RESUMEN

Lung cancer has the highest incidence and mortality rates of all cancer types in China and therefore represents a serious threat to human health. In the present study, the mechanism of rabdoternin E against the proliferation of the lung cancer cell line A549 was explored. It was found that rabdoternin E caused the accumulation of large amounts of reactive oxygen species (ROS), promoted cell S phase arrest by reducing the expression of CDK2 and cyclin A2, induced apoptosis by increasing the Bax/Bcl­2 ratio and promoted the phosphorylation of proteins in the ROS/p38 MAPK/JNK signaling pathway, which is associated with apoptosis and ferroptosis. In addition, it was also found that Z­VAD­FMK (an apoptosis inhibitor), ferrostatin­1 (ferroptosis inhibitor) and N­acetylcysteine (a ROS inhibitor) could partially or greatly reverse the cytotoxicity of rabdoternin E to A549 cells. Similarly, NAC (N­acetylcysteine) treatment notably inhibited the rabdoternin E­stimulated p38 MAPK and JNK activation. Furthermore, in vivo experiments in mice revealed that Rabdoternin E markedly reduced tumor volume and weight and regulated the expression levels of apoptosis and ferroptosis­related proteins (including Ki67, Bcl­2, Bax, glutathione peroxidase 4, solute carrier family 7 member 11 and transferrin) in the tumor tissues of mice. Histopathological observation confirmed that the number of tumor cells decreased markedly after administration of rabdoternin E. Taken together, rabdoternin E induced apoptosis and ferroptosis of A549 cells by activating the ROS/p38 MAPK/JNK signaling pathway. Therefore, the results of the present study showed that rabdoternin E is not toxic to MCF­7 cells (normal lung cells), had no significant effect on body weight and was effective and therefore may be a novel therapeutic treatment for lung cancer.

Asunto(s)

RESUMEN

BACKGROUND: Dictyophora indusiata polysaccharide is an important bioactive component of D. indusiata, playing an important role in alleviating inflammation. The present study aimed to investigate the anti-inflammatory effect and mechanism of D. indusiata polysaccharide on lipopolysaccharide (LPS)-induced intestinal inflammation in mice. RESULTS: Our results indicated that D. indusiata polysaccharide ameliorated intestinal inflammation of mice by increasing the body weight, the number of goblet cells and decreasing inflammatory cell infiltration. In addition, D. indusiata polysaccharide significantly up-regulated expression of ZO-1, Occuldin mRNA, which were 2.55-fold and 2.28-fold higher than the LPS group, respectively. In particular, D. indusiata polysaccharide effectively inhibited the Toll-like receptor 4 (TLR4)/ c-Jun NH2-terminal kinase (JNK) signalling pathway which was 0.34-fold and 0.49-fold of gene expression and 0.41-fold and 0.39-fold of protein expression in the LPS group, respectively. CONCLUSION: The results of the present study suggested that D. indusiata polysaccharide exerted anti-inflammatory and intestinal protective effects by inhibiting the TLR4/JNK signaling pathway, which will provide a basis for the potential value of D. indusiata polysaccharide as prebiotics in food applications. © 2024 Society of Chemical Industry.

RESUMEN

Ulcerative colitis (UC) poses a threat to human health. The present study attempts to unravel the efficacy and potential mechanisms of paeoniflorin (PF), a naturally sourced active ingredient, for the management of UC. By establishing a DSS (dextran sulphate sodium)-induced experimental rat model of UC, this study found that PF was effective in ameliorating UC symptoms, inhibiting oxidative stress, inflammation and apoptosis, and repairing colonic epithelial damage. In addition, metabolomics revealed that PF may alleviate UC by primarily improving linoleic acid metabolism. Mechanistically, PF inhibited the CDC42/JNK signaling pathway by targeting CDC42. In particular, HuProtTM20K proteomics, molecular docking and MST revealed that PF is a novel CDC42 inhibitor. In LPS-treated Caco-2 cells, PF similarly inhibited oxidative stress, inflammation, and apoptosis and down-regulated the CDC42/JNK signaling pathway. Overall, PF inhibits oxidative stress, inflammation and apoptosis and repairs colonic epithelial damage through modulation of serum metabolites and inhibition of the CDC42/JNK signaling pathway, leading to alleviation of UC.

