Essential Regulator Research Articles

H3 Acetylation-Induced Basal Progenitor Generation and Neocortex Expansion Depends on the Transcription Factor Pax6.

Enrichment of basal progenitors (BPs) in the developing neocortex is a central driver of cortical enlargement. The transcription factor Pax6 is known as an essential regulator in generation of BPs. H3 lysine 9 acetylation (H3K9ac) has emerged as a crucial epigenetic mechanism that activates the gene expression program required for BP pool amplification. In this current work, we applied immunohistochemistry, RNA sequencing, chromatin immunoprecipitation and sequencing, and the yeast two-hybrid assay to reveal that the BP-genic effect of H3 acetylation is dependent on Pax6 functionality in the developing mouse cortex. In the presence of Pax6, increased H3 acetylation caused BP pool expansion, leading to enhanced neurogenesis, which evoked expansion and quasi-convolution of the mouse neocortex. Interestingly, H3 acetylation activation exacerbates the BP depletion and corticogenesis reduction effect of Pax6 ablation in cortex-specific Pax6 mutants. Furthermore, we found that H3K9 acetyltransferase KAT2A/GCN5 interacts with Pax6 and potentiates Pax6-dependent transcriptional activity. This explains a genome-wide lack of H3K9ac, especially in the promoter regions of BP-genic genes, in the Pax6 mutant cortex. Together, these findings reveal a mechanistic coupling of H3 acetylation and Pax6 in orchestrating BP production and cortical expansion through the promotion of a BP gene expression program during cortical development.

Different Mechanisms in Doxorubicin-Induced Cardiomyopathy: Impact of BRCA1 and BRCA2 Mutations

Germline mutations in Breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2) cause breast, ovarian, and other cancers, and the chemotherapeutic drug doxorubicin (Dox) is widely used to treat these cancers. However, Dox use is limited by the latent induction of severe cardiotoxicity known as Dox-induced cardiomyopathy, for which there are no specific treatments currently available. Dox is administered into the systemic circulation, where it readily translocates into sub-cellular compartments and disrupts the integrity of DNA. Accumulating evidence indicates that oxidative stress, DNA damage, inflammation, and apoptosis all play a central role in Dox-induced cardiomyopathy. The BRCA1 and BRCA2 proteins are distinct as they perform crucial yet separate roles in the homologous recombination repair of DNA double-strand breaks, thereby maintaining genomic integrity. Additionally, both BRCA1 and BRCA2 mitigate oxidative stress and apoptosis in both cardiomyocytes and endothelial cells. Accordingly, BRCA1 and BRCA2 are essential regulators of pathways that are central to the development of cardiomyopathy induced by Doxorubicin. Despite extensive investigations, there exists a gap in knowledge about the role of BRCA1 and BRCA2 in Doxorubicin-induced cardiomyopathy. Here, we review the previous findings and associations about the expected role and associated mechanisms of BRCA1 and 2 in Dox-induced cardiomyopathy and future perspectives.

HAND2 suppresses favipiravir efficacy in treatment of Borna disease virus infection

Borna disease virus (BoDV-1) is a bornavirus prototype that infects the central nervous system of various animal species and can cause fatal encephalitis in various animals including humans. Among the reported anti-BoDV-1 treatments, favipiravir (T-705) is one of the best candidates since it has been shown to be effective in reducing various bornavirus titers in cell culture. However, T-705 effectiveness on BoDV-1 is cell type-dependent, and the molecular mechanisms that explain this cell type-dependent difference remain unknown. In this study, we noticed a fact that T-705 efficiently suppressed BoDV-1 in infected 293T cells, but not in infected SH-SY5Y cells, and sought to identify protein(s) responsible for this cell-type-dependent difference in T-705 efficacy. By comparing the transcriptomes of BoDV-1-infected 293T and SH-SY5Y cells, we identified heart- and neural crest derivatives-expressed protein 2 (HAND2) as a candidate involved in T-705 interference. HAND2 overexpression partly attenuated the inhibitory effect of T-705, whereas HAND2 knockdown enhanced this effect. We also demonstrated an interaction between T-705 and HAND2. Furthermore, T-705 impaired HAND2-mediated host gene expression. Because HAND2 is an essential transcriptional regulator of embryogenesis, T-705 may exhibit its adverse effects such as teratogenicity and embryotoxicity through the impairment of HAND2 function. This study provides novel insights into the molecular mechanisms underlying T-705 interference in some cell types and inspires the development of improved T-705 derivatives for the treatment of RNA viruses.

