Native mass spectrometry and structural studies reveal modulation of MsbA-nucleotide interactions by lipids.

The ATP-binding cassette (ABC) transporter, MsbA, plays a pivotal role in lipopolysaccharide (LPS) biogenesis by facilitating the transport of the LPS precursor lipooligosaccharide (LOS) from the cytoplasmic to the periplasmic leaflet of the inner membrane. Despite multiple studies shedding light on MsbA, the role of lipids in modulating MsbA-nucleotide interactions remains poorly understood. Here we use native mass spectrometry (MS) to investigate and resolve nucleotide and lipid binding to MsbA, demonstrating that the transporter has a higher affinity for adenosine 5'-diphosphate (ADP). Moreover, native MS shows the LPS-precursor 3-deoxy-D-manno-oct-2-ulosonic acid (Kdo)2-lipid A (KDL) can tune the selectivity of MsbA for adenosine 5'-triphosphate (ATP) over ADP. Guided by these studies, four open, inward-facing structures of MsbA are determined that vary in their openness. We also report a 2.7 Å-resolution structure of MsbA in an open, outward-facing conformation that is not only bound to KDL at the exterior site, but with the nucleotide binding domains (NBDs) adopting a distinct nucleotide-free structure. The results obtained from this study offer valuable insight and snapshots of MsbA during the transport cycle.

Association between maternal lipid profiles and vitamin D status in second trimester and risk of LGA or SGA: a retrospective study.

Background: Accumulating evidence has linked dyslipidemia during pregnancy to the risk of delivering infants born either large for gestational age (LGA) or small for gestational age (SGA). However, the effects of the vitamin D status on these relationships require further investigation. This study investigated whether the relationship between lipid profiles and the risk of LGA or SGA was influenced by vitamin D levels during the second trimester. Methods: Maternal lipid profile levels, including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and vitamin D levels, were measured in a cohort of 6,499 pregnant women during the second trimester. Multivariate regression models and subgroup analyses were employed to evaluate the potential associations between maternal lipid profiles, vitamin D levels, and the risk of LGA or SGA. Results: The prevalence of SGA infants was 9.8% (n=635), whereas that of LGA infants was 6.9% (n=447). Maternal TG levels were found to be positively associated with the risk of LGA (odds ratio [OR] = 1.41, 95% confidence interval [CI]:1.17-1.70), whereas a negative association was observed between maternal TG, TC, LDL-C levels, and risk of SGA. Additionally, mothers with higher HDL-C levels were less likely to give birth to an LGA infant (OR=0.58, 95% CI:0.39-0.85). Importantly, associations between TG, TC, LDL-c, and SGA as well as between TG and LGA were primarily observed among pregnant women with insufficient vitamin D levels. As for HDL-C, the risk of LGA was lower in mothers with sufficient vitamin D (OR = 0.42, 95% CI:0.18-0.98) compared to those with insufficient vitamin D (OR = 0.65, 95% CI:0.42-0.99). Conclusion: Vitamin D status during the second trimester exerts a modifying effect on the association between lipid profiles and the risk of LGA and SGA infants.

Follicular fluid lipidomics analysis reveals altered lipid signatures in patients with polycystic ovary syndrome.

BACKGROUND: This research investigates the metabolic profiles of follicular fluid (FF) samples from patients with polycystic ovary syndrome (PCOS) undergoing in vitro fertilisation and aims to identify diagnostic and therapeutic biomarkers for PCOS through lipidomic analysis. METHODS: We performed non-targeted lipid analysis of FF samples from women with PCOS (n = 6) and normal controls (n = 6) using ultra-high-performance liquid chromatography-tandem mass spectrometry. Differential lipids between the two groups were screened using multidimensional statistical analysis, followed by fold change analysis and t-tests to identify potential PCOS biomarkers. RESULTS: Multivariate statistical analysis revealed significant differences in FF lipid levels between the PCOS and control groups. Five different lipids were selected as standards, with p < .05. Phosphatidylcholine (PC), the main differentially expressed lipid, was significantly increased in the FF of the POCS group and was closely related to other lipids. CONCLUSIONS: Using ultra-high-performance liquid chromatography-tandem mass spectrometry, we investigated lipid biomarkers based on FF lipidomics to provide useful information for the discovery of diagnostic markers for PCOS. Our study identified five distinct lipids as potential markers of PCOS, with PC being the primary aberrant lipid found in the FF of patients with PCOS.

