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Background Asthma associated with obesity is a chronic disease characterized by earlier airway remodeling, severe wheezing, and increased insensitivity to hormone therapy. Reticuline, a bioactive compound of Magnoliae Flos, exerts anti‐inflammatory activity and can inhibit neutrophil recruitment. Thus, this study investigated the role of reticuline in obesity‐related asthma. Methods The BALB/c mice fed a low‐fat diet (LFD) and high‐fat diet (HFD) were intranasally challenged with house dust mites (HDMs) or ovalbumin (OVA). Reticuline (0.25 mg/kg) was administrated into mice by intragastrical gavage. Airway hyper‐responsiveness was examined after the final challenge. Body weight was measured, and bronchoalveolar lavage fluid (BALF) and lung tissues were collected. The number of inflammatory cells in BALF was estimated. Histological changes were assessed by performing hematoxylin–eosin staining, and production of proinflammatory cytokines and IgE was examined by ELISA kits. Related pathways were studied with western blotting. Results Reticuline suppressed airway resistance and inflammatory infiltration in lung tissue and reduced inflammatory cell recruitment in BALF in obesity mice with asthma. Additionally, the levels of IL‐17A, IL‐1β, IL‐5, macrophage inflammatory protein 2, and regulated on activation, normal T cell expressed and secreted in the lung were reduced by reticuline. Mechanistically, reticuline inactivated the JAK2/STAT3/SOCS3 and p38 MAPK/NF‐κB signaling pathways in obesity‐related asthma. Conclusion Reticuline alleviates airway inflammation in obesity‐related asthma by inactivating the JAK2/STAT3/SOCS3 and p38 MAPK/NF‐κB signaling pathways. Reticuline suppressed airway resistance, inhibited inflammatory infiltration, and reduced the levels of inflammatory cytokines in obesity mice with asthma. Mechanistically, reticuline inactivated the JAK2/STAT3/SOCS3 and p38 MAPK/NF‐κB signaling pathways in obesity‐related asthma.

BackgroundMouse models have shown that interleukin (IL)6 stimulates survival, proliferation and progression to cancer of intestinal epithelial cells via activation of signal transducers and activators of transcription 3 (STAT3).ObjectiveTo investigate the expression of IL6/phosphorylated STAT3 (p-STAT3)/suppressor of cytokine signalling 3 (SOCS3) in biopsy specimens from patients with ulcerative colitis (UC) and UC-related colorectal cancer (CRC) progression.MethodsBiopsy specimens from patients with inactive UC (n=18), active UC (n=28), UC with low-grade dysplasia (LGD) (n=9), UC with high-grade dysplasia (HGD) (n=7), UC-CRC (n=11) and sporadic CRC (n=14) were included. Biopsy specimens (n=9) from patients without colonic abnormalities served as control. The protein expression of IL6, p-STAT3 and SOCS3 was determined immunohistochemically.ResultsPatients with active UC had significantly more IL6 and p-STAT3-positive epithelial cells than both patients with inactive UC and controls (strong positive IL6: 53.6%, 11.1% and 0%, respectively; p-STAT3: 64.3%, 22.2% and 11.1%, respectively; all p≤0.012). SOCS3-positive cells were significantly increased in colonic epithelium of both inactive and active UC compared with controls (strong positive: 94.4%, 96.4% and 11.1%, respectively; both p<0.001). In dysplasia and cancer, significantly more epithelial cells expressed IL6 and p-STAT3 compared with controls (strong positive IL6: 72.7% and 0% respectively; p-STAT3: 54.5% and 11.1%, respectively; both p<0.05), whereas the proportion of SOCS3-positive cells in this progression reduced (LGD 33.3%; HGD 14.3%; UC-CRC 9.1%). In addition, methylation of the SOCS3 gene was detected in epithelial cells from UC-CRC biopsy specimens.ConclusionThe importance of IL6/p-STAT3 in patients with inflammation-induced CRC was demonstrated. Moreover, SOCS3 may be involved in UC pathogenesis and the absence of SOCS3 seems critical for CRC progression.

