c-Jun N-terminal Kinase Signaling Research Articles

IL-17 Facilitates VCAM-1 Production and Monocyte Adhesion in Osteoarthritis Synovial Fibroblasts by Suppressing miR-5701 Synthesis.

Osteoarthritis (OA) is characterized by the infiltration and adhesion of monocytes into the inflamed joint synovium. Interleukin (IL)-17 is a critical inflammatory mediator that participates in the progression of OA, although the mechanisms linking IL-17 and monocyte infiltration are not well understood. Our analysis of synovial tissue samples retrieved from the Gene Expression Omnibus (GEO) dataset exhibited higher monocyte marker (CD11b) and vascular cell adhesion molecule 1 (VCAM-1) levels in OA samples than in normal, healthy samples. The stimulation of human OA synovial fibroblasts (OASFs) with IL-17 increased VCAM-1 production and subsequently enhanced monocyte adhesion. IL-17 affected VCAM-1-dependent monocyte adhesion by reducing miR-5701 expression through the protein kinase C (PKC)-α and c-Jun N-terminal kinase (JNK) signaling cascades. Our findings improve our understanding about the effect of IL-17 on OA progression and, in particular, VCAM-1 production and monocyte adhesion, which may help with the design of more effective OA treatments.

Abstract 3082: Leveraging 3D organoids to identify molecular changes underlying HNSC initiation and development

Abstract Head and neck squamous cell carcinoma (HNSC) is a devastating disease accounting for 570,000 newly diagnosed cases and resulting in 344,000 deaths annually. HNSC arises from its histological precursor lesion, squamous dysplasia (HNSD); however, most patients are diagnosed with late-stage HNSC with no prior identification of pre-malignant disease. Earlier diagnosis and intervention could ameliorate the outsized burden of HNSC; therefore, there is an urgent unmet need to characterize the molecular changes underlying progression through HNSD to HNSC. To identify novel therapeutic targets or biomarkers that predict progression to HNSC, we have generated a three dimensional (3D) organoid library derived from dysplastic oral tissue harvested from mice treated with 4-Nitriquinoline N-oxide (4-NQO), a potent mimetic of tobacco smoke. Through RNA sequencing analysis of these organoids, we have identified two distinct gene expression states that accompany either early or late dysplasia. By performing gene set enrichment analysis of these two distinct gene signatures, we have identified c-Jun N-terminal Kinase (JNK) signaling as a potential biomarker that predicts or progression from HNSD to HNSC. Together, we have identified the salient transcriptional changes that accompany progression through the histological precursor lesion of HNSC. This study positions JNK signaling as a potential biomarker or therapeutic target for early intervention during the treatment of a deadly disease. Citation Format: Robert Agee, Samuel Flashner, Masataka Shimonosono, Andres Klein-Szanto, Hiroshi Nakagawa. Leveraging 3D organoids to identify molecular changes underlying HNSC initiation and development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3082.

Sperm-Associated Antigen 9 Promotes Influenza A Virus-Induced Cell Death via the c-Jun N-Terminal Kinase Signaling Pathway.

ABSTRACTUpon influenza A virus (IAV) infection, the IAV progeny ribonucleoprotein complex, with a defective viral genome, is sensed by DNA-dependent activator of interferon-regulatory factor (DAI). DAI initiates the recruitment of an array of proteins to form a multiprotein platform (PANoptosome), which triggers apoptosis, necroptosis, and pyroptosis during IAV infection. However, the mechanisms mediating the assembly of the PANoptosome are unclear. Here, we identified a scaffold protein, sperm-associated antigen 9 (SPAG9), which could interact with DAI to promote cell death during IAV infection. We further demonstrated that the cell death enhanced by SPAG9 was achieved through the DAI/SPAG9/c-Jun N-terminal kinase (JNK) axis, which could promote IAV-induced DAI-mediated cell death, including apoptosis, necroptosis, and pyroptosis. Our data further showed that the DAI/SPAG9/JNK signaling pathway enhanced the interactions among receptor-interacting serine/threonine kinase 1 (RIPK1), RIPK3, and DAI, thereby promoting IAV-induced PANoptosome formation. Overall, our study for the first time revealed a feed-forward circuit signaling pathway that enhanced IAV-induced DAI-mediated cell death, provided insights into the molecular mechanisms of cell death, and established therapeutic targets to address infectious and inflammatory diseases.

