Ramulus Cinnamomi extract attenuates neuroinflammatory responses via downregulating TLR4/MyD88 signaling pathway in BV2 cells

Ramulus Cinnamomi （RC）, a traditional Chinese herb, has been used to attenuate inflammatory responses. The purpose of this study was to investigate the effect of RC extract on lipopolysaccharide （LPS）-induced neuroinflammation in BV2 microglial cells and the underlying mechanisms involved. BV2 cells were incubated with normal medium （control group）, LPS, LPS plus 30 pg/mL RC extract, or LPS plus 100 pg/mL RC extract. The BV2 cell morphology was observed under an optical microscope and cell viability was detected by MTT assay. Nitric oxide level in BV2 cells was detected using Griess regents, and the levels of interleukin-6, interleukin-1 β, and tumor necrosis factor u in BV2 cells were determined by ELISA. The expression levels of cyclooxygenase-2, Toll-like receptor 4 and myeloid differentiation factor 88 proteins were detected by western blot assay. Compared with the LPS group, both 30 and 100 μg/mL RC extract had no significant effect on the viability of BV2 cells. The levels of nitric oxide, interleukin-6, interleukin-1β and tumor necrosis factor ct in BV2 cells were all significantly increased after LPS induction, and the levels were significantly reversed after treatment with 30 and 100 μg/mL RC extract. Furthermore, RC extract significantly inhibited the protein expression levels of cyclooxygenase-2, Toll-like receptor 4 and myeloid differentiation factor 88 in LPS-induced BV2 cells. Our findings suggest that RC extract alleviates neuroinflammation by downregulating the TLR4/MyD88 signaling pathway.

Ragweed pollen induces allergic conjunctivitis immune tolerance in mice via regulation of the NF-κB signal pathway

AIM:To investigate the feasibility and mechanism of immune tolerance in allergic conjunctivitis.METHODS:The allergic conjunctivitis immune tolerance mice model was established by ragweed pollen(RW)and the related cytokines were detected.The mice were divided into 9 groups and the maslinic acid(MA)or PBS were given for different group after modeling.The expression levels of chemokine ligand 5(CCL5)and P-65 in the conjunctival tissue were analyzed by immunohistochemistry,quantitative reverse transcription polymerase chain reaction(q RT-PCR)and Western blot.The percentage of interleukin-17(IL-17)and CD4+CD25+in the splenocyte supernatant was analyzed by flow cytometry.Fur thermore,the serum and splenocyte supernatant concentration of total-IgE,interleukin-10(IL-10),and IL-17 was analyzed by enzyme linked immune response(ELISA).RESULTS:After the model was established,symptoms of conjunctivitis were alleviated,the level of P-65,CCL5,IL-17,and total-IgE was raised,while the expression of IL-10,CD4+CD25+was decreased.This result fully demonstrated that a typical IL-17/regulatory-T-cells(Treg cells)imbalance and NF-κB activation.When the NF-κB signal pathway was suppressed,it showed that there was a further relief of conjunctivitis in mice.At the same time,the expression of total-IgE,IL-17,and CCL5 was decreased and the expression of anti-inflammatory factor(IL-10,CD4+CD25+)was increased.CONCLUSION:In the state of immune tolerance,symptoms of conjunctivitis in mice are alleviated,the Th-17 cells of allergic conjunctivitis mice are inhibited,and Treg cells activity is enhanced.

Notch1 downregulation combined with interleukin-24 inhibits invasion and migration of hepatocellular carcinoma cells

