Haiying Tang

Tanshinone IIA ameliorates bleomycin-induced pulmonary fibrosis and inhibits transforming growth factor-beta-β–dependent epithelial to mesenchymal transition

BACKGROUND Epithelial to mesenchymal transition (EMT) of alveolar epithelial cells occurs in lung fibrotic diseases. Tanshinone IIA (Tan IIA) has been reported to exert anti-inflammatory effects in pulmonary fibrosis. Nonetheless, whether Tan IIA affects lung fibrosis-related EMT remains unknown and requires for further investigations. MATERIALS AND METHODS A single intratracheal instillation of saline containing bleomycin (BLM; 5 mg/kg body weight) was performed to induce pulmonary fibrosis in Sprague-Dawley rats. Rats receiving an instillation of equivoluminal normal saline served as controls. Then, these rats were given a daily intraperitoneal administration of Tan IIA (15 mg/kg body weight) for 28 d before sacrifice. In vitro, recombinant transforming growth factor-beta 1 (TGF-β1; 10 ng/mL) was used to treat human alveolar epithelial A549 cells for 48 h. Tan IIA (10 μM) or control DMSO was used to pretreat cells for 2 h before TGF-β1 stimulation. Rat lung tissue samples and A549 cells were then subjected to further assessments. RESULTS Tan IIA was noted to alleviate BLM-induced pulmonary collagen deposition and macrophage infiltration in rats. Epithelial-cadherin expression was decreased after BLM stimulation, whereas α-smooth muscle actin, fibronectin, and vimentin were increased. These expression alterations were partially reversed by Tan IIA. Moreover, Tan IIA suppressed BLM-induced increases in TGF-β1, phosphorylated Smad-2, and -3 in rats. Additionally, pretreatment of Tan IIA inhibited TGF-β1-triggered EMT, reduced collagen Ⅰ production, and blocked TGF-β signal transduction in A549 cells. CONCLUSIONS Our research suggests that Tan IIA mitigates BLM-induced pulmonary fibrosis and suppresses TGF-β-dependent EMT of lung alveolar epithelial cells.

Tanshinone IIA attenuates bleomycin-induced pulmonary fibrosis in rats

Idiopathic pulmonary fibrosis is a chronic and progressive fibrotic lung disorder with unknown etiology and a high mortality rate. Tanshinone IIA (Tan IIA) is a lipophilic diterpene extracted from the Chinese herb Salvia miltiorrhiza Bunge with diverse biological functions. The present study was conducted to evaluate the effects of Tan IIA on bleomycin (BLM)-induced pulmonary fibrosis in rats. Rats received an intraperitoneal injection of Tan IIA and normal rats were used as controls. Severe pulmonary edema, inflammation and fibrosis were observed in the BLM-treated rats and the counts of total cells, neutrophils and lymphocytes were significantly increased in the bronchoalveolar lavage fluids of those rats. These pathological changes were markedly attenuated by subsequent treatment with Tan IIA. In addition, BLM-induced increased expression of tumor necrosis factor-α, interleukin (IL)-1β, IL-6, cyclooxygenase-2, prostaglandin E2, malondialdehyde, inducible nitric oxide synthase and nitric oxide in rats, which was also suppressed by Tan IIA injection. The present findings suggest therapeutic potential of Tan IIA for pulmonary fibrosis.

Protective role of metalloproteinase inhibitor (AE-941) on ulcerative colitis in rats

AIM To evaluate the protective role of AE-941, a matrix metalloproteinase (MMP) inhibitor, on ulcerative colitis (UC) in rats. METHODS Sprague Dawley (SD) rats were randomly divided into three groups: a control group, an AE-941 treatment group, and an UC model group. Rats were sacrificed on days 7, 21, or 56 following administration of treatment by enema and the disease activity index (DAI), colonic mucosa damage index (CMDI) and colonic expression of MMP-2 and MMP-9 were assessed. RESULTS DAI and CDMI scores in the UC model group increased significantly compared to the control group at all timepoints (P < 0.001), and also increased significantly at the 21- and 56-d timepoints compared to the AE-941-treated group (DAI: 21- and 56-d = 2.09 ± 0.25, 1.52 ± 0.30 vs 1.55 ± 0.28, 0.59 ± 0.19, respectively, P = 0.040 and 0.007, CMDI: 21- and 56-d = 3.03 ± 0.42, 1.60 ± 0.35 vs 2.08 ± 0.46, 0.86 ± 0.37, respectively, P = 0.040 and 0.005). Furthermore, the colonic expression of MMP-2 and MMP-9 in the UC model group increased significantly compared to the control group (P < 0.001), and also increased compared to the AE-941-treated group on the 21- and 56-d timepoints (MMP-2: 21- and 56-d = 0.6048 ± 0.0522, 0.4163 ± 0.0330 vs 0.3983 ± 0.0218, 0.1093 ± 0.0072, respectively, P = 0.010; MMP-9: 21- and 56-d = 0.6873 ± 0.0472, 0.4328 ± 0.0257 vs 0.5179 ± 0.0305, 0.2673 ± 0.0210, respectively, P = 0.010 and 0.040). CONCLUSION Expression of MMP-2 and MMP-9 increased significantly in rats with UC. AE-941 can reduce colonic mucosal damage by downregulating the expression of MMP-2 and MMP-9.