Selective PPARδ agonist seladelpar suppresses bile acid synthesis by reducing hepatocyte CYP7A1 via the fibroblast growth factor 21 signaling pathway

Peroxisome proliferator–activated receptor delta (PPARδ) agonists have been shown to exert beneficial effects in liver disease and reduce total bile acid levels. The mechanism(s) whereby PPARδ agonism reduces bile acid levels are, however, unknown, and therefore the aim of the present study was to investigate the molecular pathways responsible for reducing bile acid synthesis in hepatocytes, following treatment with the selective PPARδ agonist, seladelpar. We show that administration of seladelpar to WT mice repressed the liver expression of cholesterol 7 alpha-hydroxylase (Cyp7a1), the rate-limiting enzyme for bile acid synthesis, and decreased plasma 7α-hydroxy-4-cholesten-3-one (C4), a freely diffusible metabolite downstream of Cyp7a1. In primary mouse hepatocytes, seladelpar significantly reduced the expression of Cyp7a1 independent of the nuclear bile acid receptor, Farnesoid X receptor. In addition, seladelpar upregulated fibroblast growth factor 21 (Fgf21) in mouse liver, serum, and in cultured hepatocytes. We demonstrate that recombinant Fgf21 protein activated the c-Jun N-terminal kinase (JNK) signaling pathway and repressed Cyp7a1 gene expression in primary hepatocytes. The suppressive effect of seladelpar on Cyp7a1 expression was blocked by a JNK inhibitor as well as in the absence of Fgf21, indicating that Fgf21 plays an indispensable role in PPARδ-mediated downregulation of Cyp7a1. Finally, reduction of CYP7A1 expression by seladelpar was confirmed in primary human hepatocytes. In conclusion, we show that seladelpar reduces bile acid synthesis via an FGF21-dependent mechanism that signals at least partially through JNK to repress CYP7A1.

IL-28B reprograms tumor-associated macrophages to promote anti-tumor effects in colon cancer

The type III interferon family (IFN-III), including IFN-λ3 [interleukin (IL)-28B], has antiviral, anti-tumor, and immunomodulatory activities. Although the IL-28B anti-tumor effect has been extensively explored, its underlying mechanism remains unclear. Here, we explored IL-28B effects on colon cancer. Our results show that IL-28B significantly inhibits colon cancer progression in a mouse MC38 tumor cell colonization model and colitis-associated colorectal tumor model. Interestingly, IL-28B does not directly promote apoptosis or inhibit MC38 tumor cell proliferation in vitro. Rather, IL-28B treatment has indirect anti-tumor activity by downregulating tumor-associated macrophages. Furthermore, IL-28B inhibits M2 macrophage polarization in vitro, while also halting M2 macrophage differentiation predominantly via inhibition of the signal transducer and activator of transcription (STAT)3 and c-Jun N-terminal kinase (JNK) signaling pathways. Our findings revealed that IL-28B inhibits M2 macrophages in the tumor microenvironment to delay colon cancer progression. These findings provide novel evidence of IL-28B anti-tumor and immunomodulatory activities.

ANLN Serves as an Oncogene in Bladder Urothelial Carcinoma via Activating JNK Signaling Pathway

Introduction: To understand the significance of ANLN (anillin, actin-binding protein)-mediated c-Jun N-terminal kinase (JNK) signal pathway on the progression of bladder urothelial carcinoma (BLCA). Methods: The Cancer Genome Atlas (TCGA) database was utilized to perform the clinical significance of ANLN in BLCA. Then, ANLN expression was determined in human normal primary bladder epithelial cells (BdEC) and BLCA cells. Later, ANLN knockdown was performed in BLCA cells, where the expression of MAPK8, MAPK9, and p-JNK/JNK was detected. BLCA cells were divided into the Mock, siNC, siANLN, SP600125 (a selective JNK inhibitor), and ANLN + SP600125 group, followed by measurements of real-time quantitative polymerase chain reaction, 3-4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, Annexin V-FITC/PI, Wound-healing, Transwell, and immunofluorescence assays. Results: ANLN was upregulated in the BLCA tissues, which showed a relation with the stage of patients. Besides, BLCA patients with high expression of ANLN had a worse prognosis than those with low expression of ANLN. Besides, the expression of ANLN in the BLCA tissues was positively correlated with MAPK8 and MAPK9. SP600125 suppressed the JNK signal pathway, reduced the proliferation, and increased BLCA cell apoptosis, with the reductions in the invasion and migration and the upregulation of phospho-histone H3 Ser-10 (pHH3), which was abolished by the overexpression of ANLN. Conclusion: ANLN, as an oncogene of BLCA, may associate with the activation of JNK signal pathway. Inhibiting ANLN could deactivate the JNK signal pathway, thereby suppressing the proliferation, invasion, and migration while promoting the apoptosis of BLCA cells.

