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1.
Article in Chinese | WPRIM | ID: wpr-923115

ABSTRACT

@#[Abstract] Objective: To investigate the effects of fibronectin Ⅲ domain containing protein 10 (FNDC10) on the proliferation, migration and invasion of breast cancer cells, and to primarily explore the mechanism. Methods: TCGA database was used to analyze the expression of FNDC10 in breast cancer tissues. The mRNA level of FNDC10 in normal immortalized breast cells (MCF-10A) and breast cancer cells (MCF-7, MDA-MB-231, BT549, MDA-MB-468, HCC1806, HCC1937) was detected by qPCR. MCF-7 and MDA-MB-231 cells were transfected with FNDC10 siRNA or NC-siRNA for functional experiments. CCK-8 assay was used to detect the effect of FNDC10 on the proliferation of breast cancer cells. Colony forming assay was used to detect the colony forming ability of breast cancer cells. Transwell assay was used to detect the effect of FNDC10 on migration and invasion of breast cancer cells. WB was used to detect the changes of metastasis-related molecules and cell signaling pathways at protein level. Results:The expression of FNDC10 in breast cancer tissues was significantly higher than that in normal tissues (P<0.01), and the expression level of FNDC10 in breast cancer MCF-7 and MDA-MB-231 cells was higher than that in normal breast cells (P<0.01 or P<0.05). Knocking down FNDC10 expression inhibited the proliferation, migration and invasion of breast cancer cells (P<0.01 or P<0.05). The mechanism study showed that knockdown of FNDC10 expression inhibited STAT3 activation in breast cancer cells (P<0.01 or P<0.05) and enhanced the expression of EMT maker E-cadherin (P<0.05), leading to the suppression of EMT progression. Conclusion: FNDC10 promotes proliferation and EMT of breast cancer cells through activating STAT3 signaling pathway, thereby promoting the malignant progression of breast cancer.

2.
China Occupational Medicine ; (6): 260-265, 2021.
Article in Chinese | WPRIM | ID: wpr-923160

ABSTRACT

OBJECTIVE: To explore the effect of cadmium on bone formation and its mechanism in male mice. METHODS: i) The specific pathogen-free C57 BL/6 J wild-type male mice were divided into control group and cadmium exposure group, with 10 mice in each group. Mice in the cadmium exposure group were intraperitoneally injected with 2 mg/kg body weight cadmium chloride twice a week for eight weeks, and mice in the control group were intraperitoneally injected with the same amount of 0.9% sodium chloride solution. After that, the bone mineral density and bone microstructure of the femur of mice were detected by a high-resolution microcomputed tomography scanner. ii) Human SV40-transfected osteoblast cells(hFOB1.19) were divided into control group and cadmium exposure group. The cadmium exposure group was treated with 0.5 μmol/L cadmium chloride solution, cells in the control group were given an equal volume of α-low-limit minimal medium. After culture, the differentiation and mineralization ability of hFOB1.19 cells were analyzed by alkaline phosphatase(ALP) and alizarin red staining, respectively. Cell viability was examined by CCK-8 assay. The protein expression of Janus kinase 2(JAK2), total signal of transducers and activator of transcription 3(tSTAT3) and phosphorylated signal transducers and activator of transcription 3(pSTAT3) was detected by Western blotting. The expression of osteoblastic marker genes ALP, Runt-related transcription factor 2(RUNX2) and osteocalcin(OCN) was detected by real-time quantitative polymerase chain reaction.RESULTS: Compared with the control group, the average bone mineral density decreased(P<0.01), bone volume fraction decreased(P<0.05), the bone trabecula thickness became thinner(P<0.01), the number of bone trabecula decreased(P<0.05), trabecular bone spacing increased(P<0.05) in the femur of mice in cadmium exposure group. The viability of hFOB1.19 cells was decreased [(100.0±10.8)% vs(49.1±8.2)%, P<0.01]. The differentiation ability of osteoblasts was reduced and the mineralization was inhibited. The relative expression levels of JAK2 and pSTAT3 in cells decreased(all P<0.05) and the relative expression levels of osteoblast marker genes ALP, RUNX2 and OCN decreased(all P<0.01).CONCLUSION: Cadmium can induce mice bone loss, which may be due to its inhibition of osteoblastic function by reducing the expression of JAK2 and STAT3 proteins.

3.
Journal of Chinese Physician ; (12): 1176-1180, 2021.
Article in Chinese | WPRIM | ID: wpr-909683

ABSTRACT

Objective:To investigate the role and mechanism of interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3) signaling pathway in proliferation, invasion and apoptosis of cervical cancer cells infected by high-risk human papillomavirus (HPV).Methods:HPV-18 positive HeLa cells cultured in vitro were divided into control group (normal cultured), IL-6 group (stimulated with 50 ng/ml IL-6 for 24 h) and IL-6 + AG490 group (stimulated with 50 ng/ml IL-6 and 100 μmol/L STAT3 signaling pathway inhibitor AG490 for 24 h). Methyl thiazolyl tetrazolium (MTT) assay was used to detect the cell survival rate. The ability of cell clone formation was detected by plate clone formation assay. The cell invasion was detected by transwell chamber assay. The cell apoptosis was detected by flow cytometry. Western blot was used to detect the protein expression levels of STAT3, phosphorylation of (p)-STAT3, B-cell lymphoma-2 gene (Bcl-2), CyclinD1 and matrix metalloproteinase-9 (MMP-9). Results:Compared with those in the control group, the cell survival rate, clone formation rate, number of invasive cells and the protein expression levels of p-STAT3, Bcl-2, CyclinD1 and MMP-9 in IL-6 group were significantly higher, while the apoptosis rate was significantly lower ( P<0.05); at the same time, compared with those in IL-6 group, the cell survival rate, clone formation rate, the number of invasive cells and the protein expression levels of p-STAT3, Bcl-2, CyclinD1 and MMP-9 in IL-6 + AG490 group were significantly lower, while the apoptosis rate was significantly higher ( P<0.05). Conclusions:IL-6/STAT3 signaling pathway plays an important role in the malignant progression of high-risk HPV infected cervical cancer cells, and its mechanism may be related to the up-regulation of CyclinD1, MMP-9, Bcl-2 protein expressions.