AIM: To confirm the anti-invasion and anti-migration effects of down-regulation of Notch1 combined with interleukin(IL)-24 in hepatocellular carcinoma(HCC) cells.METHODS: γ-secretase inhibitors(GSIs) were used to down-regulate Notch1.Hep G2 and SMMC7721 cells were seeded in 96-well plates and treated with GSI-I or/and IL-24 for 48 h.Cell viability was measured by MTT assay.The cellular and nuclear morphology was observed under a fluorescence microscope.To further verify the apoptotic phenotype,cell cultures were also analyzed by flow cytometry with Annexin V-FITC/propidium iodide staining.The expression of Notch1,SNAIL1,SNAIL2,E-cadherin,IL-24,XIAP and VEGF was detected by Western blot.The invasion and migration capacities of HCC cells were detected by wound healing assays.Notch1 and Snail were downregulated by RNA interference,and the target proteins were analyzed by Western blot.To investigate the mechanism of apoptosis,we analyzed Hep G2 cells treated with si Notch1 or si CON plus IL-24 or not for 48h by caspase-3/7 activity luminescent assay.RESULTS: GSI-I at a dose of 2.5 μmol/L for 24 h caused a reduction in cell viability of about 38% in Hep G2 cells.The addition of 50 ng/m L IL-24 in combination with 1 or 2.5 μmol/L GSI-I reduced cell viability of about 30% and 15%,respectively.Treatment with IL-24 alone did not induce any cytotoxic effect.In SMMC7721 cells with the addition of IL-24 to GSI-I(2.5 μmol/L),the reduction of cell viability was only about 25%.Following GSI-I/IL-24 combined treatment for 6 h,the apoptotic rate of Hep G2 cells was 47.2%,while no significant effect was observed in cells treated with the compounds employed separately.Decreased expression of Notch1 and its associated proteins SNAIL1 and SNAIL2 was detected in Hep G2 cells.Increased E-cadherin protein expression was noted in the presence of IL-24 and GSI-I.Furthermore,the increased GSI-I and IL-24 in Hep G2 cell was associated with downregulation of MMP-2,XIAP and VEGF.In the absence of treatment,Hep G2 cells could migrate into the scratched space in 24 h.With IL-24 or GSI-I treatment,the wound was still open after 24 h.And the distance of the wound closure strongly correlated with the concentrations of IL-24 and GSI-I.Treatment of Notch-1 silenced Hep G2 cells with 50 ng/m L IL-24 alone for 48 h induced cytotoxic effects very similar to those observed in non-silenced cells treated with GSI-I/IL-24 combination.Caspase-3/7 activity was increased in the presence of si Notch1 plus IL-24 treatment.CONCLUSION: Down-regulation of Notch1 by GSI-I or si RNA combined with IL-24 can sensitize apoptosis and decrease the invasion and migration capabilities of Hep G2 cells.

Epigenetic regulation of Wnt signaling pathway gene SRY-related HMG-box 17 in papillary thyroid carcinoma

Background SRY-related HMG-box 17 （SOX17） encodes a member of the SOX （SRY-related HMG-box） family of transcription factors involved in the regulation of embryonic development and in the determination of the cell fate. Recently, it was considered as a tumor suppressor gene to inhibit canonical Wnt/β-catenin signaling pathway in several malignancies. However, the function of SOX17 in thyroid cancer was unknown. Therefore, we investigated the epigenetic changes and the function of SOX17 in thyroid cancer. Methods The methylation status of the promoter region of SOX17 was detected using methylation-specific PCR in 63 papillary thyroid carcinoma （PTC） tissue, 10 normal thyroid tissue, and two thyroid cancer cell lines. Semi-quantitative RT-PCR was used to assess mRNA expression of SOX17 before and after 5-aza-2＇-deoxycytidine treatment in thyroid cancer cell lines. Expression of SOX17 and β-catenin were detected by immunohistochemistry in PTC and adjacent tissue. Luciferase reporter assay, colony formation, transfection, and Western blotting were employed to analyze the effect of SOX17 on thyroid cancer cell proliferation and the function of SOX17 in the Wnt signal pathway. Results Loss of SOX17 expression was correlated to the promoter region hypermethylation in thyroid cancer cell lines. Re-expression of SOX17 was found in TPC-1 cell line after 5-aza-2＇-deoxycytidine treatment. In primary thyroid cancer, 60.3% （38/63） were methylated and 39.7% （25/63） unmethylated. But no methylation was found in noncancerous thyroid tissues. Methylation of SOX17 was associated reversely with β-catenin expression in the cytoplasm or nucleus significantly in the PTC （P 〈0.05）. Colony formation was inhibited by re-expression of SOX17 in TPC-1 cells. SOX17 suppressed the Wnt signaling pathway and the HMG domain was essential for this effect. Conclusions SOX17 was frequently methylated in human PTC. Loss of SOX17 expression was induced by promoter region hypermethylation. SOX17 inhibited thyroid cancer proliferation. Methylation of SOX17 activated the Wnt signaling pathway in human thyroid cancer.

