability, but the use of polysaccharides in this context is much less explored. Here, we report a general method for functionalizing lipid vesicles with polysaccharides by binding them to cholesterol. We incorporate the polysaccharides on the outer membrane leaflet of giant unilamellar vesicles (GUVs) and investigate their effect on membrane mechanics using micropipette aspiration. We find that the presence of the glycolipid functionalization produces an unexpected softening of GUVs with fluid-like membranes. By contrast, the functionalization of GUVs with polyethylene glycol does not reduce their stretching modulus. This work provides the potential means to study membrane-bound meshworks of polysaccharides similar to the cellular glycocalyx; moreover, it can be used for tuning the mechanical properties of drug delivery vehicles.

Elevated SCN11A concentrations associated with lower serum lipid levels in patients with major depressive disorder.

The pathogenesis of major depressive disorder (MDD) involves lipid metabolism. Our earlier research also revealed that MDD patients had much lower total cholesterol (TC) concentrations than healthy controls (HCs). However, it is still unclear why TC decreased in MDD. Here, based on the Ingenuity Knowledge Base's ingenuity pathway analysis, we found that sodium voltage-gated channel alpha subunit 11A (SCN11A) might serve as a link between low lipid levels and MDD. We analyzed the TC levels and used ELISA kits to measure the levels of SCN11A in the serum from 139 MDD patients, and 65 HCs to confirm this theory and explore the potential involvement of SCN11A in MDD. The findings revealed that TC levels were considerably lower and SCN11A levels were remarkably increased in MDD patients than those in HCs, while they were significantly reversed in drug-treatment MDD patients than in drug-naïve MDD patients. There was no significant difference in SCN11A levels among MDD patients who used single or multiple antidepressants, and selective serotonin reuptake inhibitors or other antidepressants. Pearson correlation analysis showed that the levels of TC and SCN11A were linked with the Hamilton Depression Rating Scales score. A substantial association was also found between TC and SCN11A. Moreover, a discriminative model made up of SCN11A was discovered, which produced an area under a curve of 0.9571 in the training set and 0.9357 in the testing set. Taken together, our findings indicated that SCN11A may serve as a link between low lipid levels and MDD, and showed promise as a candidate biomarker for MDD.

Inflammatory corpuscle AIM2 facilitates macrophage foam cell formation by inhibiting cholesterol efflux protein ABCA1.

The inflammatory corpuscle recombinant absents in melanoma 2 (AIM2) and cholesterol efflux protein ATP binding cassette transporter A1(ABCA1) have been reported to play opposing roles in atherosclerosis (AS) plaques. However, the relationship between AIM2 and ABCA1 remains unclear. In this study, we explored the potential connection between AIM2 and ABCA1 in the modulation of AS by bioinformatic analysis combined with in vitro experiments. The GEO database was used to obtain AS transcriptional profiling data; screen differentially expressed genes (DEGs) and construct a weighted gene co-expression network analysis (WGCNA) to obtain AS-related modules. Phorbol myristate acetate (PMA) was used to induce macrophage modelling in THP-1 cells, and ox-LDL was used to induce macrophage foam cell formation. The experiment was divided into Negative Control (NC) group, Model Control (MC) group, AIM2 overexpression + ox-LDL (OE AIM2 + ox-LDL) group, and AIM2 short hairpin RNA + ox-LDL (sh AIM2 + ox-LDL) group. The intracellular cholesterol efflux rate was detected by scintillation counting; high-performance liquid chromatography (HPLC) was used to detect intracellular cholesterol levels; apoptosis levels were detected by TUNEL kit; levels of inflammatory markers (IL-1ß, IL-18, ROS, and GSH) were detected by ELISA kits; and levels of AIM2 and ABCA1 proteins were detected by Western blot. Bioinformatic analysis revealed that the turquoise module correlated most strongly with AS, and AIM2 and ABCA1 were co-expressed in the turquoise module with a trend towards negative correlation. In vitro experiments demonstrated that AIM2 inhibited macrophage cholesterol efflux, resulting in increased intracellular cholesterol levels and foam cell formation. Moreover, AIM2 had a synergistic effect with ox-LDL, exacerbating macrophage oxidative stress and inflammatory response. Silencing AIM2 ameliorated the above conditions. Furthermore, the protein expression levels of AIM2 and ABCA1 were consistent with the bioinformatic analysis, showing a negative correlation. AIM2 inhibits ABCA1 expression, causing abnormal cholesterol metabolism in macrophages and ultimately leading to foam cell formation. Inhibiting AIM2 may reverse this process. Overall, our study suggests that AIM2 is a reliable anti-inflammatory therapeutic target for AS. Inhibiting AIM2 expression may reduce foam cell formation and, consequently, inhibit the progression of AS plaques.

