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Gossypin, a flavone found in Hibiscus vitifolius, exhibits antioxidant, antidiabetic, anti-inflammatory and anticancer effects. The present study investigated the potential of gossypin to induce apoptosis and autophagy in HT-29 human colorectal cancer (CRC) cells, and assessed its association with the MAPK/JNK pathway. Cell viability assays, DAPI staining, flow cytometry, acridine orange staining, western blotting, hematoxylin and eosin staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and immunohistochemistry were performed. The results revealed an increased number of apoptotic bodies, higher apoptosis rates and enhanced autophagy in gossypin-treated HT-29 cells. To investigate autophagy during cell death, the effects of the early autophagy inhibitor 3-methyladenine (3-MA) and the late autophagy inhibitor hydroxychloroquine on cell viability and the expression of apoptosis-related proteins were assessed. Significant increases in cell viability were observed following 3-methyladenine pretreatment, as well as a decrease in the expression levels of Bcl-2 and an increase in Bax. The analysis of MAPK pathway proteins following treatment with gossypin revealed that the levels of phosphorylated (p-)JNK and p-p38 were significantly increased in a concentration-dependent manner. The JNK inhibitor SP600125 was used to confirm the role of the JNK pathway in gossypin-induced apoptosis and autophagy. Moreover, gossypin reduced the volume of HT-29 tumors in mice, and western blotting indicated the induction of apoptosis and autophagy in these tumors in vivo. Finally, TUNEL and immunohistochemistry experiments confirmed the induction of apoptosis and p-JNK upregulation in these tumors in vivo. In conclusion, the present study suggested that gossypin may induce MAPK/JNK-mediated apoptosis and autophagy in HT-29 CRC cells, highlighting the potential of gossypin as an anticancer agent.

Stroke remains the primary cause of pain, suffering, and death in patients. One of the major thrusts in stroke therapy is to find an effective prevention strategy. Objectives of this study are to testify the neuro-protection effect of stigmasterol in ischemic/reperfusion injury model. The dosage-dependent effects (20, 40, and 80 mg/kg) of stigmasterol on physiological behaviors and oxidative stress biomarkers were investigated. Expression and phosphorylation of beclin1, microtubule-associated protein 1 light chain 3 (LC3), adenosine monophosphate-activated protein kinase (AMPK), mTOR, and N-terminal kinase (JNK) were detected. The results showed that stigmasterol was able to effectively reduce neurological deficits and infarct damage induced by the ischemic/reperfusion injury, improve histopathology changes, and restore the levels of the endogenous antioxidant defense system in a dose-response mode. Stigmasterol effectively depressed the expression level of beclin1, and the conversion of LC3 I to LC3 II, while promoted the phosphorylation of mTOR, and remarkably inhibited the phosphorylation of AMPK and JNK, as well as the expression of JNK induced by 24 hrs of reperfusion. These findings reveal that stigmasterol has neuro-protective effect against the ischemic/reperfusion injury, possibly associated with reduction of oxidative stress and inactivation of autophagy via AMPK/mTOR and JNK pathways.