New insights into the role of myostatin in fish fertility based on the findings in mstnb-deficient Nile tilapia (Oreochromis niloticus)

Myostatin (Mstn) was reported to be involved in multiple biological processes including the regulation of skeletal muscle growth, lipid metabolism and reproduction in vertebrates, therefore, it might play an essential role in the fine balance between growth and reproduction. In order to clarify the roles of Mstn in fish reproduction, we systematically investigated the gonadal development and fertility of mstnb mutants in Nile tilapia (Orochromis niloticus). In the present study, mstnb was found to be expressed in the different cell types of gonads by fluorescence in situ hybridization (FISH). Mutation of mstnb resulted in excessive proliferation of phase II follicles in the ovaries while the numbers of phase III follicles were significantly reduced at 210 days after hatching (dah). Interestingly, significant decline of cyp19a1a gene expression, the serum 17β-estradiol (E2), vitellogenin (VTG) were detected at 210 dah. At 360 dah, the ovarian development of mstnb-/- XX tilapia was partially recovered and female fish spawn regularly, however, they were subfertile and produced the poor-quality eggs with significantly lower offspring survival rate. The dramatic up-regulation of cyp19a1a gene expression and serum E2 level at 360 dah might account for the recovery of ovarian development. In mstnb-/- males, excessive proliferation of spermatogonia and retardation of testicular differentiation were found throughout the whole development stages. In mstnb-/- males, evident declines of gonadosomatic index (GSI), cyp11b2 gene expression, and 11-Ketotestosterone (11-KT) were detected at 210 dah, while the mRNA level of cyp11b2 and serum 11-KT level were significantly upregulated at 360 dah. However, mstnb-/- males were infertile since mutation of mstnb gene led to excessive increase of apoptosis of testicular cells and spermiation obstacle. Taken together, these results indicated that Mstn might be an essential regulator for the maintenance of fish fertility.

Transcriptional Coactivator BOB1 (OBF1, OCA-B) Modulates the Specificity of DNA Recognition by the POU-Domain Factors OCT1 and OCT2 in a Monomeric Configuration.

BOB1, a mammalian lymphocyte-specific transcriptional coactivator of the transcription factors OCT1 and OCT2 (OCT1/2), plays important roles in normal immune responses, autoimmunity, and hematologic malignancies. The issue of a DNA sequence preference change imposed by BOB1 was raised more than two decades ago but remains unresolved. In this paper, using the EMSA-SELEX-Seq approach, we have reassessed the intrinsic ability of BOB1 to modulate the specificity of DNA recognition by OCT1 and OCT2. Our results have reaffirmed previous conclusions regarding BOB1 selectivity towards the dimer configuration of OCT1/2. However, they suggest that the monomeric configuration of these factors, assembled on the classical octamer ATGCAAAT and related motifs, are the primary targets of BOB1. Our data further specify the DNA sequence preference imposed by BOB1 and predict the probability of ternary complex formation. These results provide an additional insight into the action of BOB1-an essential immune regulator and a promising molecular target for the treatment of autoimmune diseases and hematologic malignancies.

Innate lymphoid cells: New players in osteoimmunology.

