Protective Effect Of Tanshinone IIA Research Articles

Tanshinone IIA Promoted Autophagy and Inhibited Inflammation to Alleviate Podocyte Injury in Diabetic Nephropathy.

Tanshinone IIA (Tan-IIA) is widely used in patients with diabetic nephropathy (DN), but its protective effect on podocytes in DN has not been well studied. In this study, the effects of Tan-IIA on autophagy and inflammation of glomerular podocytes in DN were observed in vivo and in vitro, and the underlying mechanisms were investigated. Irbesartan, an angiotensin II receptor blocker, is a representative medication for the clinical treatment of DN. So irbesartan was chosen as a positive control drug. Eight-week-old male db/db mice were randomly divided into a DN group, an irbesartan group, and three groups receiving different doses of Tan-IIA. The control group consisted of the db/m littermate mice. Blood, urine, and kidney samples were taken from the mice after 12 weeks of continuous administration. Renal protection of Tan-IIA was evaluated using enzyme-linked immunosorbent assay kits, haematoxylin and eosin staining, transmission electron microscopy, Western blotting, and immunohistochemistry. In vitro, the protective effect of Tan-IIA on podocytes was explored using MPC5 cells cultured with high glucose. Tan-IIA significantly improved renal pathological injury and relieved the renal dysfunction in DN. Compared with the DN group, Tan-IIA could up-regulate the expression of Synaptopodin, Podocin, LC3II/I and Beclin-1 (p < 0.05), and down-regulate the expression of p62, F4/80, NF-κB p65, IL-1β, TNF-α and IL-6 (p < 0.05) both in vivo and in vitro, suggesting that Tan-IIA treatment alleviated podocyte injury by promoting autophagy and inhibiting inflammation during DN. The levels of p-PI3K/PI3K, p-Akt/Akt and p-mTOR/mTOR in Tan-IIA group were lower than those in DN group (p < 0.05), indicating that Tan-IIA inhibited the PI3K/Akt/mTOR signalling pathway in podocytes, which was a key pathway in regulating both autophagy and inflammation. Tan-IIA prevented podocyte injury in DN by fostering autophagy and inhibiting inflammation, at least in part via inhibition of the PI3K/Akt/mTOR signalling pathway.

The combination of Tanshinone IIA and Astragaloside IV attenuates myocardial ischemia–reperfusion injury by inhibiting the STING pathway

BackgroundAstragaloside IV (As-IV) and Tanshinone IIA (Ta-IIA) are the main ingredients of traditional Chinese medicinal Astragalus membranaceus (Fisch.) Bunge and Salvia miltiorrhiza Bunge, respectively, both of which have been employed in the treatment of cardiovascular diseases. Nevertheless, the efficacy of the combination (Co) of Ta-IIA and As-IV for cardiovascular diseases remain unclear and warrant further investigation. This study aimed to investigate the efficacy and the underlying molecular mechanism of Co in treating myocardial ischemia–reperfusion injury (MIRI).MethodsIn order to assess the efficacy of Co, an in vivo MIRI mouse model was created by temporarily blocking the coronary arteries for 30 min and then releasing the blockage. Parameters such as blood myocardial enzymes, infarct size, and ventricular function were measured. Additionally, in vitro experiments were conducted using HL1 cells in both hypoxia-reoxygenation model and oxidative stress models. The apoptosis rate, expression levels of apoptosis-related proteins, oxidative stress indexes, and release of inflammatory factors were detected. Furthermore, molecular docking was applied to examine the binding properties of Ta-IIA and As-IV to STING, and western blotting was performed to analyze protein expression of the STING pathway. Additionally, the protective effect of Ta-IIA, As-IV and Co via inhibiting STING was further confirmed in models of knockdown STING by siRNA and adding STING agonist.ResultsBoth in vitro and in vivo data demonstrated that, compared to Ta-IIA or As-IV alone, the Co exhibited superior efficacy in reducing the area of myocardial infarction, lowering myocardial enzyme levels, and promoting the recovery of myocardial contractility. Furthermore, the Co showed more potent anti-apoptosis, antioxidant, and anti-inflammation effects. Additionally, the Co enhanced the inhibitory effects of Ta-IIA and As-IV on STING phosphorylation and the activation of STING signaling pathway. However, the administration of a STING agonist attenuated the protective effects of the Co, Ta-IIA, and As-IV by compromising their anti-apoptotic, antioxidant, and anti-inflammatory effects in MIRI.ConclusionCompared to the individual administration of Ta-IIA or As-IV, the combined treatment demonstrated more potent ability in inhibiting apoptosis, oxidative stress, inflammation, and the STING signaling pathway in the context of MIRI, indicating a more powerful protective effect against MIRI.Graphical

Tanshinone IIA attenuates ox-LDL-induced endothelial cell injury by inhibiting NF-kapaB pathway via circ_0000231/miR-590-5p/TXNIP axis.

