Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis (Mtb) and is a growing public health problem worldwide. Within the innate immune response, we highlight the secretion of the antimicrobial peptide LL-37, which is crucial for Mtb elimination in infected cells. Previous reports have shown that CEBPα activation induces LL-37 independently of its main inducer, vitamin D, under endoplasmic reticulum (ER) stress. In this study, we report that infection with Mtb causes ER stress in pulmonary epithelial cells and macrophages. The stress induces the activation of CEBPα, which in turn promotes the LL-37 expression. Furthermore, the participation of CEBPα is necessary for the correct clearance of Mtb in an in vitro infection model. We identify candidate drugs (mycophenolic acid, indapamide, and glibenclamide) capable of activating CEBPα and promoting LL-37 through in silico assays. The effect of the drugs was corroborated by gene and protein expression analysis. Finally, we observed that treatment with these drugs improves bacterial clearance in infected cells. Our results lead us to suggest CEBPα as a potential therapeutic target as an adjuvant in the standard treatment of tuberculosis, seeking a reduction in treatment time, and thus a lower appearance of drug resistance.

Perfluorooctane sulfonic acid (PFOS) is a fluorinated chemical utilized in a variety of industrial and household products. PFOS has been detected in human serum and is associated with multiple human adverse health effects. Epidemiological evidence has linked PFOS exposure to endothelial dysfunction, which is a key contributor to atherosclerosis. However, the underlying mechanisms of PFOS-induced endothelial dysfunction associated atherosclerosis has not been investigated. In the present study, human microvascular endothelial cells (HMEC-1) exposed to PFOS (15 μM) for 72 h, mimicking long-term exposure. We further employed integrated RNA-sequencing (RNA-seq) and transcriptomic analysis to identify differentially expressed genes (DEGs) for biological alterations: gene ontology (GO), pathway enrichment analysis (KEGG), protein-protein interaction network and modular clustering analysis. Furthermore, the Metascape database was used for disease association, tissue specificity, and transcription factor analysis. Hub genes were verified using atherosclerosis patient data sets from the GEO dataset. Alteration of hub genes in patients was then validated using immunoblotting and ELISA. Our results revealed that PFOS altered amino acid biosynthesis, lipid metabolism and induced the ER-stress response through the HRI/eIF2α/ATF4 pathway, leading to endothelial dysfunction. Interestingly, we found that PFOS induced inflammation by increasing COX-2, ICAM-1 and IL-6 expression through NF-κB and JAK2/STAT3 pathway in endothelial cells. Moreover, up-regulated C/EBPβ and ATF4 were observed in both patients and PFOS-exposed endothelium, which may use as an early biomarker and may have a potential role in PFOS-induced endothelial dysfunction. These findings provide novel insight into the underlying molecular mechanisms of PFOS-induced endothelial dysfunction associated with atherosclerosis.

The HADHB gene encodes the beta-subunit of 3-hydroxy acyl-CoA dehydrogenase, closely related to energy metabolism, fatty acid synthesis, and catabolism. This study aimed to investigate the effect of the HADHB gene on the proliferation and differentiation of bovine preadipocytes and to gain new insights into the mechanisms of adipocyte regulation. RNA was extracted from adipose tissue of yellow cattle and the HADHB gene CDS region was cloned. Meanwhile, isolation and cultivation of preadipocytes were used for siRNA and adenovirus overexpression, quantitative real-time PCR, transcriptome sequencing, and cell proliferation and cell cycle were measured by oil red staining, CCK8 assay, and flow cytometry. Subsequently, the transcriptome data were analyzed using bioinformatics. The results showed that the HADHB gene modulates significantly the expression of critical genes involved in proliferation (CDK2 and PCNA) and differentiation (PPARγ and CEBPα), influencing preadipocyte proliferation and differentiation and altering cell cycle progression. The results of transcriptome sequencing demonstrated that the overexpression of the HADHB gene markedly altered the transcriptional profile of preadipocytes, with 170 genes exhibiting a significant increase in expression and 113 genes displaying a decrease. The HADHB gene exerts a regulatory influence on the differentiation process of precursor adipocytes by modulating the expression of key genes involved in proliferation and differentiation.These findings highlight the central role of the HADHB gene in adipocyte regulation and provide new insights into the regulatory mechanisms governing adipocyte biology.

CCAAT/enhancer-binding protein delta (CEBPD), as an evolutionarily conserved protein in mammals, belongs to the CEBP transcription factor family, which modulates many biological processes. The diversity of CEBPD functions partly depends on the cell type and cellular context. Aberrant CEBPD expression and activity are associated with multiple organ diseases, including cardiovascular diseases. In this review, we describe the basic molecular biology of CEBPD to understand its expression regulation, modifications, and functions. Here, we summarize the recent advances in genetically modified animals with CEBPD. Finally, we discuss the contribution of CEBPD to cardiovascular diseases and highlight the strategies for developing novel therapies targeting CEBPD.

There is a gap in our understanding of mechanisms promoting hepatocellular carcinoma (HCC), and this limits our ability to provide targeted therapy interventions for HCC. In HCC samples, NAD-dependent deacetylase sirtuin 2 (SIRT2) levels are increased and associated with a significantly worse prognosis, but the role of SIRT2 in hepatocarcinogenesis remains controversial.

To assess the role of SIRT2 in hepatocarcinogenesis, we used a hepatocyte-specific knockout of SIRT2 and two plasmid overexpression HCC models: c-MET (MET)/β-catenin (CAT) and protein kinase B (AKT)/Nras. RNA sequencing of mouse liver tissue was performed, and mechanistic findings were confirmed using immunohistochemistry (IHC), quantitative polymerase chain reaction, Western blot, and Cell Counting Kit-8.