Innate lymphoid cells (ILCs) are the most recently identified immune cell types existing in lymphoid and nonlymphoid organs. Albeit they lack the expression of antigen receptors, ILCs play vital roles in innate immune responses by producing multiple effector cytokines. The ILC family includes conventional natural killer cells and cytokine-producing ILCs, which are divided into group 1, group 2, and group 3 ILCs based on their effector cytokines and developmental requirements. Emerging evidence has indicated that ILCs are essential immune regulators of bone homeostasis, playing a critical role in osteoimmunology. In this mini-review, we discuss recent advances in the understanding of ILC functions in bone homeostasis under physiological and pathological conditions, with an emphasis on the communication between ILCs and bone cells including osteoclasts and osteoblasts, as well as the underlying immunoregulatory networks involving ILC-derived cytokines and growth factors. This review also discusses future research directions and the potential of targeting ILCs for the treatment of inflammation-associated bone disorders.

N-acetyltransferase NAT10 controls cell fates via connecting mRNA cytidine acetylation to chromatin signaling.

Cell fate transition involves dynamic changes of gene regulatory network and chromatin landscape, requiring multiple levels of regulation, yet the cross-talk between epitranscriptomic modification and chromatin signaling remains largely unknown. Here, we uncover that suppression of N-acetyltransferase 10 (NAT10), the writer for mRNA N4-acetylcytidine (ac4C) modification, can notably affect human embryonic stem cell (hESC) lineage differentiation and pluripotent reprogramming. With integrative analysis, we identify that NAT10-mediated ac4C modification regulates the protein levels of a subset of its targets, which are strongly enriched for fate-instructive chromatin regulators, and among them, histone chaperone ANP32B is experimentally verified and functionally relevant. Furthermore, NAT10-ac4C-ANP32B axis can modulate the chromatin landscape of their downstream genes (e.g., key regulators of Wnt and TGFβ pathways). Collectively, we show that NAT10 is an essential regulator of cellular plasticity, and its catalyzed mRNA cytidine acetylation represents a critical layer of epitranscriptomic modulation and uncover a previously unrecognized, direct cross-talk between epitranscriptomic modification and chromatin signaling during cell fate transitions.

IgG in the control of FcεRI activation: a battle on multiple fronts.

The rising global incidence of IgE-mediated allergic reactions poses a significant challenge to the quality of life of affected individuals and to healthcare systems, with current treatments being limited in effectiveness, safety, and disease-modifying capabilities. IgE acts by sensitizing the high-affinity IgE receptor FcεRI expressed by mast cells and basophils, tuning these cells for inflammatory degranulation in response to future allergen encounters. In recent years, IgG has emerged as an essential negative regulator of IgE-dependent allergic inflammation. Mechanistically, studies have proposed different pathways by which IgG can interfere with the activation of IgE-mediated inflammation. Here, we briefly summarize the major proposed mechanisms of action by which IgG controls the IgE-FcεRI inflammatory axis and how those mechanisms are currently applied as therapeutic interventions for IgE-mediated inflammation.

A vascularized 3D model of the human pancreatic islet for ex vivo study of immune cell-islet interaction

Insulin is an essential regulator of blood glucose homeostasis that is produced exclusively by β cells within the pancreatic islets of healthy individuals. In those affected by diabetes, immune inflammation, damage, and destruction of islet β cells leads to insulin deficiency and hyperglycemia. Current efforts to understand the mechanisms underlying β cell damage in diabetes rely on in vitro-cultured cadaveric islets. However, isolation of these islets involves removal of crucial matrix and vasculature that supports islets in the intact pancreas. Unsurprisingly, these islets demonstrate reduced functionality over time in standard culture conditions, thereby limiting their value for understanding native islet biology. Leveraging a novel, vascularized micro-organ (VMO) approach, we have recapitulated elements of the native pancreas by incorporating isolated human islets within a three-dimensional matrix nourished by living, perfusable blood vessels. Importantly, these islets show long-term viability and maintain robust glucose-stimulated insulin responses. Furthermore, vessel-mediated delivery of immune cells to these tissues provides a model to assess islet-immune cell interactions and subsequent islet killing—key steps in type 1 diabetes pathogenesis. Together, these results establish the islet-VMO as a novel, ex vivo platform for studying human islet biology in both health and disease.