Association Between Remnant Cholesterol and Risk of Incident Atrial Fibrillation: Population-Based Evidence From a Large-Scale Prospective Cohort Study.

BACKGROUND: Evidence for the relationship between remnant cholesterol (RC) and incident atrial fibrillation (AF) risk remains sparse and limited. METHODS AND RESULTS: Participants were enrolled between 2006 and 2010 and followed up to 2021. The multivariable Cox proportional hazards model was used to examine the relationship between RC quartiles and risk of incident AF. Subgroup analyses and sensitivity analyses were performed to explore the potential modification of the association and the robustness of the main findings. A total of 422 316 participants (mean age, 56 years; 54% women) were included for analyses. During a median follow-up of 11.9 years (first quartile-third quartile, 11.6-13.2 years), there were 24 774 AF events documented with an incidence of 4.92 events per 1000 person-years (95% CI, 4.86-4.98). Participants in higher RC quartiles had a lower risk of incident AF than those in the lowest quartile (first quartile): hazard ratio (HR)=0.96 (95% CI, 0.91-1.00) for second quartile; HR=0.92 (95% CI, 0.88-0.96) for third quartile; and HR=0.85 (95% CI, 0.81-0.89) for fourth quartile (P for trend <0.001). The association between RC quartiles and risk of incident AF was stronger in participants aged ≥65 years, in men, and in participants without history of diabetes when compared with control groups (P<0.001 for interaction). CONCLUSIONS: On the basis of data from this large-scale prospective cohort study, elevated RC was associated with a lower risk of incident AF.

The association between remnant cholesterol and bone mineral density in US adults: the National Health and Nutrition Examination Survey (NHANES) 2013-2018.

BACKGROUND: Previous evidence showed a possible link of dyslipidemia with bone health. Nevertheless, the correlation of remnant cholesterol (RC) with bone mineral density (BMD) has yet to be well investigated. This study investigated the association of RC with total spine BMD in general Americans. METHODS: This study explored the relationship of RC with total spine BMD in subjects aged ≥ 20 years from the National Health and Nutrition Examination Survey (NHANES) 2013-2018. After adjusting for covariates, multivariate linear regression and stratified analyses were conducted to determine the correlation of serum RC with total spine BMD in adult Americans. Restricted cubic spline (RCS) was applied to examine the nonlinear association of serum RC with total spine BMD. RESULTS: This study included 3815 individuals ≥ 20 years old, 1905 (49.93%) of whom were men and 1910 (50.07%) of whom were women. After adjusting for all covariates, the results showed a negative relationship of serum RC with total spine BMD (ß= -0.024, 95% CI: -0.039, -0.010). The interaction tests of age, sex, race, and BMI showed no statistically significant effects on the association. The RCS also indicated a negative linear correlation of serum RC with total spine BMD (nonlinear P = 0.068, overall P < 0.001). Moreover, RC had a stronger effect on total spine BMD than total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). CONCLUSIONS: This study found that serum RC was negatively related to total spine BMD in U.S. adults. These findings emphasized the important role of RC in bone health in American adults.

Relative biomembrane fusogenicities of the tumor-selective liposomes of RGDK- and CGKRK-lipopeptides.