Follicular fluid (FF) is a complex microenvironment involved in oocyte growth, follicular maturation and germ cell­somatic cell communication. All metabolites during oocyte growth are collected from the FF. This study used lipidomic analysis to identify differences in FF lipids between normal women and those diagnosed with polycystic ovary syndrome (PCOS). The pathogenesis of PCOS is associated with abnormal metabolism of glyceroglycolipids and sphingomyelin. Here, we found that phosphatidylcholine is the main abnormal lipid in FF in patients with PCOS. Our study informs the future research into the development of diagnostic markers for PCOS to be used in clinical practice.

Fusogenic Lipid Nanovesicle for Biomacromolecular Delivery.

Although biomacromolecules are promising cytosolic drugs which have attracted tremendous attention, the major obstacles were the cellular membrane hindering the entrance and the endosome entrapment inducing biomacromolecule degradation. How to avoid those limitations to realize directly cytosolic delivery was still a challenge. Here, we prepared oligoarginine modified lipid to assemble a nanovesicle for biomacromolecules delivery, including mRNA (mRNA) and proteins which could be directly delivered into the cytoplasm of dendritic cells through subendocytosis-mediated membrane fusion. We named this membrane fusion lipid nanovesicle as MF-LNV. The mRNA loaded MF-LNV as nanovaccines showed efficient antigen expression to elicit robust immuno responses for cancer therapy. What's more, the antigen protein loaded MF-LNV as nanovaccines elicits much stronger CD8+ T cell specific responses than lipid nanoparticles through normal uptake pathways. This MF-LNV represented a refreshing strategy for intracellular delivery of the biomacromolecule.

The density-threshold affinity: Calculating lipid binding affinities from unbiased coarse-grained molecular dynamics simulations.

Many membrane proteins are sensitive to their local lipid environment. As structural methods for membrane proteins have improved, there is growing evidence of direct, specific binding of lipids to protein surfaces. Unfortunately the workhorse of understanding protein-small molecule interactions, the binding affinity for a given site, is experimentally inaccessible for these systems. Coarse-grained molecular dynamics simulations can be used to bridge this gap, and are relatively straightforward to learn. Such simulations allow users to observe spontaneous binding of lipids to membrane proteins and quantify localized densities of individual lipids or lipid fragments. In this chapter we outline a protocol for extracting binding affinities from these localized distributions, known as the "density threshold affinity." The density threshold affinity uses an adaptive and flexible definition of site occupancy that alleviates the need to distinguish between "bound'' lipids and bulk lipids that are simply diffusing through the site. Furthermore, the method allows "bead-level" resolution that is suitable for the case where lipids share binding sites, and circumvents ambiguities about a relevant reference state. This approach provides a convenient and straightforward method for comparing affinities of a single lipid species for multiple sites, multiple lipids for a single site, and/or a single lipid species modeled using multiple forcefields.

Analyzing lipid distributions and curvature in molecular dynamics simulations of complex membranes.

We describe methods to analyze lipid distributions and curvature in membranes with complex lipid mixtures and embedded membrane proteins. We discuss issues involved in these analyses, available tools to calculate curvature preferences of lipids and proteins, and focus on tools developed in our group for visual analysis of lipid-protein interactions and the analysis of membrane curvature.

Combination of Indomethacin with Nanostructured Lipid Carriers for Effective Anticancer Therapy.