Background This study aimed to investigate the relationship of serum JNK pathway‐associated phosphatase (JKAP) expression with rheumatoid arthritis (RA) risk and clinical features, also to explore the longitudinal change of JKAP during etanercept treatment and its relationship with etanercept treatment response in RA patients. Methods A total of 87 RA patients and 44 healthy controls (HCs) were enrolled; then, their JKAP expression in serum was determined by enzyme‐linked immunosorbent assay (ELISA). Among 87 RA patients, 42 cases further received the 24‐week etanercept treatment; then, their JKAP level in serum (detected by ELISA) and clinical response (evaluated by disease activity score in 28 joints (DAS28) score) were evaluated at week 4 (W4), week 12 (W12), and week 24 (W24) after initiation of etanercept treatment. Results JKAP expression was decreased in RA patients compared to HCs, which disclosed a good predictive value for RA risk. JKAP expression was negatively associated with tender joint count, swollen joint count, erythrocyte sedimentation rate, C‐reactive protein, and DAS28 in RA patients, respectively. For RA patients who received 24‐week etanercept treatment, their clinical response rate was 0.0%, 33.3%, 50.0%, and 69% at W0, W4, W12, and W24, respectively. Importantly, JKAP was gradually increased during etanercept treatment, whose longitudinal elevation positively related to etanercept treatment response in RA patients. Conclusion Circulating JKAP links with decreased RA risk and mild disease activity, whose longitudinal elevation positively relates to etanercept treatment response. This study aimed to investigate the relationship of serum JNK pathway‐associated phosphatase (JKAP) expression with rheumatoid arthritis (RA) risk and clinical features, also to explore the longitudinal change of JKAP during etanercept treatment and its relationship with etanercept treatment response in RA patients. A total of 87 RA patients and 44 healthy controls (HCs) were enrolled; then, their JKAP expression in serum was determined by enzyme‐linked immuno sorbent assay (ELISA). Among 87 RA patients, 42 cases further received the 24‐week etanercept treatment; then, their JKAP level in serum (detected by ELISA) and clinical response (evaluated by disease activity score in 28 joints (DAS28) score) were evaluated at week 4 (W4), week 12 (W12), and week 24 (W24) after initiation of etanercept treatment. JKAP expression was decreased in RA patients compared to HCs, which disclosed a good predictive value for RA risk. JKAP expression was negatively associated with tender joint count, swollen joint count, erythrocyte sedimentation rate, C‐reactive protein, and DAS28 in RA patients, respectively. For RA patients who received 24‐week etanercept treatment, their clinical response rate was 0.0%, 33.3%, 50.0%, and 69% at W0, W4, W12, and W24, respectively. Importantly, JKAP was gradually increased during etanercept treatment, whose longitudinal elevation positively related to etanercept treatment response in RA patients. Circulating JKAP links with decreased RA risk and mild disease activity, whose longitudinal elevation positively relates to etanercept treatment response.

Osteoarthritis (OA) is a painful joint condition primarily caused by cartilage degradation, leading to pain and reduced mobility. Given the side effects of current treatments, this study investigates Osteo‐F, a novel herbal‐based functional ingredient formulated with Schizandra chinensis, Lycium chinense, and Eucommia ulmoides, traditionally valued for their bioactive and health‐promoting properties. Network pharmacology analysis identified significant interactions involving Osteo‐F within the TNF signaling pathway, highlighting its role in modulating key inflammatory processes in OA. In vivo experiments using a monosodium iodoacetate‐induced OA rat model demonstrated significant improvements in arthritis scores, bone mineral content, and bone mineral density, alongside preservation of cartilage integrity, as confirmed by histological analyses. In vitro studies further revealed that this formulation reduced the activation of JNK and NF‐κB pathways, decreasing inflammatory cytokines and matrix metalloproteinases critical in cartilage breakdown. These findings underscore the potential of Osteo‐F as a functional food candidate to reduce inflammation and support cartilage preservation in OA. Future clinical trials are required to validate these findings and explore its dietary integration in OA management. Osteo‐F, a newly developed herbal formula comprising Schisandra chinensis, Lycium chinense, and Eucommia ulmoides, was evaluated for its therapeutic effects in osteoarthritis (OA). Through network pharmacology, in vivo, and in vitro analyses, Osteo‐F was shown to regulate NF‐κB/IκB/JNK signaling and reduce inflammation, cartilage degradation, and bone loss. These findings suggest its potential as a functional food‐based strategy for OA management.