MosGILT controls innate immunity and germ cell development in Anopheles gambiae

Gene-edited mosquitoes lacking a gamma-interferon-inducible lysosomal thiol reductase-like protein, namely (mosGILTnull) have lower Plasmodium infection, which is linked to impaired ovarian development and immune activation. The transcriptome of mosGILTnull Anopheles gambiae was therefore compared to wild type (WT) mosquitoes by RNA-sequencing to delineate mosGILT-dependent pathways. Compared to WT mosquitoes, mosGILTnull A. gambiae demonstrated altered expression of genes related to oogenesis, 20-hydroxyecdysone synthesis, as well as immune-related genes. Serendipitously, the zero population growth gene, zpg, an essential regulator of germ cell development was found to be one of the most downregulated genes in mosGILTnull mosquitoes. These results provide a crucial missing link between two previous studies on the role of zpg and mosGILT in ovarian development. This study further demonstrates that mosGILT has the potential to serve as a target for the biological control of mosquito vectors and to influence the Plasmodium life cycle within the vector.

Cryptochrome PtCPF1 regulates high temperature acclimation of marine diatoms through coordination of iron and phosphorus uptake.

Increasing ocean temperatures threaten the productivity and species composition of marine diatoms. High temperature response and regulation are important for the acclimation of marine diatoms to such environments. However, the molecular mechanisms behind their acclimation to high temperature are still largely unknown. In this study, the abundance of PtCPF1 homologs (a member of the cryptochrome-photolyase family in the model diatom Phaeodactylum tricornutum) transcripts in marine phytoplankton is shown to increase with rising temperature based on Tara Oceans datasets. Moreover, the expression of PtCPF1 in P. tricornutum at high temperature (26 °C) was much higher than that at optimum temperature (20 °C). Deletion of PtCPF1 in P. tricornutum disrupted the expression of genes encoding two phytotransferrins (ISIP2A and ISIP1) and two Na+/P co-transporters (PHATRDRAFT_47667 and PHATRDRAFT_40433) at 26 °C. This further impacted the uptake of Fe and P, and eventually caused the arrest of cell division. Gene expression, Fe and P uptake, and cell division were restored by rescue with the native PtCPF1 gene. Furthermore, PtCPF1 interacts with two putative transcription factors (BolA and TF IIA) that potentially regulate the expression of genes encoding phytotransferrins and Na+/P co-transporters. To the best of our knowledge, this is the first study to reveal PtCPF1 as an essential regulator in the acclimation of marine diatoms to high temperature through the coordination of Fe and P uptake. Therefore, these findings help elucidate how marine diatoms acclimate to high temperature.

Analisis Penerapan Sistem Informasi Manajemen SMART Pada Kegiatan Purcashing Request di PT XYZ

To maintain the smooth operation of the company, efficient inventory management becomes a crucial aspect. Essential regulation involves managing the inflow and outflow pf goods. With the company’s growth, the task of managing available inventory becomes increasingly complex and high-risk. PT XYZ is one of the service-oriented industries, particularly in hospitality service. This research aims to assess the extent of efficiency in implementing softwere-based Management Information Systems (SMART) in the purchasing request or procurement of operational necessities within the hotel industry. The research methodology employed a qualitative descriptive approach, gathering data through observations, interviews, and documentation. The research findings delineated an overview of PT XYZ’s back office management information system, analyze the advantages of applying this system, identify operational challenges, as well as management hurdles and influential factors affecting the operation the back office infotmation system.

