The Nile tilapia (Oreochromis niloticus) is a globally recognised freshwater aquaculture species with high economic value. However, streptococcal disease, a bacterial infection, has the potential to inflict considerable economic losses on the aquaculture production of tilapia. Innate immune factors in fish play a pivotal role in disease resistance mechanisms. Consequently, a comprehensive study on the intrinsic immune response mechanisms of Nile tilapia against Streptococcus agalactiae is imperative. In this study, we conducted a comprehensive investigation of the Nile tilapia p38 MAPK gene, encompassing its molecular cloning, expression profile in both normal and post-stimulated fish, and the characteristics of its encoded polypeptide. The p38 gene is 1493 bp in length, with an open reading frame (ORF) of 1083 bp, which encodes a total of 360 amino acids. The deduced P38 protein contained an S_TKc structural domain, and the highest degree of homology was observed with the Neolamprologus brichardi at 98.16 %. The highest level of P38 expression was observed in the heart. LPS, Poly I:C, and S. agalactiae stimulation led to significant changes in the expression of P38 in the examined tissues. Subcellular localization studies revealed that P38 is distributed in the nucleus, cytoplasm and cell membrane. Furthermore, pull-down assays demonstrated an interaction between P38 and Tak1, but not between P38 and Tab1 proteins. These results provide a basis for further investigation of the mechanism of P38 involvement in this signalling pathway.

Lead (Pb²⁺) is a toxic metal known to induce oxidative stress and inflammation, contributing to cardiovascular diseases such as hypertension and atherosclerosis. Natural compounds like Allium sativum essential oil (ASEO) offer potential therapeutic benefits against lead-induced damage, but their cardioprotective effects remain underexplored. This study investigates the efficacy of ASEO in mitigating cardiovascular toxicity induced by lead nitrate in male Swiss albino mice.

Thirty-six male mice were divided into six groups: Control, Lead Nitrate (50 mg/kg), Lead Nitrate + Low-dose ASEO (50 mg/kg), Lead Nitrate + High-dose ASEO (80 mg/kg), Lead Nitrate + Silymarin (25 mg/kg), and Lead Nitrate + Olive Oil. After 12 days of lead exposure, treatments were administered for 30 days. Key cardiovascular parameters such as lipid profiles (total cholesterol, LDL, HDL), nitric oxide (NO), and inflammatory markers (TNF-α, IL-6, IFN-γ, IL-10, NF-κB) were evaluated alongside histological analysis of cardiac tissue.

Lead nitrate exposure significantly increased total cholesterol (88.27 µg/mL) and LDL (93.78 µg/mL) while reducing HDL (17.51 µg/mL) compared to controls (P < 0.001). High-dose ASEO lowered total cholesterol (66.07 µg/mL) and LDL (49.62 µg/mL) while increased HDL (27.2 µg/mL) (P < 0.001). NO levels, reduced by lead exposure, were significantly restored by high-dose ASEO (P < 0.001). Inflammatory markers, including TNF-α, NF-kB, and IL-6, were elevated in the lead group but decreased significantly following ASEO treatment (P < 0.001). Histological analysis showed that ASEO markedly preserved myocardial architecture, reducing degeneration and inflammation.

High-dose ASEO demonstrated significant cardioprotective effects against lead-induced toxicity by improving lipid profiles, enhancing NO levels, and modulating inflammatory markers. Further studies are warranted to validate these results.

Tau protein plays a critical role in the physiological functioning of the central nervous system by providing structural integrity to the cytoskeletal architecture of neurons and glia through microtubule assembly and stabilization. Under certain pathological conditions, tau is aberrantly phosphorylated and aggregates into neurotoxic fibrillary tangles. The aggregation and cell-to-cell propagation of pathological tau leads to the progressive deterioration of the nervous system. The clinical entity of traumatic brain injury (TBI) ranges from mild to severe and can promote tau aggregation by inducing cellular mechanisms and signalling pathways that increase tau phosphorylation and aggregation. Chronic traumatic encephalopathy (CTE), which is a consequence of repetitive TBI, is a unique tauopathy characterized by pathological tau aggregates located at the depths of the sulci and surrounding blood vessels. The mechanisms leading to increased tau phosphorylation and aggregation in CTE remain to be fully defined but are likely the result of the primary and secondary injury sequelae associated with TBI. The primary injury includes physical and mechanical damage resulting from the head impact and accompanying forces that cause blood-brain barrier disruption and axonal shearing, which primes the central nervous system to be more vulnerable to the subsequent secondary injury mechanisms. A complex interplay of neuroinflammation, oxidative stress, excitotoxicity, and mitochondrial dysfunction activate kinase and cell death pathways, increasing tau phosphorylation, aggregation and neurodegeneration. In this review, we explore the most recent insights into the mechanisms of tau phosphorylation associated with TBI and propose how multiple cellular pathways converge on tau phosphorylation, which may contribute to CTE progression.

Neurodegenerative diseases (e.g., Alzheimer's, Parkinson's, Huntington's disease, and Amyotrophic Lateral Sclerosis) are major health threats for the aging population and their prevalences continue to rise with the increasing of life expectancy. Although progress has been made, there is still a lack of effective cures to date, and an in-depth understanding of the molecular and cellular mechanisms of these neurodegenerative diseases is imperative for drug development. Protein phosphorylation, regulated by protein kinases and protein phosphatases, participates in most cellular events, whereas aberrant phosphorylation manifests as a main cause of diseases. As evidenced by pharmacological and pathological studies, protein kinases are proven to be promising therapeutic targets for various diseases, such as cancers, central nervous system disorders, and cardiovascular diseases. The mechanisms of protein phosphatases in pathophysiology have been extensively reviewed, but a systematic summary of the role of protein kinases in the nervous system is lacking. Here, we focus on the involvement of protein kinases in neurodegenerative diseases, by summarizing the current knowledge on the major kinases and related regulatory signal transduction pathways implicated in diseases. We further discuss the role and complexity of kinase-kinase networks in the pathogenesis of neurodegenerative diseases, illustrate the advances of clinical applications of protein kinase inhibitors or novel kinase-targeted therapeutic strategies (such as antisense oligonucleotides and gene therapy) for effective prevention and early intervention.

