transforming-growth-factor-beta and tanshinone

The purpose of the present study was to evaluate whether tanshinone IIA (TIIA) could treat cardiac dysfunction and fibrosis in heart failure (HF) by inhibiting oxidative stress. An HF model was induced by ligation of the left anterior descending artery to cause ischemia myocardial infarction (MI) in Sprague‑Dawley rats. Cardiac fibrosis was evaluated using Masson's staining, and the levels of collagen I, collagen III, TGF‑β, α‑smooth muscle actin (α‑SMA), matrix metalloproteinase (MMP) 2 and MMP9 were determined using PCR or western blotting. TIIA treatment reversed the decreases of left ventricular (LV) ejection fraction, fractional shortening (FS), LV systolic pressure and the maximum of the first differentiation of LV pressure (LV ± dp/dt

Topics: Abietanes; Actins; Animals; Antioxidants; Collagen; Fibrosis; Heart Failure; Male; Malondialdehyde; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Myocardial Infarction; Myocardium; NADPH Oxidases; Oxidative Stress; Rats; Rats, Sprague-Dawley; Superoxide Dismutase; Transforming Growth Factor beta

Explored the mechanism of action of tanshinone IIA (TIIA) against atherosclerosis.. ApoE mice were divided into two groups of 10: model and TIIA. A control group of 10 wild-type mice was created. ApoE mice were fed a high-fat diet for 12 weeks. The TIIA group received TIIA once daily. Mice were anesthetized, blood collected by cardiac puncture, and the aortic sinus/arch collected for histology and molecular studies, respectively.. Mice intima in the model group had large areas of plaque formation, serum levels of total cholesterol (TC), triglycerides, and low-density lipoprotein-cholesterol (LDL-C) increased significantly, and high-density lipoprotein-cholesterol (HDL-C) levels decreased significantly in the model group after 12 weeks. Staining [hematoxylin and eosin (H&E), Oil-Red-O] showed that the aorta had lesions, a higher degree of plaque formation, and considerable lipid deposition in model-group mice. After TIIA treatment, expression of HDL-C was increased significantly and that of TC, triglycerides and LDL-C decreased significantly, and plaque size and lipid deposition improved obviously. Analyses of protein phosphorylation in aortic tissue suggested that the transforming growth factor (TGF)-β/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/endothelial nitric oxide synthase (eNOS) pathway was activated in TIIA-treated mice.. TIIA can lower levels of serum lipids, stabilize atherosclerotic plaques, reduce endothelial injury, and inflammatory damage by activation of the TGF-β/PI3K/Akt/eNOS pathway.

Topics: Abietanes; Animals; Aorta, Thoracic; Atherosclerosis; Biomarkers; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Immunosuppressive Agents; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide Synthase Type III; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Transforming Growth Factor beta

Tanshinone IIA (TanIIA)-an active constituent of

Topics: Abietanes; Adaptor Proteins, Signal Transducing; Adult; Aged; Antineoplastic Agents, Phytogenic; Carcinogenesis; Cell Line, Tumor; Drug Evaluation, Preclinical; Drugs, Chinese Herbal; Female; Humans; Liver Neoplasms; Male; Middle Aged; Phytotherapy; Salvia miltiorrhiza; Smad7 Protein; Transcription Factors; Transforming Growth Factor beta; YAP-Signaling Proteins

We have evaluated the protective mechanism of tanshinone IIA in ischemia/reperfusion injury (IRI) induced by liver grafts, revealing novel supplementary immunotherapy for liver transplantation.. The tanshinone IIA preconditioning group (TP group) was pretreated with tanshinone IIA via intraperitoneal injection for 1 week before receiving orthotopic liver transplantation with hepatic arterial ischemia for 30min. The sham-operation group (SO group), control graft group (CG group) and IRI group were pretreated with an equivalent volume of normal saline. The IRI group and CG group received orthotopic liver transplantation with or without hepatic arterial ischemia. Rats were sacrificed at each time point, serum was collected for ELISA detection, and Kupffer cells (KCs) were isolated to extract total protein and RNA for western blotting and real-time PCR, respectively.. The levels of TNF-α and IL-4 in the TP group were significantly lower than those of in the IRI group; meanwhile the IL-10 and TGF-β levels were significantly higher than in the IRI group. The protein and mRNA expression levels of HMGB1 were significantly lower in TP group than in the IRI group at each time point. The TLR-4, Myd88, NLRP3 and p-NF-κb p65 expression levels in the TP groups were significantly lower than those in the IRI group, while the PTEN, PI3K and AKT phosphorylation levels in the TP groups were significantly higher than those in the IRI group.. Tanshinone IIA attenuates IRI caused by liver grafts via down-regulation of the HMGB1-TLR-4/NF-κb pathway in KCs and activation of PTEN/PI3K/AKT pathway, suggesting a potential role for prevention of liver cell IRI during liver transplantation.