Background Macrophage in the spinal cord injury (SCI) area imparts a chronic pro-inflammation effect that challenges the recovery of SCI. Previously, endothelial progenitor cell-produced exosomes (EPC-EXOs) have been noticed to facilitate revascularization and inflammation control after SCI. However, their effects on macrophage polarization remained unclear. This study aimed to investigate the EPC-EXOs' role in macrophage polarization and reveal its underlying mechanism. Methods We extracted the macrophages and EPC from the bone marrow suspension of C57BL/L mice by centrifugation. After cell identification, the EPC-EXOs were collected by ultra-high-speed centrifugation and exosome extraction kits and identified by transmission electron microscopy and nanoparticle tracking analysis. Then, macrophages were cultured with EPC-EXOs in different concentrations. We labeled the exosome to confirm its internalization by macrophage and detected the macrophage polarization marker level both in vitro and in vivo. We further estimated EPC-EXOs' protective effects on SCI by mice spinal cord tissue H&E staining and motor behavior evaluation. Finally, we performed RT-qPCR to identify the upregulated miRNA in EPC-EXOs and manipulate its expression to estimate its role in macrophage polarization, SOCS3/JAK2/STAT3 pathway activation, and motor behavior improvement. Results We found that EPC-EXOs decreased the macrophages’ pro-inflammatory marker expression and increased their anti-inflammatory marker expression on the 7 and 14 days after SCI. The spinal cord H&E staining results showed that EPC-EXOs raised the tissue-sparing area rate significantly after 28 days of SCI and the motor behavior evaluation indicated an increased BMS score and motor-evoked potential by EPC-EXOs treatment after SCI. The RT-qPCR assay identified that miR-222-3P upregulated in EPC-EXOs and its miRNA-mimic also decreased the pro-inflammatory macrophages and increased the anti-inflammatory macrophages. Additionally, miR-222-3P mimic activated the SOCS3/JAK2/STAT3 pathway, and SOCS3/JAK2/STAT3 pathway inhibition blocked miR-2223P’s effects on macrophage polarization and mouse motor behavior. Conclusion Comprehensively, we discovered that EPC-EXOs-derived miR-222-3p affected macrophage polarization via SOCS3/JAK2/STAT3 pathway and promoted mouse functional repair after SCI, which reveals EPC-EXOs’ role in modulation of macrophage phenotype and will provide a novel interventional strategy to induce post-SCI recovery.

Ginsenoside Rg1 is the principal active ingredient in ginseng. The antidepressant effects of Rg1 have been validated; however, the specific underlying mechanism of this effect needs further research. Rats were subjected to the chronic restraint stress (CRS) depression model. Rg1, or a positive control drug, was administered to the rats. Depression-like behaviours were evaluated through behavioural experiments. Cytokine, mRNA, protein, ATP, and mitochondria DNA levels were detected using the indicated methods. Lentivirus-packaged plasmids were injected into the rat brain for GAS5 overexpression or knockdown. In vitro mitochondrial dysfunction was evaluated by detecting mitochondrial reactive oxygen species and mitochondrial membrane potential. Direct interaction between GAS5 and EZH2 was validated by RNA immunoprecipitation and RNA pull-down assay. The enrichment of EZH2 and H3K27me3 was evaluated through chromatin immunoprecipitation quantitative real-time PCR. Rg1 treatment alleviated depression-like behaviours, microglial activation, and mitochondrial dysfunction in CRS rats. Similarly, GAS5 knockdown revealed a similar protective effect of Rg1 treatment. GAS5 overexpression in the rat brain compromised the protective effect of Rg1 treatment. Moreover, Rg1 treatment or GAS5 knockdown attenuated microglial activation and mitochondrial dysfunction in vitro. Mechanically, GAS5 was suppressed SOCS3 and NRF2 expression by facilitating EZH2-mediated transcriptional repression. Rg1 attenuated microglial activation and improved mitochondrial dysfunction in depression by downregulating GAS5 expression. Mechanically, GAS5 might regulate microglial activation and mitochondrial dysfunction via the epigenetic suppression of NRF2 and SOCS3.