Daifan San intervenes in forkhead box P3 and the interleukin(IL)-23/IL-17A signaling pathway to help prevent and treat primary biliary cirrhosis

OBJECTIVE:To investigate the mechanism by which Daifan San(DFS)prevents and treats primary biliary cirrhosis(PBC)via the forkhead box P3(FoxP3)and interleukin(IL)-23/IL-17A signaling pathways.METHODS:Ninety C57BL/6 mice were randomly divided into the control,model,DFS low-dose,DFS middle-dose,DFS high-dose and ursodeoxycholic acid(UDCA)groups(n=15 per group).A mouse model of PBC was induced using polyinosinic polycytidylic acids(poly I:C).Lymphocyte subset expression in the peripheral blood was analyzed via flow cytometry.The inflammatory cytokines and antimitochondrial autoantibody(AMA)levels were detected via enzyme-linked immunosorbent assays.The expressions and location of typeⅠcollagen,typeⅢcollagen,cytokeratin 19 and FoxP3 in the liver tissue were evaluated via immunohistochemistry.FoxP3,IL-23 and IL-17 expressions in the peripheral blood and liver tissue were evaluated via real-time polymerase chain reaction and western blotting.RESULTS:IL-17,IL-23,IL-8,IL-33,TNF-α,and AMA expressions were significantly increased in the model group and decreased in the DFS and UDCA groups.Conversely,Treg cell and FoxP3 expressions were significantly decreased in the model group and increased in the DFS and UDCA groups.The IL-23/IL-17A signaling pathway was closely correlated with chronic inflammation of the bile duct in PBC and functional deletion of Treg cells,leading to reduced FoxP3 levels and mediating the loss of tolerance in PBC.CONCLUSION:DFS may delay the occurrence and relieve the symptoms of PBC by downregulating IL-23/IL-17A signaling pathway expression and upregulating FoxP3 expression.

Neuronal changes in the retinal ganglion cell layer following recombinant human interleukin-2 intravitreal injection in a rat model of chronically elevated intraocular pressure

Intraperitoneal injection of recombinant human interleukin-2（rhIL-2）inhibits neuronal apoptosis in the chronic ocular hypertension retinal ganglion cell layer.Intravitreous injection was performed on retinal ganglion cells in a Wistar rat model of chronically elevated intraocular pressure to observe the effects of LY294002 and AG490 on retinal ganglion cell survival,macrophage activation,and PI3K/Akt and JAK/STAT activation.The number of retinal ganglion cells in the rhIL-2 treatment group was much greater than in the normal control and phosphate-buffered saline groups.Western blot analysis revealed low Akt and STAT3 protein expression in the retina after 3-hour intravitreous injections of rhIL-2.However,protein expression was increased at 12 hours,but decreased again at 24 hours,with very low expression at 96 hours.LY294002 and AG490,which are inhibitors of the PI3K/Akt and JAK/STAT3 signal pathways,prevented upregulation of Akt and STAT3 protein expression in the retina,respectively.Intravitreous injection of rhIL-2 exhibited neuroprotective effects by decreasing retinal ganglion cell layer damage in a rat model of chronic glaucoma.These results suggest that intravitreal injection of rhIL-2 could induce the PI3K/Akt and JAK/STAT3 signaling pathways to protect retinal ganglion cells in chronically elevated intraocular pressure models.

