Per- and polyfluoroalkyl substances (PFAS) are harmful environmental contaminants that bioaccumulate in human tissues and are linked to adverse health outcomes. While PFAS are known to bind to a variety of lipid binding proteins (LBPs), such as human serum albumin and fatty acid-binding proteins (FABPs), the broader molecular basis for their biological distribution and breadth of protein binding in humans remains unanswered. We hypothesize that some distribution and persistence of PFAS in humans arises from a distributed network of lipid transfer proteins that collectively solubilize and transport these compounds. To support this hypothesis, we investigated the interaction between various PFAS and human sterol carrier protein 2 (SCP2), a promiscuous, structurally distinct LBP with no previously reported binding with PFAS. Using a combination of screening, fluorescence displacement assays, protein structure prediction of PFAS-SCP2 complexes, and NMR experiments, we demonstrate for the first time that SCP2 is a PFAS-binding protein. Our findings establish SCP2 as a new PFAS-interacting protein, providing insights into the residues participating in these interactions and further supporting the hypothesis that PFAS engage with a broad network of LBPs to facilitate their distribution and persistence in the human body.

Mitochondrial dysfunction plays a crucial role in neuropsychiatric disorders, including delirium.To explore the causal links between mitochondrial-related druggable genes, cerebrospinal fluid metabolites, and delirium.Summary-level data on mitochondrial-related druggable genes, expression quantitative trait loci (eQTLs), 338 cerebrospinal fluid (CSF) metabolites, and delirium data were obtained from publicly accessible genome-wide association studies. A two-sample Mendelian randomization (MR) was applied to assess the causal effects of blood cis-eQTL of mitochondrial-related druggable genes on delirium. Sensitivity analyses were also undertaken to ensure the MR results' reliability. We assessed whether cerebrospinal fluid metabolites mediate the causal relationship between druggable mitochondrial genes and delirium.A total of 12 mitochondrial-related druggable genes (8 protective and 4 risk) were identified to be associated with delirium risk (p < 0.05). Furthermore, 20 CSF metabolites were significantly associated with delirium, 9 positively and 11 negatively. Sensitivity analyses showed no evidence of heterogeneity or horizontal pleiotropy. Mediation analysis indicated that 3-hydroxyoctanoate partially mediated the causal association between sterol carrier protein 2 (SCP2) and delirium, accounting for approximately 19.23% of the total effect.The present work reveals that mitochondrial-related genes and CSF metabolites may play causal roles in delirium and highlights SCP2-3-hydroxyoctanoate as a novel molecular axis. These findings expand current knowledge of delirium pathogenesis and offer a potential molecular target for diagnosis and therapy. Further experimental validation and population-diverse studies are needed to confirm these findings.

This study evaluated the larvicidal efficacy of the methanol extract of Dactyloctenium aegyptium against Aedes aegypti (L, 1762) (Diptera: Culicidae), Anopheles stephensi Liston, 1901 (Diptera: Culicidae), and Culex quinquefasciatus Say, 1823 (Diptera: Culicidae). The methanol extract exhibited the highest mortality rates, achieving 100% mortality at 250µg/mL for all species tested, and demonstrated the lowest LC50 values of 94.28µg/mL for Ae. aegypti, 119.07µg/mL for An. stephensi, and 103.71µg/mL for Cx. quinquefasciatus. In contrast, the n-hexane extract was the least effective against Ae. aegypti and Cx. quinquefasciatus, while the chloroform extract showed the least efficacy against An. stephensi. Statistical analysis confirmed the significant impact of extract concentration, type, and mosquito species on mortality rates, with the model explaining 98.4% of the variance. GC-MS analysis of the methanol extract identified several bioactive compounds, with stigmasterol being the most abundant (13.92%), followed by gamma-sitosterol (10.40%) and campesterol (5.31%). Molecular docking studies revealed that campesterol exhibited the highest binding affinity with docking scores of -9.6kcal/mol for the sterol carrier protein from Ae. aegypti (PDB ID: 1PZ4) and -10.3kcal/mol for acetylcholinesterase from Anopheles gambiae (PDB ID: 5X61). Additionally, stigmasterol and sitosterol showed significant binding affinities of -9.4 and -9.0kcal/mol against 1PZ4, and -9.5 and -9.4kcal/mol against 5X61, respectively. Citrost-7-en-3-ol demonstrated a promising affinity of -9.7kcal/mol for acetylcholinesterase. Overall, the methanol extract of D. aegyptium shows promise for mosquito control, with specific compounds identified as potential inhibitors of key targets in vector control strategies.