Follicle stimulating hormone promotes production of renin through its receptor in juxtaglomerular cells of kidney

BackgroundPost-menopausal hypertension has been attributed solely to declining estrogen levels. The purpose of the research is to elucidate the mechanism by which follicle stimulating hormone(FSH) increases renin production involved in the regulation of blood pressure.MethodsThe expression of follicle stimulating hormone receptors (FSHRs) in renal juxtaglomerular cells and a As4.1 juxtaglomerular mouse cell line was evaluated. We established a mouse model by ovariectomy (OVX). Ovariectomized mice were treated with gonadotropin-releasing hormone agonist (GnRHa) (OVX + GnRHa). Ovariectomized mice initially received physiological doses of estrogen and were then injected with recombinant FSH (OVX + E + FSH).ResultsWe found that FSHR was expressed in mouse renal juxtaglomerular cells labeled by renin antibody and in As4.1 cells. FSH promoted renin synthesis via Gsα-coupled FSHRs that activated protein kinase A, cyclic adenosine monophosphate(cAMP) response element-binding protein, extracellular signal-regulated kinase (Erk1/2), Protein kinase B(AKT), and c-Jun N-terminal kinase signaling pathways in As4.1 cells. We found increased serum FSH levels in the ovariectomized mouse with concurrent increases in renin, angiotensin II, heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial blood pressure (MAP). Additionally, increases in serum renin, angiotensin II, HR, SBP, DBP, and MAP were reduced by the additional injection of GnRHa. Exogenous FSH administration completely reversed decreases in renin, angiotensin II, HR, SBP, DBP, and MAP even in mice that received physiological doses of estrogen to maintain normal estradiol levels.ConclusionsElevated FSH stimulates renin production involving a mechanism that may be relevant to the expression of FSH receptors in renal juxtaglomerular cells.

Extract from Black Soybean Cultivar A63 Extract Ameliorates Atopic Dermatitis-like Skin Inflammation in an Oxazolone-Induced Murine Model.

Black soybean has been used in traditional medicine to treat inflammatory diseases, cancer, and diabetes and as a nutritional source since ancient times. We found that Korean black soybean cultivar A63 has more cyanidin-3-O-glucoside, (C3G), procyanidin B2 (PB2), and epicatechin (EPC) contents than other cultivars and has beneficial effects on cell viability and anti-oxidation. Given the higher concentration of anthocyanidins and their strong anti-oxidant activity, we predicted that A63 extract could relieve inflammatory disease symptoms, including those of atopic dermatitis (AD). Here, we evaluated the anti-AD activity of A63 extract in an oxazolone (OXA)-induced mouse model. A63 extract treatment significantly reduced epidermal thickness and inflammatory cell infiltration, downregulated the expression of AD gene markers, including Interleukin (IL)-4 and IL-5, and restored damaged skin barrier tissues. Furthermore, A63 extract influenced the activation of the signal transducer and activator of transcription (STAT) 3 and STAT6, extracellular regulatory kinase (ERK), and c-Jun N-terminal kinase (JNK) signaling pathways, which play a crucial role in the development of AD. Altogether, our results suggest that A63 can ameliorate AD-like skin inflammation by inhibiting inflammatory cytokine production and STAT3/6 and Mitogen-activated protein kinase (MAPK) signaling and restoring skin barrier function.

Glial regenerative response in the imaginal discs of Drosophila melanogaster.

Glial regenerative response in the imaginal discs of Drosophila melanogaster.

Major Vault Protein Prevents Atherosclerotic Plaque Destabilization by Suppressing Macrophage ASK1-JNK Signaling.

