Rheumatoid arthritis (RA) is an autoimmune chronic inflammatory disease that imposes a heavy economic burden on patients and society. Bone and cartilage destruction is considered an important factor leading to RA, and inflammation, oxidative stress, and mitochondrial dysfunction are closely related to bone erosion and cartilage destruction in RA. Currently, there are limitations in the clinical treatment methods for RA, which urgently necessitates finding new effective treatments for patients. Nuclear transcription factor-κB (NF-κB) is a signaling transcription factor that is widely present in various cells. It plays an important role as a stress source in the cellular environment and regulates gene expression in processes such as immunity, inflammation, cell proliferation, and apoptosis. NF-κB has long been recognized as a pathogenic factor of RA, and its activation can exacerbate RA by promoting inflammation, oxidative stress, mitochondrial dysfunction, and bone destruction. Conversely, inhibiting the activity of the NF-κB pathway effectively inhibits these pathological processes, thereby alleviating RA. Therefore, NF-κB may be a potential therapeutic target for RA. This article describes the physiological structure of NF-κB and its important role in RA through the regulation of oxidative stress, inflammatory response, mitochondrial function, and bone destruction. Meanwhile, we also summarized the impact of NF-κB crosstalk with other signaling pathways on RA and the effect of related drugs or inhibitors targeting NF-κB on RA. The purpose of this article is to provide evidence for the role of NF-κB in RA and to emphasize its significant role in RA by elucidating the mechanisms, so as to provide a theoretical basis for targeting the NF-κB pathway as a treatment for RA.

This article focuses on the phosphatidylethanolamine-binding protein (PEBP) family proteins, detailing PEBP1 and PEBP4 due to limited information on PEBP2 and PEBP3, in cellular signaling pathways and research in a spectrum of pathologies, including diverse cancers, metabolic disorders, immunological diseases and a subset of organ-specific diseases. It outlines the mechanisms through which PEBP1 and PEBP4 regulate essential signaling pathways that are critical for cellular processes such as proliferation, apoptosis, and metastasis. Recent advancements have shown further understanding of these proteins' roles in pathophysiology and their potential as future therapeutic targets. The findings suggest that the impact of PEBP1 and PEBP4 on the course of different diseases has underscored their potential for more in-depth medical research and novel clinically targeted therapies.

The nuclear factor kappa B (NF-κB) is a critical pathway that regulates various cellular functions, including immune response, proliferation, growth, and apoptosis. Furthermore, this pathway is tightly regulated to ensure stability in the presence of immunogenic triggers or genotoxic stimuli. The lack of control of the NF-κB pathway can lead to the initiation of different diseases, mainly autoimmune diseases and cancer, including Renal cell carcinoma (RCC). RCC is the most common type of kidney cancer and is characterized by complex genetic composition and elusive molecular mechanisms.

The current review summarizes the mechanism of NF-κB dysregulation in different subtypes of RCC and its impact on pathogenesis.

This review highlights the prominent role of NF-κB in RCC development and progression by driving the expression of multiple genes and interplaying with different pathways, including the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway. In silico analysis of RCC cohorts and molecular studies have revealed that multiple NF-κB members and target genes are dysregulated. The dysregulation includes receptors such as TLR2, signal-transmitting members including RelA, and target genes, for instance, HIF-1α. The lack of effective regulatory mechanisms results in a constitutively active NF-κB pathway, which promotes cancer growth, migration, and survival. In this review, we comprehensively summarize the role of dysregulated NF-κB-related genes in the most common subtypes of RCC, including clear cell RCC (ccRCC), chromophobe RCC (chRCC), and papillary RCC (PRCC).

Genomes adapt dynamically to alterations in the signaling milieu, including inflammation that transiently or permanently disrupts genome function. Here, we elucidate how a progenitor cell genome senses and responds to inflammation when the developmental and transcriptional regulator GATA2 is limiting, which causes bone marrow failure in humans and mice and predisposes to leukemia in humans. GATA2low murine progenitors are hypersensitive to inflammatory mediators. We discovered that the hematopoietic transcription factor PU.1 conferred transcriptional activation in GATA2low progenitors in response to Interferon-γ and Toll-Like Receptor 1/2 agonists. In a locus-specific manner, inflammation reconfigured genome activity by promoting PU.1 recruitment to chromatin or tuning activity of PU.1-preoccupied chromatin. The recruitment mechanism disproportionately required IKKβ activity. Inflammation-activated genes were enriched in motifs for RUNX factors that cooperate with GATA factors. Contrasting with the GATA2-RUNX1 cooperativity paradigm, GATA2 suppressed and RUNX1 promoted PU.1 mechanisms to endow the progenitor genome with inflammation-sensing capacity.

Ankyrin repeat (AR) motif is one of the most abundant repeat motifs found in eukaryotic proteins. It functions in mediating protein-protein interactions and regulating numerous biological functions. Interestingly, some AR-containing proteins are involved in epigenetic and transcriptional events. Our review aims to characterize the structure and post-translational modification of AR, summarize the prominent role of AR-containing proteins in epigenetic and transcriptional events, emphasizing the crucial functions mediated by AR motifs.

Nuclear factor (NF) κB as a redox sensitive, anti-apoptotic and pro-inflammatory signaling molecule has been studied extensively for more than three decades. Its role in inducing antioxidant enzymes, defending against extracellular and intracellular stress and maintaining redox homeostasis in skeletal muscle has also been recognized. New research continues to explore the polytropic nature of NFκB in cellular function, especially its crosstalk with other important signaling pathways. Understanding of the broad impact of these functions has significant implications in health and disease of skeletal muscle as an organ designed for contraction and mobility. Two important aspects of muscle wellbeing, i.e., disease and aging, are not discussed in this review. This review will provide an update on the new findings related to NFκB involvement in multiple signaling pathways and refresh our knowledge of its activation in skeletal muscle with a special reference to physical exercise.

NF-κB is a crucial transcription factor in lymphocyte signaling. It is activated by environmental cues that drive lymphocyte differentiation to combat infections and cancer. As a key player in inflammation, NF-κB also significantly impacts autoimmunity and transplant rejection, making it an important therapeutic target. While the signaling molecules regulating this pathway are well-studied, the effect of changes in NF-κB signaling levels on T lymphocyte differentiation, fate, and function is not fully understood. Advances in computational biology and new NF-κB-inducible animal models are beginning to clarify these questions. In this review, we highlight recent findings related to T cells, focusing on how environmental cues affecting NF-κB signaling levels determine T cell fate and function.