RESUMEN

The scaffold proteins JIP1 and JIP2 intervene in the c-Jun N-terminal kinase (JNK) pathway to mediate signaling specificity by coordinating the simultaneous assembly of multiple kinases. Using NMR, we demonstrate that JIP1 and JIP2 heterodimerize via their SH3 domains with the affinity of heterodimerization being comparable to homodimerization. We present the high-resolution crystal structure of the JIP2-SH3 homodimer and the JIP1-JIP2-SH3 heterodimeric complex. The JIP2-SH3 structure reveals how charge differences in residues at its dimer interface lead to formation of compensatory hydrogen bonds and salt bridges, distinguishing it from JIP1-SH3. In the JIP1-JIP2-SH3 complex, structural features of each homodimer are employed to stabilize the heterodimer. Building on these insights, we identify key residues crucial for stabilizing the dimer of both JIP1 and JIP2. Through targeted mutations in cellulo, we demonstrate a functional role for the dimerization of the JIP1 and JIP2 scaffold proteins in activation of the JNK signaling pathway.

Asunto(s)

RESUMEN

Zearalenone (ZEN) is a nonsteroidal estrogenic mycotoxin produced by Fusarium strains that is harmful to the intestinal health of animals and is widely present in contaminated crops. The objective of this study was to investigate the potential therapeutic target of ZEN-induced jejunal damage in weaned gilts. Sixteen weaned gilts either received a basal diet or a basal diet supplemented with 3.0 mg/kg ZEN in a 32-d experiment. The results showed that ZEN at the concentration of 3.0 mg/kg diet activated the inflammatory response and caused oxidative stress of gilts (P < 0.05). ZEN exposure resulted in the upregulation (P < 0.05) of the Exchange protein directly activated by the cAMP 1/Ras-related protein1/c-Jun N-terminal kinase (Epac1/Rap1/JNK) signaling pathway in the jejunum of gilts in vivo and in the intestinal porcine epithelial cells in vitro. The cell viability, EdU-positive cells, and the mRNA expression of B-cell lymphoma-2 (Bcl-2) were decreased, whereas the reactive oxygen species production and the mRNA expressions of Bcl-2-associated X (Bax) and Cysteine-aspartic acid protease 3 (Caspase3) were increased (P < 0.05) by ZEN. However, ZEN increased the mRNA expression of Bcl-2 and decreased the mRNA expressions of Bax and caspase3 (P < 0.05) after the Epac1 was blocked. These results collectively indicated that a 3.0 mg ZEN /kg diet induced jejunal damage via the Epac1/Rap1/JNK signaling pathway.

Mycotoxins have caused huge economic losses to livestock industry. This study assessed the impact of zearalenone (ZEN) on the jejunum of weaned gilts. Results revealed that significant inflammatory response and oxidative stress were stimulated by 3.0 mg/kg ZEN in the jejunum tissue of weaned gilts. Furthermore, the reactive oxygen species accumulation and apoptosis in the intestinal porcine epithelial cells (IPEC-J2) were triggered, respectively. The negative impact of ZEN on the jejunum was by activation of Epac1/Rap1/JNK signaling pathway in the jejunum and this could be reduced by blocking Epac1. A more comprehensive understanding of the underlying molecular mechanisms will facilitate the development of novel strategies to mitigate the detrimental effect of ZEN on the jejunum of weaned gilts.

Asunto(s)

RESUMEN

BACKGROUND: Glucose and fatty acid overload-induced glucolipid toxicity of pancreatic ß-cells is associated with the development of diabetes. Endoplasmic reticulum stress (ERS) plays an essential role in this process. Ghrelin, a peptide secreted by the pancreas, negatively correlates with oxidative stress. The study aimed to investigate ghrelin's role in glycolipid-induced ß-cell dysfunction and its possible mechanism. METHODS: Mouse insulinoma ß-cell, NIT-1 cells, were stimulated with high fat and high glucose to induce glucolipid toxicity. High fat and high glucose-induced NIT-1 cells were treated with acylated ghrelin (AG) or [d-Lys3]-growth hormone releasing peptide (GHRP)-6. Flow cytometry and Cell Counting Kit-8 (CCK-8) assay were performed to assess apoptosis and cell viability. The protein expression related to apoptosis, inositol-requiring kinase 1 (IRE1)/c-Jun N-terminal kinase (JNK) signaling, and ERS were investigated using western blot. Enzyme-linked immunosorbent assay (ELISA) was adopted to examine insulin's synthesis and secretion levels. RESULTS: Ghrelin treatment improved cell viability while inhibiting cell glucolipotoxicity-induced NIT-1 cell apoptosis. Ghrelin can promote the synthesis and secretion of insulin in NIT-1 cells. Mechanistically, ghrelin attenuates ERS and inhibits the IRE1/JNK signaling pathway in NIT-1 cells induced by glucolipotoxicity. CONCLUSION: Ghrelin improves ß-cellular dysfunction induced by glucolipotoxicity by inhibiting the IRE1/JNK pathway induced by ERS. It could be an effective treatment for ß-cellular dysfunction.