Macrophages are implicated in atherosclerotic plaque instability by inflammation and degradation of extracellular matrix. However, the regulatory mechanisms driving these macrophage-associated processes are not well understood. Here, we aimed to identify the plaque destabilization-associated cytokines and signaling pathways in macrophages. The atherosclerotic models of myeloid-specific MVP (major vault protein) knockout mice and control mice were generated. Atherosclerotic instability, macrophage inflammatory signaling, and active cytokines released by macrophages were examined in vivo and in vitro by using cellular and molecular biological approaches. MVP deficiency in myeloid cells exacerbated murine plaque instability by increasing production of both MMP (matrix metallopeptidase)-9 and proinflammatory cytokines in artery wall. Mechanistically, expression of MMP-9 was mediated via ASK1 (apoptosis signal-regulating kinase 1)-MKK-4 (mitogen-activated protein kinase kinase 4)-JNK (c-Jun N-terminal kinase) signaling in macrophages. MVP and its α-helical domain could bind with ASK1 and inhibit its dimerization and phosphorylation. A 62 amino acid peptide (MVP-[686-747]) in the α-helical domain of MVP showed a crucial role in preventing macrophage MMP-9 production and plaque instability. MVP may act as an inhibitor for ASK1-JNK signaling-mediated MMP-9 production in macrophages and, thereby, attenuate unstable plaque formation. Our findings suggest that suppression of macrophage ASK1-JNK signaling may be a useful strategy antagonizing atherosclerotic diseases.

The Antiepileptic Valproic Acid Ameliorates Charcot-Marie-Tooth 2W (CMT2W) Disease-Associated HARS1 Mutation-Induced Inhibition of Neuronal Cell Morphological Differentiation Through c-Jun N-terminal Kinase.

Hereditary peripheral neuropathies called Charcot-Marie-Tooth (CMT) disease affect the sensory nerves as well as motor neurons. CMT diseases are composed of a heterogeneous group of diseases. They are characterized by symptoms such as muscle weakness and wasting. Type 2 CMT (CMT2) disease is a neuropathy with blunted or disrupted neuronal morphological differentiation phenotypes including process formation of peripheral neuronal axons. In the early stages of CMT2, demyelination that occurs in Schwann cells (glial cells) is rarely observed. CMT2W is an autosomal-dominant disease and is responsible for the gene encoding histidyl-tRNA synthetase 1 (HARS1), which is a family molecule of cytoplasmic aminoacyl-tRNA synthetases and functions by ligating histidine to its cognate tRNA. Despite increasing knowledge of the relationship of mutations on responsible genes with diseases, it still remains unclear how each mutation affects neuronal differentiation. Here we show that in neuronal N1E-115 cells, a severe Asp364-to-Tyr (D364Y) mutation of HARS1 leads to formation of small aggregates of HARS1 proteins; in contrast, wild type proteins are distributed throughout cell bodies. Expression of D364Y mutant proteins inhibited process formation whereas expression of wild type proteins possessed the normal differentiation ability to grow processes. Pretreatment with the antiepileptic valproic acid recovered inhibition of process formation by D364Y mutant proteins through the c-Jun N-terminal kinase signaling pathway. Taken together, these results indicate that the D364Y mutation of HARS1 causes HARS1 proteins to form small aggregates, inhibiting process growth, and that these effects are recovered by valproic acid. This could be a potential therapeutic drug for CMT2W at the cellular levels.

The role of macrophage–fibroblast interaction in lipopolysaccharide-induced pulmonary fibrosis: an acceleration in lung fibroblast aerobic glycolysis

AbstractRecent evidence has shown that lipopolysaccharide (LPS)-induced aerobic glycolysis of lung fibroblasts is closely associated with the pathogenesis of septic pulmonary fibrosis. Nevertheless, the underlying mechanism remains poorly defined. In this study, we demonstrate that LPS promotes c-Jun N-terminal kinase (JNK) signaling pathway activation and endogenous tumor necrosis factor-α (TNF-α) secretion in pulmonary macrophages. This, in turn, could significantly promote aerobic glycolysis and increase lactate production in lung fibroblasts through 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3) activation. Culturing human lung fibroblast MRC-5 cell line with TNF-α or endogenous TNF-α (cell supernatants of macrophages after LPS stimulation) both enhanced the aerobic glycolysis and increased lactate production. These effects could be prevented by treating macrophages with JNK pathway inhibitor, by administering TNF-α receptor 1 (TNFR1) siRNA, PFKFB3 inhibitor, or by silencing PFKFB3 with fibroblasts-specific shRNA. In addition, the inhibition of TNF-α secretion and PFKFB3 expression prevented LPS-induced pulmonary fibrosis in vivo. In conclusion, this study revealed that LPS-induced macrophage secretion of TNF-α could initiate fibroblast aerobic glycolysis and lactate production, implying that inflammation-metabolism interactions between lung macrophages and fibroblasts might play an essential role in LPS-induced pulmonary fibrosis.This study demonstrates that lipopolysaccharide promotes activation of the JNK signaling pathway and endogenous TNF-α secretion in pulmonary macrophages, which facilitates lung fibroblast aerobic glycolysis and lactate production through PFKFB3 activation. These findings suggests that inflammation-metabolism interactions between lung macrophages and fibroblasts might play an essential role in lipopolysaccharide-induced pulmonary fibrosis.