In addition to the 20 standard amino acids that form the building blocks of proteins, nature employs alternative amino acids to create specialized "noncanonical peptides." These unique peptides, found in organisms from bacteria to humans, often exhibit unconventional structures and functionalities, playing critical roles in modulating cellular processes, particularly as antibiotics. Their potential has attracted significant interest for designing novel functional materials based on noncanonical peptides. This review highlights recent advances in the generation and application of noncanonical peptide assemblies. It begins with a definition of noncanonical peptides, including classic examples that showcase their distinct structures and useful biological activities. Then the applications of noncanonical peptide assemblies in developing anticancer therapeutics are discussed, focusing on recent and representative studies that demonstrate their efficacy and versatility in targeting tumor cells. Beyond oncology, it is explored how noncanonical peptide assemblies have been utilized in biomaterials, regenerative medicine, molecular imaging and catalysis. Finally, perspectives are offered on future directions in this rapidly evolving field, emphasizing exciting opportunities and remaining challenges that will drive continued innovation in designing and applying noncanonical peptide-based assemblies.

Senescence associated secretory phenotype (SASP) contributes to age-related pathology, however the role of SASP in Chronic Kidney Disease (CKD) is unclear. Here, we employ a variety of omic techniques to show that senescence signatures can separate CKD patients into distinct senescence endotypes (Sendotype).

Using specific numbers of senescent proteins, we clustered CKD patients into two distinct sendotypes based on proteomic expression. These clusters were evaluated with three independent criteria assessing inter and intra cluster distances. Differential expression analysis was then performed to investigate differing proteomic expression between sendotypes.

These clusters accurately stratified CKD patients, with patients in each sendotype having different clinical profiles. Higher expression of these proteins correlated with worsened disease symptomologies. Biological signalling pathways such as TNF, Janus kinase-signal transducers and activators of transcription (JAK-STAT) and NFKB were differentially enriched between patient sendotypes, suggesting potential mechanisms driving the endotype of CKD.

Our work reveals that, combining clinical features with SASP signatures from CKD patients may help predict whether a patient will have worsening or stable renal trajectory. This has implications for the CKD clinical care pathway and will help clinicians stratify CKD patients accurately.

Senescent proteins are upregulated in severe patients compared to mild patients Senescent proteins can stratify patients based on disease severity High expression of senescent proteins correlates with worsening renal trajectories.

The canonical model of immune response activation in Drosophila suggests that the IMD pathway is activated by Gram-negative (Gram (-)) bacteria, while the Toll pathway is activated by both Gram-positive bacteria (Gram (+)) and fungi. However, the mechanisms by which these pathogens promote cross-activation of these pathways remain controversial. In addition, the mechanisms of cross-activation in S2 cell culture remain unstudied. In this study, we investigated the role of two Gram (+) bacteria (Micrococcus luteus and Bacillus subtilis) and fungal spores (Metarhizium anisopliae) in activating the IMD pathway in S2 cell cultures. Cells were treated with Escherichia coli as a control to ensure the specificity of IMD pathway activation. Our results demonstrated a significant involvement of M. luteus in the activation of the IMD pathway in S2 cell cultures. This is evidenced by the marked activation of IMD pathway-dependent genes, as well as the proteolytic cleavage of the Relish protein, which serves as a key transcription factor for this pathway. We also observed a strong recruitment of Relish to the promoters of antimicrobial peptide (AMP) genes, along with a partial recruitment to the genes encoding peptidoglycan recognition proteins (PGRPs). Furthermore, RNA interference targeting Relish resulted in a significant reduction in the transcription levels of all AMP genes and most PGRPs. Similarly, we analyzed the contributions of B. subtilis and M. anisopliae to the cross-activation of the IMD pathway. Our data indicate that both B. subtilis and M. anisopliae also activate the IMD pathway, albeit to a lesser extent compared to M. luteus. At the same time, fungal spores exhibited minimal influence on the activation of the IMD pathway when compared to Gram (+) bacteria. Thus, we have investigated in detail the mechanisms of cross-activation of the immune response in S2 cell culture, suggesting that Relish may play a critical role in inducing a humoral immune response in Drosophila S2 cells, primarily against M. luteus and to a lesser extent against B. subtilis and M. anisopliae.

Tau regulates neuronal integrity. In tauopathy, phosphorylated tau detaches from microtubules and aggregates, and is released into the extracellular space. Microglia are the first responders to the extracellular tau, a danger/damage-associated molecular pattern (DAMP), which can be cleared by proteostasis and activate innate immune response gene expression by nuclear factor-kappa B (NF-κB). However, longitudinal NF-κB activation in tauopathies and whether pathological tau (pTau) contributes to NF-κB activity is unknown. Here, we tau oligomers from human Alzheimer's disease brain (AD-TO) activate NF-κB in mouse microglia and macrophages reducing the IκBα via promoting its secretion in the extracellular space. NF-κB activity peaks at 9- and 11-months age in PS19Luc + and hTauLuc + mice, respectively. Reducing pTau via pharmacological (DOX), genetic ( Mapt -/- ) or antibody-mediated neutralization (immunization with pT181-Qβ vaccine) reduces NF-κB activity, and together suggest pTau is a driver of NF-κB and chronic neuroinflammation tauopathies.

Neuronal tau activates microglial NF-κB constitutively by secreting its inhibitor IκBα. NF-κB activation in PS19Luc + and hTauLuc + mice peaks at 9- and 11-months of age, respectively. Neutralizing pTau with pT181-Qβ vaccine (targeting phosphorylated threonine 181 tau) alleviates NF-κB activity in tauopathy mice.

