Rheumatoid arthritis (RA) is a chronic autoimmune disease remarkably characterized by synovitis of joints, whose pathogenesis is complicated and not yet fully elucidated. A variety of cells, cytokines and intercellular signaling pathways are involved in the occurrence and development of RA. The mitogen activation protein kinase (MAPK) signaling pathway is closely related to the pathogenesis of RA, and plays an important role in the formation of pannus, synovitis, and bone destruction. This paper reviews the research progress of MAPK signaling pathway in RA from the aspects of the interaction of MAPK signaling pathway with a variety of key cells and cytokines in the pathogenesis of RA, in order to provide a direction and theoretical basis for anti-RA drug therapy research.
Objective To discuss the role of heparan sulfate (HS) in bone formation and bone remodeling and summarize the research progress in the osteogenic mechanism of HS. Methods The domestic and abroad related literature about HS acting on osteoblast cell line in vitro, HS and HS composite scaffold materials acting on the ani-mal bone defect models, and the effect of HS proteoglycans on bone development were summarized and analyzed. Results Many growth factors involved in fracture healing especially heparin-binding growth factors, such as fibroblast growth factors, bone morphogenetic protein, and transforming growth factor β, are connected noncovalently with long HS chains. HS proteoglycans protect these proteins from protease degradation and are directly involved in the regulation of growth factors signaling and bone cell function. HS can promote the differentiation of stem cells into osteoblasts and enhance the differentiation of osteoblasts. In bone matrix, HS plays a significant role in promoting the formation, maintaining the stability, and accelerating the mineralization. Conclusion The osteogenesis of HS is pronounced. HS is likely to become the clinical treatment measures of fracture nonunion or delayed union, and is expected to provide more choices for bone tissue engineering with identification of its long-term safety.
Objective To investigate the expression of SAPCD2 in the lung adenocarcinoma cells, and to study the effect of SAPCD2 regulating Hippo signaling pathway on the proliferation, invasion, migration and apoptosis of the lung adenocarcinoma cells and its mechanism. Methods Quantitative real-time PCR (qRT-PCR) and Western blot were used to detect the expression levels of SAPCD2 mRNA and protein in four types of lung cancer cells (HCC827, H1650, SK-MES-1, A549) and human normal lung epithelial cells (BESA-2B), respectively. Then, lung cancer cells with relatively high levels of SAPCD2 expression were selected for subsequent experiments. The experiment cells were divided into a normal control group (NC group), a si-SAPCD2 group, and a pathway inhibitor group (si-SAPCD2+XMU-MP-1 group). Firstly, SAPCD2 mRNA was silenced using small interfering RNA (siRNA) technology, and then qRT-PCR was used to detect the expression of SAPCD2 in transfected lung cancer cells; using clone plate assay to detect the proliferation of lung cancer cells after silencing; using flow cytometry to detect the apoptosis of lung cancer cells after silencing; observe the number of lung cancer cells at different stages through cell cycle experiments; then Transwell experiment was used to analyze the effect of silencing SAPCD2 on the migration and invasion of lung cancer cell migration. Finally, Western blot was used to detect the expression of ki-67, Bcl-2, Caspase-3, NF2, P-MST1, P-LATS1, P-YAP, YAP, and TAZ proteins.Results SAPCD2 had the highest expression level in lung adenocarcinoma A549 cells (P<0.01). Silencing SAPCD2 significantly decreased the proliferation ability of A549 cells (P<0.01), inhibited their migration (P<0.05) and invasion (P<0.01), and promoted A549 cell apoptosis (P<0.01); more than half of the cells remained in the G0/G1 phase. Compared with the NC group, A549 cells showed a significant increase in G0/G1 phase cells (P<0.01), a significant decrease in G2/M and S phase cells (P<0.01), and a significant increase in the proportion of early apoptotic cells (P<0.01). Western blot results showed that silencing SAPCD2 down-regulated the expression of ki-67, Bcl-2, YAP, and TAZ proteins compared to the NC group (P<0.01), and up-regulated the expression of Caspase-3, NF2, P-MST1, P-LATS1, and P-YAP proteins (P<0.01). Conclusions The expression of SAPCD2 in lung adenocarcinoma A549 cells is significantly higher than that in normal lung epithelial cells (BESA-2B), which promotes the proliferation, migration and invasion of A549 cells and inhibits apoptosis. The mechanism may be related to the inhibition of Hippo signaling pathway.
