Synthesis and Structure Optimization of Star Copolymers as Tunable Macromolecular Carriers for Minimal Immunogen Vaccine Delivery.

Minimal immunogen vaccines are being developed to focus antibody responses against otherwise challenging targets, including human immunodeficiency virus (HIV), but multimerization of the minimal peptide immunogen on a carrier platform is required for activity. Star copolymers comprising multiple hydrophilic polymer chains ("arms") radiating from a central dendrimer unit ("core") were recently reported to be an effective platform for arraying minimal immunogens for inducing antibody responses in mice and primates. However, the impact of different parameters of the star copolymer (e.g., minimal immunogen density and hydrodynamic size) on antibody responses and the optimal synthetic route for controlling those parameters remains to be fully explored. We synthesized a library of star copolymers composed of poly[N-(2-hydroxypropyl)methacrylamide] hydrophilic arms extending from poly(amidoamine) dendrimer cores with the aim of identifying the optimal composition for use as minimal immunogen vaccines. Our results show that the length of the polymer arms has a crucial impact on the star copolymer hydrodynamic size and is precisely tunable over a range of 20-50 nm diameter, while the dendrimer generation affects the maximum number of arms (and therefore minimal immunogens) that can be attached to the surface of the dendrimer. In addition, high-resolution images of selected star copolymer taken by a custom-modified environmental scanning electron microscope enabled the acquisition of high-resolution images, providing new insights into the star copolymer structure. Finally, in vivo studies assessing a star copolymer vaccine comprising an HIV minimal immunogen showed the criticality of polymer arm length in promoting antibody responses and highlighting the importance of composition tunability to yield the desired biological effect.

Sybil Attacks Detection and Traceability Mechanism Based on Beacon Packets in Connected Automobile Vehicles.

Connected Automobile Vehicles (CAVs) enable cooperative driving and traffic management by sharing traffic information between them and other vehicles and infrastructures. However, malicious vehicles create Sybil vehicles by forging multiple identities and sharing false location information with CAVs, misleading their decisions and behaviors. The existing work on defending against Sybil attacks has almost exclusively focused on detecting Sybil vehicles, ignoring the traceability of malicious vehicles. As a result, they cannot fundamentally alleviate Sybil attacks. In this work, we focus on tracking the attack source of malicious vehicles by using a novel detection mechanism that relies on vehicle broadcast beacon packets. Firstly, the roadside units (RSUs) randomly instruct vehicles to perform customized key broadcasting and listening within communication range. This allows the vehicle to prove its physical presence by broadcasting. Then, RSU analyzes the beacon packets listened to by the vehicle and constructs a neighbor graph between the vehicles based on the customized particular fields in the beacon packets. Finally, the vehicle's credibility is determined by calculating the edge success probability of vehicles in the neighbor graph, ultimately achieving the detection of Sybil vehicles and tracing malicious vehicles. The experimental results demonstrate that our scheme achieves the real-time detection and tracking of Sybil vehicles, with precision and recall rates of 98.53% and 95.93%, respectively, solving the challenge of existing detection schemes failing to combat Sybil attacks from the root.

Bioprospecting the American Alligator Peptidome for antiviral peptides against Venezuelan equine encephalitis virus.

The innate immune protection provided by cationic antimicrobial peptides (CAMPs) has been shown to extend to antiviral activity, with putative mechanisms of action including direct interaction with host cells or pathogen membranes. The lack of therapeutics available for the treatment of viruses such as Venezuelan equine encephalitis virus (VEEV) underscores the urgency of novel strategies for antiviral discovery. American alligator plasma has been shown to exhibit strong in vitro antibacterial activity, and functionalized hydrogel particles have been successfully employed for the identification of specific CAMPs from alligator plasma. Here, a novel bait strategy in which particles were encapsulated in membranes from either healthy or VEEV-infected cells was implemented to identify peptides preferentially targeting infected cells for subsequent evaluation of antiviral activity. Statistical analysis of peptide identification results was used to select five candidate peptides for testing, of which one exhibited a dose-dependent inhibition of VEEV and also significantly inhibited infectious titers. Results suggest our bioprospecting strategy provides a versatile platform that may be adapted for antiviral peptide identification from complex biological samples.