Autoimmune diseases arise when the immune system attacks healthy tissues, losing tolerance for self-tissues. Normally, the immune system recognizes and defends against pathogens like bacteria and viruses. The cGAS-STING pathway, activated by pattern-recognition receptors (PRRs), plays a key role in autoimmune responses. The cGAS protein senses pathogenic DNA and synthesizes cGAMP, which induces conformational changes in STING, activating kinases IKK and TBK1 and leading to the expression of interferon genes or inflammatory mediators. This pathway is crucial in immunotherapy, activating innate immunity, enhancing antigen presentation, modulating the tumor microenvironment, and integrating into therapeutic strategies. Modulation strategies include small molecule inhibitors, oligonucleotide therapies, protein and antibody therapies, genetic and epigenetic regulation, cytokine and metabolite modulation, and nanoscale delivery systems. Post-translational modifications (PTMs) of the cGAS-STING pathway, such as phosphorylation, acetylation, ubiquitination, methylation, palmitoylation, and glycosylation, fine-tune immune responses by regulating protein activity, stability, localization, and interactions. These modifications are interconnected and collectively influence pathway functionality. We summarize the functions of cGAS-STING and its PTMs in immune and non-immune cells across various diseases, and explore potential clinical applications.

As legalization of cannabis increases worldwide, vaping cannabis is gaining popularity due to the belief that it is less harmful than smoking cannabis. However, the safety of cannabis vaping remains untested. To address this, we developed a physiologically relevant method for in vitro assessment of cannabis vapor on alveolar epithelial cell cultures. We compared the transcriptional response in three in vitro models of cannabis vapor exposure using A549 epithelial cells in submerged culture, pseudo-air liquid interface (ALI) culture, and ALI culture coupled with the expoCube™ advanced exposure system. Baseline gene expression in ALI-maintained A549 cells showed higher expression of type 2 alveolar epithelial (AEC2) genes related to surfactant production, ion movement, and barrier integrity. Acute exposure to cannabis vapor significantly affected gene expression in AEC2 cells belonging to pathways related to cancer, oxidative stress, and the immune response without being associated with a DNA damage response. This study identifies potential risks of cannabis vaping and underscores the need for further exploration into its respiratory health implications.

Nuclear factor kappa B (NF-κB) is involved in various important biological processes, such as inflammation, apoptosis, and cell proliferation. Here, we analyzed the function of NF-κB in transplantation immunity and pearl formation using its inhibitor, pyrrolidinedithiocarbamic acid (PDTC), in the pearl oyster Pinctada fucata martensii. The levels of pro-inflammatory factors (IL-17 and TNF-α) were lower and activity of antioxidant-related enzymes was higher in the transplanted pearl oysters pre-treated with PDTC than in transplanted pearl oysters pre-treated with phosphate-buffered saline (PBS). Transcriptomic analysis showed that PDTC pre-treatment alleviated the immune stimulation caused by transplantation, preserved normal expression of ribosome-related genes, and inhibited the activation of apoptosis and the NF-κB signaling pathway induced by transplantation. Additionally, RIG-I-like receptor, MAPK, Toll-like receptor and NOD-like receptor signaling pathways were inhibited after PDTC treatment. A 30-day pearl cultivation experiment demonstrated a significantly higher nucleus retention rate in transplanted pearl oysters that were pre-treated with PDTC compared to the control group. These results indicate that PDTC treatment suppressed immune-related pathways, thereby alleviating the immune rejection response caused by transplantation and potentially optimizing pearl production. Our results provide valuable information for optimizing pearl cultivation in P. f. martensii.

Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) synthase (cGAS) is a cytosolic DNA sensor that produces the secondary messenger cGAMP. cGAMP activates the endoplasmic reticulum-associated adaptor stimulator of interferon genes (STING) and activates the innate immune system to produce a type I interferon response. Besides sensing microbial DNA, cGAS can also be activated by self-DNA or endogenous DNA, including that derived from genotoxic extranuclear chromatin and mitochondrially released DNA, indicating that cGAS-STING is an important mechanism in sterile inflammatory responses, autoimmunity, and cellular senescence. However, aberrant activation of the cGAS-STING pathway results in inflammatory and autoimmune diseases. cGAS-STING has emerged as a vital mechanism driving the pathogenesis of inflammation, implicating cGAS-STING signaling in neurological diseases. In this review, we first outline the principal elements of the cGAS-STING signaling cascade, summarizing recent research highlighting how cGAS-STING activation contributes to the pathogenesis of neurological diseases, including various autoimmune, autoinflammatory, and neurodegenerative diseases. Next, we outline selective small-molecule modulators that function as cGAS-STING inhibitors and summarize their mechanisms for treating multiple neurological diseases. Finally, we discuss key limitations of the current therapeutic paradigm and generate possible strategies to overcome them.

The capacity of mature adipocytes to de-differentiate into fibroblast-like cells has been demonstrated in vitro and a few, rather specific in vivo conditions. A detailed comparison between de-differentiated fat (DFAT) cells and adipose stem and progenitor cells (ASPCs) from different adipose depots is yet to be conducted. Moreover, whether de-differentiation of mature adipocytes from classical subcutaneous and visceral depots occurs under physiological conditions remains unknown.

Here, we used in vitro "ceiling culture", single cell/nucleus RNA sequencing, epigenetic anaysis and genetic lineage tracing to address these unknowns.

We show that in vitro-derived DFAT cells have lower adipogenic potential and distinct cellular composition compared to ASPCs. In addition, DFAT cells derived from adipocytes of inguinal origin have dramatically higher adipogenic potential than DFAT cells of the epididymal origin, due in part to enhanced NF-KB signaling in the former. We also show that high-fat diet (HFD) feeding enhances DFAT cell colony formation and re-differentiation into adipocytes, while switching from HFD to chow diet (CD) only reverses their re-differentiation. Moreover, HFD deposits epigenetic changes in DFAT cells and ASPCs that are not reversed after returning to CD. Finally, combining genetic lineage tracing and single cell/nucleus RNA sequencing, we demonstrate the existence of DFAT cells in inguinal and epididymal adipose depots in vivo, with transcriptomes resembling late-stage ASPCs.

These data uncover the cell type- and depot-specific properties of DFAT cells, as well as their plasticity in response to dietary intervention. This knowledge may shed light on their role in life style change-induced weight loss and regain.