Dysregulated long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) mediating chemotherapeutic drug effects and metastasis in pancreatic cancer (PC) are key reasons for the poor prognosis of this disease. lncRNA growth arrest-specific 5 (GAS5) is reported to be a tumor suppressor in multiple cancers. However, the functions of GAS5 and its related miRNAs in PC are poorly understood. This study explored the potential functions and mechanisms of GAS5 in PC gemcitabine resistance and metastasis. The results show that overexpression of GAS5 suppressed the proliferation, migration, gemcitabine resistance, stem cell-like properties, and epithelial-mesenchymal transition (EMT) of PC cells by directly binding to and suppressing miR-221 expression and enhancing suppressor of cytokine signaling 3 (SOCS3) expression. The effects of miR-221 overexpression on proliferation, migration, gemcitabine resistance, stem cell-like properties, and EMT inhibition were reversed by SOCS3 overexpression in PC cells. Additionally, GAS5 promoted gemcitabine-induced tumor growth and metastasis inhibition, as determined by Ki-67 staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), bioluminescence imaging, and the detection of cell-like properties and EMT in vivo. Thus, lncRNA GAS5 functioned as a competing endogenous RNA for miR-221, and it suppressed cell growth, metastasis, and gemcitabine resistance in PC by regulating the miR-221/SOCS3 pathway mediating EMT and tumor stem cell self-renewal.

Type I interferon (IFN-I) is induced during innate immune response and is required for initiating antiviral activity, growth inhibition, and immunomodulation. STAT1, STAT2, and STAT3 are activated in response to IFN-I stimulation. STAT1, STAT2, and IRF9 form ISGF3 complex which transactivates downstream IFN-stimulated genes and mediates antiviral response. However, the role of STAT3 remains to be characterized. Here, we review the multiple actions of STAT3 on suppressing IFN-I responses, including blocking IFN-I signaling, downregulating the expression of ISGF3 components, and antagonizing the transcriptional activity of ISGF3. Finally, we discuss the evolution of the suppressive activity of STAT3 and the therapeutic potential of STAT3 inhibitors in host defense against viral infections and IFN-I-associated diseases.

Demyelinating disease of the central nervous system is one of the most common neurological diseases and effective treatment is still under in-depth research. Our previous study showed that infection can induce demyelination injury in mouse brains and IL-17A expression was shown to be significantly increased during this process. Moreover, we found that IL-17A inhibition attenuated the demyelination caused by infection. However, the underlying mechanisms have not yet been fully elucidated. IL-17A neutralizing antibodies were injected into infected mice to decrease IL-17A levels. The activation of glial cells in the brain and the expression of cell markers were detected by a variety of methods, including real-time quantitative PCR, western blotting, and immunofluorescence staining. The relationship between IL-17A and astrocyte activation was further identified by experiments. The role of SOCS3 in the IL-17A stimulating process was determined using RNA-seq data collection of infected mice and the siRNA interference method. Demyelination of the corpus callosum was relieved after administration of IL-17A neutralizing antibody and this was accompanied by decreased activation of A1 type astrocytes around this region. The expression of SOCS3 was attenuated and activation of astrocytes by IL-17A was mediated by the IL-17RA/STAT3/SOCS3 pathway. IL-17A not only directly damaged oligodendrocytes but also indirectly damaged oligodendrocytes through A1 astrocyte mediation. Specific siRNA inhibition of IL-17A-inducible SOCS3 in astrocytes alleviated their damaging effects on oligodendrocytes. IL-17A plays an important role in demyelination induced by infection the IL-17RA/STAT3/SOCS3 pathway in A1-type astrocytes, indicating that specific blockage of IL-17A and SOCS3 activity could be a therapeutic strategy for neuroinflammatory demyelinating diseases associated with astrocyte activation.

Human glioma is known as the most frequent and primary malignant tumour of the central nervous system with high aggression and poor prognosis. Runx1 is essential for haematopoiesis and is associated with tumour progression in several types of cancers. Therefore, this study aimed to investigate the effect and the possible regulatory mechanisms of Runx1 in glioma. The expression of Runx1 in human glioma tissues was determined by qRT-PCR and immunohistochemistry (IHC). Subsequently, the effect of Runx1 on the glioma cell viability, migration, invasion and the protein level of p21, cyclin D1, MMP2, and MMP4 were detected by MTT, wound healing, transwell assays, and western blot, respectively, in U-138MG and U-251MG cell lines. We then explored the role of Runx1 by establishing a tumour-bearing mouse model. The expression of Runx1 was significantly up-regulated in human glioma tissues and closely associated with tumour grade. Glioma patients with high Runx1 expression had decreased survival rate compared to those with low Runx1 level. Runx1 knockdown inhibited glioma cell viability, migration, invasion, and clone formation, while STAT3 suppressed these inhibitions. Moreover, Runx1 inhibited the activation of SOCS3/SOCS4 promoter, which in turn activated JAK/STAT3 signalling pathway. The tumour volume and weight of the siRunx1 group were lower than in the control group and the tumour mass grow more slowly as well. Runx1 promotes the development of glioma cells via JAK/STAT signalling pathway by inhibiting the activation of SOCS3/SOCS4 promoter.