Using the MET/CAT and AKT/Nras models, we found that SIRT2 is a significant mediator of liver tumorigenesis, with the knockout of SIRT2 delaying tumor growth. RNA sequencing of MET/CAT-driven tumor tissue showed an increase in growth arrest and DNA-damage-inducible protein gamma (GADD45γ) in SIRT2 knockout mice compared with wild-type. GADD45γ is a known tumor suppressor, but the regulation of GADD45γ by SIRT2 has not been shown. CCAAT/enhancer-binding protein beta (C/EBPβ) proteins are known to regulate GADD45γ expression, and we found that C/EBPβ expression was increased in SIRT2 knockout livers and HCC cells. Also, C/EBPβ knockdown reversed GADD45γ expression and growth suppression following SIRT2 inhibition. Finally, C/EBPβ or GADD45γ overexpression significantly suppressed MET/CAT-induced HCC development.

SIRT2 is a potent tumor promotor in HCC that negatively regulates GADD45γ expression through C/EBPβ. The SIRT2-C/EBPβ-GADD45γ pathway elucidates a novel mechanism in HCC and establishes SIRT2 as a therapeutic target for patients with HCC.

Neuronal signals have emerged as critical factors that regulate group 3 innate lymphoid cell (ILC3) response and tissue homeostasis, but the molecular mechanisms underlying this regulation remain largely elusive. Here, we identified that the enteric GABAergic neuron-derived neurotransmitter γ-aminobutyric acid (GABA) inhibited proliferation and IL-17A production in ILC3s in a manner dependent on the GABA receptors Gabbr1 and Gabbr2. Conditional deletion of Gabbr1 or ablation of GABAergic neurons caused increased IL-17A production and aggravated colitis. Mechanistically, GABA suppressed the expression of the LIP isoform of the transcription factor C/EBP-β in ILC3s, which repressed the transcription of Igfbp7, which encodes the secreted factor Igfbp7. Autocrine Igfbp7 signaling through the receptor Igf1R inhibited ILC3 proliferation and IL-17A production. Suppression of signaling through the GABA-C/EBP-β-IGFBP7 pathway highly correlated with severity of intestinal inflammation in patients with inflammatory bowel disease (IBD). Collectively, our findings describe an important molecular mechanism underlying the maintenance of gut immune homeostasis.

Alzheimer's disease (AD), an age-progressive neurodegenerative disease, is featured by a relentless deterioration of cognitive abilities. In parallel with the hypotheses of Aβ and tau, microglia-mediated neuroinflammation is a core pathological hallmark of AD. Promoting the transition of microglia from M1 to M2 phenotype and inhibition of neuroinflammatory response provide new insights into the treatment of AD. And substantial studies have confirmed that overexpression of C/EBPβ accelerates the progression of AD pathology. Acupuncture is renowned for its unique advantages including safety and effectiveness, which has gained wide application in geriatric diseases, and thoroughly exploring the mechanism for its treatment of AD will provide scientific basis for its clinical application.

In this study, SAMP8 mice were employed and EA therapy was performed as the main intervention. The combination of behavioural experiments (including water maze and novel objective recognition), Immunofluorescence, Western blot, and Chip-qPCR assay were performed to compare between different groups.

EA therapy facilitates the polarization of microglia from M1 to M2 phenotype, reduces pro-inflammatory cytokines (IL-6, IL-1β and TNF-α) and promotes the expression of anti-inflammatory factors (IL-4 and IL-10), as well as attenuates neuroinflammation. Simultaneously, EA also inhibits the enrichment of H3K9ac at C/EBPβ promoter region and expression of C/EBPβ. Thus, it was evident that EA had a favorable effect on ameliorating cognitive decline in SAMP8 mice.

EA therapy may ameliorate cognitive deficits in AD via facilitating microglia shift from M1 to M2 phenotype and epigenetically regulating C/EBPβ. And further studies are required to better understand how the mechanism between microglia and epigenetic modulation of C/EBPβ are effective in reversing AD.

Alzheimer's disease (AD) stands as one of the most prevalent neurodegenerative disorders, characterized by a progressive decline in cognitive function, neuroinflammation, amyloid-beta (Aβ) plaques, and neurofibrillary tangles (NFTs). With the global aging population, the incidence of AD continues to rise, yet current therapeutic strategies remain limited in their ability to significantly alleviate cognitive impairments. Therefore, a deeper understanding of the molecular mechanisms underlying AD is imperative for the development of more effective treatments. In recent years, the transcription factor C/EBPβ has emerged as a pivotal regulator in several pathological processes of AD, including neuroinflammation, lipid metabolism, Aβ processing, and tau phosphorylation. Through intricate post-translational modifications, C/EBPβ modulates these processes and may influence the progression of AD on multiple fronts. This review systematically explores the multifaceted roles of C/EBPβ in the pathogenesis of AD, delving into its crucial involvement in neuroinflammation, Aβ production, tau pathology, and lipid metabolism dysregulation. Furthermore, we critically assess therapeutic strategies targeting C/EBPβ, examining the challenges and opportunities in regulating this factor. By synthesizing the latest research findings, we offer a more comprehensive understanding of the role of C/EBPβ in AD and discuss its potential as a therapeutic intervention target.

Inflammatory diseases impair the reparative properties of endothelial progenitor cells (EPC); however, the involvement of diabetes in EPC dysfunction associated with myocardial infarction (MI) remains unknown.

A model was established combining high-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mice with myocardial infarction. The therapeutic effects of transplanted wild-type EPC, Nlrp3 knockout EPC, and Nlrp3 overexpression EPC were evaluated. Chip and Luciferase assay revealed CEBPB regulated the transcriptional expression of Nlrp3 as a transcription factor in EPC stimulated by high glucose (HG) or advanced glycation end products (AGEs). CO-IP results suggested that USP14 selectively suppressed NLRP3 degradation. KEGG enrichment revealed PI3K/ Akt/mTOR signaling showed striking significance in the entire pathway.

In our study, wild-type, Nlrp3 knockout and Nlrp3 overexpressed EPC, intracardiac injections effectively improved cardiac function, increased angiogenesis, and reduced infarct size in mice with myocardial infarction. However, in the HFD/STZ-induced diabetic mice model combined with myocardial infarction, Nlrp3 knockout EPC significantly restored angiogenic capacity. Mechanically, CEBPB regulated the transcriptional level of Nlrp3 as a transcription factor in EPC. Meanwhile, we found that USP14 selectively suppressed NLRP3 protein degradation through the USP motif on the NACHT domain in mediating inflammasome activation. Cardiac functional outcomes in recipient mice after intramyocardial injection of shNlrp3 EPC overexpressing CEBPB or USP14 validated the modulation of EPC function by regulating Nlrp3 transcription or post-translational modification. Furthermore, KEGG enrichment and validation at the protein levels revealed PI3K/ Akt/mTOR cascade might be a downstream signal for NLRP3 inflammasome.