Purpose: The anticancer potential of indomethacin and other nonsteroidal anti-inflammatory drugs (NSAIDs) in vitro, in vivo, and in clinical trials is well known and widely reported in the literature, along with their side effects, which are mainly observed in the gastrointestinal tract. Here, we present a strategy for the application of the old drug indomethacin as an anticancer agent by encapsulating it in nanostructured lipid carriers (NLC). We describe the production method of IND-NLC, their physicochemical parameters, and the results of their antiproliferative activity against selected cancer cell lines, which were found to be higher compared to the activity of free indomethacin. Methods: IND-NLC were fabricated using the hot high-pressure homogenization method. The nanocarriers were physicochemically characterized, and their biopharmaceutical behaviour and therapeutic efficacy were evaluated in vitro. Results: Lipid nanoparticles IND-NLC exhibited a particle size of 168.1 nm, a negative surface charge (-30.1 mV), low polydispersity index (PDI of 0.139), and high encapsulation efficiency (over 99%). IND-NLC were stable for over 60 days and retained integrity during storage at 4 °C and 25 °C. The potential therapeutic benefits of IND-NLC were screened using in vitro cancer models, where nanocarriers with encapsulated drug effectively inhibited the growth of breast cancer cell line MDA-MB-468 at dosage 15.7 µM. Conclusion: We successfully developed IND-NLC for delivery of indomethacin to cancer cells and confirmed their antitumoral efficacy in in vitro studies. The results suggest that indomethacin encapsulated in lipid nanoparticles possesses high anticancer potential. Moreover, the presented strategy is highly promising and may offer a new alternative for future therapeutic drug innovations.

Lipidomic Profiling of Kidney Cortical Tubule Segments Identifies Lipotypes with Physiological Implications.

A detailed knowledge of the lipid composition of components of nephrons is crucial for understanding physiological processes and the development of kidney diseases. However, the lipidomic composition of kidney tubular segments is unknown. We manually isolated the proximal convoluted tubule (PCT), the cortical thick ascending limb of Henle's loop, and the cortical collecting duct from 5 lean and obese mice and subjected the samples to shotgun lipidomics analysis by high-resolution mass spectrometry acquisition. Across all samples, more than 500 lipid species were identified, quantified, and compared. We observed significant compositional differences among the 3 tubular segments, which serve as true signatures. These intrinsic lipidomic features are associated with a distinct proteomic program that regulates highly specific physiological functions. The distinctive lipidomic features of each of the 3 segments are mostly based on the relative composition of neutral lipids, long-chain polyunsaturated fatty acids, sphingolipids, and ether phospholipids. These features support the hypothesis of a lipotype assigned to specific tubular segments. Obesity profoundly impacts the lipotype of PCT. In conclusion, we present a comprehensive lipidomic analysis of 3 cortical segments of mouse kidney tubules. This valuable resource provides unparalleled detail that enhances our understanding of tubular physiology and the potential impact of pathological conditions.

Nanoparticles and Their Applications in Lipid Signaling.

This chapter provides an overview of the diverse range of applications associated with nanoparticles. The application of nanoparticles in the medical field has garnered considerable attention due to their unique properties and versatile compositions. They have shown promise in the treatment of cancer, fungal and viral infections, and pain management. These systems provide numerous benefits, such as increased drug stability, improved bioavailability, and targeted delivery to specific tissues or cells. The objective of this chapter is to provide a brief analysis of the differences between nanoparticles and lipid particles, focusing particularly on the importance of nanoparticle size and composition in their interactions with lipids. Additionally, the applications of nanoparticles in lipid signaling will be discussed, considering the vital roles lipids play in cellular signaling pathways. Nanoparticles have shown immense potential in the regulation and control of medical pathways. In this case, we will focus on the manufacture of liposomes, a type of nanoparticle composed of lipids. The reason behind the extensive investigation into liposomes as drug delivery vehicles is their remarkable biocompatibility and adaptability. This section will provide insights into the methods and techniques employed for liposome formulation.

Research Advances of Lipid Nanoparticles in the Treatment of Colorectal Cancer.