4.
Article in Chinese | WPRIM | ID: wpr-909595

ABSTRACT

OBJECTIVE Right ventricular (RV) remodeling is one of the essential pathological features in pulmonary arterial hypertension (PAH). RV hypertrophy or fibrosis are the leading causes of RV remodeling. Magnolol is a com?pound isolated from Magnolia officinalis. It possesses multiple pharmacological activities, such as anti-oxidation and anti-inflammation. This study aims to evaluate the effects and underlying mechanisms of magnolol on RV remodeling in hypoxia-induced PAH. METHODS ① Male SD rats (220 g) were randomly divided into 5 groups (n=10): the normoxia group, the hypoxia group, the hypoxia plus Magnolol (10 and 20 mg·kg-1·d-1) group, and the vehicle group. Rats in the normoxia group were kept in a normoxia environment for 4 weeks, while rats in the hypoxia group were kept in a hypoxic chamber (10% O2). The rats in the hypoxia plus magnolol groups were administered with magnolol at 10 or 20 mg·kg-1 (ip) once a day for 4 weeks. At the end of 4 weeks, the heart function was assessed by Doppler echocardiography, and then the rats were anesthetized with sodium pentobarbital (30 mg·kg-1, ip). The RVSP was measured by the right heart catheterization method. The heart tissues were collected and dissected to calculate the index of RV remodeling (RV/LV+IVS, RV/tibial length, or RV/body weight). Part of the RV samples was fixed with 4%paraformaldehyde for morphological analysis, while other samples were frozen at-80℃for molecular studies (measurements of ANP, BNP,α-SMA, and col?lagen Ⅰ/Ⅲ mRNA expression as well as p-JAK2/JAK2 and p-STAT3/STAT3 protein levels). ② To evaluate the effect of magnolol on hypoxia-induced myocardial hypertrophy and fibrosis, H9c2 or cardiac fibroblasts were divided into 7 groups: the control group, cells were cultured under normal conditions; the hypoxia group, cells were cultured under hypoxic condition (3% O2);the hypoxia plus magnolol 10 mg·kg-1 group, magnolol10μmol·L-1 was added to the culture medium before the hypoxia treatment;the hypoxia plus magnolol 30 mg·kg-1 group, magnolol 20μmol·L-1 was added to the culture medium before the hypoxia treatment;the hypoxia plus TG-101348 group, TG-101348 (a specific inhibitor of JAK2) 1μmol·L-1 was added to the culture medium before the hypoxia treatment;the hypoxia plus JSI-124 group, JSI-124 (a specific inhibitor of JAK2) 1μmol·L-1 was added to the culture medium before the hypoxia treatment;and the hypoxia plus vehicle group, an equal volume of vehicle (DMSO) was added to the culture medium before the hypoxia treatment. At the end of the experiments, the cells were collected for morphological and molecular analysis. RESULTS In vivo, male Sprang-Daley rats were exposed to 10% O2 for 4 weeks to establish an RV remodeling model, which showed hypertrophic and fibrotic features (increases of RV remodeling index, cellular size, hypertrophic and fibrotic marker expression), accompanied by an elevation in phosphorylation levels of JAK2 and STAT3;these changes were attenuated by treating rats with magnolol. In vitro, the cultured H9c2 cells or cardiac fibroblasts were exposed to 3% O2 for 48 h to induce hypertrophy or fibrosis, which showed hypertrophic (increases in cellular size as well as the expression of ANP and BNP) or fibrotic features (increases in the expression of collagenⅠ, collagenⅢandα-SMA). Administration of mag?nolol and TG-101348 or JSI-124 (JAK2 selective inhibitors) could prevent the process of myocardial hypertrophy and fibrosis, accompanied by the decrease in the phosphorylation level of JAK2 and STAT3. CONCLUSION Magnolol can attenuate RV hypertrophy and fibrosis in hypoxia-induced PAH rats through a mechanism involving inhibition of the JAK2/STAT3 signaling pathway.

5.
International Journal of Surgery ; (12): 489-493, 2021.
Article in Chinese | WPRIM | ID: wpr-907468

ABSTRACT

IL-17 is one of more than 30 kinds of interleukin, which plays an important role in many biological processes. Under normal circumstances, IL-17 can cause inflammation. However, under pathological conditions, IL-17 can also promote a variety of tumors. Hepatocellular carcinoma (HCC) is the most common type of liver cancer.It has rapid development, poor prognosis, easy metastasis, and obvious inflammatory reaction in tumor microenvironment. These biological characteristics suggest that the occurrence and development of HCC are related to the expression of IL-17. IL-17 can affect the growth, development and autophagy of hepatocellular carcinoma through a variety of ways. For example, promot the growth of hepatocellular carcinoma through the AKT/IL-6/JAK2/STAT3 signaling pathway and the miR-383/STAT3 axis, increase the expression of MMPs by activating the NF-κB signaling pathway to promote hepatocellular carcinoma metastasis, enhance the expression of PIAS1 through the NF-κB pathway to inhibit the anti-tumor effect of IFN-γ, and by inhibiting the degradation of Bcl2 in Bcl2-Beclin1 to inhibit autophagy of hepatocellular carcinoma cells. This article reviews the research status of IL-17 in the pathogenesis of hepatocellular carcinoma.