Mechanisms of Up-regulation of 17β-Estrodiol on β-Defensin-2 ( SBD-2) Expression in Epithelial Cells of Ovine Oviduct

[ Objective] To investigate the mechanisms involved in the Up-regulatory effects of 17β-estrodiol on β-defensin-2 （SBD-2） in epithelial cells of ovine oviduct. [ Methods] Epithelial cells of ovine oviduct were isolated and cultured; and then the cultured cells at secondary generation were divided into 17β-estradiol （E2, 10^-8 tool/L） group, estrogen nuclear receptor antagonist ICI182780 （10^-7 tool/L） group, PKA antagonist KT-5720 （1 μmol/L） group, PKC antagonist H- 7（50 μmol/L） group, nuclear factor kappa B antagonist PDTC（50μmol/L） group and the blank control group （ Control ）. Firstly, different antagonists were added into corresponding antagonist groups in order to interfere the epithelial ceils of ovine oviduct for 1 h. Then, 17β-estradiol （ 10^-8 mol/L） was added into each antagonist group and E2 group for cultivation for 6 h. Finally, real-time fluorescent quantitative RT-PCR was used to detect the changes of SBD-2 mRNA expression. [ Results] 10^-8 mol/L 17β-estrodiol had significantly Up-regulatory effects on the expression of SBD-2 mRNA （P 〈 0. 05 ）. Estrogen nuclear receptor antagonist ICI182780, NF-κB antagonist PDTC and PKC antagonist H-7 could all block the Up-regnlatory effects on SBD-2. But PKA antagonist KT-5720 showed no significant effects on the Up-regulation of SBD-2 mRNA expression induced by 17β-estrodiol. [ Conclusions] SBD-2 mRNA expression induced by 17β-estrodiol in epithelial cells of ovine oviduct was mediated by estrogen nuclear receptor ICI182780, NF-κB and PKC pathways. However, PKA pathway might not participate in the Up-regulation of SBD-2 mRNA expression.

Mechanism of Liancao-Xieli capsule in the treatment of ulcerative colitis through the differentiation of Th17 and Treg cells

Objective:To observe the effect of Liancao-Xieli Capsule on STAT signal pathway and T cell differentiation in mouse model of ulcerative colitis;Methods:Forty BALB/c mice were randomly divided into the control group,model group,mesalazine group and Liancao-Xieli capsule group.Except the control group,the other three groups were treated with 3%dextran sodium sulfate free drinking water to construct the model of ulcerative colitis.During the modeling period,each group was given corresponding drugs for intervention,while the control group and the model group were given the same volume of distilled water by gavage as the control.After treatment,HE staining was used to observe the pathological changes of colon tissue,flow cytometry was used to detect the proportion of Th17 and Treg cells in spleen and mesenteric lymph nodes,and ELISA was used to detect TGF-β,IL-6 and IL-17A in colon tissue.Western blot was used to detect the expression levels of related proteins in STAT3/ROR-γt and STAT5/Foxp3 signaling pathways.Results:Compared with the model group,the body weight,colon length and the content of TGF-βin the colon tissue of the mice in the Liancao-Xieli capsule group increased significantly after the experiment,while the DAI score,colon histopathology score,and the contents of IL-6 and IL-17A in the colon tissue were significantly reduced,and the difference was statistically significant(P<0.01).At the same time,Liancao-Xieli capsule can reduce the ratio of Th17 cells and the ratio of Th17/Treg in the spleen and mesenteric lymph node tissues of UC mice,and increase the ratio of Treg cells,and the difference is statistically significant when compared with the model group(P<0.01).In addition,compared with the model group,the expression levels of p-STAT3 and RORγt protein in the colon tissue of the Liancao-Xieli capsule group were significantly reduced,and the expression levels of p-STAT5 and Foxp3 protein were significantly increased after treatment,and the differences are statistically significant(P<0.01),while the expression levels of STAT3 and STAT5 proteins in colon tissue did not change significantly,and the difference was not statistically significant(P>0.05);Conclusion:Liancao-Xieli Capsule can regulate the immune balance of Treg/Th17 and improve the intestinal inflammation of UC.Its mechanism of action is mainly through inhibiting STAT3/ROR-γt and promoting the activation of STAT5/Foxp3 signaling pathway.