Tanshinone IIA (TSIIA) exhibits inhibitory function in atherosclerosis (AS) progression, and circular RNAs (circRNAs) are pivotal regulators in AS. However, the relation between TSIIA and circ_0000231 in AS pathogenesis remains unknown. In this study, oxidized low-density lipoprotein (ox-LDL) was used to establish AS cell model. Treatment of ox-LDL inhibited cell growth but promoted apoptosis, inflammation, and oxidative stress. Then, TSIIA was shown to attenuate ox-LDL-induced endothelial injury. Furthermore, the protective effect of TSIIA against ox-LDL-induced endothelial cell injury was reversed by circ_0000231. Circ_0000231 was identified as a miR-590-5p sponge. Also, miR-590-5p downregulation restored the protection of TSIIA for endothelial cell function. Moreover, circ_0000231 was found to upregulate thioredoxin interacting protein (TXNIP) level via targeting miR-590-5p. TXNIP overexpression mitigated the regulatory function of circ_0000231 knockdown after co-treatment with ox-LDL and TSIIA. TXNIP upregulation recovered the inhibitory regulation of TSIIA in ox-LDL-induced cell damage. In addition, TSIIA inactivated NF-kapaB (NF-κB) signaling pathway via regulating miR-590-5p/TXNIP axis by downregulating circ_0000231. All these results suggested that TSIIA inhibited ox-LDL-induced AS progression in endothelial cells by affecting NF-κB pathway via circ_0000231/miR-590-5p/TXNIP.

Protective effects of tanshinone ⅡA on sepsis-induced multiple organ dysfunction: a literature review.

TanshinoneⅡA (TanⅡA) is a noteworthy lipophilic diterpene compound derived from the dried roots of the Traditional Chinese Medicine Danshen () that has various pharmacological properties, including anti-inflammatory, antibacterial, and antioxidative effects. Sepsis is a life-threatening organ dysfunction induced by a dysregulated host response to infection. Recently, increasing attention has been paid to sepsis-induced dysfunction of the intestine, car-diovascular system, lungs, kidneys, liver, and other organs. Experimental studies have shown that TanⅡA has therapeutic potential for sepsis-induced organ dysfunction owing to its anti-inflammatory, anti-apoptotic and regulatory effects on multiple signalling pathways. The purpose of this article is to evaluate the potential multiorgan protective effects of TanⅡA in sepsis.

Tanshinone ⅡA activates PI3K/AKT signaling pathway to inhibit the apoptosis of mice cochlear pericytes induced by high glucose