A 7-Hydroxybenzoxazinone-Containing Fluorescence Turn-On Probe for Biothiols and Its Bioimaging Applications.

In this work, a novel 7-hydroxybenzoxazinone-based fluorescent probe (PBD) for the selective sensing of biothiols is reported. Upon treatment with biothiols, PBD shows a strong fluorescence enhancement (up to 70-fold) and a large Stokes shift (155 nm). Meanwhile, this probe exhibits high resistance to interference from other amino acids and competing species. PBD features good linearity ranges with a low detection limit of 14.5 nM for glutathione (GSH), 17.5 nM for cysteine (Cys), and 80.0 nM for homocysteine (Hcy), respectively. Finally, the potential utility of this probe for biothiol sensing in living HeLa cells is demonstrated.

A GWA study reveals genetic loci for body conformation traits in Chinese Laiwu pigs and its implications for human BMI.

Pigs share numerous physiological and phenotypic similarities with human and thus have been considered as a good model in nonrodent mammals for the study of genetic basis of human obesity. Researches on candidate genes for obesity traits have successfully identified some common genes between humans and pigs. However, few studies have assessed how many similarities exist between the genetic architecture of obesity in pigs and humans by large-scale comparative genomics. Here, we performed a genome-wide association study (GWAS) using the porcine 60 K SNP Beadchip for BMI and other four conformation traits at three different ages in a Chinese Laiwu pig population, which shows a large variability in fat deposition. In total, 35 SNPs were found to be significant at Bonferroni-corrected 5 % chromosome-wise level (P = 2.13 × 10-5) and 88 SNPs had suggestive (P < 10-4) association with the conformation traits. Some SNPs showed age-dependent association. Intriguingly, out of 32 regions associated with BMI in pigs, 18 were homologous with the loci for BMI in humans. Furthermore, five closest genes to GWAS peaks including HIF1AN, SMYD3, COX10, SLMAP, and GBE1 have been already associated with BMI in humans, which makes them very promising candidates for these QTLs. The result of GO analysis provided strong support to the fact that mitochondria and synapse play important roles in obesity susceptibility, which is consistent with previous findings on human obesity, and it also implicated new gene sets related to chromatin modification and Ig-like C2-type 5 domain. Therefore, these results not only provide new insights into the genetic architecture of BMI in pigs but also highlight that humans and pigs share the significant overlap of obesity-related genes.

[Simultaneous determination of 4 prenylflavonoids of Chuankezhi injection in rat plasma by LC-MS/MS].

A quantitative method for epimedin A, B, C and icariin in rat plasma was established using LC-MS/MS after intermuscular administration of Chuankezhi injection to rat. Chromatographic separation was performed on an Agilent Eclipse XDB-C(18) column (150 mm × 2.1 mm, 5.0 µm) at 40 ℃. Mobile phase consisted of acetonitrile-0.1% formic acid in water（35∶65）, and the flow rate was 0.22 m L·min(-1). The LC effluent was detected and analyzed using an ESI-triple quadrupole tandem mass spectrometer under the multiple reaction monitoring (MRM) in the negative ion mode. The plasma samples were treated with solid phase extraction prior to LC-MS/MS analysis. As a result, all of the four analytes displayed a good linearity over the concentration of 1-1 000 ng·mL(-1). The RSDs of intra-day and inter-day assays were less than 5.99% and 10.16%, respectively. The relative recovery of each analyte was between 88.1%-101.1% with RSD < 7.9% and the absolute recovery was between 72.0%-86.6%（RSD < 6.3%）. In conclusion, the established method shows good specificity, sensitivity and efficiency for quantifying the four flavonoid glycosides contained in rat plasma.

[Pharmacokinetics of epimedin A, B, C and icariin of Chuankezhi injection in rat].

