Sodium tanshinone IIA sulfonate improves adverse ventricular remodeling post MI by reducing myocardial necrosis, modulating inflammation and promoting angiogenesis

Background and Objective: Myocardial infarction (MI) leads to pathological cardiac remodeling and heart failure. Sodium tanshinone IIA sulfonate (STS) shows therapeutic values. The present study aimed to explore the potential role of STS in ventricular remodeling post-MI Methods: Mice were randomly divided into sham, MI + normal saline (NS) and MI + STS (20.8 mg/kg/day intraperitoneally) groups. MI was established following left anterior descending artery ligation. Cardiac function was evaluated using echocardiography. Scar size and myocardial fibrosis-associated markers were detected using Masson’s trichrome staining and western blot analysis (WB). Necrosis and inflammation were assessed using H&E staining, lactate dehydrogenase (LDH) detection, ELISA, immunohistochemical staining, and WB. Furthermore, angiogenesis markers and associated proteins were detected using immunohistochemical staining and WB. Results: Mice treated with STS exhibited significant improvements in cardiac function, smaller scar size, and low expression levels of α-smooth muscle actin and collagen I and III at 28 days following surgery, compared with the NS-treated group. Moreover, treatment with STS reduced eosinophil necrosis, the infiltration of inflammatory cells, plasma levels of LDH, high mobility group protein B1, interleukin-1β and tumor necrosis factor-α, and protein expression of these cytokines at 3 days. Macrophage infiltration was also decreased in the STS group in the early phase. Additionally, CD31+ vascular density, protein levels of hypoxia-inducible factor-1α, and vascular endothelial growth factor were elevated in the STS-treated mice at 28 days. Conclusion: STS improved pathological remodeling post-MI, and the associated therapeutic effects may result from a decrease in myocardial necrosis, modulation of inflammation, and an increase in angiogenesis.

Effect of Sodium Tanshinone IIA Sulfonate Injection on Blood Lipid in Patients With Coronary Heart Disease: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

Background: Lipid-lowering therapy is very important in secondary prevention of coronary heart disease (CHD). In many clinical trials, it has been found that Sodium Tanshinone IIA Sulfonate Injection (STS) have a lipid-lowering effect while reducing major cardiovascular events in patients with CHD. However, up to now, there is no system review on the effectiveness and safety of STS affecting blood lipids.Purpose: The aim of this review is to systematically assess the effects of STS on blood lipid levels in patients with CHD.Methods: Until Mar 2021, five databases (PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure, and Wanfang Database) were searched for randomized controlled trials (RCTs) about STS treating patients with CHD. Risk bias was assessed for included studies according to Cochrane handbook. The primary outcome was total cholesterol (TC). The secondary outcomes were triglycerides (TG), low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), and adverse events (AEs).Results: A total of 27 trials including 2,445 CHD patients met the eligibility criteria. Most trials had high risks in random sequence generation, allocation concealment, blinding of patients and personal, blinding of outcome assessment. Meta-analysis showed that STS significantly reduced plasma TC levels [MD = −1.34 mmol/l 95% CI (−1.59, −1.09), p < 0.00001, I2 = 98%], TG levels [MD = −0.49 mmol/l 95% CI (−0.62, −0.35), p < 0.00001, I2 = 97%], LDL-c levels [MD = −0.68 mmol/l (−0.80, −0.57), p < 0.00001, I2 = 96%], increased HDL-c levels [MD = 0.26 mmol/l (0.15, 0.37), p < 0.00001, I2 = 97%], without increasing the incidence of AEs [RR = 1.27 95% CI (0.72, 2.27), p = 0.94, I2 = 0%] in patients with CHD.Conclusion: STS can safely and effectively reduce plasma TC, TG and LDL-c levels in patients with CHD, and improve plasma HDL-c levels. However, these findings require careful recommendation due to the low overall quality of RCTs at present. More multi-center, randomized, double-blind, placebo-controlled trials which are designed follow the CONSORT 2010 guideline are needed.