Background： Cathepsin L （CatL） is a cysteine protease with strong matrix degradation activity that contributes to photoaging. Mannose phosphate-independent sorting pathways mediate ultraviolet A （UVA）-induced alternate trafficking of CatL. Little is known about signaling pathways involved in the regulation of UVA-induced CatL expression and activity. This study aims to investigate whether a single UVA irradiation affects CatL expression and activity and whether mitogen-activated protein kinase （MAPK）/activator protein- 1 （AP- 1 ） pathway is involved in the regulation of UVA-induced CatL expression and activity in human dermal fibroblasts （HDFs）. Methods： Primary HDFs were exposed to UVA. Cell proliferation was determined by a cell counting kit. UVA-induced CatL production and activity were studied with quantitative real-time reverse transcription polymerase chain reaction （RT-PCR）, Western blotting, and fluorimetric assay in cell lysates collected on three consecutive days after irradiation. Time courses of UVA-activated JNK and p38MAPK signaling were examined by Western blotting. Effects ofMAPK inhibitors and knockdown of dun and Fos on UVA-induced CatL expression and activity were investigated by RT-PCR, Western blotting, and fluorimetric assay. Data were analyzed by one-way analysis of variance. Results： UVA significantly increased CatL gene expression, protein abundance, and enzymatic activity for three consecutive days after irradiation （F = 83.11, 56.14, and 71. 19, respectively; all P 〈 0.05）. Further investigation demonstrated phosphorylation of JNK and p38MAPK activated by UVA. Importantly, inactivation of JNK pathway significantly decreased UVA-induced CatL expression and activity, which were not affected by p38MAPK inhibition. Moreover, knockdown of dun and Fos significantly attenuated basal and UVA-induced CatL expression and activity. Conclusions： UVA enhances CatL production and activity in HDFs, probably by activating JNK and downstreaming AP- 1. These findings provide a new possible molecular approach for antiphotoaging therapy.

Current experimental results indicate that endoplasmic reticulum (ER) stress activates the unfolded protein response (UPR), which rebuilds ER homeostasis, through which tumor cells can become resistant chemotherapeutic agents. Autophagy is a form of programmed cell death, but it can also play a cytoprotective role in tumor cells, indicating that it has an inverse function. The aim of the present study was to investigate whether tunicamycin (TM) induces autophagy, as well as whether the inhibition of autophagy enhances the apoptosis ofbreast cancer cells induced by TM. In addition, we wished to investigate the mechanisms through which specific UPR targets control autophagy. We found that MCF-7 and MDA-MB-231 breast cancer cells were insensitive to TM at a relatively low concentration. As shown by western blot analysis, treatment with TM increased the expression of 78 kDa glucose-regulated protein (GRP78), inositol requiring enzyme 1 (IRE1), beclin-1, IRE1α, p-JNK and microtubule-associated protein 1 light chain 3 (LC3); the expression of p62 increased at an early time point during treatment and subsequently decreased. We also used the specific inhibitor of autophagy, 3-methyladenine (3-MA), to elucidate the role of autophagy in ER stress in the breast cancer cells treated with TM. The transformation of LC3-I to LC3-II which was induced by TM, was reversed following treatment with 3-MA. The inhibition of autophagy by 3-MA treatment enhanced the inhibitory and apoptotic rates of TM in the breast cancer cells, as shown by confocal microscopy and flow cytometry. TM increased the misfolded proteins that lead to the activation of ER stress-mediated protection and induced apoptosis paralleled by autophagy in breast cancer cells which was regulated by IRE1/JNK/beclin-1. Autophagy attenuates ER stress by clearing ubiquitinated proteins and decreasing apoptosis, which plays a protective role. The inhibition of autophagy or the promotion of ER stress may be used as therapeutic targets to improve the efficacy of chemotherapeutic drugs.