Colorectal cancer (CRC) is a common type of gastrointestinal tract (GIT) cancer and poses an enormous threat to human health. Current strategies for metastatic colorectal cancer (mCRC) therapy primarily focus on chemotherapy, targeted therapy, immunotherapy, and radiotherapy; however, their adverse reactions and drug resistance limit their clinical application. Advances in nanotechnology have rendered lipid nanoparticles (LNPs) a promising nanomaterial-based drug delivery system for CRC therapy. LNPs can adapt to the biological characteristics of CRC by modifying their formulation, enabling the selective delivery of drugs to cancer tissues. They overcome the limitations of traditional therapies, such as poor water solubility, nonspecific biodistribution, and limited bioavailability. Herein, we review the composition and targeting strategies of LNPs for CRC therapy. Subsequently, the applications of these nanoparticles in CRC treatment including drug delivery, thermal therapy, and nucleic acid-based gene therapy are summarized with examples provided. The last section provides a glimpse into the advantages, current limitations, and prospects of LNPs in the treatment of CRC.

Pharmacokinetics and Histotoxic Profile of a Novel Azithromycin-Loaded Lipid-Based Nanoformulation.

Azithromycin traditional formulations possesses poor oral bioavailability which necessitates development of new formulation with enhanced bioavailability of the drug. The objective of current research was to explore the kinetics and safety profile of the newly developed azithromycin lipid-based nanoformulation (AZM-NF). In the in-vitro study of kinetics profiling, azithromycin (AZM) release was assessed using dialysis membrane enclosing equal quantity of either AZM-NF, oral suspension of azithromycin commercial product (AZM-CP), or azithromycin pure drug (AZM-PD) in simulated intestinal fluid. The ex-vivo study was performed using rabbit intestinal segments in physiological salts solution in a tissue bath. The in-vivo study was investigated by oral administration of AZM to rabbits while taking blood samples at predetermined time-intervals, followed by HPLC analysis. The toxicity study was conducted in rats to observe histopathological changes in rat's internal organs. In the in-vitro study, maximum release was 95.38 ± 4.58% for AZM-NF, 72.79 ± 8.85% for AZM-CP, and 46.13 ± 8.19% for AZM-PD (p < 0.0001). The ex-vivo investigation revealed maximum permeation of 85.68 ± 5.87 for AZM-NF and 64.88 ± 5.87% for AZM-CP (p < 0.001). The in-vivo kinetics showed Cmax 0.738 ± 0.038, and 0.599 ± 0.082 µg/ml with Tmax of 4 and 2 h for AZM-NF and AZM-CP respectively (p < 0.01). Histopathological examination revealed compromised myocardial fibers integrity by AZM-CP only, liver and kidney showed mild aberrations by both formulations, with no remarkable changes in the rest of studied organs. The results showed that AZM-NF exhibited significantly enhanced bioavailability with comparative safer profile to AZM-CP investigated.

Lipid Emulsions Inhibit Labetalol-Induced Vasodilation in the Isolated Rat Aorta.

Lipid emulsions are used as adjuvant drugs to alleviate intractable cardiovascular collapse induced by drug toxicity. We aimed to examine the effect of lipid emulsions on labetalol-induced vasodilation and the underlying mechanism in the isolated rat aorta. We studied the effects of endothelial denudation, NW-nitro-l-arginine methyl ester (l-NAME), calmidazolium, methylene blue, 1H-[1,2,4]oxadiazolo[4,3-a] quinoxalin-1-one (ODQ), and lipid emulsions on labetalol-induced vasodilation. We also evaluated the effects of lipid emulsions on cyclic guanosine monophosphate (cGMP) formation, endothelial nitric oxide synthase (eNOS) phosphorylation, and endothelial calcium levels induced by labetalol. Labetalol-induced vasodilation was higher in endothelium-intact aortas than that in endothelium-denuded aortas. l-NAME, calmidazolium, methylene blue, and ODQ inhibited labetalol-induced vasodilation in endothelium-intact aortas. Lipid emulsions inhibited labetalol-induced vasodilation in endothelium-intact and endothelium-denuded aortas. l-NAME, ODQ, and lipid emulsions inhibited labetalol-induced cGMP formation in endothelium-intact aortas. Lipid emulsions reversed the stimulatory and inhibitory eNOS (Ser1177 and Thr495) phosphorylation induced by labetalol in human umbilical vein endothelial cells and inhibited the labetalol-induced endothelial calcium increase. Moreover, it decreased labetalol concentration. These results suggest that lipid emulsions inhibit vasodilation induced by toxic doses of labetalol, which is mediated by the inhibition of endothelial nitric oxide release and reduction of labetalol concentration.

