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Twenty 9O-substituted palmatine derivatives were prepared and tested for their biological effect against collagen α1 (I) (COL1A1) promotor in human hepatic stellate LX-2 cells. The structure−activity relationship (SAR) indicated that the introduction of a benzyl motif on the 9O atom was favorable for activity. Among them, compound 6c provided the highest inhibitory effect against COL1A1 with an IC50 value of 3.98 μM, and it also dose-dependently inhibited the expression of fibrogenic COL1A1, α-soomth muscle actin (α-SMA), matrix metalloprotein 2 (MMP2) in both mRNA and protein levels, indicating extensive inhibitory activity against fibrogenesis. A further primary mechanism study indicated that it might repress the hepatic fibrogenesis via inhibiting both canonical transforming growth factor-beta 1 (TGF-β1)/Smads and non-canonical janus-activated kinase 1 (JAK1)/singal transducer and activator of transcription 3 (STAT3) signaling pathways. Additionally, 6c owned a high safety profile with the LD50 value of over 1000 mg·kg−1 in mice. These results identified palmatine derivatives as a novel class of anti-fibrogenic agents, and provided powerful information for further structure optimization.

The present study was performed to investigate the antidepressant effect of echinacoside (ECH) using chronic unpredictable mild stress (CUMS) induced depression mice and lipopolysaccharide (LPS)-stimulated N9 microglial cells. CUMS treatment was performed on C57BL/6 mice for 28 days, followed by gavaging with different doses of echinacoside (15 and 60 mg/kg) for 21 consecutive days. Sucrose preference test (SPT), open field test (OFT), tail suspension test (TST), and forced swimming test (FST) were measured to assess the effects of echinacoside on CUMS-Induced Depressive-Like Behaviors. After that, the pathological changes of hippocampus were determined by Hematoxylin and eosin (HE) staining and Nissl staining; the neurotransmitters, pro-inflammatory cytokines and indoleamine 2,3-dioxygenase (IDO) levels, and the hypothalamic–pituitary–adrenal (HPA) axis activity were determined by enzyme linked immunosorbent assay (ELISA); Iba 1were evaluated by Immunofluorescence assay; Key protein expression levels of CREB/BDNF signal pathway were measured by western blotting. Subsequently, N9 cells were stimulated with 1 μg/ml LPS to induce N9 microglia activation, and were treated with 5–20 μM of echinacoside for 24 h. After that, the levels of NO, interleukin (IL)-1β, IL-6, tumor necrosis factor alpha (TNF-α), IL-4, IL-10, and transforming growth factor beta (TGF-β) in N9 cell culture supernatants were measured by enzyme-linked immunosorbent assay (ELISA) kits; morphology and Iba 1 expression level were observed by high-content screening assay; the M1 markers of CD11b, CD86 and M2 markers of CD206 were analyzed by imaging flow cytometry. Results show that treatment with echinacoside reversed CUMS-increased immobility time in OFT, TST, FST and reversed CUMS-reduced sucrose preference in SPT. In addition, echinacoside reduced the levels of pro-inflammatory cytokines and Iba 1. Moreover, echinacoside significantly increased p-CREB/CREB ratio and BDNF level in hippocampus. Furthermore, echinacoside reduced the secretion of inflammatory factors and inhibited microglia M1 polarization in N9 cells. In conclusion, echinacoside may be beneficial for the treatment of depression diseases through regulating the microglia balance by inhibiting the polarization of microglia to M1 phenotype, and improving hippocampal neurogenesis by the CREB-BDNF signaling pathway.