A series of 1, 2, 4, 5-tetrasubstituted imidazole derivatives were synthesized and their antibiofilm potential against Candida albicans was evaluated in vitro. Two of the synthesized derivatives 5e (IC50 = 25 µg/mL) and 5m (IC50 = 6 µg/mL),displayed better antifungal and antibiofilm potential than the standard drug Fluconazole (IC50 = 40 µg/mL) against C. albicans. Based on the in vitro results, we escalated the real time polymerase chain reaction (RT-PCR) analysis to gain knowledge of the enzymes expressed in the generation and maintenance of biofilms and the mechanism of biofilm inhibition by the synthesized analogues. We then investigated the possible interactions of the synthesized compounds in inhibiting agglutinin-like proteins, namely Als3, Als4 and Als6 were prominently down-regulated using in-silico molecular docking analysis against the previously available crystal structure of Als3 and constructed structure of Als4 and Als6 using the SWISS-MODEL server. The stability and energy of the agglutinin-like proteins-ligand complexes were evaluated using molecular dynamics simulations (MDS). According to the 100 ns MDS, all the compounds remained stable, formed a maximum of 3, and on average 2 hydrogen bonds, and Gibb's free energy landscape analysis suggested greater affinity of the compounds 5e and 5m toward Als4 protein.

Some genetic variants are associated with lung function decline and chronic obstructive pulmonary disease (COPD), but functional studies are necessary to confirm causality. We investigated the genetic susceptibility-associated lung function decline with or without COPD, using data from a community-based cohort (N = 8554). A genome-wide interaction study was conducted to identify the association between genetic variants and pulmonary function, and the way variants relate to lung impairment in accordance with smoking status and amount was examined. We further used a linear mixed model to examine the association and interaction to time effect. We found annual mean FEV1 declines of 41.7 mL for men and 33.4 mL for women, and the annual rate of decline in FEV1 was the fastest for current smokers. We also found a previously identified locus near FAM13A, the most significant SNPs from the results of two likelihood ratio tests for FEV1/FVC (P = 1.56 × 10-10). These selected SNPs were located in the upstream region of FAM13A on chromosome 4 and had similar minor allele frequencies (MAFs). Furthermore, we found that certain SNPs tended to have lower FEV1/FVC values, and lung function decreased much faster with time interactions. The SNP most associated with lung function decline was the rs75679995 SNP on chromosome 7, and those SNPs located within the TAD of the DNAH11 region and the eQTL of rs9991425 revealed a higher expression of MFAP3L and AADAT genes (P = 2.28 × 10-7 and 2.01 × 10-6, respectively). This is the first study to investigate gene-time interactions in lung function decline as a risk factor for COPD in the Korean population. In addition to replicating previously known signals for FAM13A, we identified two genomic regions (DNAH11, AADAT) that are potentially involved in gene-environment interactions, warranting further investigation to confirm their roles.

Cardiovascular disease (CVD) is a serious global health issue with high mortality rates worldwide. Despite the numerous advancements in the study of CVD pathogenesis in recent years, further summarization and elaboration of specific molecular pathways are required. An extensive body of research has been conducted to elucidate the association between the MAPK signaling pathway, which is present in all eukaryotic organisms, and the pathogenesis of cardiovascular disease. This review aims to provide a comprehensive summary of the research conducted on MAPK and CVD over the past five years. The primary focus is on four specific diseases: heart failure, atherosclerosis, myocardial ischemia-reperfusion injury, and cardiac hypertrophy. The review will also address the pathophysiological mechanisms of MAPK in cardiovascular diseases, with the objective of proposing novel clinical treatment strategies for CVD.

The inhibitory avoidance (IA) task is a paradigm widely used to investigate the molecular and cellular mechanisms involved in the formation of long-term memory of aversive experiences. In this review, we discuss studies on different brain structures in rats associated with memory consolidation, such as the hippocampus, striatum, and amygdala, as well as some cortical areas, including the insular, cingulate, entorhinal, parietal and prefrontal cortex. These studies have shown that IA training triggers the release of neurotransmitters, hormones, growth factors, etc., that activate intracellular signaling pathways related to protein kinases, which induce intracellular non-genomic changes or transcriptional mechanisms in the nucleus, leading to the synthesis of proteins. We have summarized the temporal dynamics and crosstalk among protein kinase A, protein kinase C, mitogen activated protein kinase, extracellular-signal-regulated kinase, and Ca2+/calmodulin-dependent protein kinase II described in the hippocampus. Protein kinase activity has been associated with structural changes and synaptic strengthening, resulting in memory storage. However, little is known about the molecular mechanisms involved in intense IA training, which protects memory from typical amnestic treatments, such as protein synthesis inhibitors, and induces increased spinogenesis, suggesting an unexplored mechanism independent of the genomic pathway. This highly emotional experience causes an extinction-resistant memory, as has been observed in some pathological states such as post-traumatic stress disorder. We propose that the changes in spinogenesis observed after intense IA training could be generated by protein kinases via non-genomic pathways.

Pyridinyl-imidazole class p38 MAPKα/β (MAPK14/MAPK11) inhibitors including SB202190 have been shown to induce cell-type specific defective autophagy resulting in micron-scale vacuole formation, cell death, and tumor suppression. We had earlier shown that this is an off-target effect of SB202190. Here we provide evidence that this vacuole formation is independent of ATG5-mediated canonical autophagosome initiation. While SB202190 interferes with autophagic flux in many cell lines parallel to vacuolation, autophagy-deficient DU-145 cells and CRISPR/Cas9 gene-edited ATG5-knockout A549 cells also undergo vacuolation upon SB202190 treatment. Late-endosomal GTPase RAB7 colocalizes with these compartments and RAB7 GTP-binding is essential for SB202190-induced vacuolation. A screen for modulators of SB202190-induced vacuolation revealed molecules including multi-kinase inhibitor sorafenib as inhibitors of vacuolation and sorafenib co-treatment enhanced cytotoxicity of SB202190. Moreover, VE-821, an ATR inhibitor was found to phenocopy the cell-type specific vacuolation response of SB202190. To identify the factors determining the cell-type specificity of vacuolation induced by SB-compounds and VE-821, we compared the transcriptomics data from vacuole-forming and non-vacuole-forming cancer cell lines and identified a gene expression signature that may define sensitivity of cells to these small-molecules. Further analyses using small molecule tools and the gene signature discovered here, could reveal novel mechanisms regulating this interesting anti-cancer phenotype.