Comparative transcriptomic analysis reveals bioluminescence-related genes in firely Pyrocoelia pectoralis.

Plant-based insecticides are getting attention as an alternative mosquito control strategy because of the emergence of insect resistance to currently used synthetic chemicals. Further, their high safety profile makes them ideal candidates for environmental applications. The current study evaluated the insecticidal potential of Psidium guajava and Piper betle leaf extracts against Aedes aegypti through in vitro and in silico approaches. In laboratory studies, the LC50 of n-hexane extract of P. guajava and ethyl acetate extract of P. betle were 95.21 ppm and 217.7 ppm after 24-h exposure, respectively. The gas chromatography-mass spectrometry analysis identified important bioactive compounds, including caryophyllene (21.2%), globulol (19.9%), squalene (8.3%), and γ-muurolene (6.6%) in P. guajava and hydroxychavicol (57%), 5-allyl-2-hydroxyphenyl acetate (5.6%), phytol (2.3%), and safrole (1.8%) in P. betle extract. In silico analysis of these compounds with target proteins acetylcholinesterase (AChE), S-adenosylhomocysteine hydrolase (SAHH), and sterol carrier protein-2 (SCP-2) in Ae. aegypti larvae showed that squalene from P. guajava had a higher binding affinity with AChE (-8.4 kcal/mol) compared to globulol (-7.3 kcal/mol). However, conventional hydrogen bonding, which is stronger and more stable, was observed in the globulol-AChE complex. The in silico analysis of P. betle phytochemicals demonstrated that hydroxychavicol, phytol, and safrole had binding affinities of -6.1 kcal/mol, -6.0 kcal/mol, and -6.0 kcal/mol with SAHH, respectively. A minor increase in binding affinity was observed in the safrole-SAHH complex (-6.1 kcal/mol), whereas no change was observed in the 5-allyl-2-hydroxyphenyl acetate-AChE complex (-5.9 kcal/mol) in 2-ligand binding mode. Since these bioactive compounds target the important proteins in the developmental processes of mosquito larvae, they can further be evaluated to design natural and organic insecticides against Ae. aegypti.

Mitochondria have been linked with inflammatory colorectal cancer (CRC) development; however, the association between mitochondria-related genes (MRGs) and CRC remains unknown. To explore the causal relationship between MRGs and CRC, screen prognostic genes, conduct drug prediction analyses, and investigate the correlations between prognostic genes and immune cells. We obtained 1136 MRGs from the MitoCarta3.0 database and analyzed the causal relationship between MRGs expression, methylation, and protein abundance and CRC by Mendelian randomization and sensitivity testing. Prognostic genes were screened via protein-protein interaction networks, enrichment, multi-omics, and survival analyses. Selected key genes were subjected to drug prediction analyses. The prognostic genes and immune cell correlations were explored using Spearman's correlation. The results indicated that 44 MRGs showed causal relationships with CRC. Six genes (sterol carrier protein2 [SCP2], ATP binding cassette subfamily D member 3 [ABCD3], cytochrome coxidase assembly factor heme A: farnesyltransferase [COX10], mitochondrial contact site and cristae organizing system subunit 10 [MiCOS 10], glutaryl-Coenzyme A dehydrogenase [GCDH], and mitochondrial translational release factor 1-like [MTRF1L] were causally associated with CRC and showed better prognostic significance when their expression levels were high, and there were 106 drugs targeting them. SCP2, ABCD3, MICOS10, GCDH, and MTRF1L were associated with most immune cells, while COX10 was not associated with any of the 96 immune cells. The identification of causal MRGs and their prognostic significance provides new insights into mitochondria's role in CRC. Drug prediction and immune correlations may guide therapy, but validation in larger cohorts and models is needed. This study reveals causal associations between specific MRGs and CRC, identifies prognostic genes with therapeutic potential, and clarifies immune cell relationships, advancing CRC pathogenesis understanding and treatment development.