6.
Article in Chinese | WPRIM | ID: wpr-906449

ABSTRACT

Objective:To investigate the therapeutic mechanism of Wuhutang on respiratory syncytial virus (RSV)-induced asthma in mice and its influence on the expression of signal transducer and activator of transcription 3 (STAT3) in lung tissue. Method:One hundred female BALB/c mice of SPF grade were randomly divided into a normal group and an experimental group. After successful modeling via aerosol inhalation of RSV and ovalbumin (OAV), the mice in the experimental group were further randomized into the following seven groups: model, positive control (dexamethasone, 1.82 mg·kg<sup>-1</sup>), STAT3 inhibitor (STATTIC, 3.75 mg·kg<sup>-1</sup>), STAT3 inducer (colivelin, 1.0 mg·kg<sup>-1</sup>), and low-, medium-, and high-dose (1.6, 3.2, and 6.4 g·kg<sup>-1</sup>, respectively) Wuhutang groups. The corresponding drugs were administered for two weeks, followed by the detection of airway reactivity using a small animal ventilator, the pathological changes in lung tissue, mucus secretion by goblet cells and collagen deposition in airway were observed by hematoxylin-eosin (HE), periodic acid-Schiff (PAS) and Masson staining, the serum levels of interleukin-6 (IL-6), IL-10, and IL-17 were detected by enzyme-linked immunosorbent assay (ELISA). The mRNA expression levels of TGF-<italic>β</italic><sub>1</sub> and <italic>α</italic>-SMA in lung tissue were detected by fluorescence-based real-time polymerase chain reaction (Real-time PCR), autophagosomes present in lung tissue were examined by transmission electron microscopy, the protein expression levels of ATG5 and SQSTM1 in dendritic cells (DCs) and STAT3 and p-STAT3 in lung tissue were detected by Western blot. Result:The airway reactivity of the model group was enhanced in contrast to that in the model group (<italic>P<</italic>0.01), manifested as inflammatory cell infiltration around the lung tissue, excessive metaplasia of goblet cells, and extensive deposition of airway collagen, the expression levels of serum IL-6 and IL-17 were increased (<italic>P<</italic>0.01), while that of IL-10 declined (<italic>P<</italic>0.01), the mRNA expression levels of TGF-<italic>β</italic><sub>1</sub> and <italic>α</italic>-SMA were elevated (<italic>P</italic><0.01), the number of autophagosomes in the lung tissue increased. The protein expression levels of ATG5, STAT3, and p-STAT were up-regulated, while that of SQSTM1 was down-regulated (<italic>P<</italic>0.01). Compared with the model group, Wuhutang and STATTIC significantly reduced the airway hyperresponsiveness of asthmatic mice (<italic>P<</italic>0.05, <italic>P<</italic>0.01), alleviated RSV-induced pathological changes in lung tissue, reduced the contents of serum IL-6 and IL-17 (<italic>P<</italic>0.01), increased serum IL-10 and ATG5 in DCs (<italic>P<</italic>0.01), down-regulated the mRNA expression levels of TGF-<italic>β</italic><sub>1</sub> and <italic>α</italic>-SMA as well as the protein expression levels of SQSTM1, STAT3 and p-STAT3 (<italic>P<</italic>0.05,<italic>P<</italic>0.01), and elevated the number of autophagosomes. Conclusion:Wuhutang relieves airway inflammation, improves airway remodeling and reduces airway hyperresponsiveness in RSV-induced asthmatic mice by inhibiting STAT3 protein and up-regulating DC autophagy in lung tissue.

7.
Article in Chinese | WPRIM | ID: wpr-906427

ABSTRACT

Objective:To observe the effect of Yiqiyangyin Huoxuetongluo prescription on janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway and cell apoptosis in rats with diabetic nephropathy (DN), and to explore the mechanism of its intervention in DN. Method:A total of 100 SD rats were randomly divided into an experimental group (<italic>n</italic>=80) and a normal group (<italic>n</italic>=20). The DN model was induced by high-sugar and high-fat diet combined with intraperitoneal injection of streptozotocin (STZ) in the experimental group, and confirmed by the pathological changes of kidney tissues in rats (three in each group) observed under light and electron microscopes. The model rats were randomly divided into a model group (normal saline, equal volume), low-, medium-, and high-dose (5.775, 11.550, and 23.100 g·kg<sup>-1</sup>) Yiqiyangyin Huoxuetongluo prescription groups, and an irbesartan group (irbesartan tablets, 0.016 g·kg<sup>-1</sup>). After drug intervention (<italic>i.g</italic>., once a day for 16 consecutive weeks), the 24-hour urine total protein (UTP), serum total cholesterol (TC), triglyceride (TG), creatinine (SCr), and blood urea nitrogen (BUN) levels of the rats were measured. Western blot was used to detect the protein expression of JAK2/STAT3 signaling pathway. Immunohistochemistry was used to determine the protein expression of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), zonula occludens-1 (ZO-1), and actinin-4 in rat kidney tissues. Result:Compared with the normal group, the model group exhibited elevated UTP, serum TC, TG, BUN, and SCr levels (<italic>P</italic><0.05), severe pathological damage of rat kidney tissues, up-regulated expression of phospho-JAK2 (p-JAK2), phospho-STAT3 (p-STAT3), and Bax, increased renal cell apoptosis, and diminished expression of Bcl-2, ZO-1, and actinin-4 (<italic>P</italic><0.05). Compared with the model group, the Yiqiyangyin Huoxuetongluo prescription group and the irbesartan group showed dwindled UTP, serum TC, TG, BUN, and SCr levels (<italic>P</italic><0.05), relieved pathological damage of rat kidney tissues, down-regulated p-JAK2, p-STAT3, and Bax expression, and up-regulated expression of Bcl-2, ZO-1, and actinin-4 (<italic>P</italic><0.05). Conclusion:Yiqiyangyin Huoxuetongluo prescription can reduce renal cell apoptosis and improve the prognosis of DN by inhibiting the activation of JAK2/STAT3 signaling pathway.