Cutaneous squamous cell carcinoma (cSCC) is the second most common non-melanoma skin cancer, among which 82% arise from actinic keratosis (AK) characterized by lesions of epidermal keratinocyte dysplasia. It is of great significance to uncover the progression mechanisms from AK to cSCC, which will facilitate the early therapeutic intervention of AK before malignant transformation. Thus, more and more studies are trying to ascertain the potential transformation mechanisms through multi-omics, including genetics, transcriptomics, and epigenetics. In this review, we gave an overview of the specific biomarkers and signaling pathways that may be involved in the pathogenesis from AK to cSCC, pointing out future possible molecular therapies for the early intervention of AK and cSCC. We also discussed current interventions on AK and cSCC, together with future perspectives.

Reversible protein phosphorylation directs essential cellular processes including cell division, cell growth, cell death, inflammation, and differentiation. Because protein phosphorylation drives diverse diseases, kinases and phosphatases have been targets for drug discovery, with some achieving remarkable clinical success. Most protein kinases are activated by phosphorylation of their activation loops, which shifts the conformational equilibrium of the kinase toward the active state. To turn off the kinase, protein phosphatases dephosphorylate these sites, but how the conformation of the dynamic activation loop contributes to dephosphorylation was not known. To answer this, we modulated the activation loop conformational equilibrium of human p38α ΜΑP kinase with existing kinase inhibitors that bind and stabilize specific inactive activation loop conformations. From this, we identified three inhibitors that increase the rate of dephosphorylation of the activation loop phospho-threonine by the PPM serine/threonine phosphatase WIP1. Hence, these compounds are "dual-action" inhibitors that simultaneously block the active site and promote p38α dephosphorylation. Our X-ray crystal structures of phosphorylated p38α bound to the dual-action inhibitors reveal a shared flipped conformation of the activation loop with a fully accessible phospho-threonine. In contrast, our X-ray crystal structure of phosphorylated apo human p38α reveals a different activation loop conformation with an inaccessible phospho-threonine, thereby explaining the increased rate of dephosphorylation upon inhibitor binding. These findings reveal a conformational preference of phosphatases for their targets and suggest a unique approach to achieving improved potency and specificity for therapeutic kinase inhibitors.

An electrochemical tandem cyclization of enaminones with amidines has been reported for the first time using dibromomethane as an initiating agent in an undivided cell. Following this protocol, a vast variety of polysubstituted 5-acylimidazoles were obtained in moderate to good yields without the use of external oxidants. Mechanistic studies indicate that the bromide anion, electroreductively generated from dibromomethane, acts as a redox mediator to complete the catalytic cycle.

Heart failure (HF) is a complex condition characterized by the inability of the heart to pump sufficient oxygen to the organs to meet their metabolic needs. Among the altered signal transduction pathways associated with HF pathogenesis, the p38 mitogen-activated protein kinase (p38 MAPK) pathway-activated in response to stress- has attracted considerable attention for its potential role in HF progression and cardiac hypertrophy. However, the exact mechanisms by which p38 MAPK influences HF remain unclear. Addressing knowledge gaps may provide insight on why p38 inhibition has yielded inconsistent outcomes in clinical trials. Here we investigate the effects of p38 MAPK inhibition via SB203580 on cardiac remodeling in a guinea pig model of HF and sudden cardiac death. Using a well-established HF model with ascending aortic constriction and daily isoproterenol (ACi) administration, we assessed proteomic changes across three groups: sham-operated controls, untreated ACi, and ACi treated with SB203580 (ACiSB). Cardiac function was evaluated by M-mode echocardiography, while proteome and phosphoproteome profiles were analyzed using multiplexed tandem mass tag labeling and LC-MS/MS. Our findings demonstrate that chronic SB203580 treatment offers protection against progressive decline in cardiac function in HF. The proteomic data indicate that SB203580-treatment exerts broad protection of the cardiac phosphoproteome, beyond inhibiting maladaptive p38-dependent phosphorylation, extending to PKA and AMPK networks among others, ultimately protecting the phosphorylation status of critical myofibrillar and Ca2+-handling proteins. Though SB203580 had a more restricted impact on widespread protein changes in HF, its biosignature was consistent with preserved mitochondrial energetics as well as reduced oxidative and inflammatory stress.

In this study, we uncovered the novel mechanism of IL-1α-mediated downregulated in adenoma (DRA) (SLC26A3) downregulation in the context of Brachyspira spp.-induced malabsorptive diarrhea. Experimentally infected pigs with Brachyspira spp. had significantly reduced DRA expression in the colon accompanied by IL-1α upregulation. This response was recapitulated in vitro by exposing Caco-2 cells to either Brachyspira lysate or IL-1α. Both p38 and MAPK-activated protein kinase 2 (MAPKAPK-2 also referred as MK-2) showed an increased phosphorylation after exposure to either. SB203580 application, a p38 inhibitor blocked the MK-2 phosphorylation and attenuated the DRA and IL-1α response to both lysate and IL-1α. Exposure to IL-1 receptor antagonist (IL-1RA) produced a similar response. In addition, exposure of cells to either of these blockers without IL-1α or lysate results in increased DRA and decreased IL-1α expression, revealing that DRA needs IL-1α signaling for basal physiological expression. Dual inhibition with both blockers completely inhibited the effect from IL-1α while significantly attenuating the response from Brachyspira lysate, suggesting a minor contribution from another pathway. Together this demonstrates that Brachyspira activates p38 MAPK signaling driving IL-1α expression, which activates IL-1R1 causing DRA downregulation while also driving upregulation of IL-1α through p38 in a positive feedback mechanism. In conclusion, we elucidated a major pathway involved in DRA downregulation and its role in Brachyspira-induced diarrhea. In addition, these observations will aid in our understanding of other inflammatory and infectious diarrhea conditions.NEW & NOTEWORTHY The diarrheal disease caused by the two infectious spirochete spp. B. hyodysenteriae and B. hampsonii reduced the expression of DRA (SLC26A3), a major Cl-/HCO-3 exchanger involved in Cl- absorption. This is attributed to the upregulation of IL-1α driven by p38 MAPK. This work also describes a potential new mechanism in inflammatory diseases while showing the importance of IL-1α in maintaining DRA levels.