Objective： To investigate the relationship between the lipid metabolism-related gene sterol carrier protein 2(SCP2) and prostate cancer (PCa) from a multi-omics perspective using single-cell transcriptomes combined with Mendelian randomization. Methods： Single-cell transcriptome data of benign and malignant prostate tissues were obtained from GSE120716, GSE157703 and GSE141445 datasets, respectively. Integration, quality control and annotation were performed on the data to categorize the epithelial cells into high and low SCP2 expression groups, followed by further differential and trajectory analyses. Single nucleotide polymorphism (SNP) data for SCP2 expression quantitative trait loci (eQTL) were subsequently downloaded from Genotype-Tissue Expression (GTEx) and investigated from the PCa Society Cancer-Related Genomic Alteration Panel for the Investigation of Cancer-Related Alterations (PRACTICAL) to obtain PCa outcome data for Mendelian randomization analysis to validate the causal relationship between SCP2 and PCa. Results： High SCP2-expressing epithelial cells had higher energy metabolism and proliferation capacity with low immunotherapy response and metastatic tendency. Trajectory analysis showed that epithelial cells with high SCP2 expression may have a higher degree of malignancy, and SCP2 may be a key marker gene for differentiation of malignant epithelial cells in the prostate. Further Mendelian randomization results showed a significant causal relationship between SCP2 and PCa development (OR=1.045, 95% CI: 1.010 －1.083, P=0.011). Conclusion： By combining single-cell transcriptome and Mendelian randomization, the role of the lipid metabolism-related gene SCP2 in PCa development has been confirmed, and new targets and therapeutic directions for PCa treatment have been provided.

Abstract Purpose: Standard treatment for metastatic castration-resistant prostate cancer (mCRPC) includes androgen receptor (AR) pathway inhibitors (ARPIs), such as androgen deprivation therapy or enzalutamide. Despite prolonged survival with ARPI therapies, resistance is nearly universal, highlighting the urgent need to identify new resistance mechanisms and therapeutic targets. Methods: We combined systems-level and experimental approaches to identify and test actionable network nodes linked to ARPI resistance as therapeutic vulnerabilities in prostate cancer. Systems-level analyses were performed using weighted gene co-expression network analysis and Bayesian network inference. Networks were overlaid with experimental data, including ENCODE ChIP-Seq data. The in vitro efficacy of pocebrodib was evaluated in a series of enzalutamide-sensitive and -resistant prostate cancer cell lines using CellTiter-Glo, colony forming assays and 3D spheroid assays. The in vivo activity of pocebrodib was evaluated in patient-derived xenografts. Proteomics and acetylomics was used to interrogate the potential mechanisms of action for pocenbrodib. Results were validated by RT-qPCR, western blotting and flow cytometry. Knockdown studies were performed using non-targeting and SCP2-targeting siRNAs. Results: Multi-layer network inference pinpointed the CREB binding protein (CBP)/p300 complex as a key regulatory node associated with patient outcomes and ARPI resistance. Consistent with this observation, preclinical testing of the CBP/p300 inhibitor, pocebrodib, demonstrated efficacy in both enzalutamide-sensitive and -resistant lines in vitro, with IC50s of ∼1 μM. Cell growth inhibition was accompanied by downregulation of AR activity, as indicated by RNA-Seq and RT-qPCR. Pocenbrodib also demonstrated tumor growth inhibition of both enzalutamide-sensitive and -resistant patient-derived xenografts and a durable response in a patient with ARPI-resistant prostate cancer as part of the Phase I COURAGE study. Proteomics and acetylomics identified differential acetylation of both histone and non-histone proteins, including a subset of histone acetylation events altered in enzalutamide-resistant cells that are restored upon treatment with pocenbrodib. These analyses also identified enrichment of fatty acid metabolism proteins, including the sterol carrier protein 2 (SCP2) and fatty acid synthase (FASN), suggesting CBP inhibition may cause cells to sense loss of acetyltransferase activity as a reduction in free acetyl-coA, leading to alteration in fatty acid metabolism as a feedback response. Conclusion: Inhibition of the CBP/p300 axis by pocenbrodib is a promising new approach to treat ARPI-resistant prostate cancer. Future studies are aimed at clinical evaluation of pocenbrodib and exploration of downstream signaling axes to identify key biomarkers of response to pocenbrodib. Citation Format: Ananya Dutta, Beatrice C. Thomas, Pelumi Olawuni, Erik Soderblom, Eric Schadt, Bonnie Dougherty, Andrew J. Armstrong, Jason A. Jason A. Somarelli. Targeting the AR co-activator CBP/p300 in metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6920.