To study pharmacokinetic characteristics of epimedin A, B, C and icariin after intermuscular administration of Chuankezhi injection to rat. The established RRLC-MS/MS method was applied for simultaneous determination of four analytes in rat plasma and calculating their pharmacokinetic parameters. As a result, each analyte showed a good linear relationship in the concentration range of 1-1 000 µg•L⁻¹.The intra-day precise was 96.9%-107.5% with RSD<5.99%, inter-day precise was 92.3%-105.0% with RSD<10.16%. The relative recovery of four analytes was 88.1%-101.1% with RSD<7.9% and their absolute recovery was 72.0%-86.6% with RSD<6.3%. After intermuscular administration of Chuankezhi injection, the plasma concentration of four flavonoid glycosides rapidly arose to peaks at about 10 min, and then quickly declined in rat. Tmax of epimedin A, B, C and icariin was 0.21, 0.19, 0.16 and 0.49 h, respectively, and their mean elimination half-life(t1/2z) was 0.60, 0.62, 0.47 and 0.49 h. The established method was validated to be sensitive, rapid and specific for determination of the four analytes. Serum concentration of 4 species of epimedium flavonoids in Chuankezhi injection was low, and their absorption and elimination seem quickly, displaying similar pharmacokinetic characteristics in this study.

[Bronchial glomus tumor: report of 2 cases and review of the literature].

OBJECTIVE: Glomus tumor is a small, predominantly benign tumor, and typically occurs in the soft tissues, rarely in bronchus. The aim of this study was to discuss the clinical manifestation, histology, diagnosis and differential diagnosis of bronchial glomus tumor. METHODS: We studied the histopathological and immunohistochemical results of 2 cases with bronchial glomus tumor. One case was diagnosed by bronchoscopic biopsy, and another by surgery. We searched Wanfang, VIP, CNKI and PubMed database for related articles with key word "bronchial glomus tumor" both in English and in Chinese for literature review. RESULTS: Fiberoptic bronchoscopy demonstrated a bronchial neoplasm in both 2 cases. For Case one, the tumor was pink under fluorescence bronchoscopy, and was histologically composed of groups of nuclear-irregular round cells in interstices, with pale staining plasma and unclear boundary. Immunohistochemically, cytokeratin (CK) was negative, while vimentin and CD34 vascular endothelial cell were positive, smooth muscle actin (SMA) weakly positive, and Synaptophysin partially positive in tumor cells. These results led to the diagnosis of bronchial glomus tumor of right upper lobe bronchus. The tumor of Case two was histologically from the right main bronchus mesechyma, and it invaded into submucosa, but not involving the tracheal cartilage. Histological examination showed groups of medium sized tumor cells with round nuclei, and abundance of interstitial vasculature. No cellular atypia or mitoses were observed. Immunohistochemical staining demonstrated positive reactivity for vimentin, SMA and CD99. Pathological diagnosis was right main bronchus glomus tumor (malignant potential indeterminacy). We identified 16 studies from databases, of which 15 studies including 15 cases (12 males, 3 females) were applicable. Age of onset ranged from 20 to 79 years. The lesion was in the left main bronchus in 8 cases, the right main broncus in 2, the right middle lobe bronchus in 3, and the right upper lobe bronchus in 2 cases. The tumor size ranged from 0.7 to 6.5 cm. Cough, dyspnea with or without fever were observed in 7 patients. Seven cases had blood in phlegm, and 4 patients showed pulmonary atelectasis. All cases showed negative CK staining and positive SMA staining. CONCLUSION: Bronchial glomus tumor usually lacks clinical manifestations, and is often misdiagnosed as bronchial asthma. It can be classified as solid glomus tumor, ball hemangioma, ball vascular leiomyoma by histopathology. Glomus tumors show positive immunohistochemical stainings for vimentin and smooth muscle actin (SMA), and are usually negative for cytokeratin (CK) and epithelial markers. Clinical differential diagnoses such as sclerosing hemangioma, hemangiopericytoma, carcinoid tumor and epithelial tumor should be considered.

TMEM16A enhances the activity of the Cdc42-NWASP signaling pathway to promote invasion and metastasis in oral squamous cell carcinoma.