Hemolysis is associated with pulmonary hypertension (PH), but the direct contribution of circulating free heme to the PH pathogenesis remains unclear. Here, we show that the elevated levels of circulating free heme are sufficient to induce PH and inflammatory response in mice and confirm the critical role of mitogen-activated protein kinase kinase-3 (MKK3)-mediated pathway in free heme signaling. Following the continuous infusion of heme for 2 wk, wild-type (WT) but not MKK3 knockout (KO) mice develop PH, as evidenced by a significantly elevated right ventricular (RV) systolic pressure, RV hypertrophy, and pulmonary vascular remodeling. The MKK3/p38 axis, markedly activated by heme infusion in WTs, results in upregulated proliferative/cytokine signaling targets Akt, ERK1/2, and STAT3, which were abrogated in MKK3 KO mice. Moreover, the MKK3 KOs were protected against heme-mediated endothelial barrier dysfunction by restoring the tight junction protein zonula occludens-1 expression and diminishing the inflammatory cell infiltration in the lungs. Plasma cytokine multiplex analysis revealed a severe cytokine storm already 24 h after initiation of heme infusion, with a significant increase of 19 cytokines, including IL-1b, IL-2, IL-6, IL-9, and TNF-a, in WT animals and complete attenuation of cytokine production in MKK3 KO mice. Together, these findings reveal a causative role of circulating free heme in PH through activating inflammatory and proliferative responses. The central role of MKK3 in orchestrating the heme-mediated pathogenic response supports MKK3 as an attractive therapeutic target for PH and other lung inflammatory diseases linked to hemolytic anemia.NEW & NOTEWORTHY This study demonstrates that elevated levels of circulating free heme can induce pulmonary hypertension (PH) and inflammation in mice. Continuous heme infusion activated the MKK3/p38 pathway, leading to increased right ventricular pressure, right ventricular hypertrophy, and vascular remodeling. This activation upregulated signaling cascades such as Akt, ERK1/2, and STAT3, whereas MKK3 knockout mice were protected against these changes and had reduced inflammatory responses, highlighting MKK3's potential as a therapeutic target for PH.

In this study, a catalyst composite of Co-Cu was prepared from chloride-containing precursor of Co(II) and Cu(II) metals using the milky latex of the Euphorbia neriifolia plant following green principles of synthesis. The catalyst composite was characterized using XRD, EDAX, SEM, HR-TEM, FTIR, XPS and TOF-MS. The crystallinity of the mixed-oxide composite with a distorted octahedral nature was confirmed from analysis. Chemical charge analysis of the Co-Cu mixed phase based on XPS revealed Co2+ and Cu2+ oxidation states. This material was used for synthesizing 2,4,5-triaryl-1H-imidazole (TIMDZOL) derivatives. Analysis of reaction conditions revealed that EtOH : PEG at 8 : 2 ratio under microwave conditions showed better yields with less time and better reusability of the Co-Cu catalyst.

Previous studies have shown that the activation of p38MAPK signaling plays a crucial role in regulating gonadal cell fate decisions in both mouse and human. Excessive activation of p38MAPK by radiation significantly causes testicular damage and negatively affects the male reproductive function. Therefore, fine-tuned regulation of p38MAPK signaling is critical in both physiological and pathological conditions.

This review summarizes the impact of p38MAPK signaling on testicular germ cells and microenvironment under normal condition. The relationship between radiation, reactive oxygen species (ROS), and p38MAPK is summarized. In conclusion, radiation exposure triggers the overactivation of p38MAPK, which is regulated by ROS, resulting in testicular damage. Various p38MAPK-targeting agents are discussed, providing guidance for developing new strategies.

Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by the formation of amyloid β and tau protein aggregates in the brain, neuroinflammation, impaired cholinergic neurotransmission, and oxidative stress, resulting in the gradual loss of neurons and neuronal function, which leads to cognitive and memory deficits in AD patients. Chronic neuroinflammation plays a particularly important role in the progression of AD since the excessive release of proinflammatory cytokines from glial cells (microglia and astrocytes) induces neuronal damage, which subsequently causes microglial activation, thus facilitating further neurodegenerative changes. Mitogen-activated protein kinase (MAPK) p38α is one of the key enzymes involved in the control of innate immune response. The increased activation of the p38α MAPK pathway, observed in AD, has been for a long time associated not only with the maintenance of excessive inflammatory process but is also linked with pathophysiological hallmarks of this disease, and therefore is currently considered an attractive drug target for novel AD therapeutics. This review aims to summarize the current state of knowledge about the involvement of p38α MAPK in different aspects of AD pathophysiology and also provides insight into the possible therapeutic effects of novel p38α MAPK inhibitors, which are currently studied as potential drug candidates for AD treatment.

Long non-coding RNAs (lncRNAs) regulate the occurrence, development and progression of oral squamous cell carcinoma (OSCC). We elucidated the expression features of MAGEA4-AS1 in patients with OSCC and its activity as an OSCC biomarker. Furthermore, the impact of up-regulation of MAGEA4-AS1 on the cellular behaviors (proliferation, migration and invasion) of OSCC cells and intrinsic signal mechanisms were evaluated. Firstly, we analyzed MAGEA4-AS1 expression data in The Cancer Genome Atlas (TCGA) OSCC using a bioinformatics approach and in 45 pairs of OSCC tissues using qPCR. Then CCK-8, ethynyl deoxyuridine, colony formation, transwell and wound healing assays were conducted to assess changes in the cell proliferation, migration and invasion protential of shMAGEA4-AS1 HSC3 and CAL27 cells. The RNA sequence of MAGEA4-AS1 was identified using the rapid amplification of cDNA ends (RACE) assay. And whole-transcriptome sequencing was used to identify MAGEA4-AS1 affected genes. Additionally, dual-luciferase reporter system, RNA-binding protein immunoprecipitation (RIP), and rescue experiments were performed to clarify the role of the MAGEA4-AS1-p53-MK2 signaling pathway. As results, we found MAGEA4-AS1 was up-regulated in OSCC tissues. We identified a 418 nucleotides length of the MAGEA4-AS1 transcript and it primarily located in the cell nucleus. MAGEA4-AS1 stable knockdown weakened the proliferation, migration and invasion abilities of OSCC cells. Mechanistically, p53 protein was capable to activate MK2 gene transcription. RIP assay revealed an interaction between p53 and MAGEA4-AS1. MK2 up-regulation in MAGEA4-AS1 down-regulated OSCC cells restored MK2 and epithelial-to-mesenchymal transition related proteins' expression levels. In conclusion, MAGEA4-AS1-p53 complexes bind to MK2 promoter, enhancing the transcription of MK2 and activating the downstream signaling pathways, consequently promoting the proliferation and metastasis of OSCC cells. MAGEA4-AS1 may serve as a diagnostic marker and therapeutic target for OSCC patients.