The indiscriminate use of synthetic insecticides for mosquito control has resulted in significant challenges, such as environmental pollution and growing insecticide resistance. In response, there is increasing interest in eco-friendly alternatives like plant-based larvicides. This study assesses the larvicidal efficacy of Chloris virgate (Poales: Poaceae) extracts against Aedes aegypti (Diptera: Culicidae), Culex quinquefasciatus (Diptera: Culicidae), and Anopheles stephensi (Diptera: Culicidae), and investigates the bioactive chemical compounds responsible for this activity. Soxhlet individual extraction was performed using n-hexane, chloroform, and ethanol, and methanol solvents are used separately to extract bioactive compounds from C. virgata. This approach allows for the selective extraction of specific compounds based on their solubility in each solvent. The extracts were tested on fourth instar larvae, and lethal concentrations (LC50 and LC90) were calculated via probit analysis. The methanol extract exhibited the lowest LC50 and LC90 values against Culex quinquefasciatus, with LC50 at 80.11ppm and LC90 at 176.22ppm, suggesting higher toxicity and effectiveness in larvicidal activity. Methanol extracts significantly affected mosquito larvae midguts, causing cytoplasmic thinning, muscle fiber disorganization, and brush border disruption. Gas chromatography-mass spectrometry (GC-MS) analysis identified major compounds such as stigmasterol, campesterol, and γ-sitosterol. Campesterol, 4.alpha.,14-Dimethyl-5.alpha, and Lanosterol showed strong binding affinities with acetylcholine esterase (5X61), exhibiting multiple hydrophobic interactions with key residues, including TRP 441, TYR 282, and CYS 447. Campesterol also displayed significant binding to Sterol Carrier Protein-2 (1PZ4) and Odorant-Binding Protein (3OGN) with several hydrophobic interactions, achieving binding affinities of - 10.1kcal/mol and - 9.7kcal/mol, respectively. This study highlights the potential of C. virgata methanol extracts as a promising eco-friendly larvicide for mosquito population management.

The Aedes aegypti mosquito is the primary vector of dengue, a neglected disease and a serious public health problem in tropical countries. The control of this vector has been carried out using chemical insecticides, which impact human health. Thus, it is essential to develop natural larvicides that are less harmful to the environment. This study investigates the circadian cycle and larvicidal activity of essential oils from Croton blanchetianus against Aedes aegypti. The leaf oils were extracted by hydrodistillation and analyzed by GC–MS and GC–FID. The circadian study revealed variations in the chemical composition of oils extracted at different times of the day. The main constituents were α-pinene, β-phellandrene, eucalyptol, β-caryophyllene, bicyclogermacrene, and spathulenol. The larvicidal activity showed LC50 values at the following different collection times: 55.294 ± 3.209 μg/mL at 08:00 h; 95.485 ± 2.684 μg/mL at 12:00 h; and 64.883 ± 1.780 μg/mL at 17:00 h. Molecular docking simulations indicated that α-pinene, β-phellandrene, eucalyptol, and β-caryophyllene strongly interact with the active site of the sterol carrier protein, suggesting their role in larvicidal activity. These findings reinforce the potential of C. blanchetianus essential oils as an alternative for Aedes aegypti control. The predictive pharmacokinetic tests showed a PAMPA profile associated with high effective cellular permeability and microsomal stability, resulting from the metabolic stability of the derivatives (3) eucalyptol and (6) spathulenol, indicating that these compounds have the highest pharmacokinetic viability and low reactivity with respect to organ toxicity.