Asunto(s)

RESUMEN

Apoptosis signal-regulated kinase 1 (ASK1) is a member of the mitogen-activated protein kinase kinase (MAP3K) family, whose activation and regulation are intricately associated with apoptosis. ASK1 is activated in response to oxidative stress, among other stimuli, subsequently triggering downstream JNK, p38 MAPK, and mitochondria-dependent apoptotic signaling, which participate in the initiation of tumor cell apoptosis induced by various stimuli. Research has shown that ASK1 plays a crucial role in the apoptosis of lung cancer, breast cancer, and liver cancer cells. Currently, the investigation of effective ASK1 activators is a hot topic in research on tumor cell apoptosis. Synthetic compounds such as human ß-defensin, triazolothiazide derivatives and heat shock protein 27 inhibitors; natural compounds such as quercetin, Laminarina japonica polysaccharide-1 peptide and theabrownin; and nanomedicines such as cerium oxide nanoparticles, magnetite FeO nanoparticles and silver nanoparticles can activate ASK1 and induce apoptosis in various tumor cells. This review extensively investigates the roles and activation mechanisms of ASK1, explores its impact on a variety of apoptotic signaling pathways, and discusses the potential therapeutic applications of various ASK1 activators in cancer treatment. In addition, this paper provides an in-depth discussion of the future development of this field and proposes a promising method for further research and clinical progress.

Asunto(s)

RESUMEN

Following the publication of the above article, a concerned reader drew to the Editor's attention that certain of the Transwell cell invasion assay data featured in Fig. 1B and C, the immunofluorescence assay data in Fig. 2E and F, the TUNEL assay data in Fig. 4C and the immunohistochemical data in Fig. 4B and E were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes that had either already been published elsewhere prior to the submission of this paper to Oncology Reports, or which under consideration for publication at around the same time. In view of the fact that certain of these data had already apparently been published prior to the submission of this article for publication, the Editor of Oncology Reports has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 45: 82, 2021; DOI: 10.3892/or.2021.8033].

RESUMEN

The JNK signaling pathway plays crucial roles in various physiological processes, including cell proliferation, differentiation, migration, apoptosis, and stress response. Dysregulation of this pathway is closely linked to the onset and progression of numerous major diseases, such as developmental defects and tumors. Identifying and characterizing novel components of the JNK signaling pathway to enhance and refine its network hold significant scientific and clinical importance for the prevention and treatment of associated cancers. This study utilized the model organism Drosophila and employed multidisciplinary approaches encompassing genetics, developmental biology, biochemistry, and molecular biology to investigate the interplay between Tip60 and the JNK signaling pathway, and elucidated its regulatory mechanisms. Our findings suggest that loss of Tip60 acetyltransferase activity results in JNK signaling pathway activation and subsequent induction of JNK-dependent apoptosis. Genetic epistasis analysis reveals that Tip60 acts downstream of JNK, paralleling with the transcription factor FOXO. The biochemical results confirm that Tip60 can bind to FOXO and acetylate it. Introduction of human Tip60 into Drosophila effectively mitigates apoptosis induced by JNK signaling activation, underscoring conserved regulatory role of Tip60 in the JNK signaling pathway from Drosophila to humans. This study further enhances our understanding of the regulatory network of the JNK signaling pathway. By revealing the role and mechanism of Tip60 in JNK-dependent apoptosis, it unveils new insights and potential therapeutic avenues for preventing and treating associated cancers.

