Dihydromyricetin attenuates LPS-induced liver injury in chicks through the JNK signaling pathway.

Characterization of a novel inherited splice-site variant in MAPK8IP3 expands the genetic and phenotypic spectrum of neurodevelopmental disorders.

Cell migration plays crucial roles in cancer generation and metastasis. A deeper understanding of the mechanisms that govern this migratory behavior may uncover novel drug targets that could be utilized in cancer treatments. PP2AC, the catalytic subunit of protein phosphatase 2A, has been found to be expressed in various human cancers. However, the specific role of PP2AC in the context of cancer cell migration has remained elusive. In this study, we demonstrated that Mts (the ortholog of PP2AC in Drosophila) is sufficient to trigger cell migration through activating the JNK pathway. Genetic epistasis analyses data revealed that Mts acts upstream of Slpr in the JNK signaling cascade. Furthermore, we identified Rho1 as a candidate mediator through affinity purification-mass spectrometry (AP-MS), which functions downstream of Mts in the Slpr-JNK signaling cascade supported by genetic evidence. Consistently, our results revealed that Mts activates the JNK signaling pathway by increasing the protein level of Rho1. Finally, we showed that PP2AC promotes cell migration in human pancreatic adenocarcinoma (PAAD) cells and is associated with RhoA levels and JNK activation. Taken together, our research supports a model in which Mts/PP2AC functions as an upstream regulator of the Rho1-JNK signaling axis in cell migration and offers promising therapeutic strategies to combat cancer metastasis.

Study on the response of Punicalagin to AGEs - Induced inflammation based on lipidomics.

Hydroquinone (HQ), a metabolic byproduct of benzene, can cause oxidative damage. Oxidative stress triggers the excessive generation of reactive oxygen species (ROS), which in turn elicits diverse forms of cellular injury, including cell cycle arrest. This study sought to investigate the role and underlying regulatory mechanism of miR-20b-5p in HQ-induced cellular injury. The findings indicated that HQ increased the proportion of S-phase cells, indicating S-phase arrest. Furthermore, miR-20b-5p deletion facilitated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream proteins, while also stimulating the expression of downstream proteins associated with c-Jun N-terminal kinase 1 (JNK1). Therefore, we speculate that loss of miR-20b-5p exacerbates HQ-induced cytotoxicity and S-phase cell accumulation, potentially through the JNK1/Nrf2 signaling pathway or via direct regulation of Nrf2.

PACS2 deficiency ameliorates hepatic steatosis via inhibition of the JNK signaling pathway in diabetic mice.

This study aims to investigate whether butyrylcholinesterase (BChE) inhibitor QY-54 can be used to treat glioblastoma (GBM) and exert a neuroprotective profile. At the cellular level, the effects of QY-54 on the proliferation, invasion, and migration of GBM cells from different species were investigated. At the animal level, the safety of QY-54 in normal mice, its anti-tumor effects in GBM mice, and its effects on cognition protective function were examined. At the cellular level, QY-54 exhibited significant inhibitory effects on the proliferation, migration, and invasion of GBM cells derived from different species. At the animal level, QY-54 showed low toxicity in normal mice. Moreover, it significantly inhibited GBM tumor growth, promoted tumor cell apoptosis, suppressed neuroinflammation, protected neurons, and improved the general condition and cognitive function of GBM mice. In Western blot experiments, QY-54 upregulated c-jun N-terminal kinase (JNK) levels to exert an inhibitory effect on glioma. QY-54 exhibits dual effects of anti-glioblastoma and cognitive improvement, by inhibiting BChE and activating the JNK signaling pathway. QY-54 is a highly promising drug for the treatment of glioblastoma with neuroprotective profile.

Developing resistance to chemotherapy drugs and evading the killing effect of the immune system are the main obstacles in the clinical treatment of gastric cancer. However, the potential mechanism remains poorly understood. N-acetyltransferase 10 (NAT10) catalyzes the N4-acetylcytidine (ac4C) modification of mRNA and is associated with tumor occurrence, development and chemotherapy resistance. Here, we observed that elevated NAT10 levels promote cisplatin chemoresistance in gastric cancer cells. On the contrary, knockdown of NAT10 enhances the sensitivity of cisplatin-resistant gastric cancer cells to cisplatin, both in vitro and in vivo. Mechanistically, NAT10 binds to DUSP1 mRNA and catalyzes its ac4C modification at positions C327, C330, and C331 within the coding sequence (CDS) region, thereby enhancing the stability of DUSP1 mRNA and increasing the abundance of DUSP1 protein. Furthermore, NAT10 mediates resistance to cisplatin-induced apoptosis through DUSP1 via the JNK and ERK signaling pathways. Additionally, NAT10 can upregulate PD-L1 expression via FOSB. The combination of a NAT10 inhibitor and an anti-PD-1 antibody synergistically enhances the antitumor efficacy against cisplatin- resistant gastric cancer cells in murine models. Taken together, these findings offer novel insights into the role and mechanism of NAT10 in the crosstalk between cisplatin chemoresistance and immunosuppression in gastric cancer. NAT10 thus holds promise as a highly attractive target, with the potential to synergize with PD-1-based immunotherapy to reverse cisplatin resistance in gastric cancer.