Expanding the scope of copper artificial metalloenzymes: A potential fluorinase?

The study of membranes and their associated proteins is critical for understanding cellular processes. In vitro investigations utilizing membrane models often have limitations in their biological relevance due to the dissimilarity of experimentally compatible membrane mimetics to biological membranes. Development of membrane models that better mimic cellular membranes enables more biologically accurate observations of membrane associated proteins. In this work, we present upper tolerance concentrations for a range of lipids incorporated into reverse micelles (RMs), confirmed with dynamic light scattering (DLS). A breadth of lipid incorporation enabled biologically inspired RMs to be formulated based on the molar ratios of lipids present in eukaryotic membrane leaflets. Three systems were formulated matching lipid compositions of the inner leaflet of the plasma membrane (PM-RM), the outer mitochondrial membrane leaflet (MI-RM), and the outer rough endoplasmic reticulum membrane leaflet (ER-RM). The biologically-inspired RM formulations were characterized using DLS and cryo-electron microscopy (cryo-EM) and were found to have favorable properties for protein encapsulation. All three biologically inspired RM formulations effectively encapsulated fatty acid binding protein 4 (FABP4), a protein which shuttles fatty acids between membranes, confirmed by NMR. Also presented in this work is the first known high-resolution observation of the membrane-bound state of sterol carrier protein 2 (SCP2), a protein responsible for transporting an array of lipids between membranes. SCP2 was successfully encapsulated within all three RM systems, enabling NMR observation of the membrane interface of SCP2. The tolerances and formulations reported here allow for tailoring of RMs to mimic specific cellular membranes and will enhance studies of protein interactions with lipids and membranes among other investigations.

The fruit and other parts of Momordica cymbalaria are known to have medicinal properties. The study investigates the chemical composition and functional groups of M. cymbalaria fruits to assess the insecticidal potential of its bioactive metabolites. In silico approach was used to understand the mechanism behind the insecticidal nature of these metabolites. Ethyl acetate extract has 18 compounds, whereas 20 compounds were identified in methanol using gas chromatography-mass spectroscopy analysis. The extracts contain several functional groups, including alkanes, esters, carboxylic acids, amides and aromatic groups. The insecticidal bioassay using methanol and ethyl acetate extracts of M. cymbalaria on Aedes aegypti and Culex quinquefasciatus mosquito larvae shows that the LC50 value for A. aegypti was 65.7ppm, for C. quinquefasciatus was 96.9ppm and for ethyl acetate and methanol extract is 282.36 and 388.09ppm. Molecular docking of secondary metabolites was performed with five insect proteins, namely, odorant binding protein (OBP), cytochrome P450 (CYP450), prophenol oxidase (PPO), arylalkylamine n-acetyltransferease (aaNAT) and sterol carrier protein (SCP). Results show that methyl 6-cis, 9-cis, 11-trans-octadecatrienoate has high binding affinity with sterol carrier protein (SCP-2) besides showing binding with other insect proteins. The data suggest that methyl 6-cis, 9-cis, 11-trans-octadecatrienoate has multiple insecticidal actions and may serve as a green insecticide.

The proteome and metabolome changes distinguish the effect of dietary energy levels on the development of ovary in chicken during sexual maturity