Our study provides a new understanding of how diabetes affected progenitor cell-mediated cardiac repair and identifies NLRP3 as a new therapeutic target for improving myocardial infarction repair in inflammatory diseases.

Successful ovulation is essential for natural conception and fertility. Defects in the ovulatory process are associated with various conditions of infertility or subfertility in women. However, our understanding of the intra-ovarian biochemical mechanisms underlying this process in women has lagged compared to our understanding of animal models. This has been largely due to the limited availability of human ovarian samples that can be used to examine changes across the ovulatory period and delineate the underlying cellular/molecular mechanisms in women. Despite this challenge, steady progress has been made to improve our knowledge of the ovulatory process in women by: (i) collecting granulosa cells across the IVF interval, (ii) creating a novel approach to collecting follicular cells and tissues across the periovulatory period from normally cycling women, and (iii) developing unique in vitro models to examine the LH surge or hCG administration-induced ovulatory changes in gene expression, the regulatory mechanisms underlying the ovulatory changes, and the specific functions of the ovulatory factors.

The objective of this review is to summarize findings generated using in vivo and in vitro models of human ovulation, with the goal of providing new insights into the mechanisms underlying the ovulatory process in women.

This review is based on the authors' own studies and a search of the relevant literature on human ovulation to date using PubMed search terms such as 'human ovulation EGF-signaling', 'human ovulation steroidogenesis', 'human ovulation transcription factor', 'human ovulation prostaglandin', 'human ovulation proteinase', 'human ovulation angiogenesis' 'human ovulation chemokine', 'human ovulatory disorder', 'human granulosa cell culture'. Our approach includes comparing the data from the authors' studies with the existing microarray or RNA-seq datasets generated using ovarian cells obtained throughout the ovulatory period from humans, monkeys, and mice.

Current findings from studies using in vivo and in vitro models demonstrate that the LH surge or hCG administration increases the expression of ovulatory mediators, including EGF-like factors, steroids, transcription factors, prostaglandins, proteolytic systems, and other autocrine and paracrine factors, similar to those observed in other animal models such as rodents, ruminants, and monkeys. However, the specific ovulatory factors induced, their expression pattern, and their regulatory mechanisms vary among different species. These species-specific differences stress the necessity of utilizing human samples to delineate the mechanisms underlying the ovulatory process in women.

The data from human ovulation in vivo and in vitro models have begun to fill the gaps in our understanding of the ovulatory process in women. Further efforts are needed to discover novel ovulatory factors. One approach to address these gaps is to improve existing in vitro models to more closely mimic in vivo ovulatory conditions in humans. This is critically important as the knowledge obtained from these human studies can be translated directly to aid in the diagnosis of ovulation-associated pathological conditions, for the development of more effective treatment to help women with anovulatory infertility or, conversely, to better manage ovulation for contraceptive purposes.

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Endoplasmic reticulum (ER) stress due to obesity or systemic insulin resistance is an important pathogenic factor that could lead to pancreatic β-cell failure. We have previously reported that CCAAT/enhancer-binding protein β (C/EBPβ) is highly induced by ER stress in pancreatic β cells. Moreover, its accumulation hampers the response of these cells to ER stress by inhibiting the induction of the molecular chaperone 78 kDa glucose-regulated protein (GRP78). We also demonstrated that C/EBPβ is phosphorylated by CK2, which is reportedly associated with the ER stress signal. In the present study, we aimed to clarify the mechanisms underlying the effect of CK2 on pancreatic β cells using a CK2-specific inhibitor, CX4945, and shRNA-mediated knockdown and overexpression of CK2β, the regulatory subunit of CK2. The results indicate that CK2 was activated in MIN6 cells under ER stress and in pancreatic β cells of a diabetic mouse model. Under normal conditions, CK2 interacted with FL-ATF6α in MIN6 cells and regulated the expression of GRP78 and ERAD-associated proteins. Mechanistically, CK2 activation in MIN6 cells upon the overexpression of the CK2β subunit reduced ER stress signals and the accumulation of unfolded proteins via an increase in GRP78 and ERAD-associated protein levels. These results highlight the important role of CK2 in protecting against ER stress-induced apoptosis by regulating GRP78 and ERAD proteins. CK2 contributed to the clearance of unfolded or misfolded proteins in MIN6 cells under both normal and ER stress conditions. Therefore, CK2 activation could be a promising novel approach for preventing type 2 diabetes.

The online version contains supplementary material available at 10.1007/s13340-024-00775-w.

Metastatic cancer accounts for most cancer-related deaths, and identifying specific molecular targets that contribute to metastatic progression is crucial for the development of effective treatments. Hypoxia, a feature of solid tumors, plays a role in cancer progression by inducing resistance to therapy and accelerating metastasis. Here, we report that CCAAT/enhancer-binding protein beta (C/EBPβ) transcriptionally regulates hypoxia-inducible factor 1 subunit alpha (HIF1A) and thus promotes migration and invasion of non-small-cell lung cancer (NSCLC) cells under hypoxic conditions. Our results show that knockdown or forced expression of C/EBPβ was correlated with HIF-1α expression and that C/EBPβ directly bound to the promoter region of HIF1A. Silencing HIF1A inhibited the enhanced migration and invasion induced by C/EBPβ overexpression in NSCLC cells under hypoxia. Expression of the HIF-1α target gene, SLC2A1, was also altered in a C/EBPβ-dependent manner, and knockdown of SLC2A1 reduced migration and invasion enhanced by C/EBPβ overexpression. These results indicate that C/EBPβ is a critical regulator for the invasion of NSCLC cells in the hypoxic tumor microenvironment. Collectively, the C/EBPβ-HIF-1α-GLUT1 axis represents a potential therapeutic target for preventing metastatic progression of NSCLC and improving patient outcomes.