Objective: To investigate whether tanshinone ⅡA can protect the apoptosis of mice cochlear pericytes induced by high glucose and its specific protective mechanism, so as to provide experimental evidence for the prevention and treatment of diabetic hearing loss. Methods: C57BL/6J male mice were used to prepare type 2 diabetes model, which were divided into normal (NG) group, diabetic (DM) group, diabetic+tanshinone ⅡA (HG+tanshinone ⅡA) group and tanshinone ⅡA group. Each group had 10 animals. Primary cochlear pericytes were divided into NG group, HG group (high glucose 35 mmol/L), HG+tanshinone ⅡA (1, 3, 5 μmol/L) group, HG+Tanshinone ⅡA+LY294002 (PI3K/AKT pathway inhibitor) group, LY294002 group, tanshinone ⅡA group and DMSO group. Auditory brainstem response (ABR) was used to measure hearing threshold. Evans blue was used to detect the permeability of blood labyrinth barrier in each group. TBA methods were used to detect oxidative stress levels in various organs of mice. Morphological changes of stria vascularis were observed by hematoxylin-eosin staining (HE). Evans blue was used to detect the vascular labyrinth barrier permeability in cochlea. The expression of apoptosis protein in stria vascularis pericytes was observed by immunofluorescence. Pericytes apoptosis rate was observed by flow cytometry. DCFH-DA was combined with flow cytometry to detect intracellular ROS content, and Western blot was used to detect the expression of apoptotic proteins (Cleaved-caspase3, Bax), anti-apoptotic proteins (BCL-2) and pathway proteins (PI3K, p-PI3K, AKT, p-AKT). SPSS software was used for statistical analysis. Independent sample t test was performed, and P<0.05 was considered statistically significant. Results: Animal experiments: Tanshinone ⅡA decreased the hearing threshold of DM group [(35.0±3.5) dB SPL vs. (55.3±8.1) dB SPL] (t=4.899, P<0.01), decreased the oxidative stress level in cochlea (t=4.384, P<0.05), improved the structure disorder, atrophy of cochlea vascular lines, vacuole increased phenomenon. Tanshinone ⅡA alleviated the increased permeability of the blood labyrinth barrier [Evans blue leakage (6.84±0.27) AU vs. (8.59±0.85) AU] in the cochlea of DM mice (t=2.770, P<0.05), reversed the apoptotic protein: Caspase3 (t=4.956, P<0.01) and Bax (t=4.388, P<0.05) in cochlear vascularis. Cell experiments: Tanshinone ⅡA decreased intracellular ROS content in a concentration-dependent way (t=3.569, P<0.05; t=4.772, P<0.01; t=7.494, P<0.01); Tanshinone ⅡA decreased apoptosis rate and apoptotic protein, and increased the expression of anti-apoptotic protein, p-PI3K/PI3K and p-AKT/AKT in concentration-dependent manner (all P values<0.05); LY294002 reversed the protective effect of tanshinone ⅡA on pericytes apoptosis (all P values<0.05). Conclusion: Tanshinone ⅡA can inhibit the apoptosis of cochlear pericytes induced by high glucose by reducing oxidative stress level and activating PI3K/AKT signaling pathway under high glucose environment, thus playing a protective role in diabetic hearing loss.

Protective effect of tanshinone ⅡA, MAPK1, and RELA on ischemic injury after stroke

Stroke ischemic injury has become one of the major diseases threatening human health and life, and reducing the secondary damage of neurons after cerebral ischemia is an important measure to treat this disease. Inflammatory factors, oxidative stress, and excessive activation of microglia lead to the aggravation of ischemic nerve damage, and if not stopped in time, it will cause large-scale infarction of brain tissue, resulting in permanent neurological deficits. Studies have found that the use of tanshinone II. A can improve the occurrence of the above reactions by inhibiting the two targets of MAPK1 and RELA (p65). This way of inhibiting specific targets to reduce cerebral ischemic damage has become one of the hot issues in today's research. This article mainly reviews the mechanism of tanshinone II. A by inhibiting MAPK and NF-κB signaling pathways, reducing the inflammatory response, oxidative stress, and regulating microglial polarization.

Retraction: Dexmedetomidine postconditioning suppresses myocardial ischemia/reperfusion injury by activating the SIRT1/mTOR axis.

Portland Press would like to amend the retraction statement accompanying this paper as it was a previous version of the statement published in error. The journal apologises for this error and provides the correct version below.The retraction statement should read:This Retraction follows an Expression of Concern relating to this article previously published by Portland Press. This article is being retracted from Bioscience Reports at the request of the authors following receipt of a notification from a reader, alerting the Editorial Office to two regions of the figure 6b MI/R + Dex + EX527 panel that also appear in another paper by different authors (“Protective effect of tanshinone IIA against cardiac hypertrophy in spontaneously hypertensive rats through inhibiting the Cys-C/Wnt signaling pathway” (Feng et al 2017) doi: 10.18632/oncotarget.14328). The Editorial Office also has concerns regarding the western blot images. The authors wish to retract the article, and the Editor-in-Chief and Editorial Board agree with the Retraction.

Expression of Concern: Dexmedetomidine postconditioning suppresses myocardial ischemia/reperfusion injury by activating the SIRT1/mTOR axis.

The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an Expression of Concern to notify readers whilst the Editorial Office investigates. Duplications have been identified between this paper and another by Feng et al. 2017 (“Protective effect of tanshinone IIA against cardiac hypertrophy in spontaneously hypertensive rats through inhibiting the Cys-C/Wnt signaling pathway” DOI: 10.18632/oncotarget.14328). Two sections of the MI/R+Dex+EX527 panel of Figure 6b appear to be the same as sections in figure panel 2c of the Feng et al. paper, one of which is horizontally flipped. The authors have been contacted with regards to these concerns.