PurposeNeutrophilic asthma (NA) is associated with more severe symptoms and poor responsiveness to inhaled corticosteroid therapy. Macrophages are the most abundant immune cells in the airway, but the role of macrophages in NA pathogenesis has not been fully studied. We hypothesized that dysregulation of peroxisome metabolism in macrophages may drive NA.MethodsWe retrieved microarray datasets from the GEO Gene Expression Omnibus database by using induced sputum samples from eosinophilic and neutrophilic asthma patients as well as healthy controls. We identified key molecules in NA and validated the expression of the key genes in our cohort of asthma patients using quantitative polymerase chain reaction (PCR). Furthermore, immunofluorescence staining was performed to detect the expression and localization of the key molecule in bronchoalveolar lavage (BAL) cells from asthma patients and the murine model of neutrophilia-dominant allergic airway inflammation. The expression of the key molecule was also examined in mouse bone marrow-derived macrophages (BMDMs) by quantitative PCR and western blotting.ResultsEnoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase (EHHADH), sterol carrier protein 2, and peroxisomal biogenesis factor 14 were identified as the key molecules and were downregulated in patients with NA or severe asthma. The peroxisomal fatty acid metabolism pathway was significantly downregulated in NA. In our cohort of asthma patients, the expression of EHHADH, a key enzyme of the peroxisomal fatty acid beta-oxidation, was significantly decreased in non-eosinophilic asthma patients and positively correlated with airflow limitation. EHHADH was primarily expressed in macrophages in BAL cells. EHHADH was downregulated in lipopolysaccharide (LPS)-induced M1-like macrophages in mouse BMDMs. Fenofibrate, an agonist of the peroxisome pathway, significantly inhibits LPS-induced macrophage M1 polarization.ConclusionsEHHADH expression and the peroxisome metabolism pathway are downregulated in macrophages in patients with NA. This downregulation may contribute to macrophage M1 polarization and neutrophilic airway inflammation in asthma.

Ferroptosis-associated alterations in diabetes following ischemic stroke: Insights from RNA sequencing

Abstract. Objectives. The objectives of this study were twofold: to analyze the composition and content of fatty acids in various adipose tissues (including kidney, abdominal, subcutaneous, and omental) of Yanbian yellow cattle and to observe the morphology of adipocytes within these tissues and to assess the level of expression of specific genes – kinase insert domain receptor (KDR), apolipoprotein L domain containing 1 (APOLD1), stearoyl-CoA desaturase 1 (SCD1), secreted frizzled-related protein 4 (SFRP4), fatty-acid-binding protein 5 (FABP5), and sterol carrier protein-2 (SCP2) – in different adipose tissues (kidney, abdominal, posterior belly, ribeye, prothorax, striploin, upper brain, and neck) of Yanbian yellow cattle. Method. Castrated Yanbian yellow cattle, 24 months old, with identical genetic backgrounds and raised under the same breeding management conditions, were selected. The fatty acid composition and content were assessed using gas chromatography, while the size and diameter of adipocytes were analyzed via paraffin sectioning. The level of expression was determined using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Results. In total, 16 distinct fatty acids were identified in abdominal adipose tissue. Additionally, henicosanoic acid (C21:0) and behenic acid (C22:0) were detected exclusively in subcutaneous adipose tissue. Caprylic acid (C8:0) was found in both kidney and omental adipose tissues. The size of individual adipocytes in kidney adipose tissue was notably larger compared to the adipocytes in the other three regions (p&lt;0.05). Regarding gene expression, APOLD1 exhibits its highest expression in striploin adipose tissues (p&lt;0.05), while SCD1 shows its peak expression in prothorax adipose tissues (p&lt;0.05). Moreover, both FABP5 and SCP2 demonstrate their highest level of expression in prothorax adipose tissue (p&lt;0.05). Furthermore, the level of expression of KDR and SFRP4 across these seven adipose tissue regions exhibits significant differences (p&lt;0.05). Conclusion. In conclusion, Yanbian yellow cattle exhibit variations in both the composition and content of fatty acids across different adipose tissue depots, including the kidney, abdominal, subcutaneous, and omental regions. Moreover, adipocytes display distinct morphological differences across these tissue types. Furthermore, the level of expression of KDR, APOLD1, SCD1, SFRP4, FABP5, and SCP2 varies significantly among adipose tissues located in the kidney, abdominal, posterior belly, ribeye, prothorax, striploin, upper brain, and neck regions.

A proteomics-based study of the mechanism of oxymatrine to ameliorate hepatic fibrosis in mice

Harnessing nature's arsenal: Ochrobactrum bacteria metabolites in the battle against root- knot nematode – Insights from in vitro and molecular docking studies

Investigation of the insecticidal potential of curcumin derivatives that target the Helicoverpa armigera sterol carrier protein-2