MUC1-C is a target of salinomycin in inducing ferroptosis of cancer stem cells

The oncogenic MUC1-C transmembrane protein is a critical effector of the cancer stem cell (CSC) state. Addiction to MUC1-C for self-renewal in the progression of human cancers has emphasized the need for development of anti-MUC1-C agents. However, there are presently no approved small molecules for targeting MUC1-C-dependent CSCs. In screening for small molecules, we identified salinomycin (SAL), an inducer of ferroptosis, as a potent inhibitor of MUC1-C signaling. We demonstrate that SAL suppresses MUC1-C expression by disrupting a NF-κB/MUC1-C auto-inductive circuit that is necessary for ferroptosis resistance. Our results show that SAL-induced MUC1-C suppression downregulates a MUC1-C→MYC pathway that activates genes encoding (i) glutathione-disulfide reductase (GSR), and (ii) the LDL receptor related protein 8 (LRP8), which inhibit ferroptosis by generating GSH and regulating selenium levels, respectively. GSR and LRP8 contribute to the function of glutathione peroxidase 4 (GPX4), an essential negative regulator of ferroptotic cell death. We demonstrate that targeting MUC1-C genetically or with the GO-203 peptide inhibitor suppresses GPX4 expression and GPX activity in association with the induction of ferroptosis. Studies of CSCs enriched by serial passage as tumorspheres further demonstrate that the effects of SAL are mediated by downregulation of MUC1-C and thereby overcoming resistance to ferroptosis. As confirmation of these results, rescue of MUC1-C downregulation with the MUC1-C cytoplasmic domain (i) reversed the suppression of GSR, LRP8 and GPX4 expression, and (ii) attenuated the induction of ferroptosis. These findings identify SAL as a unique small molecule inhibitor of MUC1-C signaling and demonstrate that MUC1-C is an important effector of resistance to ferroptosis.

Identification and characterization of circular RNAs involved in the fertility stability of cotton CMS-D2 restorer line under heat stress

BackgroundAs a vital type of noncoding RNAs, circular RNAs (circRNAs) play important roles in plant growth and development and stress response. However, little is known about the biological roles of circRNAs in regulating the stability of male fertility restoration for cytoplasmic male sterility (CMS) conditioned by Gossypium harknessii cytoplasm (CMS-D2) cotton under high-temperature (HT) stress.ResultsIn this study, RNA-sequencing and bioinformatics analysis were performed on pollen grains of isonuclear alloplasmic near-isogenic restorer lines NH [N(Rf1rf1)] and SH [S(Rf1rf1)] with obvious differences in fertility stability under HT stress at two environments. A total of 967 circRNAs were identified, with 250 differentially expressed under HT stress. We confirmed the back-splicing sites of eight selected circRNAs using divergent primers and Sanger sequencing. Tissue-specific expression patterns of five differentially expressed circRNAs (DECs) were also verified by RT-PCR and qRT-PCR. Functional enrichment and metabolic pathway analysis revealed that the parental genes of DECs were significantly enriched in fertility-related biological processes such as pollen tube guidance and cell wall organization, as well as the Pentose and glucuronate interconversions, Steroid biosynthesis, and N-Glycan biosynthesis pathways. Moreover, we also constructed a putative circRNA-mediated competing endogenous RNA (ceRNA) network consisting of 21 DECs, eight predicted circRNA-binding miRNAs, and their corresponding 22 mRNA targets, especially the two ceRNA modules circRNA346-miR159a-MYB33 and circRNA484-miR319e-MYB33, which might play important biological roles in regulating pollen fertility stability of cotton CMS-D2 restorer line under HT stress.ConclusionsThrough systematic analysis of the abundance, characteristics and expression patterns of circRNAs, as well as the potential functions of their parent genes, our findings suggested that circRNAs and their mediated ceRNA networks acted vital biological roles in cotton pollen development, and might be also essential regulators for fertility stability of CMS-D2 restorer line under heat stress. This study will open a new door for further unlocking complex regulatory mechanisms underpinning the fertility restoration stability for CMS-D2 in cotton.

CAND1 inhibits Cullin-2-RING ubiquitin ligases for enhanced substrate specificity.

Through targeting essential cellular regulators for ubiquitination and serving as a major platform for discovering proteolysis-targeting chimera (PROTAC) drugs, Cullin-2 (CUL2)-RING ubiquitin ligases (CRL2s) comprise an important family of CRLs. The founding members of CRLs, the CUL1-based CRL1s, are known to be activated by CAND1, which exchanges the variable substrate receptors associated with the common CUL1 core and promotes the dynamic assembly of CRL1s. Here we find that CAND1 inhibits CRL2-mediated protein degradation in human cells. This effect arises due to altered binding kinetics, involving CAND1 and CRL2VHL, as we illustrate that CAND1 dramatically increases the dissociation rate of CRL2s but barely accelerates the assembly of stable CRL2s. Using PROTACs that differently recruit neo-substrates to CRL2VHL, we demonstrate that the inhibitory effect of CAND1 helps distinguish target proteins with different affinities for CRL2s, presenting a mechanism for selective protein degradation with proper pacing in the changing cellular environment.