Investigating the protective effect of tanshinone IIA against chondrocyte dedifferentiation: a combined molecular biology and network pharmacology approach.

BackgroundOsteoarthritis (OA) is a common degenerative disease with multifactorial etiology. The dedifferentiation of chondrocytes can accelerate the progress of OA. Tanshinone IIA (TIIA) has been widely used to treat OA for many years and has proved to be effective in inhibiting chondrocyte dedifferentiation. Until now, the precise mechanism of TIIA’s effect against dedifferentiation has not been well understood.MethodsThe targets of TIIA were explored from public databases using various methods. The related targets of OA were obtained from the GeneCards database and the Online Mendelian Inheritance in Man (OMIM) database. The potential targets and signaling pathways were determined using protein-protein interaction (PPI), Gene Ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Cell viability, proliferation, and metabolic activity were analyzed in vitro. The effects of TIIA on chondrocyte dedifferentiation were evaluated by assessing morphological changes, glycosaminoglycan (GAG) production, and messenger RNA (mRNA) levels of cartilage-related genes. After 48 hours of culture in medium with 100 μg/mL TIIA, chondrocytes/hydrogel spheres were implanted to repair cartilage defects in a rat model. The harvested specimens were examined with hematoxylin and eosin (H&E) staining and immunohistochemistry to evaluate cartilage regeneration.ResultsThe results showed that there were 28 genes potentially interacting in the TIIA-chondrocyte dedifferentiation network, and nine hub genes were identified. In vitro experiments showed an inhibitory effect of TIIA on chondrocyte dedifferentiation. The proliferation and viability of chondrocytes were promoted by TIIA at a concentration of 100–200 μg/mL, but inhibited by TIIA at 400 μg/mL. Furthermore, the histology results showed that chondrocyte/hydrogel spheres pre-treated with TIIA had better cartilage repair.ConclusionsThis study revealed a systematic network pharmacology approach and provided a basis for the future study of TIIA as an effective treatment for cartilage regeneration. Moreover, in vitro and in vivo results confirmed the protective effects of TIIA against chondrocyte dedifferentiation.

Protective effect of Tanshinone IIA on LPS-induced canine endometritis

Canine endometritis is a common disease in dogs. This work intends to establish the model of lipopolysaccharide (LPS) -induced canine endometritis, and investigate the effect of Tanshinone IIA (Tan IIA) on canine endometritis. At first, we tested the rectal temperature and the production of IL-1β and TNF-α at 6 h, 12 h, 18 h and 24 h after LPS administration. Then 9 beagles were divided into 3 groups on average, all beagles received intraperitoneal injection of saline solution (group 1 and 2) or Tan IIA (group 3) at 6 h before and after LPS challenge. Beagles of group 2 and 3 were performed uterine infusion of LPS, and beagles of group 1 were performed uterine infusion of saline solution. The rectal temperature was measured 6 h, 12 h, 18 h, 24 h post-LPS challenge, all uterus were collected after 24 h post-LPS challenge. The results showed that canine endometritis can be established by LPS at the concentration of 0.5 mg/kg of body weight after 24 h performance. The rectal temperature, the production of IL-1β and TNF-α increased significantly when the model was established. The results showed that rectal temperature, production of IL-1β and TNF-α and the expression of IL-6 were significantly reduced after treatment with Tan IIA compared with the group of LPS challenge only. However, the expression of IL-10 increased after Tan IIA treatment. Considering the positive anti-inflammation effect on the LPS-induced canine endometritis, Tan IIA may be used as a therapeutic agent to treat the clinical canine endometritis.

Tanshinone IIA Suppresses Hypoxia-induced Apoptosis in Medial Vestibular Nucleus Cells Via a Skp2/BKCa Axis.