Glycyrrhizic acid alleviates bleomycin-induced pulmonary fibrosis in rats

Idiopathic pulmonary fibrosis is a progressive and lethal form of interstitial lung disease that lacks effective therapies at present. Glycyrrhizic acid (GA), a natural compound extracted from a traditional Chinese herbal medicine Glycyrrhiza glabra, was recently reported to benefit lung injury and liver fibrosis in animal models, yet whether GA has a therapeutic effect on pulmonary fibrosis is unknown. In this study, we investigated the potential therapeutic effect of GA on pulmonary fibrosis in a rat model with bleomycin (BLM)-induced pulmonary fibrosis. The results indicated that GA treatment remarkably ameliorated BLM-induced pulmonary fibrosis and attenuated BLM-induced inflammation, oxidative stress, epithelial-mesenchymal transition, and activation of transforming growth factor-beta signaling pathway in the lungs. Further, we demonstrated that GA treatment inhibited proliferation of 3T6 fibroblast cells, induced cell cycle arrest and promoted apoptosis in vitro, implying that GA-mediated suppression of fibroproliferation may contribute to the anti-fibrotic effect against BLM-induced pulmonary fibrosis. In summary, our study suggests a therapeutic potential of GA in the treatment of pulmonary fibrosis.

Mechanisms of pulmonary fibrosis induced by core fucosylation in pericytes

Pulmonary fibrosis is a common outcome of a variety of pulmonary interstitial diseases, and myofibroblasts are the main culprit for this process. Recent studies have found that pericytes are one of the major sources of myofibroblasts; the transformation of which involves a complex process of activation of TGF-β/Smad2/3 and PDGFβ/Erk signaling pathways. We have reported that the transforming growth factor-β receptor and platelet-derived growth factor-β receptor (TGF-βR I and PDGFβR, respectively) are modified by glycosylation. Thus, we hope to regulate the above-mentioned signal pathways through core fucosylation (CF) catalyzed by α-1,6-fucosyltransferase (FUT8). Previous work has confirmed that TGF-β1 can induce the transformation of pericytes into myofibroblasts, while FUT8siRNA can inhibit such transformation. In the present study, we used an adenovirus packaging FUT8 shRNA to infect a bleomycin-induced pulmonary fibrosis mouse model and determined the effect of CF on pulmonary fibrosis by analyzing the mechanism of CF-mediated pericyte transformation. Our findings may shed new light on the mechanism of pulmonary interstitial fibrosis and provide a novel therapeutic target for clinical applications.

5-ASA-loaded SiO2 nanoparticles-a novel drug delivery system targeting therapy on ulcerative colitis in mice

The targeting of 5-aminosalicylic acid (5-ASA), a first-line therapeutic agent for mild to moderate active ulcerative colitis (UC), to the site of inflammation has remained a challenge and an unmet requirement in the treatment of UC. However, nanoscale carriers for targeted drug delivery are promising for pharmacotherapy, and nanoparticles improve the pharmacokinetics of the loaded therapeutics based on their physical properties. To design and prepare 5-ASA-loaded silicon dioxide nanoparticles (5-ASA-SiO2 NPs), a micro-emulsion method was conducted, and their respective therapeutic effects were validated in a mouse model of UC. Cytotoxicity of 5-ASA-SiO2 NPs was detected in vitro using the Cell Counting Kit-8 method. The therapeutic effect of 5-ASA-SiO2 NPs was assessed based on their disease activity index (DAI), colon histopathology, myeloperoxidase (MPO) and levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). SiO2 NPs were successfully prepared, and cytotoxicity of 5-ASA-SiO2 NPs was identified as being similar to 5-ASA and SiO2 NPs. DAI and colonic histopathology scores in the normal dosage, high dosage and the 5-ASA-SiO2 NP groups demonstrated a significant improvement when compared with the model group. DAI in the high dosage and 5-ASA-SiO2 NP groups also demonstrated a significant improvement when compared with the normal dosage group. However, MPO, serum IL-6 and TNF-α levels in normal dosage, high dosage and 5-ASA-SiO2 NPs groups were significantly lower than in the model group, and these indexes in the high dosage group and 5-ASA-SiO2 NP group were significantly lower than that in the normal dosage group. Expression of IL-6 and TNF-α mRNA in colonic mucosa in the normal dosage, high dosage and 5-ASA-SiO2 NP group was significantly lower than that in the model group. Colonic mucosal IL-6 and TNF-α mRNA expression in the high dosage and 5-ASA-SiO2 NP groups was significantly lower than that in the normal dosage group (P<0.05). In conclusion, 5-ASA-SiO2 NPs are a selective drug release system that target the inflamed colon, characteristics of UC, and can greatly increase therapeutic efficacy in UC.