Atropisomerism, an expression of axial chirality caused by limited bond rotation, is a prominent aspect within the field of medicinal chemistry. It has been shown that atropisomers of a wide range of compounds, including established FDA-approved drugs and experimental molecules, display markedly different biological activities. The time-dependent reversal of chirality in atropisomers poses complexity and obstacles in the process of drug discovery and development. Nonetheless, recent progress in understanding atropisomerism and enhanced characterization methods have greatly assisted medicinal chemists in the effective development of atropisomeric drug molecules. This article provides a comprehensive review of their special design thoughts, synthetic routes, and biological activities, serving as a reference for the synthesis and biological evaluation of bioactive atropisomers in the future.

Diabetic retinopathy (DR) is one of the most prevalent secondary complications associated with diabetes. Specifically, Type 1 Diabetes Mellitus (T1D) has an immune component that may determine the evolution of DR by compromising the immune response of the retina, which is mediated by microglia. In the early stages of DR, the permeabilization of the blood-retinal barrier allows immune cells from the peripheral system to interact with the retinal immune system. The use of new bioactive molecules, such as 3-(2,4-dihydroxyphenyl)phthalide (M9), with powerful anti-inflammatory activity, might represent an advance in the treatment of diseases like DR by targeting the immune systems responsible for its onset and progression. Our research aimed to investigate the molecular mechanisms involved in the interaction of specific cells of the innate immune system during the progression of DR and the reduction in inflammatory processes contributing to the pathology. In vitro studies were conducted exposing Bv.2 microglial and Raw264.7 macrophage cells to proinflammatory stimuli for 24 h, in the presence or absence of M9. Ex vivo and in vivo approaches were performed in BB rats, an animal model for T1D. Retinal explants from BB rats were cultured with M9. Retinas from BB rats treated for 15 days with M9 via intraperitoneal injection were analyzed to determine survival, cellular signaling, and inflammatory markers using qPCR, Western blot, or immunofluorescence approaches. Retinal structure images were acquired via Spectral-Domain-Optical Coherence Tomography (SD-OCT). Our results show that the treatment with M9 significantly reduces inflammatory processes in in vitro, ex vivo, and in vivo models of DR. M9 works by inhibiting the proinflammatory responses during DR progression mainly affecting immune cell responses. It also induces an anti-inflammatory response, primarily mediated by microglial cells, leading to the synthesis of Arginase-1 and Hemeoxygenase-1(HO-1). Ultimately, in vivo administration of M9 preserves the retinal integrity from the degeneration associated with DR progression. Our findings demonstrate a specific interaction between both retinal and systemic immune cells in the progression of DR, with a differential response to treatment, mainly driven by microglia in the anti-inflammatory action. In vivo treatment with M9 induces a switch in immune cell phenotypes and functions that contributes to delaying the DR progression, positioning microglial cells as a new and specific therapeutic target in DR.

Anginosus group streptococci (AGS) are opportunistic pathogens that reside in the human oral cavity. The β-hemolytic strains of Streptococcus anginosus subsp. anginosus (SAA) produce streptolysin S (SLS), a streptococcal peptide hemolysin. In recent clinical scenarios, AGS, including this species, have frequently been isolated from infections and disorders beyond those in the oral cavity. Consequently, investigating this situation will reveal the potential pathogenicity of AGS to ectopic infections in humans. However, the precise mechanism underlying the cellular response induced by secreted SLS and its relevance to the pathogenicity of AGS strains remain largely unknown. This study aims to elucidate the mechanism underlying the host cellular response of the human acute monocytic leukemia cell line THP-1 to secreted SLS. In THP-1 cells incubated with the culture supernatant of β-hemolytic SAA containing SLS as the sole cytotoxic factor, increased Ca2+ influx and elevated expression of proinflammatory cytokines were observed. Significantly reduced expression of SLS-dependent upregulated cytokine genes under Ca2+-chelating conditions suggests that Ca2+ influx triggers SLS-dependent cellular responses. Furthermore, SLS-dependent enhanced expression of IL-8 was also implicated in the activation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) signaling pathways. The findings presented in this study are crucial for a comprehensive understanding of the real pathogenicity of SLS-producing β-hemolytic AGS in the latest clinical situations.

In humans, blood Classical CD14+ monocytes contribute to host defense by secreting large amounts of pro-inflammatory cytokines. Their aberrant activity causes hyper-inflammation and life-threatening cytokine storms, while dysfunctional monocytes are associated with 'immunoparalysis', a state of immune hypo responsiveness and reduced pro-inflammatory gene expression, predisposing individuals to opportunistic infections. Understanding how monocyte functions are regulated is critical to prevent these harmful outcomes. We reveal platelets' vital role in the pro-inflammatory cytokine responses of human monocytes. Naturally low platelet counts in patients with immune thrombocytopenia or removal of platelets from healthy monocytes result in monocyte immunoparalysis, marked by impaired cytokine response to immune challenge and weakened host defense transcriptional programs. Remarkably, supplementing monocytes with fresh platelets reverses these conditions. We discovered that platelets serve as reservoirs of key cytokine transcription regulators, such as NF-κB and MAPK p38, and pinpointed the enrichment of platelet NF-κB2 in human monocytes by proteomics. Platelets proportionally restore impaired cytokine production in human monocytes lacking MAPK p38α, NF-κB p65, and NF-κB2. We uncovered a vesicle-mediated platelet-monocyte-propagation of inflammatory transcription regulators, positioning platelets as central checkpoints in monocyte inflammation.

Domestic ducks (Anas platyrhynchos domesticus) are resistant to most of the highly pathogenic avian influenza virus (HPAIV) infections. In this study, we characterized the lung proteome and phosphoproteome of ducks infected with the HPAI H5N1 virus (A/duck/India/02CA10/2011/Agartala) at 12 h, 48 h, and 5 days post-infection. A total of 2082 proteins were differentially expressed and 320 phosphorylation sites mapping to 199 phosphopeptides, corresponding to 129 proteins were identified. The functional annotation of the proteome data analysis revealed the activation of the RIG-I-like receptor and Jak-STAT signaling pathways, which led to the induction of interferon-stimulated gene (ISG) expression. The pathway analysis of the phosphoproteome datasets also confirmed the activation of RIG-I, Jak-STAT signaling, NF-kappa B signaling, and MAPK signaling pathways in the lung tissues. The induction of ISG proteins (STAT1, STAT3, STAT5B, STAT6, IFIT5, and PKR) established a protective anti-viral immune response in duck lung tissue. Further, the protein-protein interaction network analysis identified proteins like AKT1, STAT3, JAK2, RAC1, STAT1, PTPN11, RPS27A, NFKB1, and MAPK1 as the main hub proteins that might play important roles in disease progression in ducks. Together, the functional annotation of the proteome and phosphoproteome datasets revealed the molecular basis of the disease progression and disease resistance mechanism in ducks infected with the HPAI H5N1 virus.