Cyclic GMP/AMP (cGAMP) synthase (cGAS), along with the endoplasmic reticulum (ER)-associated stimulator of interferon genes (STING), are crucial elements of the type 1 interferon response. cGAS senses microbial DNA and self-DNA, labeling cGAS-STING as a crucial mechanism in autoimmunity, sterile inflammatory responses, and cellular senescence. However, chronic and aberrant activation of the cGAS-STING axis results in inflammatory and autoimmune diseases. cGAS-STING has emerged as a vital mechanism driving inflammation-related diseases, including lung diseases. Insights into the biology of the cGAS-STING pathway have enabled the discovery of small-molecule agents which have the potential to inhibit the cGAS-STING axis in lung diseases. In this review, we first outline the principal components of the cGAS-STING signaling cascade. Then, we discuss recent research that highlights general mechanisms by which cGAS-STING contributes to lung diseases. Then, we focus on summarizing a list of bioactive small-molecule compounds which inhibit the cGAS-STING pathway, reviewing their potential mechanisms.These review highlights a novel groundbreaking therapeutic possibilities through targeting cGAS-STING in lung diseases.

Major depressive disorder (MDD), as a multimodal neuropsychiatric and neurodegenerative illness with high prevalence and disability rates, has become a burden to world health and the economy that affects millions of individuals worldwide. Neuroinflammation, an atypical immune response occurring in the brain, is currently gaining more attention due to its association with MDD. Microglia, as immune sentinels, have a vital function in regulating neuroinflammatory reactions in the immune system of the central nervous system. From the perspective of steady-state branching states, they can transition phenotypes between two extremes, namely, M1 and M2 phenotypes are pro-inflammatory and anti-inflammatory, respectively. It has an intermediate transition state characterized by different transcriptional features and the release of inflammatory mediators. The timing regulation of inflammatory cytokine release is crucial for damage control and guiding microglia back to a steady state. The dysregulation can lead to exorbitant tissue injury and neuronal mortality, and targeting the cellular signaling pathway that serves as the regulatory basis for microglia is considered an essential pathway for treating MDD. However, the specific intervention targets and mechanisms of microglial activation pathways in neuroinflammation are still unclear. Therefore, the present review summarized and discussed various signaling pathways and effective intervention targets that trigger the activation of microglia from its branching state and emphasizes the mechanism of microglia-mediated neuroinflammation associated with MDD.

The ubiquitin proteasome system (UPS), driven by ubiquitin as a degradation signal, eliminates, in a highly specific manner, 'abnormal' proteins and proteins that completed their function. This process involves a hierarchical cascade of E1, E2, and E3 enzymes. The E3 ubiquitin ligases, act as specific receptors that bind their cognate substrates. We have previously shown that the ubiquitin ligase KPC1 possesses a strong tumor-suppressive characteristic caused by the p50 subunit of the NF-κB transcription factor, which is generated by limited, KPC1-mediated processing of its p105 precursor. In this study, we identified vimentin as a novel substrate of the KPC1. We demonstrated that the ligase forms a complex with vimentin and modifies it by ubiquitination. Overexpression of KPC1 in HEK293T cells downregulates vimentin expression. Conversely, deletion of KPC1 in HAP1 cells results in upregulation of vimentin. Importantly, we revealed both in vitro and in a tumor model in mice that at least part of this effect is mediated through the downregulation of vimentin. Furthermore, in human clear cell renal cell carcinoma (ccRCC) samples, we found a negative correlation between KPC1 and vimentin expression. Overall, we demonstrate that the KPC1 ubiquitin E3 ligase downregulates vimentin expression, thereby reducing migration and tumorigenicity of cancer cells.

RNA translation to protein is paramount to creating life, yet RNA and protein correlations vary widely across tissues, cells, and species. To investigate these perplexing results, we utilize a time-series fixation method that combines static stimulation and a programmable formaldehyde perfusion to map pseudo-Signaling with Omics signatures (pSigOmics) of single-cell data from hundreds of thousands of cells. Using the widely studied nuclear factor kappa B (NFκB) mammalian signaling pathway in mouse fibroblasts, we discovered a novel asynchronous pseudotime regulation (APR) between RNA and protein levels in the quintessential NFκB p65 protein using single molecule spatial imaging. Prototypical NFκB dynamics are successfully confirmed by the rise and fall of NFκB response as well as A20 negative inhibitor activity by 90 min. The observed p65 translational APR is evident in both statically sampled timepoints and dynamic response gradients from programmable formaldehyde fixation, which successfully creates continuous response measurements. Finally, we implement a graph neural network model capable of predicting APR cell subpopulations from GAPDH RNA spatial expression, which is strongly correlated with p65 RNA signatures. Successful decision tree classifiers on Potential of Heat-diffusion for Affinity-based Trajectory Embedding embeddings of our data, which illustrate partitions of APR cell subpopulations in latent space, further confirm the APR patterns. Together, our data suggest an RNA-protein regulatory framework in which translation adapts to signaling events and illuminates how immune signaling is timed across various cell subpopulations.

Cancer immunobiology is one of the hot topics of discussion amongst researchers today, and immunotherapeutic modalities are among the selected few emerging approaches to cancer treatment that have exhibited a promising outlook. However, immunotherapy is not a new kid on the block; it has been around for centuries. The origin of cancer immunotherapy in modern medicine can be traced back to the initial reports of spontaneous regression of malignant tumors in some patients following an acute febrile infection, at the turn of the twentieth century. This review briefly revisits the historical accounts of immunotherapy, highlighting some of the significant developments in the field of cancer immunobiology, that have been instrumental in bringing back the immunotherapeutic approaches to the forefront of cancer research. Some of the topics covered are: Coley's toxin-the first immunotherapeutic; the genesis of the theory of immune surveillance; the discovery of T lymphocytes and dendritic cells and their roles; the role of tumor antigens; relevance of tumor microenvironment; the anti-tumor (therapeutic) ability of Bacillus Calmette- Guérin; Melacine-the first therapeutic vaccine engineered; theories of immunoediting and immunophenotyping of cancer; and Provenge-the first FDA-approved therapeutic vaccine. In this review, head and neck cancer has been taken as the reference tumor for narrating the progression of cancer immunobiology, particularly for highlighting the advent of immunotherapeutic agents.