Effect of Etiasa on the expression of matrix metalloproteinase-2 and tumor necrosis factor-α in a rat model of ulcerative colitis

The aim of this study was to determine the disease activity index (DAI) and the colonic mucosa damage index (CMDI), and to detect the colonic mucosal expression levels of matrix metalloproteinase-2 (MMP-2) and tumor necrosis factor-α (TNF-α) in rats with ulcerative colitis (UC). We also aimed to investigate the protective role of Etiasa in UC. Sprague Dawley (SD) rats were randomly divided into three groups: the control, an Etiasa-treated group and a UC model group. Rats were sacrificed on days 14, 21, 35 or 56 following the administration of treatment by enema and the DAI, CMDI and colonic expression levels of MMP-2 and TNF-α were assessed. In the UC model group, the DAI and CDMI scores and the colonic expression levels of MMP-2 and TNF-α increased significantly compared with the control at all timepoints, and were also significantly higher than those in the Etiasa-treated group. In conclusion, the expression levels of MMP-2 and TNF-α increased significantly in rats with UC. Etiasa reduces colonic mucosal damage by downregulating the expression of MMP-2 and TNF-α.

Influence of Rosiglitazone on the Expression of PPARγ, NF-κB, and TNF-α in Rat Model of Ulcerative Colitis.

Aim. To observe the disease activity index (DAI) and the colonic mucosa damage index (CMDI), detect the colonic mucosal expression of PPARγ, NF-κB, and TNF-α in rats with ulcerative colitis (UC), and to investigate the protective role of rosiglitazone in UC. Methods. Sprague-Dawley (SD) rats were divided into three groups: a control group, a rosiglitazone treatment group, and a UC model group. Rats were sacrificed on days 7, 14, 21, or 35 following administration of treatment after enema and DAI, CMDI and colonic expression of PPARγ, NF-κB, and TNF-α were assessed. Results. In the UC model group, DAI, CDMI and the colonic expression of NF-κB and TNF-α increased significantly compared to the control group at all timepoints, but PPARγ decreased significantly. Furthermore, in the rosiglitazone treatment group, DAI and CMDI decreased significantly on the 14-day, 21-day, and 35-day timepoints compared to the UC model group; the colonic expression of NF-κB and TNF-α decreased compared to UC model group at all timepoints, but the PPARγ expression increased significantly. Conclusions. Rosiglitazone can alleviate colonic mucosal inflammation and have the protective role on UC by upregulating PPARγ expression and downregulating NF-κB and TNF-α expression.

Flt3/Flt3L Participates in the Process of Regulating Dendritic Cells and Regulatory T Cells in DSS-Induced Colitis.

The immunoregulation between dendritic cells (DCs) and regulatory T cells (T-regs) plays an important role in the pathogenesis of ulcerative colitis (UC). Recent research showed that Fms-like tyrosine kinase 3 (Flt3) and Flt3 ligand (Flt3L) were involved in the process of DCs regulating T-regs. The DSS-induced colitis model is widely used because of its simplicity and many similarities with human UC. In this study, we observe the disease activity index (DAI) and histological scoring, detect the amounts of DCs and T-regs and expression of Flt3/Flt3L, and investigate Flt3/Flt3L participating in the process of DCs regulating T-regs in DSS-induced colitis. Our findings suggest that the reduction of Flt3 and Flt3L expression may possibly induce colonic immunoregulatory imbalance between CD103+MHCII+DCs and CD4+CD25+FoxP3+T-regs in DSS-induced colitis. Flt3/Flt3L participates in the process of regulating DCS and T-regs in the pathogenesis of UC, at least, in the acute stage of this disease.

Depression and its risk factors in inpatients with gastrointestinal diseases in department of gastroenterology of general hospital

Aim: To investigate incidence of depression and its risk factors in inpatients with gastrointestinal diseases in department of gastroenterology of general hospital. Methods: A hospital cross-sectional study was performed. HAMD and SDS were used to assess the depression scores in 338 inpatients with GI diseases in department of gastroenterology of the First Affiliated Hospital of Dalian Medical University. Results: 1. The total incidence of depression was 27.50% in inpatients in gastroenterology department; 2. The incidence of depression in GI disease was 26.60%; 3. The incidence of depression was higher in female (31.9%) than that in male inpatients (22.2%)(P<;0.05); 4. In the three subtypes of GERD, the depression scores in patients with NERD were higher than that in patients with EE and BE (P<;0.05); 5. Female, unhappy marriage, recent negative life events, long course of disease and a family history of severe disease are the possible depression risk factors. Conclusion: The incidence of depression in inpatients with GI diseases in department of gastroenterology of general hospital is high, and is related with the severity of diseases. Antidepressant treatment should be given to the GI inpatients with depression, especially to those with depression risk factors.