Lipids and Lipid-Mediated Signaling in Plant-Pathogen Interactions.

Plant lipids are essential cell constituents with many structural, storage, signaling, and defensive functions. During plant-pathogen interactions, lipids play parts in both the preexisting passive defense mechanisms and the pathogen-induced immune responses at the local and systemic levels. They interact with various components of the plant immune network and can modulate plant defense both positively and negatively. Under biotic stress, lipid signaling is mostly associated with oxygenated natural products derived from unsaturated fatty acids, known as oxylipins; among these, jasmonic acid has been of great interest as a specific mediator of plant defense against necrotrophic pathogens. Although numerous studies have documented the contribution of oxylipins and other lipid-derived species in plant immunity, their specific roles in plant-pathogen interactions and their involvement in the signaling network require further elucidation. This review presents the most relevant and recent studies on lipids and lipid-derived signaling molecules involved in plant-pathogen interactions, with the aim of providing a deeper insight into the mechanisms underpinning lipid-mediated regulation of the plant immune system.

Potential of Polar Lipids Isolated from the Marine Sponge Haliclona (Halichoclona) vansoesti against Melanoma.

Marine sponges represent a good source of natural metabolites for biotechnological applications in the pharmacological, cosmeceutical, and nutraceutical fields. In the present work, we analyzed the biotechnological potential of the alien species Haliclona (Halichoclona) vansoesti de Weerdt, de Kluijver & Gomez, 1999, previously collected in the Mediterranean Sea (Faro Lake, Sicily). The bioactivity and chemical content of this species has never been investigated, and information in the literature on its Caribbean counterpart is scarce. We show that an enriched extract of H. vansoesti induced cell death in human melanoma cells with an IC50 value of 36.36 µg mL-1, by (i) triggering a pro-inflammatory response, (ii) activating extrinsic apoptosis mediated by tumor necrosis factor receptors triggering the mitochondrial apoptosis via the involvement of Bcl-2 proteins and caspase 9, and (iii) inducing a significant reduction in several proteins promoting human angiogenesis. Through orthogonal SPE fractionations, we identified two active sphingoid-based lipid classes, also characterized by nuclear magnetic resonance and mass spectrometry, as the main components of two active fractions. Overall, our findings provide the first evaluation of the anti-cancer potential of polar lipids isolated from the marine sponge H. (Halichoclona) vansoesti, which may lead to new lead compounds with biotechnological applications in the pharmaceutical field.

The Effects of Pregestational Overweight and Obesity on Maternal Lipidome in Pregnancy: Implications for Newborns' Characteristics.

Obesity is an important risk factor for the development of pregnancy complications. We investigated the effects of pregestational overweight and obesity on maternal lipidome during pregnancy and on newborns' characteristics. The study encompassed 131 pregnant women, 99 with pre-pregnancy body mass index (BMI) < 25 kg/m2 and 32 with BMI ≥ 25 kg/m2. Maternal lipid status parameters, plasma markers of cholesterol synthesis and absorption and sphingolipids were determined in each trimester. Data on neonatal height, weight and APGAR scores were assessed. The results showed a higher prevalence (p < 0.05) of pregnancy and childbirth complications among the participants with elevated pregestational BMI. Levels of total cholesterol, HDL-cholesterol (p < 0.05) and LDL-cholesterol (p < 0.01) were significantly lower, and concentrations of triglycerides were higher (p < 0.05) in women with increased pre-gestational BMI. Lower concentrations of the cholesterol synthesis marker, desmosterol, in the 2nd trimester (p < 0.01) and the cholesterol absorption marker, campesterol, in each trimester (p < 0.01, p < 0.05, p < 0.01, respectively) were also found in this group. Markers of maternal cholesterol synthesis were in positive correlation with neonatal APGAR scores in the group of mothers with healthy pre-pregnancy weight but in negative correlation in the overweight/obese group. Our results indicate that gestational adaptations of maternal lipidome depend on her pregestational nutritional status and that such changes may affect neonatal outcomes.

Small and Large Extracellular Vesicles of Porcine Seminal Plasma Differ in Lipid Profile.