Osteosarcoma (OS) is a prevalent malignancy among adolescents, commonly manifesting during childhood and adolescence. It exhibits a high degree of malignancy, propensity for metastasis, rapid progression, and poses challenges in clinical management. Chemotherapy represents an efficacious therapeutic modality for OS treatment. However, chemotherapy resistance of OS is a major problem in clinical treatment. In order to treat OS effectively, it is particularly important to explore the mechanism of chemotherapy resistance in OS.The Pregnane X receptor (PXR) is a nuclear receptor primarily involved in the metabolism, transport, and elimination of xenobiotics, including chemotherapeutic agents. PXR involves three stages of drug metabolism: stage I: drug metabolism enzymes; stage II: drug binding enzyme; stage III: drug transporter.PXR has been confirmed to be involved in the process of chemotherapy resistance in malignant tumors. The expression of PXR is increased in OS, which may be related to drug resistance of OS. Therefore, wereviewed in detail the role of PXR in chemotherapy drug resistance in OS.

Chlamys farreri, a commercially important bivalve mollusk, is extensively cultivated in China. In recent years, the frequent occurrence of diseases has led to significant mortality in scallop farms. Despite this, our understanding of scallop's innate immune mechanisms remains limited. The NF-κB signaling pathway plays a crucial role in various biological processes, including cellular, developmental, and immune defense mechanisms. Inhibitors of NF-κB (IκB) proteins block the nuclear localization and DNA binding of NF-κB, thereby inhibiting its activity. However, the role of these proteins in invertebrates is not well understood. In this study, we identified a new homolog of the IκB gene in C. farreri, named CfIκB1. The open reading frame of CfIκB1 spans 1089 bp, encoding 362 amino acids. Through sequence comparison and phylogenetic analysis, CfIκB1 was classified as a member of the invertebrate IκB family. Quantitative real-time PCR revealed that CfIκB1 transcripts are present in all examined tissues, with the highest expression observed in hemocytes. Expression levels were significantly upregulated following exposure to lipopolysaccharide, peptidoglycan, and polyinosinic:polycytidylic acid. Co-immunoprecipitation studies confirmed that CfIκB1 interacts with NF-κB family proteins CfRel-1 and CfRel. Dual-luciferase reporter assays demonstrated that CfIκB1 inhibits CfRel-dependent activation of NF-κB, ISRE, IFNβ, and AP-1. These findings suggest that CfIκB1 plays a crucial role in regulating NF-κB activity, which is integral to the innate immunity of C. farreri. This research enhances our understanding of the innate immune system in invertebrates and provides a theoretical basis for developing disease-resistant scallops at the molecular level.

The Nuclear Factor Kappa B (NF-κB) transcription factor family consists of five members: RelA (p65), RelB, c-Rel, p50 (p105/NF-κB1), and p52 (p100/NF-κB2). This family is considered a master regulator of classical biochemical pathways such as inflammation, immunity, cell proliferation, and cell death. The proteins in this family have a conserved Rel homology domain (RHD) with the following subdomains: DNA binding domain (RHD-DBD) and dimerization domain (RHD-DD). Despite the importance of the NF-κB family in biology, there is a lack of information with respect to their distribution patterns, evolution, and structural conservation concerning domains and subdomains in animals. This study aims to address this critical gap regarding NF-κB proteins. A comprehensive analysis of NF-κB family proteins revealed their distinct distribution in animals, with differences in protein sizes, conserved domains, and subdomains (RHD-DBD and RHD-DD). For the first time, NF-κB proteins with multiple RHD-DBDs and RHD-DDs have been identified, and in some cases, this is due to subdomain duplication. The presence of RelA/p65 exclusively in vertebrates shows that innate immunity originated in fishes, followed by amphibians, reptiles, aves, and mammals. Phylogenetic analysis showed that NF-κB family proteins grouped according to animal groups, signifying structural conservation after speciation. The evolutionary analysis of RHDs suggests that NF-κB family members p50/p105 and c-Rel may have been the first to emerge in arthropod ancestors, followed by RelB, RelA, and p52/p100.

Most gene functions have been discovered through phenotypic observations under loss of function experiments that lack temporal control. However, cell signaling relies on limited transcriptional effectors, having to be re-used temporally and spatially within the organism. Despite that, the dynamic nature of signaling pathways have been overlooked due to the difficulty on their assessment, resulting in important bottlenecks. Here, we have utilized the rapid and synchronized developmental transitions occurring within the zebrafish embryo, in conjunction with custom NF-kB reporter embryos driving destabilized fluorophores that report signaling dynamics in real time. We reveal that NF-kB signaling works as a clock that controls the developmental progression of hematopoietic stem and progenitor cells (HSPCs) by two p65 activity waves that inhibit cell cycle. Temporal disruption of each wave results in contrasting phenotypic outcomes: loss of HSPCs due to impaired specification versus proliferative expansion and failure to delaminate from their niche. We also show functional conservation during human hematopoietic development using iPSC models. Our work identifies p65 as a previously unrecognized contributor to cell cycle regulation, revealing why and when pro-inflammatory signaling is required during HSPC development. It highlights the importance of considering and leveraging cell signaling as a temporally dynamic entity.

Tooth-related inflammatory disorders, including caries, pulpitis, apical periodontitis (AP), and periodontitis (PD), are primarily caused by resident oral microorganisms. Although these dental inflammatory conditions are typically not life-threatening, neglecting them can result in significant complications and greatly reduce an individual's quality of life. Nuclear factor κB (NF-κB), a family formed by various combinations of Rel proteins, is extensively involved in inflammatory diseases and even cancer. This study reviews recent data on NF-κB signaling and its role in dental pulp stem cells (DPSCs), dental pulp fibroblasts (DPFs), odontoblasts, human periodontal ligament cells (hPDLCs), and various experimental animal models. The findings indicate that NF-κB signaling is abnormally activated in caries, pulpitis, AP, and PD, leading to changes in related cellular differentiation. Under specific conditions, NF-κB signaling occasionally interacts with other signaling pathways, affecting inflammation, bone metabolism, and tissue regeneration processes. In summary, data collected over recent years confirm the central role of NF-κB in dental inflammatory diseases, potentially providing new insights for drug development targeting NF-κB signaling pathways in the treatment of these conditions. Keywords: NF-κB, dental caries, pulpitis, apical periodontitis, periodontitis.