The aim of the present study was to investigate the protective effects of Tanshinone IIA (Tan IIA) on hypoxia-induced injury in the medial vestibular nucleus (MVN) cells. An in vitro hypoxia model was established using MVN cells exposed to hypoxia. The hypoxia-induced cell damage was confirmed by assessing cell viability, apoptosis and expression of apoptosis-associated proteins. Oxidative stress and related indicators were also measured following hypoxia modeling and Tan IIA treatment, and the genes potentially involved in the response were predicted using multiple GEO datasets. The results of the present study showed that Tan IIA significantly increased cell viability, decreased cell apoptosis and decreased the ratio of Bax/Bcl-2 in hypoxia treated cells. In addition, hypoxia treatment increased oxidative stress in MVN cells, and treatment with Tan IIA reduced the oxidative stress. The expression of SPhase Kinase Associated Protein 2 (SKP2) was upregulated in hypoxia treated cells, and Tan IIA treatment reduced the expression of SKP2. Mechanistically, SKP2 interacted with large-conductance Ca2+-activated K+ channels (BKCa), regulating its expression, and BKCa knockdown alleviated the protective effects of Tan IIA on hypoxia induced cell apoptosis. The results of the present study suggested that Tan IIA had a protective effect on hypoxia-induced cell damage through its anti-apoptotic and anti-oxidative activity via an SKP2/BKCa axis. These findings suggest that Tan IIA may be a potential therapeutic for the treatment of hypoxia-induced vertigo.

RasGRF1 participates in the protective effect of tanshinone IIA on depressive like behaviors of a chronic unpredictable mild stress induced mouse model.

Tanshinone IIA (Tan IIA) is reported to have neuroprotective effects to suppress cell apoptosis of cortical neurons induced by Aβ25-35 through inhibiting oxidative stress. Nevertheless, few studies have investigated the effects of Tan IIA on depressive disorder. Here, we aimed to measure the effects of Tan IIA on chronic unpredictable mild stress (CUMS) induced mouse model and its underlying mechanism. For 28days, mice were subjected to CUMS while Tan IIA was administered once daily at doses of 0, 1, 2.5, 5, or 10mg/kg. CUMS exposure increased depressive-like behaviors, as indicated by increased immobility time in the forced swim and tail suspension tests, decreased sucrose preference in the sucrose preference test, and reduced exploratory behavior in the open field test. All of these behaviors were reversed dose-dependently by Tan IIA treatment. Oxidative stress was determined by measuring malondialdehyde, glutathione peroxidase, and superoxide dismutase activity and total antioxidant capacity. Levels of pro-inflammatory factors IL-1β and IL-18, cAMP response element binding protein and brain derived neurotrophic factor were detected by ELISA and western blot assay, respectively. The results showed that CUMS increased oxidative stress and pro-inflammatory factors and decreased levels of cAMP response element binding protein and brain-derived neurotrophic factor. Tan IIA treatment again reversed these effects. Importantly, RasGRF1 expression increased in CUMS-exposed mice but decreased after Tan IIA administration. Using RasGRF1-/- mice to determine the role of RasGRF1 in mice exposed to CUMS, we found that knockdown of RasGRF1 reversed the effects of CUMS on mice, just like Tan IIA. These results indicate that Tan IIA may reverse depressive-like behaviors in CUMS-exposed mice by regulating RasGRF1.

Protective effect of tanshinone IIA on H2O2-induced oxidative stress injury in rat cardiomyocytes by activating Nrf2 pathway

To investigate the protective effect of tanshinone IIA on H2O2-induced oxidative stress injury in rat cardiomyocytes, and further to study its potential mechanisms. H9C2 cells were used to establish H2O2 injury model. The cell viability and apoptosis were detected by CCK-8 assay and flow cytometry, respectively. ELISA was used to detect the levels of lactate dehydrogenase (LDH), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px). Moreover, the levels of malondialdehyde (MDA) and catalase (CAT) were tested by TBA and visible light methods, respectively. The Nrf2 pathway-related proteins were detected by Western blot. To validate the protective effect of tanshinone IIA on rat cardiomyocytes is worked by regulating the Nrf2 pathway, we further silenced Nrf2 and the above experiments were repeated. Tanshinone IIA could promote the proliferation, and reduce the apoptosis and ROS of rat cardiomyocytes induced by H2O2. Tanshinone IIA also could increase the activity of SOD, CAT, and GSH-Px, and decreased the activity of MDA and LDH. The protein expression of Nrf2, HO-1, and NQO1 was significantly up-regulated in tanshinone IIA groups, while the protein expression of Keap1 was significantly down-regulated. A further study has shown that silenced Nrf2 has completely opposite results. All those results suggested that tanshinone IIA could protect H2O2-induced oxidative stress injury in rat cardiomyocytes by activating Nrf2 pathway.