Diabetes worsens the outcomes of a number of vascular disorders including peripheral arterial disease (PAD) at least in part through induction of chronic inflammation. However, in experimental PAD, recovery requires the nuclear factor-kappa B (NF-κB) activation. Previously we showed that individually, both ischemia and high glucose activate the canonical and non-canonical arms of the NF-κB pathway, but prolonged high glucose exposure specifically impairs ischemia-induced activation of the canonical NF-κB pathway through activation of protein kinase C beta (PKCβ). Although a cascade of phosphorylation events propels the NF-κB signaling, little is known about the impact of hyperglycemia on the canonical and non-canonical NF-κB pathway signaling. Moreover, signal upstream of PKCβ that lead to its activation in endothelial cells during hyperglycemia exposure have not been well defined. In this study, we used endothelial cells exposed to hyperglycemia and ischemia (HGI) and an array of approximately 250 antibodies to approximately 100 proteins and their phosphorylated forms to identify the NF-κB signaling pathway that is altered in ischemic EC that has been exposed to high glucose condition. Comparison of signals from hyperglycemic and ischemic cell lysates yielded a number of proteins whose phosphorylation was either increased or decreased under HGI conditions. Pathway analyses using bioinformatics tools implicated BLNK/BTK known for B cell antigen receptor (BCR)-coupled signaling. Inhibition of BLNK/BTK in endothelial cells by a specific pharmacological inhibitor terreic acid attenuated PKC activation and restored the IκBα degradation suggesting that these molecules play a critical role in hyperglycemic attenuation of the canonical NF-κB pathway. Thus, we have identified a potentially new component of the NF-κB pathway upstream of PKC in endothelial cells that contributes to the poor post ischemic adaptation during hyperglycemia.

Cathelicidins are an important family of antimicrobial peptides (AMPs) involved in the innate immunity in vertebrates. The mammalian cathelicidins have been well characterized, but the relationship between structure and function in amphibian cathelicidins is still not well understood. In this study, a novel 29-residue cathelicidin antimicrobial peptide (BugaCATH) was identified from the skin of Bufo gargarizans. Unlike other AMPs, BugaCATH does not display any direct antimicrobial effects in vitro. However, it effectively promotes full-thickness wound repair in mice. Following injury, BugaCATH initiates and expedites the inflammatory stage by recruiting neutrophils and macrophages to the wound site. BugaCATH not only regulates neutrophil phagocytic activity but also stimulates the generation of cytokines (TNF-α, IL-6, and IL-1β) and chemokines (CXCL1, CXCL2, CCL2, and CCL3) in macrophages and in mice. Furthermore, it promotes macrophage M2 polarization that facilitates the conversion from a pro-inflammatory macrophage-dominated wound environment to an anti-inflammatory one during the mid to late stages, which is crucial for reducing inflammation and effective wound repair. The MAPK (ERK, JNK, and p38) and NF-κB-NLRP3 signaling pathways are involved in the activity. Moreover, BugaCATH directly enhances the migration of keratinocytes and vascular endothelial cells without affecting their proliferation. Notably, BugaCATH significantly improves the proliferation of keratinocytes and endothelial cells in the presence of macrophages. The current study revealed that in addition to proliferation of keratinocytes and endothelial cells, BugaCATH possesses the ability to modulate inflammatory processes during skin injury through its regulatory effect on phagocytes. The combination of these capabilities makes BugaCATH a potent candidate for skin wound therapy.

PBC is an autoimmune-mediated liver disease, and intrahepatic biliary epithelial cells (IBECs) are the target cells of early damage. Previous studies found that miRNAs and inflammation is closely related to PBC. In this study, we extracted exosomes from serum and human IBECs supernatant, and RNA-sequence analyzed the expression profiles of miRNAs. Elisa measured the levels of inflammatory cytokines. RT- qPCR and western blot detected the levels of miR-122-5p, p38 and p-p38. The results showed that 263 differentially expressed (DE) miRNAs were identified in serum exosomes of PBC patients. The levels of IL-1β, IL-6, IL-12, IL-17 A, IFN-γ, TNF-α and TGF-β1 in peripheral blood of PBC patients were higher than those of normal controls. According to the validation results and previous literature, exosomal miR-122-5p was finally selected as the study object, and correlated with inflammatory factors. In vitro experiments further found that exosomal miR-122-5p may derive from hepatic stellate cells (HSCs), and can be HIBECs intake, and influence HIBECs inflammatory factor levels though p38 MAPK signaling pathways. This may provide a new strategy for the treatment of PBC.

Lead (Pb2+) is a hazardous heavy metal that is pervasive in the human environment as a result of anthropogenic activity, and poses serious health risks, particularly in children. Due to its innumerable unique physical and chemical properties, it has various applications; therefore, it has become a common environmental pollutant. Lead may cause oxidative stress, and accumulating evidence indicates that oxidative stress influences the pathophysiology of lead poisoning, also called plumbism. The immune system is continually exposed to various environmental pathogens and xenobiotics, including heavy metals such as lead, and appears to be one of the most vulnerable targets. After being exposed to lead, cells are subjected to oxidative stress as a result of reactive oxygen species (ROS) production. When the generation and consumption of ROS are out of equilibrium, various cell structures, particularly phospholipids are disrupted leading to lipid peroxidation. Various inflammatory signalling pathways are activated as a consequence, along with reduced disease resistance, inflammation, autoimmunity, sensitization and disruption of the cell-mediated and humoral immune systems. Lead negatively affects the metabolism of cytokines, including the interleukins IL-2, IL-1b, IL-6, IL-4, IL-8, tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN), as well as the expression and functioning of inflammatory enzymes such as cyclooxygenases. However, the cause of toxicity depends on the kind of lead, dosage, route of entry, exposure period, age, host and genetic predisposition.

This experiment successfully isolated the rat colonic epithelial cells and established a TNF-α-induced intestinal inflammation model. Western Blot was used to detect the related protein expression levels of the MAPKs signaling pathway. QPCR technology was used to detect the expression of aquaporins, intestinal mucosal repair factor, and inflammatory factors. The results show that 25 μM β-carotene pretreatment at 24 h can inhibit MAPKs signaling pathway activated by TNF-α, change the relative mRNA expression of inflammatory cytokines, intestinal mucosal repair factors, and aquaporins, and the phosphorylated protein expression of p38, ERK, and NF-κB were attenuated to reduce inflammatory damage. After inhibiting p38 and ERK, the effect of β-carotene was reduced significantly (P < 0.05). In conclusion, β-carotene can alleviate the abnormal expression of aquaporins caused by inflammation through the MAPKs signaling pathway. This is for β-carotene as a functional nutrient that provides new insights.