Calcium deposition in vascular smooth muscle cells (VSMCs), a form of ectopic ossification in blood vessels, can result in rigidity of the vasculature and an increase in cardiac events. Here, we report that CCAAT/enhancer-binding protein beta (C/EBPβ) potentiates calcium deposition in VSMCs and mouse aorta induced by inorganic phosphate (Pi) or vitamin D3. Based on cDNA microarray and RNA sequencing data of Pi-treated rat VSMCs, C/EBPβ was found to be upregulated and thus selected for further evaluation. Quantitative RT-PCR and Western blot analysis confirmed that C/EBPβ was upregulated in Pi-treated A10 cells, a rat VSMC line, as well as vitamin D3-treated mouse aorta. The overexpression of C/EBPβ in A10 cells increased bone runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP), and osteopontin (OPN) mRNA in the presence of Pi, as well as potentiating the Pi-induced increase in calcium contents. The Runx2 expression was increased by C/EBPβ through Runx2 P2 promotor. Our results suggest that a Pi-induced increase in C/EBPβ is a critical step in vascular calcification.

Transcription factors (TFs) have an important role in the regulation of the gene expression network. The role of TFs in the immune response of freshwater crayfish is poorly understood, but leveraging the regulatory mechanisms of immune response could augment the resistance against the invasive oomycete pathogen, Aphanomyces astaci. Previous studies indicated that the TFs CCAAT/enhancer-binding protein (C/EBP) and putative Krüppel homolog-1 protein (Kr-h1) might play a role in immune and stress response of the noble crayfish (Astacus astacus). Here, we aimed to further characterise these two gene products to gain a better understanding of their evolutionary origin, domain organisation and expression patterns across different crayfish tissues. Furthermore, we conducted an immune stimulation experiment to observe the potential changes in the gene expression of C/EBP and Kr-h1 under immune challenge in different crayfish tissues. Our results showed that both C/EBP and Kr-h1 are closely related to other C/EBPs and Kr-h1s in Malacostraca. Gene expression analysis revealed that both TFs are present in all analysed tissues, with higher expression of C/EBP in the gills and Kr-h1 in the abdominal muscle. Immune stimulation with laminarin (mimicking β-1-3-glucan in the oomycete cell wall) showed an activation of the crayfish immune system, with an overall increase in the total haemocyte count (THC) compared to untreated control and crayfish buffered saline (CBS) treatment. On the gene expression level, an up-regulation of the C/EBP gene was detected in the laminarin treated group in hepatopancreas and heart, while no changes were observed for the Kr-h1 gene. Our results indicate an early change in C/EBP expression in multiple tissues during immune stimulation and suggest its involvement in the immune response of the noble crayfish.

Since the outbreak of COVID-19, genome-wide association studies have tried to discover the role of genetic predisposition in the clinical variability of this viral infection. The findings of various investigations have led to several loci for COVID-19 genetic susceptibility. Among candidate regions, the 3p21.31 locus has been in the spotlight among scientists, as it can increase the risk of severe COVID-19 by almost two fold. In addition to its substantial association with COVID-19 severity, this locus is related to some common diseases, such as diabetes, malignancies, and coronary artery disease. This locus also harbors evolutionary traces of Neanderthal genomes, which is believed to be the underlying reason for its association with COVID-19 severity. Additionally, the inheritance of this locus from Neanderthals seems to be under positive selection. This review aims to summarize a collection of evidence on the 3p21.31 locus and its impact on COVID-19 outcomes by focusing on the risk variants originated from the Neanderthal genome. Moreover, we discuss candidate genes at this locus and the possible mechanisms by which they influence the progression of COVID-19 symptoms. Better insights into human genetic susceptibility to newly emerging diseases such as COVID-19 and its evolutionary origin can provide fundamentals for risk assessment of different populations as well as the development of personalized prevention and treatments based on genomic medicine.

CYP24A1 is a crucial gene within the cytochrome P450 superfamily, responsible for encoding the enzyme 25-hydroxyvitamin D3-24-hydroxylase. This enzyme is involved in the catabolism of 1,25-dihydroxyvitamin D3, the biologically active form of vitamin D3, by hydroxylating its side chain. Through this process, CYP24A1 tightly regulates the bioavailability and physiological impact of vitamin D3 in the body. Dysregulation of CYP24A1, particularly its overexpression, has been increasingly associated with the progression of various diseases, including cancers, autoimmune disorders, and chronic inflammatory conditions. Elevated levels of CYP24A1 can lead to excessive degradation of vitamin D3, resulting in diminished levels of this critical hormone, which is essential for calcium homeostasis, immune function, and cellular proliferation. This review explores into the structural characteristics of CYP24A1, exploring how it influences its enzymatic activity. Furthermore, it examines the expression patterns of CYP24A1 across different diseases, emphasizing the enzyme's role in disease pathology. The review also discusses the regulatory mechanisms governing CYP24A1 expression, including genetic mutations, epigenetic modifications, and metabolite-mediated regulation. By understanding these mechanisms, the review provides insight into the potential therapeutic strategies that could target CYP24A1, aiming to alleviate its overexpression and restore vitamin D3 balance in disease states.

Programmed death-1 (PD-1) checkpoint blockade has revolutionized cancer therapy, yet its clinical success is confined to a subset of patients, underscoring the urgent need to understand the molecular underpinnings of programmed cell death ligand 1 (PD-L1) expression to combat immunotherapy resistance.

Employing CRISPR/Cas9 screening, we identified key regulators of PD-L1 in non-small cell lung cancer (NSCLC) cells, focusing on the transcription factor CEBPB and its isoform liver-enriched inhibitory protein (LIP). Through chromatin immunoprecipitation (ChIP) and luciferase reporter assays, we explored the interaction between LIP and basic-helix-loop-helix E22 (BHLHE22) in controlling PD-L1 transcription. We also used immunofluorescence and NBD-CI assays to examine how N-terminal acetylation affects LIP's subcellular localization. The impact of LIP on tumor growth was assessed via subcutaneous tumorigenicity assays, while immunohistochemistry and immunofluorescence were used to analyze LIP-induced alterations in the tumor immune microenvironment.