OBJECTIVE: We explored the relationship between TMEM16A and metastasis and development in oral squamous cell carcinoma (OSCC). STUDY DESIGN: The University of Alabama at Birmingham and Gene Expression Profiling Interactive Analysis Databases were employed to analyze the relationship between the expression of TMEM16A and the survival of patients with OSCC. TMEM16A was knocked down and overexpressed in CAL27 and SCC-4 cells, respectively, and the malignant behavior and expression of key proteins were detected. The Cdc42-NWASP pathway was inhibited, and the effects of TMEM16A and the Cdc42-NWASP pathway on promoting the malignant behavior of cancer cells were verified. A xenograft tumor model was constructed, and tumor growth, cell proliferation index, apoptosis, and Cdc42-NWASP signal pathway activity were detected. RESULTS: The expression of TMEM16A in oral cancer tissues was significantly higher than in adjacent tissues, and mice with high expression of TMEM16A had shorter survival. Overexpression of TMTM16A could significantly promote the occurrence of cancer and reduce the apoptosis of cancer cells, whereas the activity of the Cdc42 pathway was higher. Knocking down TMEM16A or inhibiting the Cdc42-NWASP pathway could reverse these results. CONCLUSION: The activation of the Cdc42-NWASP pathway by high TMEM16A expression is closely related to OSCC and may become a new therapeutic target to prevent OSCC metastasis.

Short-chain fatty acids in nonalcoholic fatty liver disease: New prospects for short-chain fatty acids as therapeutic targets.

Nonalcoholic fatty liver disease (NAFLD) is a stress-induced liver injury related to heredity, environmental exposure and the gut microbiome metabolism. Short-chain fatty acids (SCFAs), the metabolites of gut microbiota (GM), participate in the regulation of hepatic steatosis and inflammation through the gut-liver axis, which play an important role in the alleviation of NAFLD. However, little progress has been made in systematically elucidating the mechanism of how SCFAs improve NAFLD, especially the epigenetic mechanisms and the potential therapeutic application as clinical treatment for NAFLD. Herein, we adopted PubMed and Medline to search relevant keywords such as 'SCFAs', 'NAFLD', 'gut microbiota', 'Epigenetic', 'diet', and 'prebiotic effect' to review the latest research on SCFAs in NAFLD up to November 2023. In this review, firstly, we specifically discussed the production and function of SCFAs, as well as their crosstalk coordination in the gut liver axis. Secondly, we provided an updated summary and intensive discussion of how SCFAs affect hepatic steatosis to alleviate NAFLD from the perspective of genetic and epigenetic. Thirdly, we paid attention to the pharmacological and physiological characteristics of SCFAs, and proposed a promising future direction to adopt SCFAs alone or in combination with prebiotics and related clinical drugs to prevent and treat NAFLD. Together, this review aimed to elucidate the function of SCFAs and provide new insights to the prospects of SCFAs as a therapeutic target for NAFLD.

Phenylboronic Acid Functionalized Calix[4]pyrrole-Based Solid-State Supramolecular Electrolyte.

Solid-state polymer electrolytes (SPEs) suffer from the low ionic conductivity and poor capability of suppressing lithium (Li) dendrites, which limits their utility in the preparation of all solid-state Li-metal batteries (LMBs). It is reported here a flexible solid supramolecular electrolyte that incorporates a new anion capture agent, namely a phenylboronic acid functionalized calix[4]pyrrole (C4P), into a poly(ethylene oxide) (PEO) matrix. The resulting solid-state supramolecular electrolyte demonstrates high ionic conductivity (1.9 × 10-3  S cm-1 at 60 °C) and a high Li+ transference number ( t Li + ${t}_{{\mathrm{Li}}^{\mathrm{ + }}}$  = 0.70). Furthermore, the assembled Li|C4P-PEO-LiTFSI|LiFePO4 cell allows for stable cycling over 1200 cycles at 1 C at 60 °C, as well as good rate performance. The favorable performance of the C4P-PEO-LiTFSI SPE leads to suggest it can prove useful in the creation of high energy density solid-state LMBs.

Epigenetic regulation of key gene of PCK1 by enhancer and super-enhancer in the pathogenesis of fatty liver hemorrhagic syndrome.