JOURNAL/nrgr/04.03/01300535-202408000-00034/figure1/v/2023-12-16T180322Z/r/image-tiff Spinal cord injury-induced motor dysfunction is associated with neuroinflammation. Studies have shown that the triterpenoid lupenone, a natural product found in various plants, has a remarkable anti-inflammatory effect in the context of chronic inflammation. However, the effects of lupenone on acute inflammation induced by spinal cord injury remain unknown. In this study, we established an impact-induced mouse model of spinal cord injury, and then treated the injured mice with lupenone (8 mg/kg, twice a day) by intraperitoneal injection. We also treated BV2 cells with lipopolysaccharide and adenosine 5'-triphosphate to simulate the inflammatory response after spinal cord injury. Our results showed that lupenone reduced IκBα activation and p65 nuclear translocation, inhibited NLRP3 inflammasome function by modulating nuclear factor kappa B, and enhanced the conversion of proinflammatory M1 microglial cells into anti-inflammatory M2 microglial cells. Furthermore, lupenone decreased NLRP3 inflammasome activation, NLRP3-induced microglial cell polarization, and microglia pyroptosis by inhibiting the nuclear factor kappa B pathway. These findings suggest that lupenone protects against spinal cord injury by inhibiting inflammasomes.

NIK (NF-κB inducing kinase) belongs to the mitogen-activated protein kinase family, which activates NF-κB and plays a vital role in immunology, inflammation, apoptosis, and a series of pathological responses. In NF-κB noncanonical pathway, NIK and IKKα have been often studied in mammals and zebrafish. However, few have explored the relationship between NIK and other subunits of the IKK complex. As a classic kinase in the NF-κB canonical pathway, IKKβ has never been researched with NIK in fish. In this paper, the full-length cDNA sequence of grass carp (Ctenopharyngodon idella) NIK (CiNIK) was first cloned and identified. The expression level of CiNIK in grass carp cells was increased under GCRV stimuli. Under the stimulation of GCRV, poly (I:C), and LPS, the expression of NIK in various tissues of grass carp was also increased. This suggests that CiNIK responds to viral stimuli. To study the relationship between CiNIK and CiIKKβ, we co-transfected CiNIK-FLAG and CiIKKB-GFP into grass carp cells in coimmunoprecipitation and immunofluorescence experiments. The results revealed that CiNIK interacts with CiIKKβ. Besides, the degree of autophosphorylation of CiNIK was enhanced under poly (I:C) stimulation. CiIKKβ was phosphorylated by CiNIK and then activated the activity of p65. The activity change of p65 indicates that NF-κB downstream inflammatory genes will be functioning. CiNIK or CiIKKβ up-regulated the expression of IL-8. It got higher when CiNIK and CiIKKβ coexisted. This paper revealed that NF-κB canonical pathway and noncanonical pathway are not completely separated in generating benefits.

The spleen is the largest peripheral immune organ of the organism, accounting for 25% of the total lymphoid tissue of the body. During HS, the spleen is damaged due to the elevated environment, which seriously affects life performance and broilers' health. This study aimed to investigate the mechanism of chronic HS damage to broiler spleen tissues. The broilers were typically raised until they reached 21 days of age, after which they were arbitrarily allocated into two groups: an HS group and a cntrol group. The HS group was subjected to a temperature of 35 °C for 10 h each day, starting at 21 days of age. At 35 and 42 days of age, spleen and serum samples were obtained from the broilers. The results showed that after HS, a significant decrease in productive performance was observed at 42 days of age (p < 0.01), and the spleen index, and bursa index were significantly decreased (p < 0.01). T-AOC of the organism was significantly decreased (p < 0.05), GSH-PX, SOD, and CAT antioxidant factors were significantly decreased (p < 0.01), and MDA was significantly elevated (p < 0.01). HS also led to a significant increase in cytokines IL-6, TNF-α, and INF-γ and a significant decrease in IL-4 in the spleen. The histopathologic results showed that the spleen's red-white medulla was poorly demarcated. The cells were sparsely arranged after HS. After HS, the expression of TLRs, MYD88, and NF-κB genes increased significantly. The expression of HSP70 increased significantly, suggesting that HS may induces an inflammatory response in broiler spleens through this signaling pathway, which may cause pathological damage to broiler spleens, leading to a decrease in immune function and progressively aggravating HS-induced damage with the prolongation of HS.

Breast cancer is the most common type of cancer and is the second leading cause of cancer-related mortality in women. Chemotherapy, targeted therapy, endocrine therapy, and radiotherapy are all effective in destroying tumor cells, but they also activate the defense and protection systems of cancer cells, leading to treatment resistance. Breast cancer is characterized by a highly inflammatory tumor microenvironment. The NF-κB pathway is essential for connecting inflammation and cancer, as well as for tumor growth and therapy resistance. An increase in NF-κB signaling boosts the growth potential of breast cancer cells and facilitates the spread of tumors to bone, lymph nodes, lungs, and liver. This review focuses on the mechanisms by which chemotherapy, targeted therapy, endocrine therapy, and radiotherapy induce breast cancer resistance through NF-κB signaling. Additionally, we investigate therapeutic regimens, including single agents or in combination with target inhibitors, plant extracts, nanomedicines, and miRNAs, that have been reported in clinical trials, in vivo, and in vitro to reverse resistance. In particular, NF-κB inhibitors combined with tamoxifen were shown to significantly increase the sensitivity of breast cancer cells to tamoxifen. Combination therapy of miRNA-34a with doxorubicin was also found to synergistically inhibit the progression of doxorubicin-resistant breast cancer by inhibiting Notch/NF-κB signaling.

The NFκB pathway, known as the central regulator of inflammation, has a well-established role in colorectal cancer (CRC) initiation, progression, and therapy resistance. Due to the pathway's overarching roles in CRC, there have been efforts to characterise NFκB family members and target the pathway for therapeutic intervention. Initial research illustrated that the canonical NFκB pathway, driven by central kinase IKKβ, was a promising target for drug intervention. However, dose limiting toxicities and specificity concerns have resulted in failure of IKKβ inhibitors in clinical trials. The field has turned to look at targeting the less dominant kinase, IKKα, which along with NFκB inducing kinase (NIK), drives the lesser researched non-canonical NFκB pathway. However prognostic studies of the non-canonical pathway have produced conflicting results. There is emerging evidence that IKKα is involved in other signalling pathways, which lie outside of canonical and non-canonical NFκB signalling. Evidence suggests that some of these alternative pathways involve a truncated form of IKKα, and this may drive poor cancer-specific survival in CRC. This review aims to explore the multiple components of NFκB signalling, highlighting that NIK may be the central kinase for non-canonical NFκB signalling, and that IKKα is involved in novel pathways which promote CRC.