ObjectiveTo investigate the expression pattern and significance of Sonic Hedgehog (Shh) signaling pathway by observing whether the Shh signaling pathway components express in the adult rat after spinal cord injury (SCI). MethodsSixty-four healthy male Sprague-Dawley rats were randomly divided into normal group (group A, 8 rats), sham group (group B, 8 rats), and SCI group (group C, 48 rats). In group A, the rats served as controls without any treatment; a decompressive laminectomy was performed on T7-9 levels without SCI in group B; and modified Allen's method was used to make SCI model in group C. Basso Beattie Bresnahan (BBB) scale was used to assess the hind limb motor function at 12 hours, 1 day, 3 days, 7 days, 14 days, and 21 days after SCI; the immunofluorescence staining, real-time PCR, and Western blot were performed to detect the mRNA and protein expression levels of Shh and Glioma-associated oncogene homolog-1 (Gli-1) in SCI zone. ResultsThe BBB score slowly increased with time in group C, but the scores at each time point in group C were significantly lower than those in group A and group B (P<0.05). The results of immunofluorescence staining showed that Shh and Gli-1 rapidly increased after SCI in astrocytes. Real-time PCR and Western blot showed that the relative expression levels of Shh and Gli-1 mRNA and protein were gradually increased in group C and reached a maximum at 7 days. In addition, the relative expression levels of Shh and Gli-1 mRNA and protein in group C were significantly higher than those in group A and group B (P<0.05). On the other hand, compared with group A, the expression of Gli-1 protein was reduced in the cytoplasm but increased in nucleus in group C. ConclusionAstrocytes synthesize and secrete Shh and Gli-1 signaling molecules after SCI, both Shh and Gli-1 significantly up-regulate and exhibit dynamic changes, which suggests Shh signaling pathway may be involved in nerve cell regeneration after SCI.
ObjectiveTo understand the research status of phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) signaling pathway in the thyroid cancer (TC), as well as its role in the occurrence, cell differentiation, invasion, and metastasis of the TC, so as to find potential targets for treatment of TC. MethodThe literature about the research of PI3K/AKT signaling pathway in the TC was searched and summarized. ResultsThe PI3K/AKT signaling pathway was abnormally activated directly or indirectly in the TC, resulting in inhibition of cell apoptosis, malignant proliferation, accelerated cycle progression, invasion, and metastasis, etc., which promoted the occurrence and development of the TC. There were also some tumor suppressor genes, microRNAs, long chain non-coding RNAs, etc., which indirectly inhibited the activation of PI3K/AKT signaling pathway, or directly acted on it inhibiting its activity to inhibit the occurrence and development of the TC. ConclusionsFor the TC, some proteins, genes, microRNAs, and long chain non-coding RNAs directly or indirectly activate the PI3K/AKT signaling pathway through different targets to promote the occurrence and development of TC. At the same time, many targets inhibit the activation of the PI3K/AKT signaling pathway, which inhibits the malignant proliferation, invasion, and metastasis of TC. At present, there have been studies trying to use PI3K/AKT signaling pathway as a breakthrough for the treatment of TC. In-depth exploration of the role of PI3K/AKT signaling pathway in different TC is of great significance to find new targets for the treatment of TC.
ObjectiveTo summarize the latest progress of microRNA (miRNA or miR) in colorectal cancer (CRC)-related signaling pathways in the past three years, and provide new ideas for miRNA-targeted intervention or miRNA as tumor molecular markers for early diagnosis of CRC. MethodThe literature on the roles of miRNA in the CRC-related signaling pathways was retrieved and reviewed. ResultsMiRNAs were associated with cancers in nearly all critical pathways, which regulated almost all important signaling pathways associated with CRC. At present, the signaling pathways and miRNAs related to CRC mainly included Wnt-β-catenin (miR-520e, miR-8063, miR-576-5p, miR-142-3p, miR-19a-3p, miR-381, miR-411, miR-1205), phosphatidylinositol-3-kinaset-Akt (miR-19a, miR-493-5p, miR-3064-5p, mi-196b-5p, miR-3651), mitogen-activated protein kinase (miR-1288-3p, miR-3651, miR-152-3p), transforming growth factor-β (miR-183-5p, miR-21-5p, miR-195-5p, miR-581, miR-2911, miR-128-3p, let-7a), nuclear factor kappa B (miR-155, miR-129, miR-21), Janus kinase/signal transducers and activators of transcription (miR-198, miR-452, miR-128-3p, miR-495), Notch (miR-223, miR-10b, miR-449a), Hippo (miR-30a-5p, miR-375, miR-9), and Hedgehog (miR-372, miR-373), etc. signaling pathways. ConclusionsMiRNA play a role in one or more signaling pathways at the same time, and play an important regulatory role in the occurrence and development of CRC. MiRNAs have great potential as tumor markers in the diagnosis, treatment, and prognosis of colorectal cancer.