OBJECTIVE: Rare study of the non-coding and regulatory regions of the genome limits our ability to decode the mechanisms of fatty liver hemorrhage syndrome (FLHS) in chickens. METHODS: Herein, we constructed the high-fat diet-induced FLHS chicken model to investigate the genome-wide active enhancers and transcriptome by H3K27ac target chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-Seq) profiles of normal and FLHS liver tissues. Concurrently, an integrative analysis combining ChIP-seq with RNA-Seq and a comparative analysis with chicken FLHS, rat non-alcoholic fatty liver disease (NAFLD) and human NAFLD at the transcriptome level revealed the enhancer and super enhancer target genes and conservative genes involved in metabolic processes. RESULTS: In total, 56 and 199 peak-genes were identified in upregulated peak-genes positively regulated by H3K27ac (Cor (peak-gene correlation) ≥0.5 and log2(FoldChange) ≥1) (PP) and downregulated peak-genes positively regulated by H3K27ac (Cor (peak-gene correlation) ≥0.5 and log2(FoldChange)≤-1) (PN), respectively; then we screened key regulatory targets mainly distributing in lipid metabolism (PCK1, APOA4, APOA1, INHBE) and apoptosis (KIT, NTRK2) together with MAPK and PPAR signaling pathway in FLHS. Intriguingly, PCK1 was also significantly covered in up-regulated super-enhancers (SEs), which further implied the vital role of PCK1 during the development of FLHS. CONCLUSION: Together, our studies have identified potential therapeutic biomarkers of PCK1 and elucidated novel insights into the pathogenesis of FLHS, especially for the epigenetic perspective.

Omics-based construction of regulatory variants can be applied to help decipher pig liver-related traits.

Genetic variants can influence complex traits by altering gene expression through changes to regulatory elements. However, the genetic variants that affect the activity of regulatory elements in pigs are largely unknown, and the extent to which these variants influence gene expression and contribute to the understanding of complex phenotypes remains unclear. Here, we annotate 90,991 high-quality regulatory elements using acetylation of histone H3 on lysine 27 (H3K27ac) ChIP-seq of 292 pig livers. Combined with genome resequencing and RNA-seq data, we identify 28,425 H3K27ac quantitative trait loci (acQTLs) and 12,250 expression quantitative trait loci (eQTLs). Through the allelic imbalance analysis, we validate two causative acQTL variants in independent datasets. We observe substantial sharing of genetic controls between gene expression and H3K27ac, particularly within promoters. We infer that 46% of H3K27ac exhibit a concomitant rather than causative relationship with gene expression. By integrating GWAS, eQTLs, acQTLs, and transcription factor binding prediction, we further demonstrate their application, through metabolites dulcitol, phosphatidylcholine (PC) (16:0/16:0) and published phenotypes, in identifying likely causal variants and genes, and discovering sub-threshold GWAS loci. We provide insight into the relationship between regulatory elements and gene expression, and the genetic foundation for dissecting the molecular mechanism of phenotypes.

Ropivacaine as a novel AKT1 specific inhibitor regulates the stemness of breast cancer.

BACKGROUND: Ropivacaine, a local anesthetic, exhibits anti-tumor effects in various cancer types. However, its specific functions and the molecular mechanisms involved in breast cancer cell stemness remain elusive. METHODS: The effects of ropivacaine on breast cancer stemness were investigated by in vitro and in vivo assays (i.e., FACs, MTT assay, mammosphere formation assay, transwell assays, western blot, and xenograft model). RNA-seq, bioinformatics analysis, Western blot, Luciferase reporter assay, and CHIP assay were used to explore the mechanistic roles of ropivacaine subsequently. RESULTS: Our study showed that ropivacaine remarkably suppressed stem cells-like properties of breast cancer cells both in vitro and in vivo. RNA-seq analysis identified GGT1 as the downstream target gene responding to ropivacaine. High GGT1 levels are positively associated with a poor prognosis in breast cancer. Ropivacaine inhibited GGT1 expression by interacting with the catalytic domain of AKT1 directly to impair its kinase activity with resultant inactivation of NF-κB. Interestingly, NF-κB can bind to the promoter region of GGT1. KEGG and GSEA analysis indicated silence of GGT1 inhibited activation of NF-κB signaling pathway. Depletion of GGT1 diminished stem phenotypes of breast cancer cells, indicating the formation of NF-κB /AKT1/GGT1/NF-κB positive feedback loop in the regulation of ropivacaine-repressed stemness in breast cancer cells. CONCLUSION: Our finding revealed that local anesthetic ropivacaine attenuated breast cancer stemness through AKT1/GGT1/NF-κB signaling pathway, suggesting the potential clinical value of ropivacaine in breast cancer treatment.