Our research indicates that CEBPB, particularly its LIP isoform, significantly suppresses PD-L1 expression in NSCLC cells. This suppression is contingent on LIP's N-terminal acetylation by the N-terminal acetyltransferase A complex, which facilitates LIP's nuclear entry and interaction with BHLHE22. This interaction leads to the formation of a co-repressor complex at the PD-L1 promoter, effectively reducing PD-L1 expression and enhancing the tumor immune response.

Identifying CEBPB, especially the LIP isoform, as a pivotal regulator of PD-L1 expression sheds light on the mechanisms behind PD-1 blockade resistance in NSCLC. Our findings suggest that modulating LIP's function or its molecular interactions might offer a novel approach to boosting the efficacy of immunotherapies.

Persistent infection with hepatitis B virus (HBV) often leads to disruptions in lipid metabolism. Apolipoprotein AII (apoAII) plays a crucial role in lipid metabolism and is implicated in various metabolic disorders. However, whether HBV could regulate apoAII and contribute to HBV-related dyslipidemia and the underlying mechanism remain unclear. This study revealed significant reductions in apoAII expression in HBV-expressing cell lines, the serum, and liver tissues of HBV-transgenic mice. The impact of HBV on apoAII is related to small hepatitis B virus surface antigen (SHBs). Overexpression of SHBs decreased apoAII levels in SHBs-expressing hepatoma cells, transgenic mice, and the serum of HBV-infected patients, whereas suppression of SHBs increased apoAII expression. Mechanistic investigations demonstrated that SHBs repressed the apoAII promoter activity through a HNF4α- and C/EBPγ-dependent manner; SHBs simultaneously upregulated C/EBPγ and downregulated HNF4α by inhibiting the PI3K/AKT signaling pathway through activating endoplasmic reticulum (ER) stress. Serum lipid profile assessments revealed notable decreases in high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG) in SHBs-transgenic mice compared to control mice. However, concurrent overexpression of apoAII in these mice effectively counteracted these reductions in lipid levels. In HBV patients, SHBs levels were negatively correlated with serum levels of HDL-C, LDL-C, TC, and TG, whereas apoAII levels positively correlated with lipid content. This study underscores that SHBs contributes to dyslipidemia by suppressing the PI3K/AKT pathway via inducing ER stress, leading to altered expression of HNF4α and C/EBPγ, and subsequently reducing apoAII expression.IMPORTANCEThe significance of this study lies in its comprehensive examination of how the hepatitis B virus (HBV), specifically through its small hepatitis B virus surface antigen (SHBs), impacts lipid metabolism-a key aspect often disrupted by chronic HBV infection. By elucidating the role of SHBs in regulating apolipoprotein AII (apoAII), a critical player in lipid processes and associated metabolic disorders, this research provides insights into the molecular pathways contributing to HBV-related dyslipidemia. Discovering that SHBs downregulates apoAII through mechanisms involving the repression of the apoAII promoter via HNF4α and C/EBPγ, and the modulation of the PI3K/AKT signaling pathway via endoplasmic reticulum (ER) stress, adds critical knowledge to HBV pathogenesis. The research also shows an inverse correlation between SHBs expression and key lipid markers in HBV-infected individuals, suggesting that apoAII overexpression could counteract the lipid-altering effects of SHBs, offering new avenues for understanding and managing the metabolic implications of HBV infection.

Maternal education was strongly correlated with adolescent brain morphology, cognitive performances, and mental health. However, the molecular basis for the effects of maternal education on the structural neurodevelopment remains unknown. Here, we conducted gene-environment-wide interaction study using the Adolescent Brain Cognitive Development cohort. Seven genomic loci with significant gene-environment interactions (G×E) on regional gray matter volumes were identified, with enriched biological functions related to metabolic process, inflammatory process, and synaptic plasticity. Additionally, genetic overlapping results with behavioral and disease-related phenotypes indicated shared biological mechanism between maternal education modified neurodevelopment and related behavioral traits. Finally, by decomposing the multidimensional components of maternal education, we found that socioeconomic status, rather than family environment, played a more important role in modifying the genetic effects on neurodevelopment. In summary, our study provided analytical evidence for G×E effects regarding adolescent neurodevelopment and explored potential biological mechanisms as well as social mechanisms through which maternal education could modify the genetic effects on regional brain development.

The regulatory mechanisms governing expression of genes encoding lignin-modifying enzymes (LME) in white-rot fungi remain largely unexplored. Although molecular cloning has identified CCAAT-boxes frequently located 5'-upstream of these genes, their role in transcriptional regulation is not well understood. This study examines the function of hap2, a gene encoding a hypothetical protein homologous to a component of the CCAAT-binding Hap complex, in the white-rot fungus Pleurotus ostreatus. Deletion of hap2 resulted in significantly reduced Mn2+-dependent peroxidase activity and lignin-degrading capacity compared to the parental strain 20b grown on beech wood sawdust (BWS) medium. Real-time PCR revealed that vp2 transcript levels were significantly lower in hap2 deletants than in 20b grown when cultured on the three solid media consisting of BWS, holocellulose, or Avicel, but not on yeast-malt-glucose (YMG) agar plates. Additionally, glutathione S-transferase (GST) pulldown and electrophoretic mobility shift assays demonstrated that recombinant P. ostreatus Hap2, Hap3, and Hap5 expressed in Escherichia coli form a complex capable of binding to the CCAAT sequence 5'-upstream of vp2 in vitro. These results suggest that Hap2, as part of the CCAAT-binding complex, is essential for transcriptional upregulation of vp2 in P. ostreatus growing on lignocellulosic substrates. KEY POINTS: • P. ostreatus hap2 deletants were generated. • Lignin-degrading capacity was significantly reduced in the hap2 deletants. • vp2 was significantly downregulated upon hap2 deletion.