Topics: Abietanes; Animals; HMGB1 Protein; Interleukin-10; Interleukin-4; Kupffer Cells; Liver; Liver Diseases; Liver Transplantation; Male; Myeloid Differentiation Factor 88; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Phosphatidylinositol 3-Kinases; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Signal Transduction; Toll-Like Receptor 4; Transcription Factor RelA; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The present study aimed to investigate the effect of tanshinone IIA on the degradation of articular cartilage in a rat model of osteoarthritis (OA). The OA rat model was established by anterior cruciate ligament transection (ACLT) and medial meniscus resection (MMx). The animals were treated for 28 days with 0.25‑0.5 mg/kg doses of tanshinone IIA following ACLT + MMx. The knee joints of the rats in the ACLT + MMx group exhibited marked alterations in articular cartilage histopathology and higher Mankin scores, compared with those in the normal group. Tanshinone IIA treatment at a dose of 0.5 mg/kg significantly inhibited cartilage degradation and improved Mankin scores in the OA rat model (P<0.002). Tanshinone IIA treatment completely inhibited the ACLT + MMx‑induced accumulation of inflammatory cells and disintegration of synovial lining in the rats. An increase in the dose of tanshinone IIA between 0.25 and 0.5 mg/kg reduced the proportion of apoptotic chrondrocytes from 41 to 2% on day 29. Treatment of the rats in the ACLT + MMx group with 0.5 mg/kg doses of tanshinone IIA markedly inhibited the expression level of matrix metalloproteinase and increased the expression of tissue inhibitor of metalloproteinase in the rat articular cartilage tissues. Tanshinone IIA treatment significantly reduced the levels of inflammatory cytokines, including interleukin‑1β, tumor necrosis factor‑α and nitric oxide in rat serum samples. The protein expression levels of bone morphogenetic protein and transforming growth factor‑β were significantly increased by tanshinone IIA in the ACLT + MMx rats. Therefore, tanshinone IIA inhibited articular cartilage degradation through inhibition of apoptosis and expression levels of inflammatory cytokines, offering potential for use in the treatment of OA.

Topics: Abietanes; Animals; Anterior Cruciate Ligament; Apoptosis; Bone Morphogenetic Proteins; Cartilage, Articular; Chondrocytes; Cytokines; Disease Models, Animal; Inflammation; Interleukin-1beta; Male; Menisci, Tibial; Nitric Oxide; Osteoarthritis; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

In traditional Chinese medicine, Tanshinone IIA is used to treat chronic kidney disease (CKD). However, its biological activity and mechanism of action in renal fibrosis and inflammation are not fully identified. The current study was conducted to determine the effects of Tanshinone IIA treatment on CKD by assessing potential modulation of the TGF-β/Smad and NF-κB signaling pathway.. CKD was produced in rats by 5/6 nephrectomy. They were then divided into the following groups: control (sham operation); CKD (5/6 nephrectomy); 5/6 nephrectomy+Tanshinone IIA (10mg/kg in average, once a day for 16 weeks). Serum and urine samples were obtained from animals in each group, and serum creatinine (Scr), blood urea nitrogen (BUN) levels and 24h urinary protein excretion were measured. Tissue samples from the kidney were used for morphometric studies (Masson's trichrome). The expression of fibronectin protein and collagen types I, III, IV, and TGF-β, TNF-α, CXCL-1, MCP-1, RANTES mRNA were evaluated using immunohistochemistry and RT-PCR analysis; the TGF-β/Smad and NF-κB signaling pathway was detected by immunohistochemistry and Western blot analysis.. The following effects were observed in CKD rats treated with Tanshinone IIA: (1) marked improvements in Scr, and 24h urine protein excretion; (2) significant reductions in protein and mRNA levels of fibronectin, collagen III, and collagen IV and TNF-α, MCP-1, and CXCL-1; (3) significantly inhibited the TGF-β/Smad and NF-κB signaling activation.. These results suggest that Tanshinone IIA suppresses renal fibrosis and inflammation via altering expression of TGF-β/Smad and NF-κB pathway in the remnant kidney, thus supporting the potential of Tanshinone IIA as a new therapeutic agent for slowing the progression of CKD.

Topics: Abietanes; Animals; Blotting, Western; Disease Models, Animal; Drugs, Chinese Herbal; Fibrosis; Gene Expression; Immunohistochemistry; Kidney; Kidney Function Tests; Male; Medicine, Chinese Traditional; Nephrectomy; NF-kappa B; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Renal Insufficiency, Chronic; Signal Transduction; Smad Proteins; Transforming Growth Factor beta