Cancer is the second leading cause of death globally after heart diseases. Currently used highly cytotoxic anti-cancer drugs not only kill cancer cells but also often kill non-cancerous healthy body cells, causing adverse side effects. Efforts are now being directed towards developing tumor-selective chemotherapy. Tumor/tumor endothelial cell selective peptide ligands are being covalently grafted onto the exo-surfaces of drug carriers such as liposomes, polymers, etc. A number of prior studies used conjugation of tumor/tumor endothelial cell-selective RGDK- or CGKRK-peptide ligands on the outer surfaces of liposomes, metal-based nanoparticles, single walled carbon nanotubes (SWNTs), etc. However, studies aimed at examining the relative cell membrane fusogenicities and the relative degrees of cellular uptake for the RGDK- and CGKRK-ligand-grafted nanometric drug carriers have not yet been undertaken. Herein, using the widely used liposomes of DOPC, DOPE, DOPS and cholesterol (45 : 25 : 20 : 15, w/w ratio) as the model biomembranes and the fluorescence resonance energy transfer (FRET) assay for measuring membrane fusogenicities, we show that the liposomes of the RGDK-lipopeptide are more biomembrane fusogenic than the liposomes of the CGKRK-lipopeptide. Notably, such FRET assay-derived relative biomembrane fusogenicities of the liposomes of RGDK- and CGKRK-lipopeptides were found to be consistent with their relative degrees of cellular uptake in cultured cancer cells. The present findings open the door for undertaking in-depth in vivo studies aimed at evaluating the relative therapeutic potential of different nanocarriers of drugs/genes/siRNA having tumor-targeting RGDK- and CGKRK-peptides on their exo-surfaces.

A Coronin 1-Derived Peptide Inhibits Membrane Fusion by Modulating Membrane Organization and Dynamics.

Membrane fusion is considered the first step in the entry of enveloped viruses into the host cell. Several targeted strategies have been implemented to block viral entry by limiting the fusion protein to form a six-helix bundle, which is a prerequisite for fusion. Nonetheless, the development of broad-spectrum fusion inhibitors is essential to combat emerging and re-emerging viral infections. TG-23, a coronin 1, a tryptophan-aspartate-rich phagosomal protein-derived peptide, demonstrated inhibition of fusion between small unilamellar vesicles (SUVs) by modulating the membrane's physical properties. However, its inhibitory efficacy reduces with an increasing concentration of membrane cholesterol. The present work aims to develop a fusion inhibitor whose efficacy would be unaltered in the presence of membrane cholesterol. A stretch of the tryptophan-aspartic acid-containing peptide with a similar secondary structure and hydrophobicity profile of TG-23 from coronin 1 was synthesized, and its ability to inhibit SUV-SUV fusion with varying concentrations of membrane cholesterol was evaluated. Our results demonstrate that the GG-21 peptide inhibits fusion irrespective of the cholesterol content of the membrane. We have further evaluated the peptide-induced change in the membrane organization and dynamics utilizing arrays of steady-state and time-resolved fluorescence measurements and correlated these results with their effect on fusion. Interestingly, GG-21 displays inhibitory efficacy in a wide variety of lipid compositions despite having a secondary structure and physical properties similar to those of TG-23. Overall, our results advocate that the secondary structure and physical properties of the peptide may not be sufficient to predict its inhibitory efficacy.

Hypocholesterolemic potential of Bacillus amyloliquefaciens KAVK1 modulates lipid accumulation on 3T3-L1 adipose cells and high fat diet-induced obese rat model.

The significance of microorganisms occurring in foods is predominantly targeted due to their application for identifying a novel range of the bacterial spectrum. Diverse microbial species are capable of exhibiting potential pharmacological activities like antimicrobial and anticancer. Microbial strains capable of reducing obesity-related syndromes have also been reported. In the present study, the hypocholesterolemic efficacy of Bacillus amyloliquefaciens isolated from dairy products was scrutinised by in vitro (3T3-L1 adipose cells) and in vivo (high-fat diet-induced obese Wistar albino rats) methods. Potential cholesterol-lowering isolates were screened using a plate assay method and optimised by physical parameters. Molecular identification of the topmost five cholesterol-lowering isolates was acquired by amplification of the 16 S rRNA gene region. Bacillus amyloliquefaciens strain KAVK1, followed by strains KAVK2, KAVK3, KAVK4, and KAVK5 were molecularly determined. Further, cholesterol-lowering strains degraded the spectral patterns determined by the side chain of a cholesterol molecule. The anti-lipase activity was demonstrated using the porcine pancreatic lipase inhibitory method and compared with the reference compound Atorvastatin. Lyophilised strain KAVK1 revealed maximum pancreatic lipase inhibition. Strain KAVK1 attenuated lipid accumulation in 3T3-L1 adipose cell line predicted by Oil Red O staining method. Significant reduction of body weight and change in lipid profile was recognised after the supplement of KAVK1 to obese rats. Histopathological changes in organs were predominantly marked. The result of this study implies that the cholesterol-lowering B. amyloliquefaciens KAVK1 strain was used to treat hypercholesterolemia.