Metconazole (MEZ) is a novel chiral triazole fungicide that is widely used to prevent and control soil-borne fungal pathogens and other fungal diseases. However, it has a long half-life in aquatic environments and thus poses potential environmental risks. This study evaluates the acute and stereoselective cardiotoxicity of MEZ in zebrafish (Danio rerio) embryos. In addition, transcriptomics, real-time quantitative PCR, enzyme activity determination, and molecular docking are performed to evaluate the molecular mechanisms underlying the cardiotoxicity of MEZ in zebrafish. MEZ decreases the heart rate while increasing the pericardial oedema rate; additionally, it induces stereoselective cardiotoxicity. 1S,5S-MEZ exhibits stronger cardiotoxicity than 1R,5R-MEZ. Furthermore, MEZ increases the expression of Ahr-associated genes and the transcription factors il6st, il1b, and AP-1. Heart development-related genes, including fbn2b, rbm24b, and tbx20 are differentially expressed. MEZ administration alters the activities of catalase, peroxidase, and glutathione-S-transferase in zebrafish larvae. Molecular docking indicates that 1R,5R-MEZ binds more strongly to the inhibitor-binding sites of p38 in the AGE-RAGE signalling pathway than to other MEZ enantiomers. Studies conducted in vivo and in silico have established the enantioselective cardiotoxicity of MEZ and its underlying mechanisms, highlighting the need to evaluate the environmental risk of chiral MEZ in aquatic organisms at the enantiomeric level.

Senile plaques induced by β-amyloid (Aβ) abnormal aggregation and neurofibrillary tangles (NFT) caused by tau hyperphosphorylation are important pathological manifestations of Alzheimer's disease (AD). Glycogen synthase kinase-3 (GSK-3) is a conserved kinase; one member GSK-3β is highly expressed in the AD brain and involved in the formation of NFT. Hence, pharmacologically inhibiting GSK-3β activity and expression is a good approach to treat AD. As summarized in this article, multiple GSK-3β inhibitors has been comprehensively summarized over recent five years. However, only lithium carbonate and Tideglusib have been studied in clinical trials of AD. Besides ATP-competitive and non-ATP-competitive inhibitors, peptide inhibitors, allosteric inhibitors and other types of inhibitors have gradually attracted more interest. Moreover, considering the close relationship between GSK-3β and other targets involved in cholinergic hypothesis, Aβ aggregation hypothesis, tau hyperphosphorylation hypothesis, oxidative stress hypothesis, neuro-inflammation hypothesis, etc., diverse multifunctional molecules and multi-target directed ligands (MTDLs) have also been disclosed. We hope that these recent advances and critical perspectives will facilitate the discovery of safe and effective GSK-3β inhibitors for AD treatment.

P38γ (MAPK12) is predominantly expressed in triple negative breast cancer cells (TNBC) and induces stem cell (CSC) expansion resulting in decreased survival of the patients due to metastasis. Abundance of G-rich sequences at MAPK12 promoter implied the functional probability to reverse tumorigenesis, though the formation of G-Quadruplex (G4) structures at MAPK12 promoter is elusive. Here, we identified two evolutionary consensus adjacent G4 motifs upstream of the MAPK12 promoter, forming parallel G4 structures. They exist in an equilibria between G4 and duplex, regulated by the binding turnover of Sp1 and Nucleolin that bind to these G4 motifs and regulate MAPK12 transcriptional homeostasis. To underscore the gene-regulatory functions of G4 motifs, we employed CRISPR-Cas9 system to eliminate G4s from TNBC cells and synthesized a naphthalene diimide (NDI) derivative (TGS24) which shows high-affinity binding to MAPK12-G4 and inhibits MAPK12 transcription. Deletion of G4 motifs and NDI compound interfere with the recruitment of the transcription factors, inhibiting MAPK12 expression in cancer cells. The molecular basis of NDI-induced G4 transcriptional regulation was analysed by RNA-seq analyses, which revealed that MAPK12-G4 inhibits oncogenic RAS transformation and trans-activation of NANOG. MAPK12-G4 also reduces CD44High/CD24Low population in TNBC cells and downregulates internal stem cell markers, arresting the stemness properties of cancer cells.

Resistance to therapy and disease progression are the main causes of mortality in most cancers. In particular, the development of resistance is an important limitation affecting the efficacy of therapeutic alternatives for cancer, including chemotherapy, radiotherapy, and immunotherapy. Signaling pathways are largely responsible for the mechanisms of resistance to cancer treatment and progression, and multiple myeloma is no exception. p38 mitogen-activated protein kinase (p38) is downstream of several signaling pathways specific to treatment resistance and progression. Therefore, in recent years, developing therapeutic alternatives directed at p38 has been of great interest, in order to reverse chemotherapy resistance and prevent progression. In this review, we discuss recent findings on the role of p38, including recent advances in our understanding of its expression and activity as well as its isoforms, and its possible clinical role based on the mechanisms of resistance and progression in multiple myeloma.

A simple method for the preparation of 5-(trifluoroacetyl)imidazoles was elaborated.

The reaction of trifluoromethyl(α-bromoalkenyl)ketones with benzimidamides was employed to afford the target heterocycles in good yields.

The assembly of imidazole core proceeds via aza-Michael adduct formation followed by intramolecular nucleophilic substitution and spontaneous aromatization as an oxidation sequence.

The yields of target imidazoles can be improved by the use of soft oxidizing agents.