BackgroundDuchenne muscular dystrophy (DMD) constitutes a severe, incurable disorder inherited in an X-linked manner, characterized by continuous skeletal muscle degeneration, chronic inflammatory responses, and profound metabolic alterations. Although miRNA-mRNA regulatory networks are thought to contribute to DMD pathogenesis, their key drivers remain insufficiently defined.MethodsIn this study, we integrated bulk RNA-seq (GSE38417, GSE109178), small RNA-seq (GSE157668), and single-cell RNA-seq (GSE213925) data and combined differential expression analysis, target gene prediction, functional pathway enrichment mapping, and protein-protein interaction network analysis to screen candidate miRNA-mRNA axes, which were subsequently validated in mdx mice, C2C12 myoblasts, and primary skeletal muscle cells.ResultsWe identified 100 differentially expressed miRNAs (DEMs) in DMD muscle, with miR-30c-5p being the most downregulated and possessing the highest number of predicted targets. Integrated analysis revealed SOCS3 as a key upregulated hub gene targeted by miR-30c-5p. ScRNA-seq showed elevated SOCS3 expression in myocytes from DMD muscle, where SOCS3+ cells exhibited enriched inflammatory pathways and suppressed metabolic processes. In mdx mice, miR-30c-5p expression showed a pronounced reduction (P < 0.001). In contrast, SOCS3 expression increased at both the transcriptional (P < 0.001) and translational (P < 0.01) levels. Functional experiments further showed that overexpression of miR-30c-5p reduced SOCS3 expression, whereas inhibition of miR-30c-5p increased SOCS3 levels in C2C12 cells and primary skeletal muscle cells. Dual-luciferase reporter assay further supported direct binding of miR-30c-5p to the SOCS3 3′UTR. In mdx-derived primary skeletal muscle cells, miR-30c-5p restoration was also accompanied by reduced TNF-α and increased IL-10 levels, and rescue experiments supported that these anti-inflammatory effects were at least partly SOCS3-dependent.ConclusionThese findings suggest that the miR-30c-5p/SOCS3 axis is associated with inflammation- and metabolism-related alterations in DMD and warrants further investigation.

Diabetic retinopathy (DR) is a serious-threatening complication of diabetes and urgently needed to be treated. Evidence has accumulated indicating that microglia inflammation within the retina plays a critical role in DR. Microglial matrix metalloproteinase 9 (MMP-9) has an important role in the destruction of the integrity of the blood-retinal barrier (BRB) associated with the development of DR. MMP-9 was also considered important for regulating inflammatory responses. Paeoniflorin, a monoterpene glucoside, has a potent immunomodulatory effect on microglia. We hypothesized that paeoniflorin could significantly suppress microglial MMP-9 activation induced by high glucose and further relieve DR. BV2 cells were used to investigate the effects and mechanism of paeoniflorin. The activation of MMP-9 was measured by gelatin zymography. Cell signaling was measured by western blot assay and immunofluorescence assay. High glucose increased the activation of MMP-9 in BV2 cells, which was abolished by HMGB1, TLR4, p38 MAPK, and NF-κB inhibition. Phosphorylation of p38 MAPK induced by high glucose was decreased by TLR4 inhibition in BV2 cells. Paeoniflorin induced suppressor of cytokine signaling 3 (SOCS3) expression and reduced MMP-9 activation in BV2 cells. The effect of paeoniflorin on SOCS3 was abolished by the TLR4 inhibitor. In streptozotocin (STZ)-induced diabetes mice, paeoniflorin induced SOCS3 expression and reduced MMP-9 activation. Paeoniflorin suppressed STZ-induced IBA-1 and IL-1β expression and decreased STZ-induced high blood glucose level. In conclusion, paeoniflorin suppressed high glucose-induced retinal microglia MMP-9 expression and inflammatory response via inhibition of the TLR4/NF-κB pathway through upregulation of SOCS3 in diabetic retinopathy.