ObjectiveTo investigate the effects of telmisartan on the proliferation, migration and apoptosis of non-small cell lung cancer A549 and the mechanism of regulating Wnt signaling pathway.MethodsNon-small cell lung cancer cell line A549 was cultured in vitro. Cell counting kit-8 (CCK-8) assay was used to detect the effect of telmisartan at different concentrations on the proliferative activity of A549 cells. The survival fraction of A549 treated with different concentrations of telmisartan was determined by colony-formation assay. The effect of telmisartan at different concentrations on the migration ability of A549 cells was examined in the wounding healing assay. Hoechst staining was used to detect the effects of telmisartan at different concentrations on the apoptosis of A549. Western bloting was used to detect the expressions of β-actin, proliferating cell nuclear antigen (PCNA), Bax, Bcl-2, Wnt-3a, Beta-catenin (β-catenin), serine protein kinase 3β (p-GSK-3β), glycogen synthase kinase-3β (GSK-3β) and c-myc.ResultsDifferent concentrations of telmisartan treatment inhibited the proliferation activity, colony-formation rate and migration of A549 cells, and reduced the expression of PCNA in a concentration-dependent manner. Telmisartan treatment promoted the apoptosis of A549 cells, significantly increased the expression of pro-apoptotic protein Bax and decreased the expression of anti-apoptotic protein Bcl-2. The expression levels of Wnt-3a, β-catenin, p-GSK-3β, and c-myc in A549 cells increased after treatment with telmisartan, while the expression levels of GSK-3β decreased.ConclusionTelmisartan may play a role in the proliferation, migration and apoptosis of non-small cell lung cancer A549 cells, and inhibiting the Wnt/β-catenin signaling pathway may be one of the mechanisms.
In this study, we aim to investigat the effect of microgravity on osteoblast differentiation in osteoblast-like cells (MC3T3-E1). In addition, we explored the response mechanism of nuclear factor-kappa B (NF-κB) signaling pathway to " zero-g” in MC3T3-E1 cells under the simulated microgravity conditions. MC3T3-E1 were cultured in conventional (CON) and simulated microgravity (SMG), respectively. Then, the expression of the related osteoblastic genes and the specific molecules in NF-κB signaling pathway were measured. The results showed that the mRNA and protein levels of alkaline phosphatase (ALP), osteocalcin (OCN) and type Ⅰ collagen (CoL-Ⅰ) were dramatically decreased under the simulated microgravity. Meanwhile, the NF-κB inhibitor α (IκB-α) protein level was decreased and the expressions of phosphorylation of IκB-α (p-IκB-α), p65 and phosphorylation of p65 (p-p65) were significantly up-regulated in SMG group. In addition, the IL-6 content in SMG group was increased compared to CON. These results indicated that simulated microgravity could activate the NF-κB pathway to regulate MC3T3-E1 cells differentiation.
The pathogenesis of Vogt-Koyanagi Harada disease (VKH) has not yet been fully defined. Current studies mainly suggest that VKH is actually an autoimmune disease, especially related to the immune response mediated by various signal transduction pathways involved in the function of T cells. In recent years, the influence of the balance imbalance of various T cell subsets in cellular immunity on the pathogenesis of VKH has been a hot research direction. Currently, T helper cell 17/T regulatory cells, balance is the focus of clinical research, meanwhile, new discoveries and potential clinical treatment schemes have been made for related cellular pathways, particularly the Janus kinase/signal transducers and activators of transcription pathway and NF-kappa B pathway. The exploration of B cells in the pathogenesis of VKH has also achieved initial results through the successful application of various targeted drugs. In the future, further screening and localization of genes or proteins that are abnormally regulated or expressed in VKH, for which early comprehensive and in-depth exploration will be helpful, thus improve the efficacy of clinical treatment programs and develop new therapeutic targets.
ObjectiveTo investigate the effect of maresin-1 (MaR1) on lung inflammation and MAPK signaling pathway in asthmatic mice.MethodsTwenty-four female BALB/c mice were randomly divided into normal group, asthma model group, MaR1 group and dexamethasone group. The asthma model was successfully established by using ovalbumin (OVA) combined with aluminum hydroxide, and then MaR1 and dexamethasone were respectively given to asthmatic mice. Serum, bronchoalveolar lavage fluid (BALF) and lung tissue were collected for further analysis. Pathological changes of lung tissue in mice were detected by hematoxylin-eosin and periodic acid-Schiff. Proportion of inflammatory cells in BALF classified by Swiss-Giemsa staining. Th2-related inflammatory cytokines, interleukin (IL)-4, IL-5, IL-13 and IgE in serum and BALF were detected by enzyme linked immunosorbent assay. The protein concentration of p-p38 and p-JNK in lung tissues were detected by Western blot.ResultsCompared with the normal group, the asthma model group had increased both airway inflammation and the number of goblet cells significantly (P<0.05). The number of various inflammatory cells in BALF had also increased significantly (P<0.05). The levels of IL-4, IL-5 and IL-13 in BALF and IgE and OVA-specific-IgE in serum were significantly increased (P<0.05). The protein contents of p-p38 and p-JNK in lung tissues were significantly increased (P<0.05). Compared with the asthma model group, both MaR1 and dexamethasone group had reduced inflammation and mucus secretion in lung tissue, number of inflammatory cells in BALF (P<0.05), levels of related inflammatory cytokines in BALF and IgE in serum (P<0.05), and expression of p-p38 and p-JNK proteins in lung tissue (P<0.05).ConclusionsMaR1 can inhibit the production and release of both Th2-related inflammatory cytokines and IgE, effectively reduce the inflammatory response and mucus production in lung tissues of asthmatic mice, with similar effect to dexamethasone. The mechanism may be related to the down-regulation of MAPKs signaling pathway.