Intrinsic disorder in proteins associated with oxidative stress-induced JNK signaling.

The c-Jun N-terminal kinase (JNK) signaling cascade is a mitogen-activated protein kinase (MAPK) signaling pathway that can be activated in response to a wide range of environmental stimuli. Based on the type, degree, and duration of the stimulus, the JNK signaling cascade dictates the fate of the cell by influencing gene expression through its substrate transcription factors. Oxidative stress is a result of a disturbance in the pro-oxidant/antioxidant homeostasis of the cell and is associated with a large number of diseases, such as neurodegenerative disorders, cancer, diabetes, cardiovascular diseases, and disorders of the immune system, where it activates the JNK signaling pathway. Among different biological roles ascribed to the intrinsically disordered proteins (IDPs) and hybrid proteins containing ordered domains and intrinsically disordered protein regions (IDPRs) are signaling hub functions, as intrinsic disorder allows proteins to undertake multiple interactions, each with a different consequence. In order to ensure precise signaling, the cellular abundance of IDPs is highly regulated, and mutations or changes in abundance of IDPs/IDPRs are often associated with disease. In this study, we have used a combination of six disorder predictors to evaluate the presence of intrinsic disorder in proteins of the oxidative stress-induced JNK signaling cascade, and as per our findings, none of the 18 proteins involved in this pathway are ordered. The highest level of intrinsic disorder was observed in the scaffold proteins, JIP1, JIP2, JIP3; dual specificity phosphatases, MKP5, MKP7; 14-3-3ζ and transcription factor c-Jun. The MAP3Ks, MAP2Ks, MAPKs, TRAFs, and thioredoxin were the proteins that were predicted to be moderately disordered. Furthermore, to characterize the predicted IDPs/IDPRs in the proteins of the JNK signaling cascade, we identified the molecular recognition features (MoRFs), posttranslational modification (PTM) sites, and short linear motifs (SLiMs) associated with the disordered regions. These findings will serve as a foundation for experimental characterization of disordered regions in these proteins, which represents a crucial step for a better understanding of the roles of IDPRs in diseases associated with this important pathway.

Soluble C-Type Lectin-Receptor Ligands Stimulate ROS Production in Dendritic Cells and Potentiate Killing of MRSA as Well as the MRSA Induced IL-12 Production.

Methicillin resistant Staphylococcus aureus (MRSA) has developed resistance to most β-lactam antibiotics leaving few treatment options against infections with MRSA. Through mannose receptors, mannan potentiates IL-12 production induced by Gram-positive bacteria, a cytokine crucial in the clearance of S. aureus infection. We investigated the IL-12 potentiating effect of mannan pre-treatment of bone marrow-derived dendritic cells prior to stimulation with clinical MRSA strains. Mannan almost doubled IL-12 as well as IFN-β production in response to USA300, also when USA300 was treated with the β-lactam cefoxitin. The MRSA-induced IL-12 production was dependent on bacterial uptake and reactive oxygen species (ROS). Mannan alone induced ROS production, and in combination with USA300, the ROS produced corresponded to the sum induced by mannan and USA300. Addition of a monoclonal antibody against the mannose receptor likewise enhanced USA300-induced IL-12 and induced ROS production. Mannan addition further increased the endocytosis as well as the rate of endosomal killing of bacteria. Pre-treatment with soluble β-glucans also induced ROS and potentiated the USA300-induced IL-12 indicating that other C-type receptors may play a similar role. In the presence of the pro-inflammatory mediators, GM-CSF or IFN-γ, the mannan-enhanced IL-12 production increased further. The USA300-induced and the mannan-facilitated enhanced IFN-β and IL-12 showed same dependency on MAPK c-Jun N-terminal kinase signaling, suggesting that mannan enhances the signals already induced by the bacteria, rather than changing them. We suggest that the C-type lectin-induced ROS production is a key factor in the IFN-β and IL-12 potentiation.