Alterations in signaling pathways and modulation of cell metabolism are associated with the pathogenesis of cancers, including hepatocellular carcinoma (HCC). Small ubiquitin-like modifier (SUMO) proteins and NF-κB family play major roles in various cellular processes. The current study aims to determine the expression profile of SUMO and NF-κB genes in HCC tumors and investigate their association with the clinical outcome of HCC. The expression of 5 genes - SUMO1, SUMO2, SUMO3, NF-κB p65, and NF-κB p50 - was quantified in tumor and adjacent non-tumor tissues of 58 HBV-related HCC patients by real-time quantitative PCR and was analyzed for the possible association with clinical parameters of HCC. The expression of SUMO2 was significantly higher in HCC tumor tissues compared to the adjacent non-tumor tissues (P = .01), while no significant difference in SUMO1, SUMO3, NF-κB p65, and NF-κB p50 expression was observed between HCC tumor and non-tumor tissues (P > .05). In HCC tissues, a strong correlation was observed between the expression of SUMO2 and NF-κB p50, between SUMO3 and NF-κB p50, between SUMO3 and NF-κB p65 (Spearman rho = 0.83; 0.82; 0.772 respectively; P < .001). The expression of SUMO1, SUMO2, SUMO3, NF-κB p65, and NF-κB p50 was decreased in grade 3 compared to grades 1 and 2 in HCC tumors according to the World Health Organization grades system. Our results highlighted that the SUMO2 gene is upregulated in tumor tissues of patients with HCC, and is related to the development of HCC, thus it may be associated with the pathogenesis of HCC.

Glucolipid metabolism disorder (GLMD) is a complex chronic disease characterized by glucose and lipid metabolism disorders with a complex and diverse etiology and rapidly increasing incidence. Many studies have identified the role of flavonoids in ameliorating GLMD, with mechanisms related to peroxisome proliferator-activated receptors, nuclear factor kappa-B, AMP-activated protein kinase, nuclear factor (erythroid-derived 2)-like 2, glucose transporter type 4, and phosphatidylinositol-3-kinase/protein kinase B pathway. However, a comprehensive summary of the flavonoid effects on GLMD is lacking. This study reviewed the roles and mechanisms of natural flavonoids with different structures in the treatment of GLMD reported globally in the past 5 years and provides a reference for developing flavonoids as drugs for treating GLMD.

Early diagnosis and effective therapy are the fundamental challenge for modern oncology. Hence, many researchers focus on the search for new or improved biomarkers. Due to the great importance of nuclear factor kappa B (NF-κB) in physiological and pathological processes, we focused on assessing its usefulness as a biomarker in OPSCC. The purpose of the research presented here was to evaluate the prevalence and the level of NF-κB in the serum of OPSCC patients (ELISA). Serum NF-κB levels were also assessed depending on the degree of histological differentiation of the tumor and TN classification. Additionally, we considered the existence of a correlation between the concentration of NF-κB and EBV antibody titers, viral load and selected MMPs-MMP3 and MMP9. Taken together, the obtained results demonstrated that NF-κB level was significantly higher among patients with EBV-related OPSCC than among those without EBV. In addition, the level of NF-κB was significantly higher in more advanced clinical stages. Moreover, a positive correlation was found between the concentration of NF-κB and the level of selected EBV antibodies, viral load and both tested MMPs. The diagnostic accuracy of NF-κB was confirmed by ROC analysis.

Tumor heterogeneity poses a significant challenge in osteosarcoma (OS) treatment. In this regard, the "omics" era has constantly expanded our understanding of biomarkers and altered signaling pathways (i.e., PI3K/AKT/mTOR, WNT/β-catenin, NOTCH, SHH/GLI, among others) involved in OS pathophysiology. Despite different players and complexities, many commonalities have been described, among which the nuclear factor kappa B (NF-κB) stands out. Its altered activation is pervasive in cancer, with pleiotropic action on many disease-relevant traits. Thus, in the scope of this article, we highlight the evidence of NF-κB dysregulation in OS and its integration with other cancer-related pathways while we summarize the repertoire of compounds that have been described to interfere with its action. In silico strategies were used to demonstrate that NF-κB is closely coordinated with other commonly dysregulated signaling pathways not only by functionally interacting with several of their members but also by actively participating in the regulation of their transcription. While existing inhibitors lack selectivity or act indirectly, the therapeutic potential of targeting NF-κB is indisputable, first for its multifunctionality on most cancer hallmarks, and secondly, because, as a common downstream effector of the many dysregulated pathways influencing OS aggressiveness, it turns complex regulatory networks into a simpler picture underneath molecular heterogeneity.

Tumor biomarkers, the substances which are produced by tumors or the body's responses to tumors during tumorigenesis and progression, have been demonstrated to possess critical and encouraging value in screening and early diagnosis, prognosis prediction, recurrence detection, and therapeutic efficacy monitoring of cancers. Over the past decades, continuous progress has been made in exploring and discovering novel, sensitive, specific, and accurate tumor biomarkers, which has significantly promoted personalized medicine and improved the outcomes of cancer patients, especially advances in molecular biology technologies developed for the detection of tumor biomarkers. Herein, we summarize the discovery and development of tumor biomarkers, including the history of tumor biomarkers, the conventional and innovative technologies used for biomarker discovery and detection, the classification of tumor biomarkers based on tissue origins, and the application of tumor biomarkers in clinical cancer management. In particular, we highlight the recent advancements in biomarker-based anticancer-targeted therapies which are emerging as breakthroughs and promising cancer therapeutic strategies. We also discuss limitations and challenges that need to be addressed and provide insights and perspectives to turn challenges into opportunities in this field. Collectively, the discovery and application of multiple tumor biomarkers emphasized in this review may provide guidance on improved precision medicine, broaden horizons in future research directions, and expedite the clinical classification of cancer patients according to their molecular biomarkers rather than organs of origin.