The clinical treatment of castration-resistant prostate cancer (CRPC) is currently a major challenge. This study explored a new combination strategy for CRPC that targeted androgen receptor (AR)-dependent and AR-independent mechanisms. First, the degradation efficiency of AR by ARV-110 was verified. CCK-8 and CellTiter-Glo assays were used to evaluate the viability of CRPC cells after treatment. The combination index of platelet-derived growth factor receptor (PDGFR) inhibitors combined with ARV-110 was calculated using CompuSyn software. Transcriptome sequencing was used to explore the in-depth mechanisms of the combination strategy. Chromatin immunoprecipitation and dual-luciferase reporter assays were used to clarify the transcriptional regulatory relationships. Coimmunoprecipitation was used to evaluate protein interactions. The results showed that ARV-110 significantly promoted AR degradation. The combination of ARV-110 and ponatinib exerted a significant inhibitory and synergistic effect on CRPC cells. The effective targets were AR and PDGFR. The combination of ARV-110 and the PDGFR-selective inhibitor JNJ10198409 effectively induced the apoptosis of CRPC cells. ARV-110 alone promoted the transcription of PDGFA. And the combination strategy further induced JNK signaling pathway activation and promoted cell apoptosis by inhibiting PDGFR activity. Additionally, the substantial accumulation of reactive oxygen species induced by the combination strategy was related to the joint downregulation of catalase by the two drugs through different mechanisms. In conclusion, this study described a new strategy for the treatment of CRPC and clarified the molecular mechanisms of the combination strategy, providing a new theoretical basis for the precision treatment of CRPC.

Chaihu Shugan San exerts antidepressant effects by driving microglial M2 polarization via inhibition of the IL-1β/JNK signaling pathway.

Metabolomics profiles associated with SARS-CoV-2 -IgG serostatus as an alternative diagnostic approach.

The role of sleep deprivation in prostate cancer and a preliminary exploration of its mechanisms.

Angiogenesis is a pivotal process for tumor progression and metastasis in non-small cell lung cancer (NSCLC). However, the molecular mechanisms by which WNT1-inducible signaling pathway protein 3 (WISP-3) contributes to NSCLC angiogenesis remain poorly defined. This study investigated the role of WISP-3 in regulating pro-angiogenic signaling in lung adenocarcinoma (LUAD) cells. Conditioned medium from H1299 and A549 cells treated with recombinant WISP-3 (0-100 ng/mL) significantly and dose-dependently enhanced the tube formation of human umbilical vein endothelial cells (HUVECs). WISP-3 selectively upregulated platelet-derived growth factor A (PDGF-A) expression at both mRNA and protein levels in NSCLC cell lines, while other angiogenic factors remained unaffected. Notably, knockdown of PDGF-A using siRNA markedly abolished WISP-3-induced HUVEC tube formation, confirming PDGF-A as a critical mediator in this process. Mechanistically, WISP-3 rapidly triggered the phosphorylation of p38 and JNK signaling pathways. These activations led to the phosphorylation of the transcription factor c-Jun, which in turn promoted PDGF-A gene expression. Pharmacological inhibition of p38 (Adezmapimod), JNK (SP600125), or c-Jun (T-5224) effectively suppressed WISP-3-induced c-Jun activation, PDGF-A expression, and subsequent angiogenesis. Collectively, our findings identify a novel WISP-3/p38-JNK/c-Jun/PDGF-A signaling axis that drives vascular remodeling in NSCLC. Targeting WISP-3 or its downstream effectors may represent a promising therapeutic strategy for anti-angiogenic treatment in lung cancer.

Secreted phosphoprotein 1-positive (SPP1+) macrophages play a critical role in the progression of silicosis, but their regulatory mechanisms remain unclear. In this study, we integrated single-cell RNA sequencing and spatial transcriptomics to characterize crucial macrophage subpopulations and their associated regulatory pathways during silicosis. Our results demonstrate that silica exposure significantly promotes the accumulation of SPP1 + macrophages within silicotic nodules. These macrophages contribute to inflammation by releasing pro-inflammatory cytokines such as TNF-α, MCP-1, and IL-6. Concurrently, they exhibit elevated ACTA2 RNA transcription levels, which enhances TGF-β production and drives fibrotic progression. These functional transitions are regulated by the ERK1/2 and JNK signaling pathways. Inhibition of SPP1 markedly attenuated silica-induced lung inflammation and fibrosis. Moreover, plasma SPP1 levels in silicosis patients were strongly correlated with disease onset and severity. Collectively, our findings indicate that SPP1 + macrophages are involved throughout the entire course of silicosis development, under the regulation of ERK/JNK signaling. Targeting SPP1 + macrophages may thus represent a promising therapeutic strategy for silicosis.