Triple-negative breast cancer (TNBC), the most aggressive subtype, presents a critical challenge due to the absence of approved targeted therapies. Hence, there is an urgent need to identify effective therapeutic targets for this condition. While epidermal growth factor receptor (EGFR) is prominently expressed in TNBC and recognized as a therapeutic target, anti-EGFR therapies have yet to gain approval for breast cancer treatment due to their associated side effects and limited efficacy. Here, we discovered that intercellular adhesion molecule-1 (ICAM-1) exhibits elevated expression levels in metastatic breast cancer and serves as a pivotal binding adaptor for EGFR activation, playing a crucial role in malignant progression. The activation of EGFR by tumor-expressed ICAM-1 initiates biased signaling within the JAK1/STAT3 pathway, consequently driving epithelial-to-mesenchymal transition and facilitating heightened metastasis without influencing tumor growth. Remarkably, ICAM-1-neutralizing antibody treatment significantly suppressed cancer metastasis in a breast cancer orthotopic xenograft mouse model. In conclusion, our identification of ICAM-1 as a novel tumor intrinsic regulator of EGFR activation offers valuable insights for the development of TNBC-specific anti-EGFR therapies.

Lung injury is a common complication in critical sepsis. PRMT5 is implicated in endothelial inflammation and lung diseases, but its role in sepsis‐associated lung injury remains unclear. This study collected clinical sepsis samples and detected the mRNA expression of PRMT5. Subsequently, a murine sepsis model (CLP) was constructed to assess disease severity (survival, sepsis score, temperature, weight). Then, lung histopathology was evaluated with HE staining. ELISA evaluated the expression of inflammatory cytokines in mice blood, and immunohistochemistry detected PRMT5 expression. In vitro, a sepsis cell model was generated by LPS stimulation of human pulmonary microvascular endothelial cells (HPMECs). qRT‐PCR confirmed transfection efficiency. CCK‐8 assay, ELISA, MDA/T‐AOC kits, and flow cytometry tested cell viability, inflammatory cytokines, oxidative stress markers, and apoptosis, respectively. Bioinformatic analysis predicted PRMT5‐interacting proteins, validated by Co‐IP and immunofluorescence. JAK1 arginine methylation, JAK1 protein stability, and activation of the JAK1/STAT3 pathway were assessed by Western blot. The results showed that PRMT5 was upregulated in sepsis patients. PRMT5 knockdown attenuated septic symptoms in CLP mice, manifested by increased survival, reduced sepsis scores, restored physiological parameters, and alleviated lung injury. PRMT5 silencing reversed LPS‐induced decreased viability of HPMECs, inflammatory cytokine release, and oxidative product accumulation. Mechanistically, PRMT5 stabilizes JAK1 protein through arginine methylation, activates the JAK1/STAT3 signaling pathway, and thereby promotes inflammatory responses and oxidative damage. In summary, PRMT5 regulates sepsis‐induced lung injury through a methylation‐dependent JAK1/STAT3 pathway, serving as a potential target for clinical intervention.

CUE domain containing protein 1 (CUEDC1) is implicated in tumor progression; however, its specific role in esophageal cancer (ESCA) remains unclear. In esophageal cancer, the expression of CUEDC1 is notably low, which correlates with reduced survival rates and adverse clinical outcomes. Overexpression of CUEDC1 results in decreased activity of the JAK1/STAT3 signaling pathway in cells, consequently diminishing their proliferation, migration, and invasion capabilities. This mechanism operates through the direct binding of CUEDC1 to STAT3, facilitating its ubiquitination and triggering the ubiquitin-proteasome degradation pathway, ultimately leading to a significant reduction in intracellular STAT3 levels. This study suggests that CUEDC1 can reduce intracellular STAT3 protein levels, thereby inhibiting JAK1/STAT3 signaling transduction and suppressing the progression of ESCA. This study aims to elucidate the regulatory mechanism of CUEDC1 on STAT3, which will enhance our understanding of the regulatory pathways involved in the treatment of esophageal cancer and potentially other tumors. Future breakthroughs and innovations may emerge from molecular research and development targeting this pathway.