Free-Standing DNA Origami Superlattice to Facilitate Cryo-EM Visualization of Membrane Vesicles.

Technological breakthroughs in cryo-electron microscopy (cryo-EM) methods open new perspectives for highly detailed structural characterizations of extracellular vesicles (EVs) and synthetic liposome-protein assemblies. Structural characterizations of these vesicles in solution under a nearly native hydrated state are of great importance to decipher cell-to-cell communication and to improve EVs' application as markers in diagnosis and as drug carriers in disease therapy. However, difficulties in preparing holey carbon cryo-EM grids with low vesicle heterogeneities, at low concentration and with kinetic control of the chemical reactions or assembly processes, have limited cryo-EM use in the EV study. We report a straightforward membrane vesicle cryo-EM sample preparation method that assists in circumventing these limitations by using a free-standing DNA-affinity superlattice for covering holey carbon cryo-EM grids. Our approach uses DNA origami to self-assemble to a solution-stable and micrometer-sized ordered molecular template in which structure and functional properties can be rationally controlled. We engineered the template with cholesterol-binding sites to specifically trap membrane vesicles. The advantages of this DNA-cholesterol-affinity lattice (DCAL) include (1) local enrichment of artificial and biological vesicles at low concentration and (2) isolation of heterogeneous cell-derived membrane vesicles (exosomes) from a prepurified pellet of cell culture conditioned medium on the grid.

Relationship between remnant cholesterol and risk of kidney stones in U.S. Adults: a 2007-2016 NHANES analysis.

PURPOSE: Remnant cholesterol (RC) is the cholesterol content of triglyceride-rich lipoproteins. This study aimed to investigate the association between RC levels and kidney stones in U.S. adults. METHODS: Data were obtained from the 2007 to 2016 National Health and Nutrition Examination Survey (NHANES). A total of 10,551 participants with complete data were included and analyzed in this study. Univariate and multivariate logistic regression analysis, restricted cubic spline function, subgroup analysis and mediation analysis were preformed to estimate the independent relationship between RC levels and kidney stones. RESULTS: Participants with stone formation had higher levels of RC than those with without stone formation (25.78 ± 13.83 vs 23.27 ± 13.04, p< 0.001). The results of logistic regression analysis and dose-response risk curves revealed a positive nonlinear association between RC levels and risk of kidney stones [univariate: adjusted odds ratio (aOR) =2.388, 95% CI: 1.797-3.173, p< 0.001; multivariate: aOR = 1.424, 95% CI: 1.050-1.929, p = 0.023]. Compared with the discordantly low RC group, the discordantly high RC group was associated with increased risk of kidney stones (aOR = 1.185, 95% CI: 1.013-1.386, p= 0.034). Similar results were demonstrated according to the discordance of different clinical cut points. And metabolic syndrome parameters and vitamin D levels parallelly mediated the association between RC and kidney stone risk. CONCLUSIONS: Higher RC levels were independently associated with an increased risk of kidney stone incidence.

Higher remnant cholesterol levels were independently associated with an increased risk of kidney stone incidence.

The association between alcohol consumption and blood lipids in Chinese children and adolescent: findings from the China Health and Nutrition Survey.

BACKGROUND: Alcohol consumption by children and adolescents is receiving increasing attention. It may cause dyslipidemia, a risk factor for cardiovascular disease. However, the association between alcohol consumption and blood lipids in children and adolescents is unclear, and so we aimed to characterize this association. METHODS: Data from the China Health and Nutrition Survey were extracted from children and adolescents aged 7-18 years for whom information was available on alcohol consumption. The population was divided into drinking and nondrinking groups. The χ2, Student's t, or Mann-Whitney U test was used to compare groups. Univariate and multivariate linear regression and propensity score matching (PSM) analysis were used to identify the association between alcohol consumption and blood lipids. RESULTS: This study included 408 children and adolescents with 35 drinkers and 373 nondrinkers. The drinkers had significantly lower values of total cholesterol (TC) (3.8 mmol/L for nondrinkers versus 3.5 mmol/L for drinkers, p = 0.002) and high-density lipoprotein cholesterol (HDL-C) (1.3 mmol/L for nondrinkers versus 1.2 mmol/L for drinkers, p = 0.007), but not for low-density lipoprotein cholesterol (LDL-C) (2.1 mmol/L for nondrinkers versus 2.0 mmol/L for drinkers, p = 0.092) or triglyceride (TG) (0.9 mmol/L for nondrinkers versus 0.8 mmol/L for drinkers, p = 0.21). The univariate and multivariate analyses led to the same conclusions. After PSM there was still a significant negative association between alcohol consumption and TC or HDL-C. CONCLUSION: Alcohol consumption in children and adolescents exhibited significant negative associated with TC and HDL-C, but not with LDL-C or TG. These findings need to be confirmed in future prospective research, and the health effects of blood lipid changes caused by drinking in children and adolescents need to be clarified.