IL-17 signaling in host defense and inflammatory diseases

Interleukin(IL)-17,the signature cytokine secreted by T helper(Th)17 cells,plays important roles in host defense against extracellular bacterial infection and fungal infection and contributes to the pathogenesis of various autoimmune inflammatory diseases.Here we review the recent advances in IL-17-mediated functions with emphasis on the studies of IL-17-mediated signal transduction,providing perspective on potential drug targets for the treatment of autoimmune inflammatory diseases.

Effect of interleukin-6 / signal transducer and activator of transcription 3 pathway on cyclooxygenase- 2 expression in THP- 1 monocyte

Objective To investigate the relationship between the interleukin-6(IL-6)/signal transducer and activator of transcription 3(STAT3)signaling pathway and cyclooxygenase-2(COX-2)expression in THP-1 monocytes.Methods Human THP-1 monocyte was used as the research cell,and the time-dependent expressions of STAT3 phosphorylation and COX-2 were detected

Effect of cigarette smoke extract on lipopolysaccharide-activated mitogen-activated protein kinase signal transduction pathway in cultured cells

Background Lipopolysaccharide （LPS） forms outer membrane of the wall of Gram-negative cells. LPS can directly cause damage to epithelia of respiratory tract and is the major factor responsible for the chronic inflammation of respiratory passage. The mitogen-activated protein kinase （MAPK） signal transduction pathway of the airway epithelia is intimately associated with the action of LPS. The chronic inflammation of respiratory tract and smoking are interrelated and entwined in the development and progression of chronic lung diseases. This study was designed to examine the effects of cigarette smoke extract （CSE） and LPS on MAPK signal transduction pathway in order to further understand the roles CSE and LPS play in chronic lung inflammation. Methods Cultured primary human epithelial cells of airway were divided into four groups according to the stimulants used： blank control group, LPS-stimulation group, CSE-stimulation group and CSE plus LPS group. Western blotting was employed for the detection of phosphorylation level of extracellular-signal-regulated-kinase （ERK1/2）, p38 MAPK and c-Jun N-terminal kinase （JNK）. The expression of cytokines of MAPK transduction pathway （granulocyte-macrophage colony stimulating factor （GM-CSF） and mRNA of IL-8） in the primary epithelial cells of respiratory tract was also determined. Results Western blotting revealed that the phosphorylation levels of ERK1/2, p38 MAPK and JNK were low and 2 hours after the LPS stimulation, the phosphorylation of ERK1/2, p38 MAPK and JNK were all increased. There was a significant difference in the phosphorylation between the LPS-stimulation group and blank control group （P〈0.05）; no significant difference was found between CSE-stimulation group and blank control group （P〉0.05）; there was a significant difference between CSE ＋ LPS group and blank control group and between CSE ＋ LPS group and LPS group （P〈0.05）. The phosphorylation of CSE-LPS group was higher than that of blank control group but lower than that of LPS group. In blank control group, the expression of IL-8 and GM-CSF mRNA was low in the epithelial cells of airway and the release of IL-8 and GM-CSF was also at a low level. One hour after LPS stimulation, the level of IL-8 mRNA increased （P〈0.05） and reached a peak after 2 hours. On the other hand, GM-CSF mRNA level increased 2 hours after the stimulation （P〈0.05） and reached the highest level 4 hours after the stimulation. Two hours after LPS stimulation, IL-8 and GM-CSF protein level began to rise （P〈0.05）, and the level was the highest 8 hours after the stimulation （P〈0.01）. Stimulation with CSE alone had no effect on the release of IL-8 and GM-CSF and expression of IL-8 mRNA （P〉0.05）, but pre-treatment with CSE could delay the LPS-induced release of IL-8 and GM-CSF and the expression of IL-8 mRNA and its peak was lower. Conclusions LPS stimulation can significantly increase the phosphorylation of ERK1/2, p38 MAPK and JNK in the epithelial cells of airway and activate the MAPK transduction pathway, thereby can activate the downstream signal transduction pathway, and can ultimately result in the release of cytokines by the epithelial cells of airway. CSE can partially abolish the LPS-induced activation of MAPK signal transduction pathway and the expression of cytokines of the pathway, which might contribute to the development and progression of the inflammatory reactions in COPD patients.