The imbalance that occurs in bone remodeling induced by irradiation (IR) is the disruption of the balance between bone formation and bone resorption. In this study, primary osteocytes (OCYs) of femoral and tibial origin were cultured and irradiated. It was observed that irradiated OCY showed extensive DNA damage, which led to the initiation of a typical phenotype of cellular senescence, including the secretion of senescence-associated secretory phenotype (SASP), especially the C-C motif chemokine ligand 5 (CCL5). In order to explore the regulation of osteoclastogenic potential by IR-induced senescent OCYs exocytosis factor CCL5, the conditioned medium (CM) of OCYs was co-cultured with RAW264.7 precursor cells. It was observed that in the irradiated OCY co-cultured group, the migration potential increased compared with the vehicle culture group, accompanied by an enhancement of typical mature OCs; the expression of the specific function of enzyme tartrate-resistant acid phosphatase (TRAP) increased; and the bone-destructive function was enhanced. However, a neutralizing antibody to CCL5 could reverse the extra-activation of osteoclastogenesis. Accordingly, the overexpression of p-STAT3 in irradiated OCY was accompanied by CCL5. It was concluded that CCL5 is a potential key molecule and the interventions targeting CCL5 could be a potential strategy for inhibiting osteoclastogenesis and restoring bone remodeling.

Wo Q, Shi L, Shi J, Mao Y, Xie L. J Inflamm Res. 2024;17:8659-8680. The authors have advised that Figure 13F on page 8676 is incorrect. Due to an error in image processing during revision, the images for the \"CAF + AG490\" and \"CAF + AG490 + si-NC\" groups were mistakenly replaced by the \"CAF\" group image, resulting in three duplicated images. The correct Figure 13 is as follows. Figure 13 Continued. Figure 13 HHIP influences the stemness of PCa cells by regulating the inflammatory response of CAFs through the JAK1-STAT3 pathway. (A) The expression of HHIP and the JAK1-STAT3 pathway-related proteins was detected (n=3); (B) The secretion of inflammatory factors was detected (n=3); (C) The activity of cancer cells was detected (n=3); (D) The proliferation of cancer cells was detected (n=3); (E) The colony formation of cancer cells (n=3); (F) The migration of cancer cells (n=3) (Bar, 100 μm); (G) The invasion of cancer cells (n=3) (Bar, 100 μm); (H) The sphere-forming ability of cancer cells (n=3) (Bar, 500 μm), *p<0.05, **p<0.01. The authors apologies for this error.

Adipose-derived stem cells (ADSCs) demonstrate therapeutic potential for ischemic stroke, primarily through paracrine actions. However, the specific intracellular signaling pathways underlying these benefits remain unclear. This study investigates the critical role of JAK1/STAT3 signaling in neuroprotection mediated by ADSC-conditioned medium (ADSC-CM). We employed a dual-model approach. rats subjected to transient middle cerebral artery occlusion (tMCAO) received intravenous ADSC-CM or vehicle at 2, 24, and 48 h post-ischemia, with or without the JAK1 inhibitor GLPG0634. Neurological function was evaluated over a period of 7 days. Subsequently, infarct volume, brain edema, neuronal survival, neurovascular regeneration, synaptic ultrastructure, mitochondrial function, and energy metabolism were analyzed. , primary cortical neurons subjected to oxygen-glucose deprivation (OGD) were treated with ADSC-CM with or without GLPG0634 to assess neurite outgrowth. Activation of the JAK1/STAT3 pathway was confirmed by Western blot in both models. , ADSC-CM significantly improved neurological function, reduced infarct volume and brain edema, and enhanced neuronal survival, nerve fiber regeneration, angiogenesis, synaptic plasticity, and mitochondrial function in tMCAO rats. , ADSC-CM promoted neurite outgrowth in OGD-injured neurons. Crucially, all these multifaceted neuroprotective effects were completely abolished by co-treatment with GLPG0634. Mechanistically, ADSC-CM robustly activated JAK1 and STAT3 phosphorylation in both models, an effect effectively inhibited by GLPG0634. The neuroprotective effects of ADSC-CM are mechanistically linked to the activation of the JAK1/STAT3 pathway, which mitigates ischemic damage by promoting neuronal salvage, neurovascular regeneration, synaptic plasticity, and metabolic recovery, thereby enhancing neurological functional recovery after stroke.