The Molecular Structure and Role of Humanin in Neural and Skeletal Diseases, and in Tissue Regeneration.

Humanin (HN) belongs to a member of mitochondrial-derived peptides (MDPs) which are encoded by mitochondrial genes. HN shares sequence homology with thirteen HN-like proteins, named MTRNR2L1 to MTRNR2L13, which encompass 24–28 amino acid residues in length. HN mediates mitochondrial status and cell survival by acting via an intracellular mechanism, or as a secreted factor via extracellular signals. Intracellularly, it binds Bcl2-associated X protein (BAX), Bim and tBid, and IGFBP3 to inhibit caspase activity and cell apoptosis. When released from cells as a secreted peptide, HN interacts with G protein-coupled formyl peptide receptor-like 1 (FPRL1/2) to mediate apoptosis signal-regulating kinase (ASK) and c-Jun N-terminal kinase (JNK) signalling pathways. Additionally, it interacts with CNTFR-α/gp130/WSX-1 trimeric receptors to induce JAK2/STA3 signalling cascades. HN also binds soluble extracellular proteins such as VSTM2L and IGFBP3 to modulate cytoprotection. It is reported that HN plays a role in neuronal disorders such as Alzheimer’s disease, as well as in diabetes mellitus, infertility, and cardiac diseases. Its roles in the skeletal system are emerging, where it appears to be involved with the regulation of osteoclasts, osteoblasts, and chondrocytes. Understanding the molecular structure and role of HN in neural and skeletal diseases is vital to the application of HN in tissue regeneration.

Anti-Inflammatory Properties of MSF, a Lactiplantibacillus plantarum K8 Lysate Fermented with Filipendula glaberrima Extract

Inflammation plays an important role in the pathogenesis of metabolic syndrome, which increases the risk of heart disease, stroke, type 2 diabetes, atherosclerosis, non-alcoholic fatty liver disease (NAFLD), and obesity. Here, we produced potent anti-inflammatory probiotic lysates, termed MSF (miracle synergistic material made using Filipendula glaberrima), using fermentation with F. glaberrima extracts. MSF inhibited lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α production through down-regulation of c-Jun N-terminal kinase (JNK) signaling. MSF-induced tolerance for TNF-α was mediated by induction of TNF alpha-induced protein 3 (TNFAIP3 or A20). On the other hand, MSF showed a synergistic effect on interleukin (IL)-1β production in LPS-stimulated human monocytic leukemia cell line (THP-1 cells). This synergistic effect of the combination of MSF and LPS might be mediated by nuclear factor kappa B (NF-kB) signaling. The inhibitory effect of TNF-α and synergistic effect of IL-1β due to combining MSF and LPS were significantly higher than those of a combination of L. plantarum K8 lysates and LPS. The MSF and LPS combination showed reduced mouse mortality compared to a combination of L. plantarum K8 lysates and LPS, which correlated with decreased levels of cytokines, hepatic alanine aminotransferase (ALT), and aspartate aminotransferase (AST) in the blood and liver. These results show that probiotic lysates fermented with natural extracts such as F. glaberrima have higher anti-inflammatory efficacy than conventional probiotic lysates or natural extracts.

Cover Image

Coronal section of a day 15.5 mouse embryo. NetrinG1-positive thalamocortical axons (red) project from the thalamus, through the internal capsule, into the cortex of a mouse with constitutive deletion of Jnk2 and Jnk3. Dlx5/6-CIE positive cells are labeled with EGFP, Hoechst nuclear counterstain is in blue. Image acquired on Olympus VS120 Slide Scanner at 10x. From: Early construction of the thalamocortical axon pathway requires c-Jun N-terminal kinase signaling within the ventral forebrain; Jessica G. Cunningham, James D. Scripter, Stephany A. Nti, Eric S. Tucker; https://doi.org/10.1002/dvdy.416; DevDyn 251:3, pp. 459-480.

The anti-tumor effects of the combination of microwave hyperthermia and lobaplatin against breast cancer cells in vitro and in vivo.