Association between pathologic complete response and biochemical indicators after neoadjuvant therapy for HER2-positive breast cancer.

PURPOSE: This study investigated the changes in the fasting blood glucose (FBG), fasting triglyceride (FTG), and fasting total cholesterol (FTC) levels during neoadjuvant therapy (NAT) for human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) and the association with pathologic complete response (pCR). METHODS: Relevant data from Sichuan Cancer Hospital from June 2019 to June 2022 were collected and analyzed, and FBG, FTG, and FTC were divided into baseline, change, and process groups, which were grouped to analyze the changes after receiving NAT and the association with pCR. RESULTS: In the estrogen receptor (ER)-negative subgroup, patients with low levels of FTG in the process group were more likely to achieve pCR compared to high levels, and in the progesterone receptor (PR)-negative subgroup, patients with lower FTG compared to higher FTG after receiving NAT was more likely to achieve pCR. CONCLUSIONS: Patients with HER2-positive BC undergoing NAT develop varying degrees of abnormalities (elevated or decreased) in FBG, FTG, and FTC; moreover, the status of FTG levels during NAT may predict pCR in ER-negative or PR-negative HER2-positive BC.Early monitoring and timely intervention for FTG abnormalities may enable this subset of patients to increase the likelihood of obtaining a pCR along with management of abnormal markers.

Effects of Chronic Inflammatory Activation of Murine and Human Arterial Endothelial Cells at Normal Lipoprotein and Cholesterol Levels In Vivo and In Vitro.

The activation of endothelial cells is crucial for immune defense mechanisms but also plays a role in the development of atherosclerosis. We have previously shown that inflammatory stimulation of endothelial cells on top of elevated lipoprotein/cholesterol levels accelerates atherogenesis. The aim of the current study was to investigate how chronic endothelial inflammation changes the aortic transcriptome of mice at normal lipoprotein levels and to compare this to the inflammatory response of isolated endothelial cells in vitro. We applied a mouse model expressing constitutive active IκB kinase 2 (caIKK2)-the key activator of the inflammatory NF-κB pathway-specifically in arterial endothelial cells and analyzed transcriptomic changes in whole aortas, followed by pathway and network analyses. We found an upregulation of cell death and mitochondrial beta-oxidation pathways with a predicted increase in endothelial apoptosis and necrosis and a simultaneous reduction in protein synthesis genes. The highest upregulated gene was ACE2, the SARS-CoV-2 receptor, which is also an important regulator of blood pressure. Analysis of isolated human arterial and venous endothelial cells supported these findings and also revealed a reduction in DNA replication, as well as repair mechanisms, in line with the notion that chronic inflammation contributes to endothelial dysfunction.

Cholesterol-Modified Anti-Il6 siRNA Reduces the Severity of Acute Lung Injury in Mice.

Small interfering RNA (siRNA) holds significant therapeutic potential by silencing target genes through RNA interference. Current clinical applications of siRNA have been primarily limited to liver diseases, while achievements in delivery methods are expanding their applications to various organs, including the lungs. Cholesterol-conjugated siRNA emerges as a promising delivery approach due to its low toxicity and high efficiency. This study focuses on developing a cholesterol-conjugated anti-Il6 siRNA and the evaluation of its potency for the potential treatment of inflammatory diseases using the example of acute lung injury (ALI). The biological activities of different Il6-targeted siRNAs containing chemical modifications were evaluated in J774 cells in vitro. The lead cholesterol-conjugated anti-Il6 siRNA after intranasal instillation demonstrated dose-dependent therapeutic effects in a mouse model of ALI induced by lipopolysaccharide (LPS). The treatment significantly reduced Il6 mRNA levels, inflammatory cell infiltration, and the severity of lung inflammation. IL6 silencing by cholesterol-conjugated siRNA proves to be a promising strategy for treating inflammatory diseases, with potential applications beyond the lungs.