The CCAAT enhancer binding protein alpha (CEBPA) is crucial for myeloid differentiation and the balance of haematopoietic stem and progenitor cell (HSPC) quiescence and self-renewal, and its dysfunction can drive leukemogenesis. However, its role in HSPC generation has not been fully elucidated. Here, we utilized various zebrafish cebpa mutants to investigate the function of Cebpa in the HSPC compartment. Co-localization analysis showed that cebpa expression is enriched in nascent HSPCs. Complete loss of Cebpa function resulted in a significant reduction in early HSPC generation and the overall HSPC pool during embryonic haematopoiesis. Interestingly, while myeloid differentiation was impaired in cebpa N-terminal mutants expressing the truncated zP30 protein, the number of HSPCs was not affected, indicating a redundant role of Cebpa P42 and P30 isoforms in HSPC development. Additionally, epistasis experiments confirmed that Cebpa functions downstream of Runx1 to regulate HSPC emergence. Our findings uncover a novel role of Cebpa isoforms in HSPC generation and maintenance, and provide new insights into HSPC development.

The overdevelopment of adipose tissues, accompanied by excess lipid accumulation and energy storage, leads to adipose deposition and obesity. With the increasing incidence of obesity in recent years, obesity is becoming a major risk factor for human health, causing various relevant diseases (including hypertension, diabetes, osteoarthritis and cancers). Therefore, it is of significance to antagonize obesity to reduce the risk of obesity-related diseases. Excess lipid accumulation in adipose tissues is mediated by adipocyte hypertrophy (expansion of pre-existing adipocytes) or hyperplasia (increase of newly-formed adipocytes). It is necessary to prevent excessive accumulation of adipose tissues by controlling adipose development. Adipogenesis is exquisitely regulated by many factors in vivo and in vitro, including hormones, cytokines, gender and dietary components. The present review has concluded a comprehensive understanding of adipose development including its origin, classification, distribution, function, differentiation and molecular mechanisms underlying adipogenesis, which may provide potential therapeutic strategies for harnessing obesity without impairing adipose tissue function.

Parturition is an inflammation process. Exaggerated inflammatory reactions in infection lead to preterm birth. Although nuclear factor kappa B (NF-κB) has been recognized as a classical transcription factor mediating inflammatory reactions, those mediated by NF-κB per se are relatively short-lived. Therefore, there may be other transcription factors involved to sustain NF-κB-initiated inflammatory reactions in gestational tissues in infection-induced preterm birth.

Cebpd-deficient mice were generated to investigate the role of CCAAT enhancer-binding protein δ (C/EBPδ) in lipopolysaccharide (LPS)-induced preterm birth, and the contribution of fetal and maternal C/EBPδ was further dissected by transferring Cebpd-/- or WT embryos to Cebpd-/- or WT dams. The effects of C/EBPδ pertinent to parturition were investigated in mouse and human myometrial and amnion cells. The interplay between C/EBPδ and NF-κB was examined in cultured human amnion fibroblasts.

The mouse study showed that LPS-induced preterm birth was delayed by Cebpd deficiency in either the fetus or the dam, with further delay being observed in conceptions where both the dam and the fetus were deficient in Cebpd. Mouse and human studies showed that the abundance of C/EBPδ was significantly increased in the myometrium and fetal membranes in infection-induced preterm birth. Furthermore, C/EBPδ participated in LPS-induced upregulation of pro-inflammatory cytokines as well as genes pertinent to myometrial contractility and fetal membrane activation in the myometrium and amnion respectively. A mechanistic study in human amnion fibroblasts showed that C/EBPδ, upon induction by NF-κB, could serve as a supplementary transcription factor to NF-κB to sustain the expression of genes pertinent to parturition.

C/EBPδ is a transcription factor to sustain the expression of gene initiated by NF-κB in the myometrium and fetal membranes in infection-induced preterm birth. Targeting C/EBPδ may be of therapeutic value in the treatment of infection-induced preterm birth.

Macrophages have important roles in mammary gland development and tissue homeostasis, but the specific mechanisms that regulate macrophage function need further elucidation. We have identified C/EBPβ as an important transcription factor expressed by multiple macrophage populations in the normal mammary gland. Mammary glands from mice with C/EBPβ-deficient macrophages (Cebpb ΔM) show a significant decrease in alveolar budding during the diestrus stage of the reproductive cycle, whereas branching morphogenesis remains unchanged. Defects in alveolar budding were found to be the result of both systemic hormones and local macrophage-directed signals. RNA sequencing shows significant changes in PR-responsive genes and alterations in the Wnt landscape of mammary epithelial cells of Cebpb ΔM mice, which regulate stem cell expansion during diestrus. Cebpb ΔM macrophages demonstrate a shift from a pro-inflammatory to a tissue-reparative phenotype, and exhibit increased phagocytic capacity as compared to WT. Finally, Cebpb ΔM macrophages down-regulate Notch2 and Notch3, which normally promote stem cell expansion during alveolar budding. These results suggest that C/EBPβ is an important macrophage factor that facilitates macrophage-epithelial crosstalk during a key stage of mammary gland tissue homeostasis.

Kidney disease represents a major medical and economic burden for which improved treatments are urgently needed. Emerging data have implicated Th17 cells and IL-17 signaling in the underlying pathogenesis of autoantibody-induced glomerulonephritis (AGN). However, the downstream transduction pathways mediated by IL-17 in autoimmunity are not well defined. In this article, we show that CCAAT/enhancer-binding protein (C/EBP) δ is elevated in kidney biopsies from multiple manifestations of human AGN. C/EBPδ is similarly upregulated in a mouse model of anti-glomerular basement membrane protein-mediated kidney disease, and Cebpd-/- mice were fully refractory to disease. Although C/EBPδ is expressed in a variety of cell types, C/EBPδ was required only in the radioresistant compartment to drive GN pathology. C/EBPδ induced expression of several IL-17-induced kidney injury markers and cytokines implicated in disease, including Il6 and Lcn2. Because mouse AGN models do not progress to fibrosis, we employed a nephrotoxic injury model using aristolochic acid I to assess the contribution of the IL-17-C/EBPδ pathway to renal fibrotic events. Surprisingly, deficiency of either C/EBPδ or the IL-17 receptor caused kidney fibrosis to be enhanced. Thus, C/EBPδ and IL-17 play divergent and apparently stage-specific roles in the pathogenesis of kidney disease.