Liver fibrosis is a progressive disease caused by chronic inflammation and the activation of hepatic stellate cells (HSCs). This disease manifests as the abnormal proliferation and migration of HSCs, as well as the excessive deposition of the extracellular matrix. Chalcone analogues exhibit various biological activities, including anti-inflammatory, anti-proliferative, and apoptotic modulation properties, making them promising candidates for anti-fibrotic drug development. To enhance anti-fibrotic activities and decrease their side-effects, 31 novel chalcone derivatives were synthesized and evaluated. Among all the compounds, c31 exhibited the strongest anti-inflammatory activity, and its IC50 is 3.05 ± 0.12 µM; and it effectively inhibited the activation and proliferation of HSC-T6 cells. Mechanistic studies revealed that c31 inhibits HSC activation by downregulating the expression levels of inflammatory factors, such as TNF-α, IL-6, and IL-1β, and by interfering with NF-κB and JNK signaling pathways. Additionally, c31 inhibited HSC-T6 proliferation and promoted apoptosis by blocking a G2/M phase cell cycle; and it also significantly inhibited HSC-T6 cell migration. In a rat model of CCl₄-induced liver fibrosis, c31 improved pathological symptoms, decreasing collagen deposition, fibrotic protein expression, and ALT and AST levels. Meanwhile, it also reduced the secretion of inflammatory factors, thereby alleviating CCl₄-induced liver fibrosis. In summary, c31 had significant anti-inflammatory and anti-fibrotic effects in both in vivo and in vitro; this indicates c31 has the potential to be used as a therapeutic candidate for hepatic inflammation and fibrosis.

Erianin induces ferroptosis in ovarian cancer cells by upregulating PDP2 and activating the JNK signaling pathway.

Protective Effect of Auricularia polytricha Water Extract Against UVB-Induced Keratinocyte Damage by Inhibition of Ferroptosis and Apoptosis

4-Methyl-5-Acetylthiazole (Q11), a novel CYP2E1 inhibitor, has a protective effect on the hepatotoxicity induced by acetaminophen.

Elevated nonesterified fatty acid (NEFA) levels, resulting from excessive fat mobilization, are recognized as the pathological basis for fatty liver in dairy cows. Hepatotoxicity of high NEFA is antagonized by the activity of Sirtuin 3 (SIRT3). However, it is unclear whether SIRT3 antagonizes ferroptosis in bovine hepatocytes. Hence, we aimed to investigate the interplay between NEFA and SIRT3 on ferroptosis. High NEFA caused ferroptosis in cultured bovine hepatocytes, as validated by lipid peroxidation measurement, ultrastructure observation, and key gene expression. SIRT3 overexpression alleviated high NEFA-induced ferroptosis. RNA-seq revealed that NEFA-induced ferroptosis was inhibited by SIRT3 through the JNK signaling pathway, and this was further confirmed by the JNK signaling agonist assay. Dairy cows with fatty liver showed reduced hepatic SIRT3 protein levels alongside heightened JNK signaling activity. These results highlight the potential for targeting the SIRT3-JNK axis to prevent or alleviate NEFA-induced hepatotoxicity during the periparturient period.

Osteoporosis (OP) is a chronic bone metabolic disease in which the balance between osteoblasts and osteoclasts is broken. Leonurine can protect BMSCs from oxidative stress, while the role and molecular mechanism of leonurine on OP is unclear. The primary BMSCs from OP rats (OP-BMSCs) were extracted and cultured invitro. Next, we observed the effects of different concentrations of leonurine on cell viability, ROS level and osteoblast differentiation. Additionally, the change levels of ferroptosis and bone microstructure were examined. RNA sequencing was used to analyze the signaling pathway and the MAPK signaling pathway was explored invitro. Finally, the functions of osteoclasts were estimated. Leonurine downregulated ROS levels, upregulated the expression of antioxidative genes and osteogenic-related markers in OP-BMSCs via inhibiting ferroptosis depending on upregulating the phosphorylation of JNK. Additionally, the supernatant of OP-BMSCs promoted the M1 polarization and inhibited M2 polarization, which will be suppressed after co-culture of leonurine and OP-BMSCs invitro. Leonurine could promote the osteogenic function of BMSCs via the inhibition of ferroptosis depending on the JNK signaling pathway and inhibit osteoclastic differentiation by the promotion of M2 polarization, which represents a potential therapeutic approach for OP.