Interaction of IL-22/IL-22R1 promotes cell proliferation and suppresses apoptosis of colorectal cancer via phosphorylation of STAT3

Interleukin-22(IL-22)is a member of IL-10 cytokine family which is expressed in activated T cells predominantly and in activated natural killer cells at lower levels.Previous studies have demonstrated the link between elevated levels of IL-22 and disease severity of psoriasis,Crohn’s disease,rheumatoid arthritis and interstitial lung diseases.However,the function of IL-22 in the development and progression of colorectal cancer(CRC)remains elusive.In this study,we first evaluated the IL-22/IL-22R1 level in CRC patients,and found that tumor tissues have more active expression of IL-22 and IL-22R1 than normal tissues,presenting correlation with the degree of differentiation of tumor tissues.Subsequently,caspase and cell viability assays were performed on SW-480 cell line,which expresses high level of IL-22R1,to examine if the supplementation of IL-22 has an impact on apoptosis and proliferation.In comparison with treatment of 5-FU,supplementation of IL-22 promoted cell proliferation and ameliorated apoptosis.To unveil signal transduction upon activation of IL-22R,we examined the phosphorylation of STAT3 in SW-480 cell line following supplementation of IL-22.The treatment of IL-22 also increased the level of p-Akt,an essential component in PI3K/Akt pathway.Although the link between STAT3 phosphorylation and PI3K/Akt activation remains to be explored,our study revealed the mechanism underlying the effects of IL-22R activation on apoptosis as well as tumor differentiation,indicating the prognostic value of IL-22/IL-22R.

白细胞介素-17通过信号转导与转录激活因子3调节类风湿关节炎成纤维样滑膜细胞的增殖

目的 研究IL-17对RA患者成纤维样滑膜细胞（FLSs）生长增殖的作用,并探究其作用是否有信号转导与转录激活因子3（STAT3）的参与.方法 原代培养RA患者FLSs,培养细胞分为3组：正常培养FLSs（对照组）,IL-17处理组,STAT3靶向沉默后IL-17处理组.蛋白质印迹法检测STAT3及p-STAT3在各组FLSs中的表达;蛋白质印迹法检测Bcl-2及Bax的表达;四甲基偶氮唑盐（MTT）检测FLSs增殖.采用方差分析和LSD-t检验进行统计学分析.结果 IL-17促进FLSs的生长及增殖,抑制其凋亡.IL-17上调抗凋亡因子Bcl-2的表达（t=2.723,P＜0.05）并下调促凋亡因子Bax的表达（t=2.612,P＜0.05）.靶向沉默STAT3的表达可抑制IL-17对FLSs的作用（t=2.745,P＜0.05）[对照组：Bax（3.814±1.623）,Bcl-2（1.429±0.311）;IL-17处理组：Bax （0.972±0.017）,Bcl-2（3.175±1.356）;STAT3沉默后IL-17处理组：Bax（5.729±1.236）,Bcl-2 （0.637±0.006）].结论 STAT3对IL-17促进RA患者FLSs的生长及增殖有着重要的作用,IL-17/STAT3信号通路有可能成为新的RA治疗策略.