Asunto(s)

RESUMEN

BACKGROUND: Cockroaches are widely acknowledged as significant vectors of pathogenic microorganisms. The Periplaneta fuliginosa densovirus (PfDNV) infects the smoky-brown cockroach P. fuliginosa and causes host mortality, which identifies the PfDNV as a species-specific and environmentally friendly biopesticide. However, although the biochemical characterization of PfDNV has been extensively studied, the immune response against PfDNV remains largely unclear. RESULTS: Here, we investigated the replication of PfDNV and its associated pathological phenotype in the foregut and hindgut. Consequently, we dissected and performed transcriptome sequencing on the foregut, midgut, and hindgut separately. We revealed the up-regulation of immune response signaling pathway c-Jun N-terminal kinase (JNK) and apoptosis in response to viral infection. Furthermore, knockdown of the JNK upstream gene Ben resulted in a decrease in virus titer and delayed host mortality. CONCLUSION: Taken together, our findings provide evidence that the Ben-JNK signaling plays a crucial role in PfDNV infection, leading to excessive apoptosis in intestinal tissues and ultimately resulting in the death of the host. Our results indicated that the host response to PfDNV fosters viral infection, thereby increasing host lethality. This underscores the potential of PfDNV as a viable, environmentally friendly biopesticide. © 2024 Society of Chemical Industry.

Asunto(s)

RESUMEN

Gliomas are the most common primary intracranial tumor worldwide. The maintenance of telomeres serves as an important biomarker of some subtypes of glioma. In order to investigate the biological role of RTEL1 in glioma. Relative telomere length (RTL) and RTEL1 mRNA was explored and regression analysis was performed to further examine the relationship of the RTL and the expression of RTEL1 with clinicopathological characteristics of glioma patients. We observed that high expression of RTEL1 is positively correlated with telomere length in glioma tissue, and serve as a poor prognostic factor in TERT wild-type patients. Further in vitro studies demonstrate that RTEL1 promoted proliferation, formation, migration and invasion ability of glioma cells. In addition, in vivo studies also revealed the oncogene role of RTEL1 in glioma. Further study using RNA sequence and phospho-specific antibody microarray assays identified JNK/ELK1 signaling was up-regulated by RTEL1 in glioma cells through ROS. In conclusion, our results suggested that RTEL1 promotes glioma tumorigenesis through JNK/ELK1 cascade and indicate that RTEL1 may be a prognostic biomarker in gliomas.

Asunto(s)

RESUMEN

This study aimed to explore the role of melatonin in oxidative stress-induced injury on retinal ganglion cells and the underlying mechanisms. The immortalized RGC-5 cells were treated with H2O2 to induce oxidative injury. Cell viability was measured by Cell Counting Kit-8, and apoptosis was determined by flow cytometry and western blot assays. Reactive oxygen species (ROS), lactate dehydrogenase (LDH), and malondialdehyde (MDA) levels were examined to evaluate oxidative stress levels. In addition, Thioredoxin-1 (Trx1) was silenced in RGC-5 cells using small interfering RNA followed by signaling pathway examination to explore the underlying mechanisms of melatonin in alleviating oxidative injury. Melatonin pre-treatment significantly alleviated H2O2-induced apoptosis in RGC-5 cells. Melatonin also markedly reversed the upregulation of cleaved-caspase 3, cleaved-caspase 9, and Bax expression and downregulation of Bcl-2 expression induced by H2O2. Further analyses presented that melatonin significantly attenuated the increase of ROS, LDH, and MDA levels in RGC-5 cells after H2O2 treatment. Melatonin also abolished the downregulated expression of Superoxide dismutase type 1, Trx1, and Thioredoxin reductase 1, and the reduced activity of thioredoxin reductase in RGC-5 cells after H2O2 treatment. Notably, Trx1 knockdown significantly mitigated the protective effect of melatonin in alleviating H2O2-induced apoptosis and oxidative stress, while administration of compound C, a common inhibitor of c-Jun N-terminal kinase (JNK) signaling, partially reversed the effect of Trx1 silencing, thereby ameliorating the apoptosis and oxidative injury induced by H2O2 in RGC-5 cells. Melatonin could significantly alleviate oxidative stress-induced injury of retinal ganglion cells via modulating Trx1-mediated JNK signaling pathway.