Salvia miltiorrhiza Bunge has been reported to possess excellent antifibrotic activity. In this study, we have investigated the effect and mechanism of tanshinone IIA (Tan-IIA), salvianolic acid A (Sal-A) and salvianolic acid B (Sal-B), the important active compounds of Salvia miltiorrhiza Bunge, on areca nut extract (ANE)-induced oral submucous fibrosis (OSF) in vitro. Through human procollagen gene promoter luciferase reporter plasmid assay, hydroxyproline assay, gelatin zymography assay, qRT-PCR, ELISA and Western blot assay, the influence of these three compounds on ANE-stimulated cell viability, collagen accumulation, procollagen gene transcription, MMP-2/-9 activity, MMP-1/-13 and TIMP-1/-2 expression, cytokine secretion and the activation of PI3K/AKT, ERK/JNK/p38 MAPK and TGF-β/Smads pathways were detected. The results showed that Tan-IIA, Sal-A and Sal-B could significantly inhibit the ANE-stimulated abnormal viability and collagen accumulation of mice oral mucosal fibroblasts (MOMFs), inhibit the transcription of procollagen gene COL1A1 and COL3A1, increase MMP-2/-9 activity, decrease TIMP-1/-2 expression and inhibit the transcription and release of CTGF, TGF-β1, IL-6 and TNF-α; Tan-IIA, Sal-A and Sal-B also inhibited the ANE-induced activation of AKT and ERK MAPK pathways in MOMFs and the activation of TGF-β/Smads pathway in HaCaT cells. In conclusion, Tan-IIA, Sal-A and Sal-B possess excellent antifibrotic activity in vitro and can possibly be used to promote the rehabilitation of OSF patients.

Topics: Abietanes; Animals; Areca; Benzofurans; Caffeic Acids; Cell Line; Cell Survival; Collagen; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Fibroblasts; Gene Expression Regulation; Humans; In Vitro Techniques; Lactates; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Nuts; Oral Submucous Fibrosis; Plant Exudates; Proto-Oncogene Proteins c-akt; Signal Transduction; Smad Proteins; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2; Transforming Growth Factor beta

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.. 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.. 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.. Our research suggests that Tan IIA mitigates BLM-induced pulmonary fibrosis and suppresses TGF-β-dependent EMT of lung alveolar epithelial cells.

Topics: Abietanes; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biomarkers; Bleomycin; Blotting, Western; Cell Line; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Epithelial-Mesenchymal Transition; Humans; Pulmonary Alveoli; Pulmonary Fibrosis; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Transforming Growth Factor beta; Transforming Growth Factor beta1

Pulmonary fibrosis (PF) is a common complication in those interstitial lung diseases patients, which will result in poor prognosis and short survival. Traditional therapeutic methods such as glucocorticoid and cytotoxic drugs are insufficient for treating PF and may cause severe side effects. Recent studies showed that traditional Chinese herbal abstraction such as Tanshinone IIA (TIIA) was displayed significant anti-PF effects in animal models. However, the exact mechanisms underlying the protective effects of TIIA were not fully understood. Here we further investigated the protective effects of TIIA and its mechanisms underlying. PF models of rat were induced by bleomycin (BLM); TIIA was administered subsequently. The PF changes were identified by histopathological analyses. The results showed that BLM resulted in severe PF and alveolar inflammation; together with significant elevation of transforming growth factor-β 1 (TGF-β1). Angiotensin-converting enzyme 2 (ACE-2) together with angiotensin-(1-7) [ANG-(1-7)] were both greatly reduced after BLM administration. TIIA treatment notably attenuated BLM induced PF and inflammation, decreased expression of TGF-β1 and reversed ACE-2 and ANG-(1-7) production in rat lungs. Thus we may draw the conclusion that TIIA may exert protective effects on BLM induced PF in rats, and the ACE-2/ANG-(1-7) axis may ascribe to those protective effects.

Topics: Abietanes; Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Bleomycin; Humans; Inflammation; Peptide Fragments; Peptidyl-Dipeptidase A; Pulmonary Fibrosis; Rats; Transforming Growth Factor beta

Tanshinone ⅡA (TⅡA) is widely used for the treatment of a number human diseases, including diabetic nephropathy (DN) (1). The present study was performed to examine the role of the transforming growth factor β (TGFβ)/p65 pathway under TⅡA treatment in a glomerular mesangial cell model of DN. Firstly, it was identified that TⅡA inhibited the proliferation of HBZY‑1 cells, while simultaneously suppressing the expression of TGFβ and p65. In addition, glucose-induced HBZY‑1 cells were treated with TⅡA, si‑TGFβ and si‑p65. The results revealed that si‑TGFβ or si‑p65 were able to inhibit the proliferation of HBZY‑1 cells as well. Finally, the expression of TGFβ and p65 in a rat model of DN treated with TⅡA was detected. The results demonstrated that renal hypertrophy and 24 h urinary protein excretion were ameliorated in TⅡA-treated rats with DN. Furthermore, it was revealed that the protein levels of TGFβ and p65 were decreased in the DN rats following TⅡA treatment. In conclusion, the present study demonstrated that TGFβ and p65 were activated by TⅡA in HBZY‑1 cells. In addition, the expression of TGFβ and of p65 was downregulated in rats with DN treated with TⅡA.

Topics: Abietanes; Animals; Cell Line; Cell Proliferation; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Male; Neoplasm Proteins; Nucleocytoplasmic Transport Proteins; Rats; Rats, Sprague-Dawley; Signal Transduction; Transforming Growth Factor beta