Microenvironment-responsive metal-phenolic network release platform with ROS scavenging,anti-pyroptosis,and ECM regeneration for intervertebral disc degeneration

Intervertebral disc degeneration(IVDD)can be caused by aging,injury,and genetic factors.The pathological changes associated with IVDD include the excessive accumulation of reactive oxygen species(ROS),cellular pyroptosis,and extracellular matrix(ECM)degradation.There are currently no approved specific molecular therapies for IVDD.In this study,we developed a multifunctional and microenvironment-responsive metal-phenolic network release platform,termed TMP@Alg-PBA/PVA,which could treat(IL-1β)-induced IVDD.The metal-phenolic network(TA-Mn-PVP,TMP)released from this platform targeted mitochondria to efficiently scavenge ROS and reduce ECM degradation.Pyroptosis was suppressed through the inhibition of the IL-17/ERK signaling pathway.These findings demonstrate the versatility of the platform.And in a rat model of IVDD,TMP@Alg-PBA/PVA exhibited excellent therapeutic effects by reducing the progression of the disease.TMP@Alg-PBA/PVA,therefore,presents clinical potential for the treatment of IVDD.

Transcriptome sequencing and metabolome analysis reveal the mechanism of Shuanghua Baihe Tablet in the treatment of oral mucositis

Oral mucositis(OM) caused by cancer therapy is the most common adverse reaction in the radiotherapy of head and neck tumors. In severe cases, it can lead to the interruption of treatment, which affects the control of the disease and the quality of life.Shuanghua Baihe Tablet(SBT) is a traditional Chinese medicine(TCM) formula, which is administerd to treat OM in China. It has been clinically effective for more than 30 years, but the underlying mechanism is not completely understood. With the development of multiple omics, it is possible to explore the mechanism of Chinese herbal compound prescriptions. Based on transcriptomics and metabolomics, we explored the underlying mechanism of SBT in the treatment of OM. An OM model of rats was established by 5-FU induction, and SBT was orally administered at dosages of 0.75 and 3 g·kg;·d;. In order to search for SBT targets and related metabolites, the dysregulated genes and metabolites were detected by transcriptomics and metabolomics. Immune related indicators such as interleukin-17(IL-17) and tumor necrosis factor-α(TNF-α) were detected by ELISA. Treg cell disorders was analyzed by flow cytometry. Our results showed that SBT significantly alleviated the symptoms of OM rats and the inflammatory infiltration of ulcer tissues.After SBT administration, inflammatory related metabolic pathways including linoleic acid metabolism, valine, leucine and isoleucine biosynthesis were significantly altered. Furthermore, the production of proinflammatory factors like IL-17 and TNF-α, were also dramatically reduced after SBT administration. Besides, the infiltration degree of Treg cells in the spleen of OM modeling rats was significantly improved by SBT administration, thus maintaining the immune balance of the body. The current study demonstrates that SBT regulates inoleic acid metabolism, glycerophospholipid metabolism and amino acid metabolism, and inhibits IL-17/TNF signal transduction to restore Treg and Th17 cell homeostasis in OM rats, thereby alleviating chemotherapy-induced OM.

A novel PI3K inhibitor XH30 suppresses orthotopic glioblastoma and brain metastasis in mice models

Glioblastoma is carcinogenesis of glial cells in central nervous system and has the highest incidence among primary brain tumors.Brain metastasis,such as breast cancer and lung cancer,also leads to high mortality.The available medicines are limited due to blood-brain barrier.Abnormal activation of phosphatidylinositol 3-kinases(PI3 K)signaling pathway is prevalent in glioblastoma and metastatic tumors.Here,we characterized a 2-amino-4-methylquinazoline derivative XH30 as a potent PI3 K inhibitor with excellent anti-tumor activity against human glioblastoma.XH30 significantly repressed the proliferation of various brain cancer cells and decreased the phosphorylation of key proteins of PI3 K signaling pathway,induced cell cycle arrest in G1 phase as well.Additionally,XH30 inhibited the migration of glioma cells and blocked the activation of PI3 K pathway by interleukin-17 A(IL-17 A),which increased the migration of U87 MG.Oral administration of XH30 significantly suppressed the tumor growth in both subcutaneous and orthotopic tumor models.XH30 also repressed tumor growth in brain metastasis models of lung cancers.Moreover,XH30 reduced IL-17 A and its receptor IL-17 RA in vivo.These results indicate that XH30 might be a potential therapeutic drug candidate for glioblastoma migration and brain metastasis.