8.
Article in Chinese | WPRIM | ID: wpr-906332

ABSTRACT

Objective:To explore the effects and mechanism of zedoary turmeric oil and its active components on the vascular endothelial growth factor A (VEGFA), signal transducer and activator of transcription 3 (STAT3), and mechanistic target of rapamycin (mTOR) in the ovarian cancer (OC). Method:Network pharmacology technology was employed to analyze the mechanism of Curcumae Rhizoma on OC. Bioinformatics was used to analyze the expression of VEGFA, STAT3, and mTOR in OC and the effect on the prognosis of OC to explore the feasibility of zedoary turmeric oil in regulating VEGFA, STAT3, and mTOR in OC.The xenograft tumor model of nude mice was established, and the effects of zedoary turmeric oil and its active components on VEGFA, STAT3, and mTOR in OC were observed by hematoxylin-eosin (HE) staining, real-time fluorescence-based quantitative polymerase chain reaction (Real-time PCR), Western blot, and immunohistochemistry (IHC). Result:Bioinformatics analysis and literature research showed that VEGFA, STAT3, and mTOR played a special regulatory role in the occurrence and development of OC, and were potential key targets for the proliferation of OC. Network pharmacology analysis revealed that Curcumae Rhizoma could regulate multiple disease targets of OC, and mediate VEGFA, STAT3, and mTOR in OC through these multiple targets. As demonstrated by HE staining, the tumor cells in the model group were densely arranged, with no erosion on the edge and no vesicles inside. Compared with the model group, the cell density in other treatment groups was reduced, and strip-shaped erosion on the edge and small empty vesicles were observed in the tumor tissue, especially in the zedoary turmeric oil group. According to the results of Real-time PCR and IHC, zedoary turmeric oil and its active components could inhibit the mRNA and protein expression of VEGFA, STAT3, and mTOR in the OC tissue (<italic>P</italic><0.05). Conclusion:Zedoary turmeric oil and its active components could reduce the expression of VEGFA, STAT3, and mTOR in tumor tissue of nude mice, and inhibited the proliferation of OC through VEGFA, STAT3, and mTOR.

9.
Article in Chinese | WPRIM | ID: wpr-906268

ABSTRACT

Objective:To investigate the therapeutic effect and mechanism of modified Wenjingtang on endometriosis (EM) rats with kidney deficiency and blood stasis. Method:The 10 from 105 SPF female healthy SD rats were randomly selected as the blank group. The rest constructed the rat model of kidney deficiency and blood stasis by compound factorial method. After the model was successfully established, 10 rats were randomly selected as the sham operation group, with only laparotomy and no intima suture, and the remaining rats were established with EM kidney deficiency and blood stasis type by autologous intimal transplantation. Fifty rats which were randomly selected from 56 successful rats were treated with the modified Wenjingtang (5,10,20 g·kg<sup>-1</sup>) and danazol group(63 mg·kg<sup>-1</sup>), 1 time daily , for 4 weeks. The endometrial tissues of each group were stained with hematoxylin eosin (HE) to observe the histopathology. The levels of inflammatory factors interleukin-10 (IL-10) and interleukin-17 (IL-17) in serum supernatant were detected by enzyme linked immunosorbent assay (ELISA). Measuring the length(D<sub>1</sub>),width (D<sub>2</sub>) and height (D<sub>3</sub>) of the heterotopic foci in each group before and after treatment. Then calculating the volume of them. The expression of tyrosine kinase 2(JAK2),transcription factor 3 (STAT3),phosphorylation transcription factor 3 (p-STAT3), vascular endothelial growth factor (VEGF), tumor necrosis factor-<italic>α</italic> (TNF-<italic>α</italic>) and thrombospondin-1 (TSP-1) were detected by immunohistochemistry (IHC). The expression of VEGF,TNF-<italic>α</italic> and TSP-1 was detected by Western blot. Result:Microscopic pathological observation showed that the endometrial glandular cells of the blank group were arranged in order, and the glandular and stromal cells grew well, compared with the blank group, the endometrial structure of the model group was complete, showing a cavity like or annular closed structure, with cyst formation, and the epithelium was cubic or columnar epithelium, most of the epithelial cells had secretion, the stroma was dense, and the matrix showed a little fibrosis There were a few glands and inflammatory cell infiltration. Compared with the blank group, the content of IL-10 in serum of model group was significantly decreased (<italic>P</italic><0.01), and the content of IL-17 was significantly increased (<italic>P</italic><0.01), the protein expression of JAK2, STAT3,p-STAT3, VEGF, TNF-<italic>α</italic> in endometrial tissue of model group was significantly increased (<italic>P</italic><0.05), and the expression of TSP-1 protein was significantly decreased (<italic>P</italic><0.05). Compared with the model group, the serum IL-10 content of rats in modified Wenjingtang treatment group increased significantly (<italic>P</italic><0.01), the IL-17 content decreased significantly <italic>(P</italic><0.01), and the volume of ectopic foci decreased significantly (<italic>P</italic><0.01). While the level of JAK2,STAT3,p-STAT3,TNF-<italic>α</italic>,VEGF protein in intimal tissue of modified Wenjingtang high and middle dose group decreased significantly (<italic>P</italic><0.05) and the level of TSP-1 protein increased significantly (<italic>P</italic><0.05). Conclusion:Modified Wenjingtang can inhibit the invasion of ectopic foci in EM rats with kidney deficiency and blood stasis, the mechanism may be related to the intervention of immune barrier and block angiogenesis function mediated by JAK2/STAT3 signaling pathway activation.