Tanshinone IIA Ameliorates CNS Autoimmunity by Promoting the Differentiation of Regulatory T Cells.

Tanshinone IIA (TSA), an important natural lipophilic diterpene compound from the traditional Chinese herb Salvia miltiorrhiza Bunge, has long been widely used for the prevention and treatment of various diseases because of its anti-inflammatory activities; however, the anti-inflammatory mechanism remains unknown. In the present work, we examined the effects of TSA on experimental autoimmune encephalomyelitis (EAE), a model of autoreactive T/B cell-mediated central nervous system (CNS) autoimmunity. The data showed that TSA significantly attenuates the severity of EAE when administered at the pre-onset and peak of clinical disease. In vivo, the protective effects of TSA on EAE mice are correlated with diminished inflammatory infiltration, demyelination, and GM-CSF-producing CD4+ T cells in the spinal cord and selectively increased regulatory T (Treg) cell frequencies in both the spinal cord and spleen. We further confirm that TSA can promote the polarization of naïve CD4+ T cells into Treg cells both by targeting dendritic cells (DCs) to drive transforming growth factor β1 (TGF-β1) upregulation and by directly targeting naïve CD4+ T cells in vitro. Most importantly, we showed that TSA-induced Treg cells display an effective suppressive activity at a level comparable to TGF-β1-polarized Treg Cells in vitro and in vivo. Taken together, our data provide evidence that TSA can promote Treg cell differentiation, and TSA may have a promising application as a therapeutic agent for the treatment of neuroinflammatory diseases.

DNA Methylome and Transcriptome Alterations in High Glucose-Induced Diabetic Nephropathy Cellular Model and Identification of Novel Targets for Treatment by Tanshinone IIA.

Diabetic nephropathy (DN) is a diabetes complication that comes from overactivation of Renin-Angiotensin System, excessive pro-inflammatory factors, reactive oxygen species (ROS) overproduction, and potential epigenetic changes. Tanshinone IIA (TIIA), a diterpene quinone phytochemical, has been shown to possess powerful antioxidant, anti-inflammatory, epigenetics, and protective effects against different diseases including DN by inhibiting ROS induced by high glucose (HG). However, epigenomic and transcriptomic study of DN and the protective effect of TIIA are lacking. In this study, next-generation sequencing of RNA and DNA methylation profiles on the potential underlying mechanisms of a DN model in mouse kidney mesangial mes13 cells challenged with HG and treatment with TIIA were conducted. Bioinformatic analysis coupled with Ingenuity Pathway analysis of RNA-seq was performed, and 1780 genes from HG/LG and 1416 genes from TIIA/HG were significantly altered. Several pro-inflammatory pathways like leukotriene biosynthesis and eicosanoid signaling pathways were activated by HG stimulation, while TIIA treatment would enhance glutathione-mediated detoxification pathway to overcome the excess oxidative stress and inflammation triggered by HG. Combination analysis of RNA-seq and Methyl-seq data sets, DNA methylation, and RNA expression of a list of DN associated genes, Nmu, Fgl2, Glo, and Kcnip2, were found to be altered in HG-induced mes13 DN model, and TIIA treatment would effectively restore the alterations. Taken together, these findings provide novel insights into the understanding of how epigenetic/epigenomic modifications could affect the progression of DN and the potential preventive effect of TIIA in DN.

TanshinoneⅡA attenuates carotid artery atherosclerosis by deactivating mast cells in adventitia