Multiwalled Carbon Nanotubes-Reprogrammed Macrophages Facilitate Breast Cancer Metastasis via NBR2/TBX1 Axis.

In recent years, carbon nanotubes have emerged as a widely used nanomaterial, but their human exposure has become a significant concern. In our former study, we reported that pulmonary exposure of multiwalled carbon nanotubes (MWCNTs) promoted tumor metastasis of breast cancer; macrophages were key effectors of MWCNTs and contributed to the metastasis-promoting procedure in breast cancer, but the underlying molecular mechanisms remain to be explored. As a follow-up study, we herein demonstrated that MWCNT exposure in breast cancer cells and macrophage coculture systems promoted metastasis of breast cancer cells both in vitro and in vivo; macrophages were skewed into M2 polarization by MWCNT exposure. LncRNA NBR2 was screened out to be significantly decreased in MWCNTs-stimulated macrophages through RNA-seq; depletion of NBR2 led to the acquisition of M2 phenotypes in macrophages by activating multiple M2-related pathways. Specifically, NBR2 was found to positively regulate the downstream gene TBX1 through H3k27ac activation. TBX1 silence rescued NBR2-induced impairment of M2 polarization in IL-4 & IL-13-stimulated macrophages. Moreover, NBR2 overexpression mitigated the enhancing effects of MWCNT-exposed macrophages on breast cancer metastasis. This study uncovered the molecular mechanisms underlying breast cancer metastasis induced by MWCNT exposure.

Genome-Wide Profiling of H3K27ac Identifies TDO2 as a Pivotal Therapeutic Target in Metabolic Associated Steatohepatitis Liver Disease.

H3K27ac has been widely recognized as a representative epigenetic marker of active enhancer, while its regulatory mechanisms in pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) remain elusive. Here, a genome-wide comparative study on H3K27ac activities and transcriptome profiling in high fat diet (HFD)-induced MASLD model is performed. A significantly enhanced H3K27ac density with abundant alterations of regulatory transcriptome is observed in MASLD rats. Based on integrative analysis of ChIP-Seq and RNA-Seq, TDO2 is identified as a critical contributor for abnormal lipid accumulation, transcriptionally activated by YY1-promoted H3K27ac. Furthermore, TDO2 depletion effectively protects against hepatic steatosis. In terms of mechanisms, TDO2 activates NF-κB pathway to promote macrophages M1 polarization, representing a crucial event in MASLD progression. A bovine serum albumin nanoparticle is fabricated to provide sustained release of Allopurinol (NPs-Allo) for TDO2 inhibition, possessing excellent biocompatibility and desired targeting capacity. Venous injection of NPs-Allo robustly alleviates HFD-induced metabolic disorders. This study reveals the pivotal role of TDO2 and its underlying mechanisms in pathogenesis of MASLD epigenetically and genetically. Targeting H3K27ac-TDO2-NF-κB axis may provide new insights into the pathogenesis of abnormal lipid accumulation and pave the way for developing novel strategies for MASLD prevention and treatment.

Lipopolysaccharide binding protein resists hepatic oxidative stress by regulating lipid droplet homeostasis.

Oxidative stress-induced lipid accumulation is mediated by lipid droplets (LDs) homeostasis, which sequester vulnerable unsaturated triglycerides into LDs to prevent further peroxidation. Here we identify the upregulation of lipopolysaccharide-binding protein (LBP) and its trafficking through LDs as a mechanism for modulating LD homeostasis in response to oxidative stress. Our results suggest that LBP induces lipid accumulation by controlling lipid-redox homeostasis through its lipid-capture activity, sorting unsaturated triglycerides into LDs. N-acetyl-L-cysteine treatment reduces LBP-mediated triglycerides accumulation by phospholipid/triglycerides competition and Peroxiredoxin 4, a redox state sensor of LBP that regulates the shuttle of LBP from LDs. Furthermore, chronic stress upregulates LBP expression, leading to insulin resistance and obesity. Our findings contribute to the understanding of the role of LBP in regulating LD homeostasis and against cellular peroxidative injury. These insights could inform the development of redox-based therapies for alleviating oxidative stress-induced metabolic dysfunction.