FOXO1-mediated lipid metabolism maintains mammalian embryos in dormancy

Mammalian developmental timing is adjustable in vivo by preserving pre-implantation embryos in a dormant state called diapause. Inhibition of the growth regulator mTOR (mTORi) pauses mouse development in vitro, yet how embryonic dormancy is maintained is not known. Here we show that mouse embryos in diapause are sustained by using lipids as primary energy source. In vitro, supplementation of embryos with the metabolite l-carnitine balances lipid consumption, puts the embryos in deeper dormancy and boosts embryo longevity. We identify FOXO1 as an essential regulator of the energy balance in dormant embryos and propose, through meta-analyses of dormant cell signatures, that it may be a common regulator of dormancy across adult tissues. Our results lift a constraint on in vitro embryo survival and suggest that lipid metabolism may be a critical metabolic transition relevant for longevity and stem cell function across tissues.

EIF4A3-mediated biogenesis of circSTX6 promotes bladder cancer metastasis and cisplatin resistance

BackgroundCisplatin (CDDP)-based chemotherapy is a standard first-line treatment for metastatic bladder cancer (BCa) patients, and chemoresistance remains a major challenge in clinical practice. Circular RNAs (circRNAs) have emerged as essential regulators in carcinogenesis and cancer progression. However, the role of circRNAs in mediating CDDP chemosensitivity has yet to be well elucidated in BCa.MethodsCircSTX6 (hsa_circ_0007905) was identified by mining the public circRNA datasets and verified by Sanger sequencing, agarose gel electrophoresis, RNase R treatment and qRT-PCR assays. Then, function experiments were performed to evaluate the effects of circSTX6 on BCa metastasis. Luciferase reporter assay, RNA pull-down, RNA immunoprecipitation (RIP), RNA stability assay, Fluorescence in situ hybridization (FISH) and Immunofluorescence (IF) were conducted to evaluate the interaction among circSTX6, miR-515-3p, PABPC1 and SUZ12. Animal experiments were performed to explore the function of circSTX6 in tumor metastasis and CDDP sensitivity.ResultsWe identified that circSTX6 was significantly upregulated in clinical samples and cells of BCa. Functionally, circSTX6 promoted cell migration and invasion both in vitro and in vivo. Mechanistically, circSTX6 could act as a miR-515-3p sponge and abolish its effect on SUZ12. Moreover, circSTX6 was confirmed to increase the stability of SUZ12 mRNA by interacting with a mRNA stabilizer PABPC1 and subsequently promote the expression of SUZ12. Importantly, silencing of circSTX6 improved the chemosensitivity of CDDP-resistant bladder cancer cells to CDDP. Furthermore, in vivo analysis supported that knockdown of circSTX6 attenuated CDDP resistance in BCa tumors.ConclusionThese studies demonstrate that circSTX6 plays a pivotal role in BCa metastasis and chemoresistance, and has potential to serve as a therapeutic target for treatment of BCa.

Decoding the gene regulatory network of endosperm differentiation in maize

The persistent cereal endosperm constitutes the majority of the grain volume. Dissecting the gene regulatory network underlying cereal endosperm development will facilitate yield and quality improvement of cereal crops. Here, we use single-cell transcriptomics to analyze the developing maize (Zea mays) endosperm during cell differentiation. After obtaining transcriptomic data from 17,022 single cells, we identify 12 cell clusters corresponding to five endosperm cell types and revealing complex transcriptional heterogeneity. We delineate the temporal gene-expression pattern from 6 to 7 days after pollination. We profile the genomic DNA-binding sites of 161 transcription factors differentially expressed between cell clusters and constructed a gene regulatory network by combining the single-cell transcriptomic data with the direct DNA-binding profiles, identifying 181 regulons containing genes encoding transcription factors along with their high-confidence targets, Furthermore, we map the regulons to endosperm cell clusters, identify cell-cluster-specific essential regulators, and experimentally validated three predicted key regulators. This study provides a framework for understanding cereal endosperm development and function at single-cell resolution.