Ruscogenin-1-O-[β-D-glucopyranosyl (1→2)][β-D-xylopyranosyl (1→3)] -β-D-fucopyranoside (Rus-GXF) is a ruscogenin glycoside of (Decaisne) L. H. Bailey, yet its protective effects against acute lung injury-a condition characterized by exacerbated inflammation and barrier damage have not been fully elucidated. In this study, the preventive and therapeutic effects of Rus-GXF on acute lung injury (ALI) were investigated using transcriptome RNA sequencing, network pharmacology, molecular docking, molecular dynamics simulation and other and experiments. Rus-GXF suppressed inflammatory responses in two key cell types involved in lung injury. In immune cells (RAW264.7), it inhibited the production of pivotal pro-inflammatory mediators and their regulatory genes. Similarly, in pulmonary epithelial cells (BEAS-2B), it reduced the expression of inflammatory signals and concurrently enhanced markers of cellular tight junction proteins. In mice, Rus-GXF alleviated ALI severity, evidenced by decreased lung wet/dry ratio, bronchoalveolar lavage fluid protein content, pro-inflammatory cytokine levels, and histopathological scores. Integrated network pharmacology and transcriptomics indicated that Rus-GXF acts through multi-target mechanisms in ALI. Molecular docking and dynamics simulations revealed that Rus-GXF acts as an allosteric inhibitor of JAK1, thereby preventing its activation and subsequent STAT3 phosphorylation. The inhibitory effect of Rus-GXF on the JAK1/STAT3 signaling pathway was investigated by immunohistochemistry (IHC) and Western blot analysis (WB). These results demonstrate that Rus-GXF suppresses the macrophage-derived cytokine storm, alleviates inflammation, and improves barrier function. It functions as a JAK1 inhibitor to regulate ALI progression via the JAK1/STAT3 signaling pathway.

Growth differentiation factor 15 (GDF15) is involved in the occurrence and development of many diseases, and there are few studies on its relationship with sepsis. This article aims to explore the clinical value of GDF15 in sepsis and to preliminarily explore its prospective regulatory effect on macrophage inflammation and its functions. We recruited 320 subjects (132 cases in sepsis group, 93 cases in nonsepsis group, and 95 cases in control group), then detected the serum GDF15 levels and laboratory indicators, and further investigated the correlation between GDF15 and laboratory indicators, and also analyzed the clinical value of GDF15 in sepsis diagnosis, severity assessment, and prognosis. In vitro , we used LPS to stimulate THP-1 and RAW264.7 cells to establish the inflammatory model, and detected the expression of GDF15 in the culture medium and cells under the inflammatory state. After that, we added GDF15 recombinant protein (rGDF15) pretreatment to explore its prospective regulatory effect on macrophage inflammation and its functions. The results showed that the serum GDF15 levels were significantly increased in the sepsis group, which was correlated with laboratory indexes of organ damage, coagulation indexes, inflammatory factors, and SOFA score. GDF15 also has a high AUC in the diagnosis of sepsis, which can be further improved by combining with other indicators. The dynamic monitoring of GDF15 levels can play an important role in the judgment and prognosis of sepsis. In the inflammatory state, the expression of intracellular and extracellular GDF15 increased. GDF15 can reduce the levels of cytokines, inhibit M1 polarization induced by LPS, and promote M2 polarization. Moreover, GDF15 also enhances the phagocytosis and bactericidal function of macrophages. Finally, we observed a decreased level of the phosphorylation of JAK1/STAT3 signaling pathway and the nuclear translocation of NF-κB p65 with the pretreatment of rGDF15. In summary, our study found that GDF15 has good clinical application value in sepsis and plays a protective role in the development of sepsis by regulating the functions of macrophages and inhibiting the activation of JAK1/STAT3 pathway and nuclear translocation of NF-κB p65.