Background: Breast cancer is the main lethal disease among females. The combination of lobaplatin and microwave hyperthermia plays a crucial role in several kinds of cancer in the clinic, but its possible mechanism in breast cancer has remained indistinct.Methods: Mouse models were used to detect breast cancer progression. Cell growth was explored with MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulphonyl)-2H-tetrazolium) and colony formation assays. Cell migration and invasion were investigated with a transwell assay. Cell apoptosis was probed with flow cytometry. The expression of apoptosis-associated proteins was examined with Western blots.Result: Combination treatment decreased breast cancer cell viability, colony formation, cell invasion and metastasis. In addition, the treatment-induced breast cancer cell apoptosis and autophagy, activated the c-Jun N-terminal kinase (JNK) signaling pathway, suppressed the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway, and down-regulated IAP and Bcl-2 family protein expression.Conclusion: These results indicate that lobaplatin is an effective breast cancer anti-tumor agent. Microwave hyperthermia was a useful adjunctive treatment. Combination treatment was more efficient than any single therapy. The possible mechanism for this effect was mainly associated with activation of the JNK signaling pathway, inactivation of the AKT/mTOR signaling pathway and down-regulation of the Bcl-2 and IAP families.

Cell Fusion-Related Proteins and Signaling Pathways, and Their Roles in the Development and Progression of Cancer.

Cell fusion is involved in many physiological and pathological processes, including gamete binding, and cancer development. The basic processes of cell fusion include membrane fusion, cytoplasmic mixing, and nuclear fusion. Cell fusion is regulated by different proteins and signaling pathways. Syncytin-1, syncytin-2, glial cell missing 1, galectin-1 and other proteins (annexins, myomaker, myomerger etc.) involved in cell fusion via the cyclic adenosine-dependent protein kinase A, mitogen-activated protein kinase, wingless/integrase-1, and c-Jun N-terminal kinase signaling pathways. In the progression of malignant tumors, cell fusion is essential during the organ-specific metastasis, epithelial-mesenchymal transformation, the formation of cancer stem cells (CSCs), cancer angiogenesis and cancer immunity. In addition, diploid cells can be induced to form polyploid giant cancer cells (PGCCs) via cell fusion under many kinds of stimuli, including cobalt chloride, chemotherapy, radiotherapy, and traditional Chinese medicine. PGCCs have CSC-like properties, and the daughter cells derived from PGCCs have a mesenchymal phenotype and exhibit strong migration, invasion, and proliferation abilities. Therefore, exploring the molecular mechanisms of cell fusion can enable us better understand the development of malignant tumors. In this review, the basic process of cell fusion and its significance in cancer is discussed.

Noncanonical Wnt5a/JNK Signaling Contributes to the Development of D-Gal/LPS-Induced Acute Liver Failure.

Acute liver failure (ALF) is a deadly clinical disorder with few effective treatments and unclear pathogenesis. In our previous study, we demonstrated that aberrant Wnt5a expression was involved in acute-on-chronic liver failure. However, the role of Wnt5a in ALF is unknown. We investigated the expression of Wnt5a and its downstream c-Jun N-terminal kinase (JNK) signaling in a mouse model of ALF established by coinjection of D-galactosamine (D-Gal) and lipopolysaccharide (LPS) in C57BL/6 mice. We also investigated the role of Box5, a Wnt5a antagonist, in vivo. Moreover, the effect of Wnt5a/JNK signaling on downstream inflammatory cytokine expression, phagocytosis, and migration in THP-1 macrophages was studied in vitro. Aberrant Wnt5a expression and JNK activation were detected in D-Gal/LPS-induced ALF mice. Box5 pretreatment reversed JNK activation and eventually decreased the mortality rate of D-Gal/LPS-treated mice, with reduced hepatic necrosis and apoptosis, serum ALT and AST levels, and liver inflammatory cytokine expression, although the latter was not significant. We further demonstrated that recombinant Wnt5a (rWnt5a)-induced tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) mRNA expression and increased THP-1 macrophage phagocytosis in a JNK-dependent manner, which could be restored by Box5. In addition, rWnt5a-induced migration of THP-1 macrophages was also reversed by Box5. Our findings suggested that Wnt5a/JNK signaling plays an important role in the development of ALF and that Box5 could have particular hepatoprotective effects in ALF.