Current concepts of the crosstalk between lncRNA and E2F1: shedding light on the cancer therapy.

Long noncoding RNAs (lncRNAs) constitute a distinctive subset of RNA molecules with limited protein-coding potential, which exert crucial impacts on various biological activities. In the context of cancer, dysregulated lncRNAs function as essential regulators that affect tumor initiation and malignant progression. These lncRNAs serve as competitive endogenous RNAs (ceRNAs) through sponging microRNAs and regulating the expression of targeted genes. Moreover, they also directly bind to RNA-binding proteins, which can be integrated into a complex mechanistic network. E2F1, an extensively studied transcription factor, mediates multiple malignant behaviors by regulating cell cycle progression, tumor metastasis, and therapeutic response. Emerging evidence suggests that lncRNAs play a pivotal role in regulating the E2F1 pathway. This review aims to elucidate the intricate gene regulatory programs between lncRNAs and E2F1 in cancer progression. We elaborate on distinct mechanistic networks involved in cancer progression, emphasizing the potential of the lncRNAs/E2F1 axes as promising targets for cancer therapy. Additionally, we provide novel perspectives on current evidence, limitations, and future directions for targeting lncRNAs in human cancers. Fully deciphering the intricate network of lncRNA/E2F1-mediated regulatory mechanisms in cancer could facilitate the translation of current findings into clinical course, such efforts ultimately significantly improve the clinical prognosis of cancer patients.

Transient receptor potential vanilloid 1 interacts with Toll-like receptor 4 (TLR4)/cluster of differentiation 14 (CD14) signaling pathway in lipopolysaccharide-mediated inflammation in macrophages.

Transient receptor potential vanilloid 1 (TRPV1), a ligand-gated cation channel, is a receptor for vanilloids on sensory neurons and is also activated by capsaicin, heat, protons, arachidonic acid metabolites, and inflammatory mediators on neuronal or non-neuronal cells. However, the role of the TRPV1 receptor in pro-inflammatory cytokine secretion and its potential regulatory mechanisms in lipopolysaccharide (LPS)-induced inflammation has yet to be entirely understood. To investigate the role and regulatory mechanism of the TRPV1 receptor in regulating LPS-induced inflammatory responses, bone marrow-derived macrophages (BMDMs) harvested from wild-type (WT) and TRPV1 deficient (Trpv1-/-) mice were used as the cell model. In WT BMDMs, LPS induced an increase in the levels of tumor necrosis factor-α, IL-1β, inducible nitric oxide synthase, and nitric oxide, which were attenuated in Trpv1-/- BMDMs. Additionally, the phosphorylation of inhibitor of nuclear factor kappa-Bα and mitogen-activated protein kinases, as well as the translocation of nuclear factor kappa-B and activator protein 1, were all decreased in LPS-treated Trpv1-/- BMDMs. Immunoprecipitation assay revealed that LPS treatment increased the formation of TRPV1-Toll-like receptor 4 (TLR4)-cluster of differentiation 14 (CD14) complex in WT BMDMs. Genetic deletion of TRPV1 in BMDMs impaired the LPS-triggered immune-complex formation of TLR4, myeloid differentiation protein 88, and interleukin-1 receptor-associated kinase, all of which are essential regulators in LPS-induced activation of the TLR4 signaling pathway. Moreover, genetic deletion of TRPV1 prevented the LPS-induced lethality and pro-inflammatory production in mice. In conclusion, the TRPV1 receptor may positively regulate the LPS-mediated inflammatory responses in macrophages by increasing the interaction with the TLR4-CD14 complex and activating the downstream signaling cascade.