Alu retrotransposons, which form the largest family of mobile DNA elements in the human genome, have recently come to attention as a potential source of regulatory novelties, most notably by participating in enhancer function. Even though Alu transcription by RNA polymerase III is subjected to tight epigenetic silencing, their expression has long been known to increase in response to various types of stress, including viral infection. Here we show that, in primary human fibroblasts, adenovirus small e1a triggered derepression of hundreds of individual Alus by promoting TFIIIB recruitment by Alu-bound TFIIIC. Epigenome profiling revealed an e1a-induced decrease of H3K27 acetylation and increase of H3K4 monomethylation at derepressed Alus, making them resemble poised enhancers. The enhancer nature of e1a-targeted Alus was confirmed by the enrichment, in their upstream regions, of the EP300/CBP acetyltransferase, EP400 chromatin remodeler and YAP1 and FOS transcription factors. The physical interaction of e1a with EP400 was critical for Alu derepression, which was abrogated upon EP400 ablation. Our data suggest that e1a targets a subset of enhancer Alus whose transcriptional activation, which requires EP400 and is mediated by the e1a-EP400 interaction, may participate in the manipulation of enhancer activity by adenoviruses.

Nutrient metabolism is regulated by several factors. Social determinants of health with or without genetics are the primary regulator of metabolism, and an unhealthy lifestyle affects all modulators and mediators, leading to the adaptation and finally to the exhaustion of cellular functions. Hepatic steatosis is defined by presence of fat in more than 5% of hepatocytes. In hepatocytes, fat is stored as triglycerides in lipid droplet. Hepatic steatosis results from a combination of multiple intracellular processes. In a healthy individual nutrient metabolism is regulated at several steps. It ranges from the selection of nutrients in a grocery store to the last step of consumption of ATP as an energy or as a building block of a cell as structural component. Several hormones, peptides, and genes have been described that participate in nutrient metabolism. Several enzymes participate in each nutrient metabolism as described above from ingestion to generation of ATP. As of now several publications have revealed very intricate regulation of nutrient metabolism, where most of the regulatory factors are tied to each other bidirectionally, making it difficult to comprehend chronological sequence of events. Insulin hormone is the primary regulator of all nutrients' metabolism both in prandial and fasting states. Insulin exerts its effects directly and indirectly on enzymes involved in the three main cellular function processes; metabolic, inflammation and repair, and cell growth and regeneration. Final regulators that control the enzymatic functions through stimulation or suppression of a cell are nuclear receptors in especially farnesoid X receptor and peroxisome proliferator-activated receptor/RXR ligands, adiponectin, leptin, and adiponutrin. Insulin hormone has direct effect on these final modulators. Whereas blood glucose level, serum lipids, incretin hormones, bile acids in conjunction with microbiota are intermediary modulators which are controlled by lifestyle. The purpose of this review is to overview the key players in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) that help us understand the disease natural course, risk stratification, role of lifestyle and pharmacotherapy in each individual patient with MASLD to achieve personalized care and target the practice of precision medicine. PubMed and Google Scholar databases were used to identify publication related to metabolism of carbohydrate and fat in states of health and disease states; MASLD, cardiovascular disease and cancer. More than 1000 publications including original research and review papers were reviewed.

Glioblastoma (GBM) is an aggressive brain cancer with limited therapeutic options. Natural killer (NK) cells are innate immune cells with strong anti-tumor activity and may offer a promising treatment strategy for GBM. We compared the anti-GBM activity of NK cells engineered to express interleukin (IL)-15 or IL-21. Using multiple in vivo models, IL-21 NK cells were superior to IL-15 NK cells both in terms of safety and long-term anti-tumor activity, with locoregionally administered IL-15 NK cells proving toxic and ineffective at tumor control. IL-21 NK cells displayed a unique chromatin accessibility signature, with CCAAT/enhancer-binding proteins (C/EBP), especially CEBPD, serving as key transcription factors regulating their enhanced function. Deletion of CEBPD resulted in loss of IL-21 NK cell potency while its overexpression increased NK cell long-term cytotoxicity and metabolic fitness. These results suggest that IL-21, through C/EBP transcription factors, drives epigenetic reprogramming of NK cells, enhancing their anti-tumor efficacy against GBM.

Adenoid cystic carcinoma (ACC) is a rare malignant epithelial neoplasm that arises in secretory glands and commonly metastasizes to the lungs. MYBL1 is frequently overexpressed in ACC and has been suggested to be a driver of the disease. In this study, we identified a circular RNA (circRNA) derived from MYBL1 pre-mRNA that was accompanied by the overexpression of MYBL1 in ACC. Overexpression of circMYBL1 was correlated with increased lung metastasis and poor overall survival in patients with ACC. Ectopic circMYBL1 overexpression promoted malignant phenotypes and lung metastasis of ACC cells. Mechanistically, circMYBL1 formed a circRNA-protein complex with CCAAT enhancer-binding protein β (CEBPB), which inhibited ubiquitin-mediated degradation and promoted nuclear translocation of CEBPB. In the nucleus, circMYBL1 increased the binding of CEBPB to the CD44 promoter region and enhanced its transcription. In addition, circMYBL1 was enriched in small extracellular vesicles (sEV) isolated from the plasma of patients with ACC. Treatment with sEVs containing circMYBL1 in sEVs enhanced prometastatic phenotypes of ACC cells, elevated the expression of CD44 in human pulmonary microvascular endothelial cells (HPMEC), and enhanced the adhesion between HPMECs and ACC cells. Moreover, circMYBL1 encapsulated in sEVs increased the arrest of circulating ACC cells in the lung and enhanced lung metastatic burden. These data suggest that circMYBL1 is a tumor-promoting circRNA that could serve as a potential biomarker and therapeutic target for ACC. Significance: circMYBL1 stabilizes CEBPB and upregulates CD44 to promote adhesion between cancer cells and endothelial cells and enables lung metastasis of adenoid cystic carcinoma, suggesting that inhibition of this axis could improve patient outcomes.