Loss of LBP triggers lipid metabolic disorder through H3K27 acetylation-mediated C/EBPß- SCD activation in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is associated with mutations in lipopolysaccharide-binding protein ( LBP), but the underlying epigenetic mechanisms remain understudied. Herein, LBP -/- rats with NAFLD were established and used to conduct integrative targeting-active enhancer histone H3 lysine 27 acetylation (H3K27ac) chromatin immunoprecipitation coupled with high-throughput and transcriptomic sequencing analysis to explore the potential epigenetic pathomechanisms of active enhancers of NAFLD exacerbation upon LBP deficiency. Notably, LBP -/- reduced the inflammatory response but markedly aggravated high-fat diet (HFD)-induced NAFLD in rats, with pronounced alterations in the histone acetylome and regulatory transcriptome. In total, 1 128 differential enhancer-target genes significantly enriched in cholesterol and fatty acid metabolism were identified between wild-type (WT) and LBP -/- NAFLD rats. Based on integrative analysis, CCAAT/enhancer-binding protein ß (C/EBPß) was identified as a pivotal transcription factor (TF) and contributor to dysregulated histone acetylome H3K27ac, and the lipid metabolism gene SCD was identified as a downstream effector exacerbating NAFLD. This study not only broadens our understanding of the essential role of LBP in the pathogenesis of NAFLD from an epigenetics perspective but also identifies key TF C/EBPß and functional gene SCD as potential regulators and therapeutic targets.

Advances in Medicinal Chemistry of Estrogen-related Receptor Alpha (ERRα) Inverse Agonists.

Estrogen-related receptor alpha (ERRα), a member of the nuclear receptor superfamily, is strongly expressed in breast cancer cells. Its overexpression is associated with poor prognosis in triple- negative Breast Cancer (TNBC). ERRα expression could be inhibited by the downregulation of upstream oncogenic growth factors mTOR, HER2, and PI3K. Low expression of ERRα could suppress the migration and angiogenesis of tumor cells by inhibiting the activity of its downstream signals VEGF and WNT11. Studies have confirmed that ERRα inverse agonists can inhibit ERRα expression to treat breast cancer. Inverse agonists of ERRα could disrupt the interactions of ERRα with its coactivators and inhibit tumor development. Existing ERRα inverse agonists have shown moderate efficacy in inhibiting the growth of breast cancer cells. Clinical inverse agonists of ERRα have not been found in the literature. This review focuses on the research progress and the structureactivity relationship of ERRα inverse agonists, providing guidance for the research and discovery of new anti-tumor compounds for TNBC.

A comparative investigation on H3K27ac enhancer activities in the brain and liver tissues between wild boars and domesticated pigs.

Dramatic phenotypic differences between domestic pigs and wild boars (Sus scrofa) provide opportunities to investigate molecular mechanisms underlying the formation of complex traits, including morphology, physiology and behaviour. Most studies comparing domestic pigs and wild boars have focused on variations in DNA sequences and mRNA expression, but not on epigenetic changes. Here, we present a genome-wide comparative study on H3K27ac enhancer activities and the corresponding mRNA profiling in the brain and liver tissues of adult Bama Xiang pigs (BMXs) and Chinese wild boars (CWBs). We identified a total of 1,29,487 potential regulatory elements, among which 11,241 H3K27ac peaks showed differential activity between CWBs and BMXs in at least one tissue. These peaks were overrepresented by binding motifs of FOXA1, JunB, ATF3 and BATF, and overlapped with differentially expressed genes that are involved in female mating behaviour, response to growth factors and hormones, and lipid metabolism. We also identified 4118 nonredundant super-enhancers from ChIP-Seq data on H3K27ac. Notably, we identified differentially active peaks located close to or within candidate genes, including TBX19, MSTN, AHR and P2RY1, which were identified in DNA sequence-based population differentiation studies. This study generates a valuable dataset on H3K27ac profiles of the brain and liver from domestic pigs and wild boars, which helps gain insights into the changes in enhancer activities from wild boars to domestic pigs.