Necrotising enterocolitis (NEC) has a complex pathophysiology but the common end-point is ischaemia reperfusion injury (IRI) and intestinal necrosis. We have previously reported that RIC significantly reduces the intestinal injury in a rat model of NEC. Here we describe the changes in intestinal mRNA occurring in the intestine of animals exposed to IRI, both with and without RIC. Related rat-pups were randomly assigned to four groups: SHAM, IRI only, RIC only and RIC + IRI. IRI animals, underwent 40 min of intestinal ischaemia, and 90 min of reperfusion. Animals that underwent RIC had three cycles of 5 min of alternating ischaemia/reperfusion by means of a ligature applied to the hind limb. Samples from the terminal ileum were immediately stored in RNA-preserving media for later next generation sequencing and transciptome analysis using R v 3.6.1. Differential expression testing showed that 868 genes differentially expressed in animals exposed to RIC alone compared to SHAM and 135 in the IRI and RIC group compared to IRI alone. Comparison between these two sets showed that 25 genes were differentially expressed in both groups. Pro-inflammatory molecules: NF-ĸβ2, Cxcl1, SOD2 and Map3k8 all show reduced expression in response to RIC. Targeted gene analysis revealed increased expression in PI3K which is part of the so-called RISK-pathway which is a key part of the protective mechanisms of RIC in the heart. Overall, this transcriptomic analysis shows that RIC provides a protective effect to the intestine via anti-inflammatory pathways. This could be particularly relevant to treating and preventing NEC.

Protein glycosylation is an extensively studied field, with the most studied forms being oxygen or nitrogen-linked N-acetylglucosamine (O-GlcNAc or N-GlcNAc) glycosylation. Particular residues on proteins are targeted by O-GlcNAcylation, which is among the most intricate post-translational modifications. Significantly contributing to an organism's proteome, it influences numerous factors affecting protein stability, function, and subcellular localization. It also modifies the cellular function of target proteins that have crucial responsibilities in controlling pathways related to the central nervous system, cardiovascular homeostasis, and other organ functions. Under conditions of acute stress, changes in the levels of O-GlcNAcylation of these proteins may have a defensive function. Nevertheless, deviant O-GlcNAcylation nullifies this safeguard and stimulates the advancement of several ailments, the prognosis of which relies on the cellular milieu. Hence, this review provides a concise overview of the function and comprehension of O-GlcNAcylation in ischemia diseases, aiming to facilitate the discovery of new therapeutic targets for efficient treatment, particularly in patients with diabetes.

Stress is a common denominator of complex disorders and the FK-506 binding protein (FKBP)51 plays a central role in stress. Hence, it is not surprising that multiple studies imply the involvement of the FKBP51 protein and/or its coding gene, FKBP5, in complex disorders. This review summarizes such reports concentrating on three disorder clusters-neuropsychiatric, cancer, and type 2 diabetes mellitus (T2DM). We also attempt to point to potential mechanisms suggested to mediate the effect of FKBP5/FKBP51 on these disorders. Neuropsychiatric diseases considered in this paper include (i) Huntington's disease for which increased autophagic cellular clearance mechanisms related to decreased FKBP51 protein levels or activity is discussed, Alzheimer's disease for which increased FKBP51 activity has been shown to induce Tau phosphorylation and aggregation, and Parkinson's disease in the context of which FKBP12 is mentioned; and (ii) mental disorders, for which significant association with the single nucleotide polymorphism (SNP) rs1360780 of FKBP5 intron 7 along with decreased DNA methylation were revealed. Since cancer is a large group of diseases that can start in almost any organ or tissue of the body, FKBP51's role depends on the tissue type and differences among pathways expressed in those tumors. The FKBP51-heat-shock protein-(Hsp)90-p23 super-chaperone complex might function as an oncogene or as a tumor suppressor by downregulating the serine/threonine protein kinase (AKt) pathway. In T2DM, two potential pathways for the involvement of FKBP51 are highlighted as affecting the pathogenesis of the disease-the peroxisome proliferator-activated receptor-γ (PPARγ) and AKt.

Nuclear factor κB (NF-κB) plays roles in various diseases. Many inflammatory signals, such as circulating lipopolysaccharides (LPSs), activate NF-κB via specific receptors. Using whole-genome CRISPR-Cas9 screens of LPS-treated cells that express an NF-κB-driven suicide gene, we discovered that the LPS receptor Toll-like receptor 4 (TLR4) is specifically dependent on the oligosaccharyltransferase complex OST-A for N-glycosylation and cell-surface localization. The tool compound NGI-1 inhibits OST complexes in vivo, but the underlying molecular mechanism remained unknown. We did a CRISPR base-editor screen for NGI-1-resistant variants of STT3A, the catalytic subunit of OST-A. These variants, in conjunction with cryoelectron microscopy studies, revealed that NGI-1 binds the catalytic site of STT3A, where it traps a molecule of the donor substrate dolichyl-PP-GlcNAc2-Man9-Glc3, suggesting an uncompetitive inhibition mechanism. Our results provide a rationale for and an initial step toward the development of STT3A-specific inhibitors and illustrate the power of contemporaneous base-editor and structural studies to define drug mechanism of action.

To investigate the antitumor effects of human placenta hydrolysate (HPH) peptides on three hormone-dependent human cell lines: prostate adenocarcinoma, breast carcinoma, and ovarian cancer by metabolic analysis of cell cultures.

The effect of HPH on tumor and control tumor cell lines was evaluated. Study stages: (A) de novo peptide sequencing by collision-induced dissociation mass spectrometry; (B) detection of peptides with anti-tumor properties; (C) expert analysis of the obtained lists of peptides.

Dose-dependent cytotoxic effects of HPH on three tumor cell lines are shown: PC-3 (human prostate adenocarcinomas), OAW-42 (human ovarian cancer), BT-474 (human breast carcinomas), and IC50 constants (1.3-2.8 mg/ml) were obtained. The analysis of the HPH peptide fraction showed more than 70 peptides with antitumor properties in the composition of this HPH, including kinase inhibitors: mitogen-activated protein kinases, kappa-bi nuclear factor inhibitor kinase, AKT serine/threonine kinase 1, protein kinase C zeta, interleukin-1 receptor-associated kinase 4 and cyclin-dependent kinase 1.

The results of the study indicate not only the oncological safety of the HPH used in therapy but also the mild antitumor effects of this HPH at high concentrations.