Seminal plasma contains a heterogeneous population of extracellular vesicles (sEVs) that remains poorly characterized. This study aimed to characterize the lipidomic profile of two subsets of differently sized sEVs, small (S-) and large (L-), isolated from porcine seminal plasma by size-exclusion chromatography and characterized by an orthogonal approach. High-performance liquid chromatography-high-resolution mass spectrometry was used for lipidomic analysis. A total of 157 lipid species from 14 lipid classes of 4 major categories (sphingolipids, glycerophospholipids, glycerolipids, and sterols) were identified. Qualitative differences were limited to two cholesteryl ester species present only in S-sEVs. L-sEVs had higher levels of all quantified lipid classes due to their larger membrane surface area. The distribution pattern was different, especially for sphingomyelins (more in S-sEVs) and ceramides (more in L-sEVs). In conclusion, this study reveals differences in the lipidomic profile of two subsets of porcine sEVs, suggesting that they differ in biogenesis and functionality.

Systematic Review of Randomized Controlled Trials in Uses of Nigella Sativa (Black Seed) in Metabolic Syndrome.

BACKGROUND: Metabolic syndrome as defined by The National Cholesterol Education Panel-Adult Treatment Panel III (NCEPATP III), is the presence of obesity, dyslipidaemia, the elevation of arterial blood pressure, and glucose intolerance. It affects 25% to 40% of the adult population of Malaysia and is associated with other medical conditions, especially cardiovascular disease. In this systematic review, the objective is to assess the effects of Nigella Sativa on parameters that reflect metabolic syndromes, such as lipid profile, blood pressure, blood glucose, and anthropometry indices. METHODS: This systematic review was conducted by performing searches for relevant publications on two databases (PubMed and Scopus). The publication period was limited from January 2011 to December 2021. Cochrane collaboration tools were used for the risk of bias assessment of each trial. RESULT: Six out of 8 randomised controlled trials (n:776) demonstrated a significant improvement in lipid profile (p <0.05), 5 out of 7 trials (n:701) showed a significant reduction in glycaemic indices (p <0.05), 1 out of 5 trials (n:551) demonstrated significant improvements in blood pressure (p <0.05), and 2 out of 7 trials (n:705) showed a significant reduction in anthropometric measurements (p <0.05). CONCLUSION: Nigella Sativa has proved to have a significant positive effect on lipid profile and glycaemic index. The results showed in the parameters of blood pressure and anthropometric indices are less convincing, as results were inconsistent across studies. Nigella Sativa can therefore be recommended as an adjunct therapy for metabolic syndrome.

CONTEXTE: Le syndrome métabolique, tel que défini par le National Cholesterol Education Panel-Adult Treatment Panel III (NCEP-ATP III), se caractérise par la présence d'obésité, de dyslipidémie, d'hypertension artérielle et d'intolérance au glucose. Il affecte 25% à 40% de la population adulte en Malaisie et est associé à d' autres affections médicales, notamment les maladies cardiovasculaires. L'objectif de cette revue systématique est d'évaluer les effets de Nigella Sativa sur des paramètres reflétant le syndrome métabolique, tels que le profil lipidique, la pression artérielle, la glycémie et les indices anthropométriques. MÉTHODES: Cette revue systématique a été réalisée en effectuant des recherches de publications pertinentes dans deux bases de données (PubMed et Scopus). La période de publication était limitée de janvier 2011 à décembre 2021. Les outils de la collaboration Cochrane ont été utilisés pour évaluer le risque de biais de chaque essai. RÉSULTATS: Six des huit essais contrôlés randomisés (n : 776) ont montré une amélioration significative du profil lipidique (p <0,05), cinq des sept essais (n : 701) ont montré une réduction significative des indices glycémiques (p <0,05), un des cinq essais (n : 551) a démontré des améliorations significatives de la pression artérielle (p<0,05), et deux des sept essais (n : 705) ont montré une réduction significative des mesures anthropométriques (p <0,05). CONCLUSION: Nigella Sativa a prouvé avoir un effet positif significatif sur le profil lipidique et les indices glycémiques. Les résultats concernant les paramètres de la pression artérielle et des indices anthropométriques sont moins convaincants, car les résultats étaient incohérents entre les études. Nigella Sativa peut donc être recommandée comme thérapie adjuvante pour le syndrome métabolique. MOTS CLÉS: Nigella Sativa, Graines de nigelle, Essai contrôlé randomisé, Syndrome métabolique.