RESUMEN

Introduction: Osteosarcoma is a prevalent and highly malignant primary bone tumor. However, current clinical therapeutic drugs for osteosarcoma are not suitable for long-term use due to significant side effects. Therefore, there is an urgent need to develop new drugs with fewer side effects. Dipsacus asperoides C. Y. Cheng et T. M. Ai, a traditional Chinese medicine, is commonly used for its anti-inflammatory, anti-pain, bone fracture healing, and anti-tumor effects. In this study, we investigated the effects of exosome-like nanoparticles derived from Dipsacus asperoides (DAELNs) on osteosarcoma cells in vitro and in vivo. Methods: DAELNs were isolated and purified from Dipsacus asperoides and their physical and chemical properties were characterized using transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). The cellular uptake of DAELNs in osteosarcoma cells was analyzed by PKH26 staining. The proliferation, invasion, migration, and apoptosis of osteosarcoma cells were assessed using CCK8 assay, EdU assay, colony-formation assay, transwell assay, wound healing assay, and mitochondrial membrane potential measurement, respectively. The regulatory mechanism of DAELNs inhibiting the progression of osteosarcoma via activating P38/JNK signaling pathway was investigated using Western blotting and immunohistochemistry. Moreover, the therapeutic effects of DAELNs were evaluated using in vivo small animal imaging assay, HE staining, and immunohistochemistry. Results: Our results showed that DAELNs inhibited the proliferation, invasion, migration, and fostered the apoptosis of osteosarcoma cells in vitro and suppressed the tumor growth of osteosarcoma cells in a xenograft nude mouse model. Furthermore, the bio-distribution of DiD-labeled DAELNs showed preferential targeting of osteosarcoma tumors and excellent biosafety in histological analysis of the liver and kidney. Mechanistically, DAELNs activated the P38/JNK signaling pathway-induced apoptosis. Conclusion: Taken together, DAELNs are novel, natural, and osteosarcoma-targeted agents that can serve as safe and effective therapeutic approaches for the treatment of osteosarcoma.

Asunto(s)

RESUMEN

BACKGROUND: The benzophenanthridine Sanguinarine (Sng) is one of the most abundant root alkaloids with a long history of investigation and pharmaceutical applications. The cytotoxicity of Sng against various tumor cells is well-established; however, its antiproliferative and apoptotic potential against the cutaneous squamous cell carcinoma (cSCC) cells remains unknown. In the present study, we investigated the anti-cancer potential of Sng against cSCC cells and elucidated the underlying mechanisms relevant to the drug action. METHODS: The inhibitory effect of Sng on cSCC cells was evaluated by analyzing cell viability, colony-forming ability and multi-caspase activity. Apoptosis was quantified through Annexin-V/Propidium iodide flow cytometric assay and antagonized by pan-caspase inhibitor z-VAD-FMK. Mitochondrial membrane potential (ΔΨm) dysfunction was analyzed by JC-1 staining, whereas reactive oxygen species (ROS) generation was confirmed by pretreatment with N-acetylcysteine (NAC) and fluorogenic probe-based flow cytometric detection. The expression of cell cycle regulatory proteins, apoptotic proteins and MAPK signaling molecules was determined by Western blotting. Involvement of JNK, p38-MAPK and MEK/ERK in ROS-mediated apoptosis was investigated by pretreatment with SP600125 (JNK inhibitor), SB203580 (p38 inhibitor) and U0126 (ERK1/2 inhibitor), respectively. The stemness-targeting potential of Sng was assessed in tumor cell-derived spheroids. RESULTS: Treatment with Sng decreased cell viability and colony formation in primary (A431) and metastatic (A388) cSCC cells in a time- and dose-dependent manner. Sng significantly inhibited cell proliferation by inducing sub-G0/G1 cell-cycle arrest and apoptosis in cSCC cells. Sng evoked ROS generation, intracellular glutathione (GSH) depletion, ΔΨm depolarization and the activation of JNK pathway as well as that of caspase-3, -8, -9, and PARP. Antioxidant NAC inhibited ROS production, replenished GSH levels, and abolished apoptosis induced by Sng by downregulating JNK. Pretreatment with z-VAD-FMK inhibited Sng-mediated apoptosis. The pharmacological inhibition of JNK by SP600125 mitigated Sng-induced apoptosis in metastatic cSCC cells. Finally, Sng ablated the stemness of metastatic cSCC cell-derived spheroids. CONCLUSION: Our results indicate that Sng exerts a potent cytotoxic effect against cSCC cells that is underscored by a mechanism involving multiple levels of cooperation, including cell-cycle sub-G0/G1 arrest and apoptosis induction through ROS-dependent activation of the JNK signaling pathway. This study provides insight into the potential therapeutic application of Sng targeting cSCC.