Proper development of mucosal immunity is critical for human health. Over the past decade, it has become evident that in humans, this process begins in utero. However, there are limited data on the unique features and functions of fetal mucosal immune cells. To address this gap, we integrated several single-cell ribonucleic acid sequencing datasets of the human small intestine (SI) to create an SI transcriptional atlas throughout the human life span, ranging from the first trimester to adulthood, with a focus on immune cells. Fetal SI displayed a complex immune landscape comprising innate and adaptive immune cells that exhibited distinct transcriptional programs from postnatal samples, especially compared with pediatric and adult samples. We identified shifts in myeloid populations across gestation and progression of memory T-cell states throughout the human lifespan. In particular, there was a marked shift of memory T cells from those with stem-like properties in the fetal samples to fully differentiated cells with a high expression of activation and effector function genes in adult samples, with neonatal samples containing both features. Finally, we demonstrate that the SI developmental atlas can be used to elucidate improper trajectories linked to mucosal diseases by implicating developmental abnormalities underlying necrotizing enterocolitis, a severe intestinal complication of prematurity. Collectively, our data provide valuable resources and important insights into intestinal immunity that will facilitate regenerative medicine and disease understanding.

Adipogenesis significantly contributes to healthy adipose tissue expansion in obesity. Increasing adipocyte number or function to alleviate adipose tissue overload could serve as a therapeutic strategy for both lipodystrophy and obesity-related metabolic syndrome. Inorganic pyrophosphatase (PPA1) is an enzyme that catalyzes the hydrolysis of pyrophosphate (PPi) and is involved in many biochemical reactions, but its function in adipose tissue has not been studied previously. In this study, we demonstrated that adipose-specific PPA1 knockout (PPA1AKO) mice showed lipodystrophy and spontaneously developed hepatic steatosis and severe insulin resistance under normal chow diet feeding. PPA1 deficiency suppressed the differentiation of primary adipocyte precursors and 3T3-L1 cells. Notably, PPA1 overexpression can restore inhibited adipogenesis in preadipocytes isolated from db/db mice and type 2 diabetes patients. Mechanistic studies have revealed that PPA1 acts as a positive regulator of early adipocyte differentiation by promoting CCAAT/enhancer-binding proteinβ and δ (C/EBPβ and δ) protein stability. Moreover, the function of PPA1 in adipogenesis is independent of its PPi catalytic activity. Collectively, our in vivo and in vitro findings demonstrated that PPA1 is a novel critical upstream regulator of adipogenesis, controlling adipose tissue development and whole-body metabolic homeostasis.

Adipocytes are crucial for maintaining energy balance. Adipocyte differentiation involves distinct stages, including the orientation stage, clone amplification stage, clone amplification termination stage, and terminal differentiation stage. Understanding the regulatory mechanisms governing adipogenic differentiation is essential for comprehending the physiological processes and identifying potential biomarkers and therapeutic targets for metabolic diseases, ultimately improving glucose and fat metabolism. Adipogenic differentiation is influenced not only by key factors such as hormones, the peroxisome proliferator-activated receptor (PPAR) family, and the CCATT enhancer-binding protein (C/EBP) family but also by noncoding RNA, including microRNA (miRNA), long noncoding RNA (lncRNA), and circular RNA (circRNA). Among these, lncRNA has been identified as a significant regulator in adipogenic differentiation. Research has demonstrated various ways in which lncRNAs contribute to the molecular mechanisms of adipogenic differentiation. Throughout the adipogenesis process, lncRNAs modulate adipocyte differentiation and development by influencing relevant signaling pathways and transcription factors. This review provides a brief overview of the function and mechanism of lncRNAs in adipogenic differentiation.

CCAAT enhancer binding protein delta (CEBPD) is a transcription factor and plays an important role in apoptosis and oxidative stress, which are the main pathogenesis of ischemic stroke. However, whether CEBPD regulates ischemic stroke through targeting apoptosis and oxidative stress is unclear. Therefore, to answer this question, rat middle cerebral artery occlusion (MCAO) reperfusion model and oxygen-glucose deprivation/reoxygenation (OGD/R) primary cortical neuron were established to mimic ischemic reperfusion injury. We found that CEBPD was upregulated and accompanied with increased neurological deficit scores and infarct size, and decreased neuron in MCAO rats. The siRNA targeted CEBPD inhibited CEBPD expression in rats, and meanwhile lentivirus system was used to blocked CEBPD expression in primary neuron. CEBPD degeneration decreased neurological deficit scores, infarct size and brain water content of MCAO rats. Knockdown of CEBPD enhanced cell viability and reduced apoptosis as well as oxidative stress in vivo and in vitro. CEBPD silencing promoted the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) to the nucleus and the expression of heme oxygenase 1 (HO-1). Newly, CEBPD facilitated the transcription of cullin 3 (CUL3), which intensified ischemic stroke through Nrf2/HO-1 pathway that was proposed by our team in the past. In conclusion, targeting CEBPD-CUL3-Nrf2/HO-1 axis may be contributed to cerebral ischemia therapy.

The development of osteoarthritis (OA) involves subchondral bone lesions, but the role of osteoblastic autophagy-related genes (ARGs) in osteoarthritis is unclear. Through integrated analysis of single-cell dataset, Bulk RNA dataset, and 367 ARGs extracted from GeneCards, 40 ARGs were found. By employing multiple machine learning algorithms and PPI networks, three key genes (DDIT3, JUN, and VEGFA) were identified. Then the RF model constructed from these genes indicated great potential as a diagnostic tool. Furthermore, the model's effectiveness in predicting OA has been confirmed through external validation datasets. Moreover, the expression of ARGs was examined in osteoblasts subject to excessive mechanical stress, human and mouse tissues. Finally, the role of ARGs in OA was confirmed through co-culturing explants and osteoblasts. Thus, osteoblastic ARGs could be crucial in OA development, providing potential diagnostic and treatment strategies.