Objective: To investigate the effects of tanshinone ⅡA on atherosclerosis plaque formation and adventitial mast cells activation in high-fat-diet induced Apo E(-/-) mice model. Methods: Sixteen 8-week-old Apo E(-/-)male mice and eight 8-week-old C57BL/6 male mice were randomly allocated into following group: the control group (C57BL/6 + carboxymethyl cellulose per gavage), the atherogenic group (Apo E(-/-)+carboxymethyl cellulose per gavage) and the tanshinoneⅡA intervention group (Apo E(-/-)+30 mg/kg tanshinone ⅡA per gavage). All three groups were fed with high-fat-diet for 26 weeks. Tanshinone ⅡA/carboxymethyl cellulose was applied by the method of gavage administration 6 weeks before execution. After 26 weeks, tumor necrosis factor-α (TNF-α) andinterleukin (IL)-6 levels in serum were assessed by ELISA. Carotid artery was removed, fixed with paraformaldehyde, embedded with paraffin and sectioned. Percentage of stenosis was evaluated on HE stained sections. Plaque progression was assessed by Movat staining. Toluidine blue staining was used to evaluate mast cells infiltration and activation. Immunochemistry staining was used to assess 5-HT, TNF-α and IL-6 expression. mRNA expression of mast cell marker Fcer1a in adventitial tissue was detected by real time-PCR. Results: After high-fat-diet for 26 weeks, the mice in the atherogenic group showed advanced atherosclerosis, tanshinoneⅡA intervention reduced the percentage of carotid artery stenosis caused by atherosclerotic plaque formation ((58.48±8.07)% vs. (80.31±4.08)%, P<0.05). Compared with the atherogenic group, tanshinone ⅡA intervention group had lower level of TNF-α ((12.39±1.62)pg/ml vs. (17.44±1.42)pg/ml) and IL-6 ((116.24±12.16)pg/ml vs. (166.05±19.09)pg/ml) in serum, lower TNF-α ((20 145±1 556) vs. (25 288±1 671)) and IL-6 ((25 688±1 604) vs. (35 286±4 198)) expression in adventitia (all P<0.05). TanshinoneⅡA intervention also decreased the number of mast cells infiltration and activation, reduced 5-HT expression and mast cell marker Fcer1a mRNA relative expression in adventitia (all P<0.05). Conclusions: Tanshinone ⅡA could attenuate induced by high-fat-diet carotid artery atherosclerosis in Apo E(-/-) mice. The protective effect of tanshinoneⅡA is probably mediated through reducing the number and activation percentage of mast cells, decreasing the release of inflammatory cytokines and inflammation of carotid artery in adventitia.

Tanshinone IIA protects against lipopolysaccharide-induced lung injury through targeting Sirt1.

This study was designed to investigate the effects and the mechanism of Tanshinone IIA (TIIA) on endotoxic shock-induced lung injury in a mouse model. Mice were administered intraperitoneally with TIIA (10mg/kg) 0.5h before lipopolysaccharide (LPS) challenge and then received additional injections every 24h during the 3-day experimental period. The physiological indexes, thesurvival rate and the parameters for lung injury were examined. The protein levels of Sirt1, and the acetylation and activation of NF-κB p65 were determined.The expression and secretion of pro-inflammatory factors were evaluated, respectively. Treatment with TIIA significantly improved physiological indexes and increased the survival rate of mice in response to LPS challenge. TIIA treatment displayed an obvious up-regulation of Sirt1 protein, in accompany with reduced acetylation and activation of NF-κB p65 following LPS stimulation. In addition, TIIA attenuated LPS-induced lung injury and prevented the expression and secretion of pro-inflammatory factors. However, the protective effects of TIIA were abolished by Sirt1 inhibitor. Tanshinone IIA prevents LPS-induced secretion of pro-inflammatory cytokines thus exerts protective effects against acute lung injury, probably via modulation of Sirt1/NF-κB signalling pathway.

Tanshinone IIA protects lens epithelial cells from H2 O 2 -induced injury by upregulation of lncRNA ANRIL.

Tanshinone IIA is a lipophilic diterpene extracted from the Salvia miltiorrhiza bunge, possessing antiapoptotic and antioxidant activities. The purpose of this study was to explore the effects of Tanshinone IIA on age-related nuclear cataract. Human lens epithelial cell line SRA01/04 was subjected to H 2 O 2 to mimic a cell model of cataract. Cell Counting Kit-8 assay, flow cytometer, and reactive oxygen species (ROS) detection were performed to evaluate the effect of Tanshinone IIA pretreatment on SRA01/04 cells injured by H 2 O 2 . Besides, the real-time quantitative polymerase chain reaction was used to assess the expression of long noncoding RNA (lncRNA) antisense noncoding RNA in the INK4 locus (ANRIL). Western blot analysis was performed to detect the expression of core proteins involved in cell survival and nuclear factor-κB (NF-κB) pathway. H 2 O 2 significantly decreased SRA01/04 cells viability, whereas increased apoptosis and ROS generation. This phenomenon was coupled with the upregulated p53, p21, Bax, cleaved caspase-3, and the downregulated cyclinD1, CDK4, and Bcl-2. Tanshinone IIA pretreatment protected SRA01/04 cells against H 2 O 2 -induced injury. In the meantime, the expression of lncRNA ANRIL was upregulated by Tanshinone IIA. And, the protective effects of Tanshinone IIA on H 2 O 2 -stimulated SRA01/04 cells were abolished when lncRNA ANRIL was silenced. Moreover, the elevated expression of lncRNA ANRIL induced by Tanshinone IIA was abolished by BAY 11-7082 (an inhibitor of NF-κB). To conclude, Tanshinone IIA protects SRA01/04 cells from apoptosis triggered by H 2 O 2 . Tanshinone IIA confers its protective effects possibly via modulation of NF-κB signaling and thereby elevating the expression of lncRNA ANRIL.