10.
Article in Chinese | WPRIM | ID: wpr-906234

ABSTRACT

Objective:To study the anti-inflammatory effects of low, middle, and high doses of Anchang decoction on ulcerative colitis in SD rats, and also explore the possible mechanism of Anchang decoction in the prevention and treatment of ulcerative colitis through the effect of different doses on miRNA-146a/non-receptor tyrosine protein kinase(JAK)/signal transduction and activator of transcription 3(STAT3)/cytokine signaling protein-3(SOCS-3) signal pathway and its downstream proteins. Method:The experimental rats were divided into control group , model group , mesalazine group(1 g·kg<sup>-1</sup>) and Anchang decoction low(6 g·kg<sup>-1</sup>), middle(12 g·kg<sup>-1</sup>)and high dose groups(24 g·kg<sup>-1</sup>), with 10 rats in each group. Except for the control group, 2,4,6-trinitrobenzenesulfonic acid (TNBS)/ethanol enema was used in all the other groups to establish a rat model of ulcerative colitis for 14 days respectively. The general changes of the mental state, stool traits, hair and other general conditions of the rats were observed, and score was graded with reference to the disease activity index (DAI) table. The pathological changes of colon tissue of rats in each group were observed by hematoxylin-eosin (HE) staining. The levels of serum tumor necrosis factor-<italic>α</italic>(TNF-<italic>α</italic>), interleukin-10(IL-10), interleukin-17(IL-17), interleukin-1<italic>β</italic>(IL-1<italic>β</italic>)and interleukin-6(IL-6)were detected by enzyme linked immunosorbent assay (ELISA). The expression levels of JAK2, phosphorylation STAT3 (p-STAT3), STAT3 and inhibitor of SOCS-3 in colon tissue were detected by Western blot. Real-time fluorescence quantitative polymerase chain reaction (Real-time PCR) was used to detect the expression of JAK2, p-STAT3, STAT3, SOCS-3 mRNA in rat colon and miRNA-146a in rat plasma. Result:Compared with the normal group, the expression of JAK2, p-STAT3, STAT3 protein and the expression of JAK2, p-STAT3 and STAT3 mRNA in the model group increased (<italic>P</italic><0.05), and the relative expression of miRNA-146a, SOCS-3 mRNA and SOCS-3 protein decreased in the model group (<italic>P</italic><0.05). Compared with the model group, the mental state, food intake, coat color, etc. of rats in the administration groups were significantly improved, the DAI score was significantly reduced (<italic>P</italic><0.05), the colonic ulcer tissues of rats in the administration groups were improved significantly, the expression levels of JAK2, p-STAT3, STAT3 protein and the expression of JAK2, p-STAT3 and STAT3 mRNA in the colon tissue of the administration groups were decreased (<italic>P</italic><0.05), and the relative expression levels of miRNA-146a, SOCS-3 mRNA and SOCS-3 protein were increased in the administration groups (<italic>P</italic><0.05). Conclusion:Anchang decoction can alleviate ulcerative colitis and reduce the activation of inflammatory factors by affecting the expression of genes and proteins related to miRNA-146a/JAK/STAT/SOCS-3 signal transduction pathway.

11.
Article in Chinese | WPRIM | ID: wpr-905986

ABSTRACT

Objective:To investigate the therapeutic effect of polydatin on ulcerative colitis (UC) in mice and its regulation of protein kinase C<italic>θ</italic>(PKC<italic>θ</italic>)/signal transducer and activator of transcription 3(STAT3) signaling on T helper cell 17(Th17) and its mechanism in the treatment of UC. Method:The 32 male C57BL/6 mice were randomly divided into normal group, model group, polydatin group (0.045 g·kg<sup>-1</sup>) and sulfasalazine group (0.5 g·kg<sup>-1</sup>). The UC model was established by giving 3% dextran sodium sulfate (DSS) solution to free drinking water in mice. Polydatin and sulfasalazine groups were given by gavage 0.5 h before modeling for 7 days. The normal group and model group were given the same amount of normal saline. After the last administration, the colonic tissue was taken and hematoxylin-eosin (HE) was used to observe the pathological changes of colonic tissue. Flow cytometry was used to detect the proportion of Th17 in the lamina propria of colonic mucosa. The expression of interleukin-17A (IL-17A) in serum was detected by enzyme-linked immunosorbent assay (ELISA). Polydatin was added to CD4<sup>+ </sup>T cells purified from spleen of C57BL/6 mice by magnetic-activated cell sorting (MACS) under the stimulation of cell stimulation cocktail <italic>in vitro </italic>in order to detect its impact on PKC<italic>θ</italic> and STAT3 phosphorylation. Result:Compared with normal group, the body weight was significantly decreased, and disease activity index (DAI) scores of the model group was significantly increased (<italic>P</italic><0.01), the colonic mucosal epithelium was damaged and inflammatory cells infiltration in the mucosa and submucosa was obvious, the proportion of Th17 in the lamina propria of colonic mucosa was significantly increased (<italic>P</italic><0.01), and the content of serum IL-17A was significantly increased (<italic>P</italic><0.01). Compared with the model group, the weight and DAI score of polydatin and sulfasalazine groups were significantly improved (<italic>P</italic><0.01), the degree of colon tissue damage was significantly improved, the proportion of Th17 in colon mucosa lamina propria was significantly decreased (<italic>P</italic><0.01), and the content of IL-17A in serum was significantly decreased (<italic>P</italic><0.01). <italic>In vitro</italic> experiments showed that polydatin could significantly inhibit the phosphorylation of PKC<italic>θ</italic> and STAT3 in Th17 (<italic>P</italic><0.01) as well as IL-17A secretion. Conclusion:Polydatin can improve the ulcerative colitis in mice via inhibiting the phosphorylation of PKC<italic>θ</italic> and STAT3 to preclude IL-17A secreting in Th17.