A new series of quinoxaline derivatives possessing the hydrazone moiety were designed, synthesized, and screened for in-vitro anti-inflammatory activity by the bovine serum albumin (BSA) denaturation technique, and for antioxidant activity, by the (2,2'-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. The synthesized compounds were also tested for p38α mitogen-activated protein (MAP) kinase inhibition. The in-vivo anti-inflammatory activity was assessed by the carrageenan-induced rat paw edema inhibition method. All the compounds (4a-n) exhibited moderate to high in-vitro anti-inflammatory activity. Compound 4a displayed the highest inhibitory activity in the BSA assay (83.42%) in comparison to the standard drug diclofenac sodium (82.90%), while 4d exhibited comparable activity (81.87%). The DPPH assay revealed that compounds 4a and 4d have free radical scavenging potential (74.70% and 74.34%, respectively) comparable to the standard butylated hydroxyanisole (74.09%). Furthermore, the p38α MAP kinase inhibition assay demonstrated that compound 4a is highly selective against p38α MAP kinase (IC50  = 0.042) in comparison to the standard SB203580 (IC50  = 0.044). The five most active compounds (4a-4d and 4f) with good in-vitro profiles were selected for in-vivo anti-inflammatory studies. Compounds 4a and 4d were found to display the highest activity (83.61% and 82.92% inhibition, respectively) in comparison to the standard drug diclofenac sodium (82.65% inhibition). These compounds (4a and 4d) also exhibited better ulcerogenic and lipid peroxidation profiles than diclofenac sodium. The molecular docking and molecular dynamics simulation studies were also performed and found to be in agreement with the p38α MAP kinase inhibitory activity.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been used clinically to treat inflammatory diseases clinically. However, the adverse effects of NSAIDs cannot be ignored. Therefore, it is critical for us to find alternative anti-inflammatory drugs that can reduce adverse reactions to herbal medicine, such as Iris tectorum Maxim., which has therapeutic effects and can treat inflammatory diseases and liver-related diseases.

This study aimed to isolate active compounds from I. tectorum and investigate their anti-inflammatory effects and action mechanisms.

Fourteen compounds were isolated from I. tectorum using silica gel column chromatography, Sephadex LH-20, ODS and high performance liquid chromatography, and their structures were identified by examining physicochemical properties, ultraviolet spectroscopy, infrared spectroscopy, mass spectrometry, and nuclear magnetic resonance spectroscopy. Classical inflammatory cell models were established using lipopolysaccharide (LPS)-stimulated RAW264.7 cells and rat primary peritoneal macrophages to examine the effect of these compounds. To examine the action mechanisms, the nitric oxide (NO) levels were measured by Griess reagent and the levels of inflammatory cytokines in the supernatant were measured by ELISA; The expressions of major proteins in prostaglandin E2 (PGE2) synthesis and the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways were examined by Western blotting, and the mRNA expression levels were measured by quantitative real-time polymerase chain reaction; and the nuclear translocation of p65 was examined by high content imaging. Molecular docking was used to predict the binding of active compound to target protein.

Our findings revealed that Iristectorigenin C (IT24) significantly inhibited the levels of NO and PGE2 without affecting cyclooxygenase (COX)-1/COX-2 expression in LPS-induced RAW264.7 cells and rat peritoneal macrophages. Furthermore, IT24 was shown to decrease the expression of microsomal prostaglandin synthetase-1 (mPGES-1) in LPS-induced rat peritoneal macrophages. IT24 did not suppress the phosphorylation and nuclear translocation of proteins in the NF-κB pathway, but it inhibited the phosphorylation of p38/JNK in LPS-stimulated RAW264.7 cells. Additionally, molecular docking analysis indicated that IT24 may directly bind to the mPGES-1 protein.

IT24 might inhibit mPGES-1 and the p38/JNK pathway to exert its anti-inflammatory effects and could be also developed as an inhibitor of mPGES-1 to prevent and treat mPGES-1-related diseases, such as inflammatory diseases, and holds promise for further research and drug development.

Protein kinases play a major role in cellular activation processes, including signal transduction by diverse immunoreceptors. Given their roles in cell growth and death and in the production of inflammatory mediators, targeting kinases has proven to be an effective treatment strategy, initially as anticancer therapies, but shortly thereafter in immune-mediated diseases. Herein, we provide an overview of the status of small molecule inhibitors specifically generated to target protein kinases relevant to immune cell function, with an emphasis on those approved for the treatment of immune-mediated diseases. The development of inhibitors of Janus kinases that target cytokine receptor signalling has been a particularly active area, with Janus kinase inhibitors being approved for the treatment of multiple autoimmune and allergic diseases as well as COVID-19. In addition, TEC family kinase inhibitors (including Bruton's tyrosine kinase inhibitors) targeting antigen receptor signalling have been approved for haematological malignancies and graft versus host disease. This experience provides multiple important lessons regarding the importance (or not) of selectivity and the limits to which genetic information informs efficacy and safety. Many new agents are being generated, along with new approaches for targeting kinases.

Hepatic inflammation is the major risk factor of hepatocellular carcinoma (HCC). However, the underlying mechanism by which hepatic inflammation progresses to HCC is poorly understood. This study was designed to investigate the role of ETS translocation variant 4 (ETV4) in linking hepatic inflammation to HCC.

Quantitative real-time PCR and immunoblotting were used to detect the expression of ETV4 in HCC tissues and cell lines. RNA sequencing and luciferase reporter assays were performed to identify the target genes of ETV4. Hepatocyte-specific ETV4-knockout (ETV4fl/fl, alb-cre ) and transgenic (ETV4Hep-TG ) mice and diethylnitrosamine-carbon tetrachloride (DEN-CCL4 ) treatment experiments were applied to investigate the function of ETV4 in vivo. The Cancer Genome Atlas (TCGA) database mining and pathological analysis were carried out to determine the correlation of ETV4 with tumor necrosis factor-alpha (TNF-α) and mitogen-activated protein kinase 11 (MAPK11).

We revealed that ETV4 was highly expressed in HCC. High levels of ETV4 predicted a poor survival rate of HCC patients. Then we identified ETV4 as a transcription activator of TNF-α and MAPK11. ETV4 was positively correlated with TNF-α and MAPK11 in HCC patients. As expected, an increase in hepatic TNF-α secretion and macrophage accumulation were observed in the livers of ETV4Hep-TG mice. The protein levels of TNF-α, MAPK11, and CD68 were significantly higher in the livers of ETV4Hep-TG mice compared with wild type mice but lower in ETV4fl/fl, alb-cre mice compared with ETV4fl/fl mice as treated with DEN-CCL4 , indicating that ETV4 functioned as a driver of TNF-α/MAPK11 expression and macrophage accumulation during hepatic inflammation. Hepatocyte-specific knockout of ETV4 significantly prevented development of DEN-CCL4 -induced HCC, while transgenic expression of ETV4 promoted growth of HCC.

ETV4 promoted hepatic inflammation and HCC by activating transcription of TNF-α and MAPK11. Both the ETV4/TNF-α and ETV4/MAPK11 axes represented two potential therapeutic targets for highly associated hepatic inflammation and HCC. ETV4+TNF-α were potential prognostic markers for HCC patients.