Tanshinone IIA ameliorates acute lung injury by inhibition of the NLRP3 inflammasome

Tanshinone IIA is the phenanthrenequinone derivative extracted from the perennial plant Salvia miltiorrhiza Bunge (red sage). We investigated whether inhibition of the nucleotide-binding oligomerization domain (NOD)-like receptor family protein 3 (NLRP3) inflammasome mediates the protective effect of tanshinone IIA in acute lung injury (ALI) induced in rats by oleic acid (OA) injection. Compared with the control treatment, OA injection induced pulmonary histological impairment, increased the lung wet/dry weight ratio (7.0?1.1 vs 4.?0.6 ) and CO2 partial pressure (PaCO2) (52?6.4 vs 40?3.6 mmHg), decreased arterial O2 partial pressure (PaO2) (63?8.4 vs 100?3.0 mmHg), and increased tumor necrosis factor ? (TNF?) (8.8?2.3 vs 5.2 ?1.5 pg/mL), monocyte chemoattractant protein-1 (MCP-1) (36.1?4.9 vs 25.2?6.6 pg/mL) and interleukin-1? (IL-1?) (15.9?3.2 vs 4.6?1.3 pg/mL) in the bronchoalveolar lavage (BAL) fluid. Tanshinone IIA provided protection against ALI, observed as a reduction in the lung wet/dry weight ratio and CO2 partial pressure, and increased O2 partial pressure. The cytokine increase was also prevented. Tanshinone IIA attenuated increased protein levels of NLRP3, caspase-1 and IL-1? in pulmonary tissues, suggesting that it ameliorates ALI by preventing NLRP3 inflammasome activation.

Protective effects of tanshinone IIA on SH-SY5Y cells against oAβ1–42-induced apoptosis due to prevention of endoplasmic reticulum stress

Endoplasmic reticulum (ER) stress caused by β-amyloid protein (Aβ) may play an important role in the pathogenesis of Alzheimer disease (AD). Our previous data have indicated that tanshinone IIA (tan IIA) protected primary neurons from Aβ induced neurotoxicity. To further explore the neuroprotection of tan IIA, here we study the effects of tan IIA on the ER stress response in oligomeric Aβ1-42 (oAβ1-42)-induced SH-SY5Y cell injury. Our data showed that tan IIA pretreatment could increase cell viability and inhibit apoptosis caused by oAβ1-42. Furthermore, tan IIA markedly suppressed ER dilation and prevented oAβ1-42-induced abnormal expression of glucose regulated protein 78 (GRP78), initiation factor 2α (eIF2α), activating transcription factor 6 (ATF6), as well as inhibited the activation of C/EBP homologous protein (CHOP) and c-Jun N-terminal kinase (JNK) pathways. Moreover, tan IIA ameliorated oAβ1-42-induced Bcl-2/Bax ratio reduction, prevented cytochrome c translocation into cytosol from mitochondria, reduced oAβ1-42-induced cleavage of caspase-9 and caspase-3, suppressed caspase-3/7 activity, and increased mitochondrial membrane potential (MMP) and ATP content. Meanwhile, oAβ1-42-induced cell apoptosis and activation of ER stress can also be attenuated by the inhibitor of ER stress 4-phenylbutyric acid (4-PBA). Taken together, these data indicated that tan IIA protects SH-SY5Y cells against oAβ1-42-induced apoptosis through attenuating ER stress, modulating CHOP and JNK pathways, decreasing the expression of cytochrome c, cleaved caspase-9 and cleaved caspase-3, as well as increasing the ratio of Bcl-2/Bax, MMP and ATP content. Our results strongly suggested that tan IIA may be effective in treating AD associated with ER stress.