12.
Article in Chinese | WPRIM | ID: wpr-905864

ABSTRACT

Objective:To observe the effect of Jianpi Xiaoai prescription on long non-coding RNA Hox transcript antisense intergenic RNA (lncRNA HOTAIR)/Janus kinase 2 (JAK2) /signal transducer and activator of transcription 3 (STAT3) signaling pathway and to explore the potential mechanism of Jianpi Xiaoai prescription in suppressing the metastasis of colon cancer. Method:The expression of lncRNA HOTAIR in different cells was analyzed. Following the treatment of HCT116 cells with 10%,15%,and 20% Jianpi Xiaoai prescription -containing serum, the invasive ability of Jianpi Xiaoai prescription on HCT116 cells was assessed by transwell assay. The mRNA expression levels of lncRNA HOTAIR,JAK2,and STAT3 were measured by Real-time polymerase chain reaction (Real-time PCR), and the protein expression levels of JAK2, phosphorylated STAT3 (p-STAT3) and STAT3 by Western blot. Result:The highest expression of lncRNA HOTAIR was detected in HCT116 cells. Compared with the blank group, each Jianpi Xiaoai prescription group exhibited a decreased number of invasive cells (<italic>P</italic><0.05, <italic>P</italic><0.01). The relative JAK2 mRNA expression in the middle-dose Jianpi Xiaoai prescription group was down-regulated (<italic>P</italic><0.05), and the relative lncRNA HOTAIR mRNA expression in the middle- and high-dose Jianpi Xiaoai prescription groups and the relative JAK2 mRNA expression in the high-dose Jianpi Xiaoai prescription group were remarkably down-regulated (<italic>P</italic><0.01). Compared with the blank group,the relative p-STAT3 protein expression was down-regulated in the middle-dose Jianpi Xiaoai prescription group (<italic>P</italic><0.05), and the relative JAK2 protein expression in the middle- and high-dose Jianpi Xiaoai prescription groups and the relative p-STAT3 protein expression in the high-dose Jianpi Xiaoai prescription group were remarkably down-regulated (<italic>P</italic><0.01). Conclusion:Jianpi Xiaoai prescription effectively inhibits the metastasis of colon cancer cells, which may be related to the inhibition of lncRNA HOTAIR/JAK2/STAT3 signaling pathway.

13.
Article in Chinese | WPRIM | ID: wpr-904751

ABSTRACT

Objective To find small molecules binding specifically to signal transducer and activator of transcription3 (STAT3) based on surface plasmon resonance (SPR) technology and confirm their inhibitory activities to STAT3. Methods The biomolecular interaction analysis T200 system based on SPR technology was used to couple the purified protein STAT3 to CM5 chip under the optimal pH conditions. The compounds with high binding response value were screened out from 50 candidate compounds derived from traditional Chinese medicines and the binding specificity was then confirmed. Biological experiments were performed to confirm the inhibitory effects of the screened compounds on STAT3. The binding pattern of STAT3 and the compound was fitted by molecular docking technique. Results More than 10 candidate molecules exhibited binding activities to STAT3 and kinetics assays revealed that only one candidate molecule, apigenin, showed specific binding. Western-blot analysis exhibited that apigenin inhibited the phosphorylation of STAT3 dose-dependently. Luciferase reporter gene assays demonstrated that apigenin also inhibited IL-6-induced STAT3 transcriptional activity in a dose-dependent manner. Molecular docking results showed that apigenin binds to the SH2 domain of STAT3, and interacts with key residues Glu638, Gln644, Gly656 and Lys658 by hydrogen bonds and with Tyr657 through π-π interactions. Conclusion Apigenin was a direct inhibitor of STAT3.

14.
Journal of Medical Biomechanics ; (6): E818-E823, 2021.
Article in Chinese | WPRIM | ID: wpr-904477

ABSTRACT

Bone homeostasis is a relative balance between bone formation and resorption. Signal transducer and activator of transcription 3 (STAT3), which is closely related to bone homeostasis, takes part in multiple intracellular and extracellular signal pathways. STAT3 participates in the process of osteoblast differentiation regulated by several factors. It can also maintain bone homeostasis by regulating the recruitment, differentiation and activation of osteoclasts. In addition, STAT3 is involved in the interaction between osteoblasts and osteoclasts. Patients with STAT3 mutations can have several inherited bone metabolism diseases. Furthermore, STAT3 plays a critical role in load-driven bone remodeling. Mechanical stimulation promotes osteoblast differentiation and bone formation through activating or enhancing STAT3 expression during bone remodeling process. This review summarizes the participation of STAT3 in maintaining bone homeostasis together with its possible mechanisms and discusses the connection between STAT3 and mechanical stimulation in bone remodeling, so as to provide a potential pharmacological target for the treatment of bone diseases.