Asunto(s)

RESUMEN

PURPOSE: To explore the key genes and molecular pathways in the progression of thyroid papillary carcinoma (PTC) promoted by testosterone using RNA-sequencing technology, and to provide new drug targets for improving the therapeutic effect of PTC. METHODS: Orchiectomy (ORX) was carried out to construct ORX mouse models. TPC-1 cells were subcutaneously injected for PTC formation in mice, and the tumor tissues were collected for RNA-seq. The key genes were screened by bioinformatics technology. Tnnt1 expression in PTC cells was knocked down or overexpressed by transfection. Cell counting kit-8 (CCK-8), colony formation assay, scratch assay and transwell assay were adopted, respectively, for the detection of cell proliferation, colony formation, migration and invasion. Besides, quantification real-time polymerase chain reaction (qRT-PCR) and western blot were utilized to determine the mRNA and protein expression levels of genes in tissues or cells. RESULTS: Both estradiol and testosterone promoted the growth of PTC xenografts. The key gene Tnnt1 was screened and obtained by bioinformatics technology. Functional analysis revealed that overexpression of Tnnt1 could markedly promote the proliferation, colony formation, migration, invasion, and epithelial-to-mesenchymal transition (EMT) process of PTC cells, as well as could activate p38/JNK pathway. In addition, si-Tnt1 was able to inhibit the cancer-promoting effect of testosterone. CONCLUSION: Based on the outcomes of bioinformatics and basic experiments, it is found that testosterone can promote malignant behaviors such as growth, migration, invasion and EMT process of PTC by up-regulating Tnnt1 expression. In addition, the function of testosterone may be achieved by activating p38/JNK signaling pathway.

Asunto(s)

RESUMEN

Cerebral ischemia (CI) is the main cause of stroke morbidity and disability. This study aims to identify the early molecular regulation responsible for the therapeutic effectiveness of the Herb pair Danshen-Honghua (DH) for CI. The major targets of DH were identified by searching the public database of traditional Chinese medicine (TCM). In addition, GeneCards, Disgenet, and GeneMap databases in OMIM were used to determine the disease targets of CI. A total of 88 common targets of DH and CI were selected, a protein-protein interaction (PPI) network was established by Cytoscape, and 19 core targets were screened. These genes were primarily enriched in biological processes including wound healing, reaction to oxidative stress, and response to peptides, lipid and atherosclerosis, Age-rage signaling pathway, and TNF signaling pathway by KEGG and GO enrichments. The effective components of DH had stable binding to these key targets by molecular docking. Finally, it was verified that the mechanism of DH on CI treatment may be related to the activation of the TNF-α/JNK signaling pathway by establishing the middle cerebral artery occlusion (MCAO) rat model.

Asunto(s)

RESUMEN

Aim To study the mechanism of quereetin (Que) inhibiting mitochondrial damage induced by Aβ

RESUMEN

The pathogenesis of osteoarthritis (OA) is still unclear. Fatty acid binding protein 4 (FABP4), a novel adipokine, has been found to play a role in OA. This study aimed to explore the role of NF-κB in FABP4-induced OA. In the in vivo study, four pairs of 12-week-old male FABP4 knockout (KO) and wild-type (WT) mice were included. The activation of NF-κB was assessed. In parallel, 24 6-week-old male C57/Bl6 mice were fed a high-fat diet (HFD) and randomly allocated to four groups: daily oral gavage with (1) PBS solution; (2) QNZ (NF-κB-specific inhibitor, 1 mg/kg/d); (3) BMS309403 (FABP4-specific inhibitor, 30 mg/kg/d); and (4) BMS309403 (30 mg/kg/d) + QNZ (1 mg/kg/d). The diet and treatment were sustained for 4 months. The knee joints were obtained to assess cartilage degradation, NF-κB activation, and subchondral bone sclerosis. In the in vitro study, a mouse chondrogenic cell line (ATDC5) was cultured. FABP4 was supplemented to stimulate chondrocytes, and the activation of NF-κB was investigated. In parallel, QNZ and NF-κB-specific siRNA were used to inhibit NF-κB. In vivo, the FABP4 WT mice had more significant NF-κB activation than the KO mice. Dual inhibition of FABP4 and NF-κB alleviated knee OA in mice. FABP4 has no significant effect on the activation of the JNK signaling pathway. In vitro, FABP4 directly activated NF-κB in chondrocytes. The use of QNZ and NF-κB-siRNA significantly alleviated the expression of catabolic markers of chondrocytes induced by FABP4. FABP4 induces chondrocyte degeneration by activating the NF-κB pathway.

Asunto(s)