Lung adenocarcinoma (LUAD) is a leading cause of cancer-related death due to its aggressive nature and metastatic potential. The present study aimed to explore the expression of phospholipid phosphatase 2 (PPAP2C) in LUAD, and its effect on cell migration and invasion, with a particular focus on its association with the ERK/JNK signaling pathway and epithelial-mesenchymal transition (EMT). The expression of PPAP2C in LUAD was analyzed using data from The Cancer Genome Atlas database. Pearson's correlation coefficient analysis was used to assess the correlation between PPAP2C and genes such as MAPK1, MAPK3, MAPK8, CDH1, CDH2 and SNAI1. Subsequently, the PPAP2C gene was silenced in A549 and H1299 LUAD cell lines using siRNA vectors, followed by assessments of gene expression, cell migration, invasion and protein interaction using reverse transcription-quantitative PCR, western blotting, wound healing assay, Transwell invasion assay, molecular docking analysis, co-immunoprecipitation and immunofluorescence staining. The results showed that PPAP2C was significantly upregulated in LUAD tissues compared with that in normal tissues. In addition, high levels of PPAP2C were significantly correlated with MAPK3, MAPK8, CDH1 and SNAI1. Notably, PPAP2C silencing significantly inhibited cell migration and invasion. Additionally, it reduced the phosphorylation levels of ERK and JNK proteins. PPAP2C showed specific binding sites with ERK1, and co-precipitated with ERK1 in both A549 and H1299 cells. Furthermore, PPAP2C silencing decreased the expression levels of N-cadherin and Snail, while increasing E-cadherin expression, thereby inhibiting EMT. In conclusion, PPAP2C may be highly expressed in LUAD tissues, and could promote cell migration and invasion by activating the ERK/JNK signaling pathway and inducing EMT. These findings provide a novel potential target for the diagnosis and treatment of LUAD.

Pyroptosis is a new form of programmed cell death generated by some inflammasomes, piloting the cleavage of gasdermin (GSDM) and stimulation of dormant cytokines like IL‐18 and IL‐1β; these reactions are narrowly linked to certain diseases like diabetic nephropathy and atherosclerosis. Doxorubicin, a typical anthracycline, and famous anticancer drug has emerged as a prominent medication in several cancer chemotherapies, although its application is accompanied with expending of dose‐dependent, increasing, irreversible and continuing cardiotoxic side effects. However, the exact path that links the induced pyroptosis to the mechanism by which Doxorubicin (DOX) acts against breast cancer cells is still puzzling. The present study seeks to elucidate the potential link between DOX‐induced cell death and pyroptosis in two human breast cancer cell lines (MDA‐MB‐231 and T47D). We proved that treatment with DOX reduced the cell viability in a dose‐dependent way and induced pyroptosis morphology in MDA‐MB‐231 and T47D cells. Also, protein expression analyses revealed GSDME as a key regulator in DOX‐induced pyroptosis and highlighted the related role of Caspase‐3 activation. Furthermore, DOX treatments induced intracellular accumulation of ROS, stimulated the phosphorylation of JNK, and Caspase‐3 activation, subsequently. In conclusion, the study suggests that GSDME triggered DOX‐induced pyroptosis in the caspase‐3 dependent reactions through the ROS/JNK signalling pathway. Additionally, it showed that the DOX‐induced cardiotoxicity and pyroptosis in breast cancer cells can be minimized by reducing the protein level of GSDME; thus, these outcomes provide a new research target and implications for the anticancer investigations and therapeutic applications.

[This corrects the article DOI: 10.3389/fphar.2022.1007839.].

Disruption of the blood–brain barrier (BBB) accompanies many brain diseases, including stroke, neurodegenerative diseases, and brain tumors, leading to swelling, increased neuroinflammation, and neuronal death. In recent years, it has become clear that the c-Jun N-terminal kinase (JNK) signaling pathway is involved in disruption of the structural integrity of the BBB. Activation of the JNK signaling pathway has a negative effect on the functioning of the cellular elements of the neurovascular unit that form the BBB. The aim of this review is to assess the role of the JNK signaling pathway in the disruption of the structural integrity of the BBB in animal models of stroke (MCAO/R, middle cerebral artery occlusion with reperfusion), Alzheimer’s disease, and brain tumors and to analyze the effects of compounds of various natures that directly or indirectly affect the activity of the JNK signaling pathway. These compounds can reduce damage to the BBB and brain edema, reduce neuroinflammation and oxidative stress, reduce the expression of proapoptotic factors, and increase the expression of tight junction proteins. Certain compounds mitigate BBB dysfunction, being promising candidates for neuroprotective therapies. These agents exert their effects, in part, through inhibition of the c-Jun N-terminal kinase (JNK) signaling pathway, a mechanism linked to reduced neuronal damage and improved BBB integrity.