15.
Acta Pharmaceutica Sinica B ; (6): 2726-2737, 2021.
Article in English | WPRIM | ID: wpr-888884

ABSTRACT

Integrins are transmembrane receptors that have been implicated in the biology of various human physiological and pathological processes. These molecules facilitate cell-extracellular matrix and cell-cell interactions, and they have been implicated in fibrosis, inflammation, thrombosis, and tumor metastasis. The role of integrins in tumor progression makes them promising targets for cancer treatment, and certain integrin antagonists, such as antibodies and synthetic peptides, have been effectively utilized in the clinic for cancer therapy. Here, we discuss the evidence and knowledge on the contribution of integrins to cancer biology. Furthermore, we summarize the clinical attempts targeting this family in anti-cancer therapy development.

16.
Article in English | WPRIM | ID: wpr-922764

ABSTRACT

Cervical cancer (CC) is recognized as the most common neoplasm in the female reproductive system worldwide. The lack of chemotherapeutic agents with outstanding effectiveness and safety severely compromises the anti-cipated prognosis of patients. Aloperine (ALO) is a natural quinolizidine alkaloid with marked anti-cancer effects on multiple malignancies as well as favorable activity in relieving inflammation, allergies and infection. However, its therapeutic efficacy and underlying mechanism in CC are still unclear. In the current study, MTT assay was employed to evaluate the viability of HeLa cells exposed to ALO to preliminarily estimate the effectiveness of ALO in CC. Then, the effects of ALO on the proliferation and apoptosis of HeLa cells were further investigated by plate colony formation and flow cytometry, respectively, while the migration and invasion of ALO-treated HeLa cells were evaluated using Transwell assay. Moreover, nude mice were subcutaneously inoculated with HeLa cells to demonstrate the anti-CC properties of ALO in vivo. The molecular mechanisms underlying these effects of ALO were evaluated by Western blot and immunohistochemical analysis. This study experimentally demonstrated that ALO inhibited the proliferation of HeLa cells via G2 phase cell cycle arrest. Simultaneously, ALO promoted an increase in the percentage of apoptotic HeLa cells by increasing the Bax/Bcl-2 ratio. Additionally, the migration and invasion of HeLa cells were attenuated by ALO treatment, which was considered to result from inhibition of epithelial-to-mesenchymal transition. For molecular mechanisms, the expression and activation of the IL-6-JAK1-STAT3 feedback loop were markedly suppressed by ALO treatment. This study indicated that ALO markedly suppresses the proliferation, migration and invasion and enhances the apoptosis of HeLa cells. In addition, these prominent anti-CC properties of ALO are associated with repression of the IL-6-JAK1-STAT3 feedback loop.


Subject(s)
Animals , Apoptosis , Cell Line, Tumor , Cell Movement , Cell Proliferation , Feedback , Female , HeLa Cells , Humans , Interleukin-6/genetics , Janus Kinase 1 , Mice , Mice, Nude , Quinolizidines , STAT3 Transcription Factor/genetics , Signal Transduction , Uterine Cervical Neoplasms/drug therapy
17.
Article in Chinese | WPRIM | ID: wpr-911186

ABSTRACT

Objective:To evaluate the relationship between silence information regulator 1 (SIRT1) and signal transducers and activators of transcription 3 (STAT3) acetylation during high glucose-induced cardiac microvascular endothelial cell injury.Methods:Cardiac microvascular endothelial cells of Sprague-Dawley rats were cultured.The cells at the logarithmic growth phase were selected and divided into 3 groups ( n=24 each) using a random number table method: control group (C group), high glucose group (HG group) and high glucose+ SIRT1 agonist SRT1720 group (HG+ SRT group). The cardiac microvascular endothelial cells were seeded in a 6- or 96-well cell culture plate at a density of 2×10 5 cells/ml.When the cell density reached 50%, the culture medium was then replaced with high-glucose (glucose 33 mmol/L) DMEM culture medium containing with 10% fetal bovine serum and 1% double antibody in HG and HG+ SRT groups.In group HG+ SRT, 20 μmol/L SRT1720 was added simultaneously, and the cells were cultured at 37 ℃ in an incubator with 5% CO 2 for 24 h. The cell viability was determined by CCK-8 assay, the activity of superoxide dismutase (SOD) was detected using a spectrophotometer, the levels of lactic dehydrogenase (LDH), interleukin-6 (IL-6) and tumor necrosis factor-β (TNF-β) in the supernatant were detected by enzyme-linked immunosorbent assay, and the expression of SIRT1, acetylated STAT3 (ac-STAT3) and phosphorylated STAT3 (p-STAT3) was determined by Western blot. Results:Compared with C group, the cell viability and SOD activity were significantly decreased, levels of LDH, IL-6 and TNF-β in the supernatant were increased, expression of SIRT1 was down-regulated, and expression of ac-STAT3 and p-STAT3 was up-regulated in group HG and group HG+ SRT ( P<0.05). Compared with group HG, the cell viability and SOD activity were significantly increased, levels of LDH, IL-6 and TNF-β in the supernatant were decreased, expression of SIRT1 was up-regulated, and expression of ac-STAT3 and p-STAT3 was down-regulated in group HG+ SRT ( P<0.05). Conclusion:SIRT1 can alleviate high glucose-induced cardiac microvascular endothelial cell injury by promoting STAT3 deacetylation.

18.
Article in Chinese | WPRIM | ID: wpr-862478

ABSTRACT

Signal transducer and activator of transcription 3 (STAT3) is a signal transcription protein that exists in the cytoplasm. The abnormal activation of STAT3 is closely related to cell proliferation, differentiation, and canceration. It has abnormal expression in cancer stem cells such as breast cancer, pancreatic cancer, lymphoma, and lung cancer. Therefore, inhibiting the abnormal expression of STAT3 has become a new approach for antitumor therapy.