[Associations between 4 lipid biomarkers and cardiometabolic multimorbidity development in middle aged and old adults in China].

Objective: To estimate the longitudinal association between serum lipid biomarkers and the development of cardiometabolic multimorbidity (CMM) in middle-aged and old adults (≥45) in China, while examining effect differences among degree of dyslipidemia aggregation and various dyslipidemia combination patterns. Methods: Based on data from the China Health and Retirement Longitudinal Study (2011-2018), logistic regression analysis was used to evaluate the associations of TC, LDL-C, HDL-C, TG (4 forms of dyslipidemias), degree and pattern of dyslipidemia combination with CMM. We also used restricted cubic splines to show the dose-response associations between 4 lipid biomarkers and CMM development. Results: Of the 6 522 participants included, 590 (9.05%) developed CMM. After adjusting for covariates, all 4 forms of dyslipidemias were positively associated with CMM development (high TC: OR=1.33, 95%CI: 1.03-1.71; high LDL-C: OR=1.35, 95%CI: 1.05-1.75; low HDL-C: OR=1.45, 95%CI: 1.19-1.77; high TG: OR=1.50, 95%CI: 1.20-1.88). The U-shaped dose-response relationship between LDL-C and CMM development was observed (P for non-linear =0.022). The odds of CMM increased with the increase of dyslipidemias forms, which was highest in those with ≥3 forms of dyslipidemias (OR=2.02, 95%CI: 1.33-3.06). In various dyslipidemia form combinations, the possibility of CMM development was highest in those with high TC, high LDL-C and low HDL-C (OR=3.54, 95%CI: 1.40-8.67). High TC and high LDL-C were significantly associated with CMM development in people without cardiometabolic diseases. Low HDL-C was positively associated with diabetes and CMM development in participants without cardiometabolic diseases, cardiovascular disease (CVD) followed by diabetes, and diabetes followed by CVD. High TG was positively associated with diabetes and CMM in participants without cardiometabolic diseases, and diabetes followed by CVD. Conclusions: A total of 4 forms of dyslipidemia were all independently associated with CMM development in middle-aged and old adults in China. The dose-response relationship between LDL-C level and CMM development was U-shaped. The aggregation of 4 forms of dyslipidemia were associated with the development of CMM. Low HDL-C and high TG were significantly associated with multiple patterns of cardiometabolic diseases development.

Solid Lipid Nanoparticles Encapsulating a Benzoxanthene Derivative in a Model of the Human Blood-Brain Barrier: Modulation of Angiogenic Parameters and Inflammation in Vascular Endothelial Growth Factor-Stimulated Angiogenesis.

Lignans, a class of secondary metabolites found in plants, along with their derivatives, exhibit diverse pharmacological activities, including antioxidant, antimicrobial, anti-inflammatory, and antiangiogenic ones. Angiogenesis, the formation of new blood vessels from pre-existing ones, is a crucial process for cancer growth and development. Several studies have elucidated the synergistic relationship between angiogenesis and inflammation in various inflammatory diseases, highlighting a correlation between inflammation and vascular endothelial growth factor (VEGF)-induced angiogenesis. Thus, the identification of novel molecules capable of modulating VEGF effects presents promising prospects for developing therapies aimed at stabilizing, reversing, or even arresting disease progression. Lignans often suffer from low aqueous solubility and, for their use, encapsulation in a delivery system is needed. In this research, a bioinspired benzoxantene has been encapsulated in solid lipid nanoparticles that have been characterized for their pharmacotechnical properties and their thermotropic behavior. The effects of these encapsulated nanoparticles on angiogenic parameters and inflammation in VEGF-induced angiogenesis were evaluated using human brain microvascular endothelial cells (HBMECs) as a human blood-brain barrier model.