19.
Article in Chinese | WPRIM | ID: wpr-885987

ABSTRACT

Objective: To observe the effects of herb-partitioned moxibustion and ginger-partitioned moxibustion on the growth of colon tumors in rats with colitis-associated colon cancer (CACC), and explore the mechanism of moxibustion intervening CACC through the purinergic receptor P2X ligand-gated ion channel 7 (P2X7R)/signal transducer and activator of transcription 3 (STAT3)/vascular endothelial growth factor (VEGF) pathway. Methods: A total of 26 male Sprague-Dawley rats were selected. According to the random number table method, 6 rats were selected as the normal group. The remaining 20 rats were injected intraperitoneally with azoxymethane (AOM) combined with oral dextran sodium sulfate (DSS) to prepare the CACC model. After the model was successfully established, 2 rats were randomly selected for model identification. The remaining 18 rats which were successfully modeled were randomly divided into a model group, a herb-partitioned moxibustion group and a ginger-partitioned moxibustion group, with 6 rats in each group. Moxibustion intervention was performed in the herb-partitioned moxibustion group and the ginger-partitioned moxibustion group at Qihai (CV 6) and bilateral Tianshu (ST 25). Moxibustion was performed twice at each point each time, once a day, at a 1-day interval after 6 consecutive interventions, for a total of 30 interventions. After intervention, the colon tumor load, pathological change and histopathological score were observed. Immunohistochemistry was used to detect the expressions of VEGF, P2X7R, phospho-STAT3 (p-STAT3), and nuclear factor-kappa B p65 (NF-κB p65) proteins in rat colon tissue. Western blot was used to detect the levels of p-STAT3 and NF-κB p65 proteins in rat colon tissue. Results: Compared with the normal group, the colon tumor load and histopathological score in the model group were significantly increased (both P<0.001), and different grades of dysplasia were observed in colon tissue from the model group, reaching the degree of adenocarcinoma; the expression level of P2X7R protein in colon tissue was significantly decreased (P<0.001), and the expression levels of p-STAT3, NF-κB p65 and VEGF proteins were significantly increased (all P<0.001) in the model group. Compared with the model group, the colon tumor load, colon histopathological score and the levels of p-STAT3, NF-κB p65 and VEGF proteins in colon tissue were significantly decreased (all P<0.05) in the herb-partitioned moxibustion group and the ginger-partitioned moxibustion group while the expression levels of P2X7R protein in colon tissue were significantly increased (both P<0.05). Conclusion: Both herb-partitioned moxibustion and ginger-partitioned moxibustion can reduce the colon tumor load in CACC rats and delay the progression of colon adenomas. The mechanism may be mediated by the P2X7R/STAT3 pathway to inhibit STAT3 phosphorylation, thereby reducing VEGF protein expression.

20.
China Pharmacy ; (12): 1565-1571, 2021.
Article in Chinese | WPRIM | ID: wpr-881456

ABSTRACT

OBJECTIVE:To study the effects of ferulic acid on t he proliferation ,invasion and apoptosis of HepG 2 hepatocelluar carcinoma cells. METHODS :CCK-8 assay was used to screen the concentration of ferulic acid. Western blot assay was adopted to screen the optimal concentration of interleukin 6(IL-6)to induce HepG 2 cell model with high expression of phosphorylated signal transduction protein and activator 3(p-STAT3)protein. HepG 2 cell were divided into blank control group , model group ,ferulic acid group (0.5 mmol/L)and positive control group (p-STAT3 inhibitor C 188-9,10 μmol/L). Except for blank control group ,model group treated with IL- 6,while administration groups were treated with IL- 6 and relevant drugs. Cell survival rate ,invasion and apoptosis rate in early and late stage were detected by CCK- 8 assay,Transwell assay and Annexin V-FITC/PI double staining ,respectively. Western blot assay was used to detect the expression of p-STAT 3,caspase-3,ZBP-89 and vimentin proteins in each group. On the basis of the PDB protein database ,using 1BG1,a highly similar crystal structure of STAT3,as docking template ,using the region around Tyr 705 as the putative binding pocket ,the docking analysis of ferulic acid with STAT 3 protein was carried out. RESULTS :It is selected to use 0.5 mmol/L ferulic acid intervention for 48 h as the follow-up experimental condition ;50 ng/mL IL- 6 was selected as the modeling condition. Compared with blank control group ,the number of cell invasion ,p-STAT3/STAT3 ratio and protein expression of vimentin were increased significantly in model group (P<0.05 or P<0.01),while late apoptosis rate and protein expression 20 of caspase- 3 were decreased significantly (P<0.05 or P< 0.01). Compared with model group ,cell survival rate ,the number of cell invasion ,p-STAT3/STAT3 ratio and protein expression of vimentin were d ecreased significantly in ferulic acid group and positive control group (P<0.05 or P<0.01);early apoptotic rate (except for ferulic acid group ),late apoptotic rate,the protein expression of caspase- 3 and ZBP- 89(except for positive control group )were increased significantly (P<0.05 or P<0.01). The results of molecular docking showed that the carboxylic groups of ferulic acid could interact with 1.9 Å hydrogen bond of Asn 581 and 2.0 Å hydrogen bond of Lys 591,with binding energy of -4.4 kcal/mol. CONCLUSIONS :Ferulic acid may inhibit the activity of p-STAT 3 by directly binding to the phosphorylation site of STAT 3;it may up-regulate the protein expression of caspase- 3 via STAT 3 dependent pathway ,or up-regulate the protein expression of ZBP- 89 via STAT 3 independent pathway and then down-regulate the protein expression of vimentin ,so as to inhibit the proliferation ,invasion and apoptosis of HepG 2 cells.

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