Sodium tanshinone IIA sulfonate attenuates cigarette smoke extract-induced mitochondrial dysfunction, oxidative stress and apoptosis in alveolar epithelial cells by enhancing SIRT1 pathway

Emphysema is one of the most important phenotypes for chronic obstructive pulmonary disease (COPD). Apoptosis in alveolar epithelial cells (AECs) causes the emphysematous alterations in the smokers and patients with COPD. Sirtuin 1 (SIRT1) is able to attenuate mitochondrial dysfunction, oxidative stress, and to modulate apoptosis. It has been shown that sodium tanshinone IIA sulfonate (STS), a water-soluble derivative of tanshinone IIA, protects against cigarette smoke (CS)-induced emphysema/COPD in mice. However, the mechanisms underlying these findings remain unclear. Here, we investigate whether and how STS attenuates on AEC apoptosis via a SIRT1-dependent mechanism. We found that STS treatment decreased CS extract (CSE)-induced apoptosis in human alveolar epithelial A549 cells. STS reduced oxidative stress, improved mitochondrial function and mitochondrial membrane potential (ΔΨm), and restored mitochondrial dynamics-related protein expression. Moreover, STS promoted mitophagy, and increased oxidative phosphorylation (OXPHOS) protein levels (Complexes I-IV) in CSE-stimulated A549 cells. The protective effects of STS were associated with SIRT1 upregulation, since SIRT1 inhibition by EX 527 significantly attenuated or abolished the ability of STS to reverse the CSE-induced mitochondrial damage, oxidative stress, and apoptosis in A549 cells. In conclusion, STS ameliorates CSE-induced AEC apoptosis by improving mitochondrial function and reducing oxidative stress via enhancing SIRT1 pathway. These findings provide novel mechanisms underlying the protection of STS against CS-induced COPD.

Sodium Tanshinone IIA Sulfonate Improves Cognitive Impairment via Regulating Aβ Transportation in AD Transgenic Mouse Model

Alzheimer’s disease (AD) is a most common neurodegenerative disease. Sodium Tanshinone IIA Sulfonate (STS) has been reported to ameliorate AD pathology. However, the underlying mechanism is still unclear. In this study, APP/PS1 mouse model was used to explore the potential mechanism of STS against AD. Morris water maze and Y-maze tests showed that administration of STS (10 or 20 mg/kg/day) improved learning and memory abilities of APP/PS1 mice. STS reduced the levels of ROS and MDA, while improved the activity of SOD in both hippocampus and cortex in APP/PS1 mice. STS inhibited the activity of AChE, while improved the activity of ChAT in APP/PS1 mice. In addition, STS elevated the protein expressions of neurotrophic factors (BDNF and NGF) and synapse-related proteins (PSD93, PSD95 and SYP) in both the hippocampus and cortex in APP/PS1 mice. At last, STS improved the protein expressions of GLUT1 and LRP1. These results indicated that the potential mechanism of STS on AD might be related to Aβ transportation function via GLUT1/LRP1 pathway.

Tanshinones induce tumor cell apoptosis via directly targeting FHIT

The liposoluble tanshinones are bioactive components in Salvia miltiorrhiza and are widely investigated as anti-cancer agents, while the molecular mechanism is to be clarified. In the present study, we identified that the human fragile histidine triad (FHIT) protein is a direct binding protein of sodium tanshinone IIA sulfonate (STS), a water-soluble derivative of Tanshinone IIA (TSA), with a Kd value of 268.4 ± 42.59 nM. We also found that STS inhibited the diadenosine triphosphate (Ap3A) hydrolase activity of FHIT through competing for the substrate-binding site with an IC50 value of 2.2 ± 0.05 µM. Notably, near 100 times lower binding affinities were determined between STS and other HIT proteins, including GALT, DCPS, and phosphodiesterase ENPP1, while no direct binding was detected with HINT1. Moreover, TSA, Tanshinone I (TanI), and Cryptotanshinone (CST) exhibited similar inhibitory activity as STS. Finally, we demonstrated that depletion of FHIT significantly blocked TSA’s pro-apoptotic function in colorectal cancer HCT116 cells. Taken together, our study sheds new light on the molecular basis of the anti-cancer effects of the tanshinone compounds.

Sodium Tanshinone IIA Sulfonate Ameliorates Injury-Induced Oxidative Stress and Intervertebral Disc Degeneration in Rats by Inhibiting p38 MAPK Signaling Pathway

Objective. Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivative of tanshinone IIA, a representative traditional Chinese medicine. The aim of the study was to investigate the capability of STS to reverse injury-induced intervertebral disc degeneration (IDD) and explore the potential mechanisms. Methods. Forty adult rats were randomly allocated into groups (control, IDD, STS10, and STS20). An IDD model was established by puncturing the Co8-9 disc using a needle. Rats in the STS groups were administered STS by daily intraperitoneal injection (10 or 20 mg/kg body weight) while rats in the control and IDD groups received the same quantity of normal saline. After four weeks, the entire spine from each rat was scanned for X-ray and MRI analysis. Each Co8-9 IVD underwent histological analysis (H&E, Safranin-O Fast green, and alcian blue staining). A tissue was analyzed by immunohistochemical (IHC) staining to determine the expression levels of collagen II (COL2), aggrecan, matrix metalloproteinase-3/13 (MMP-3/13), interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α). Levels of oxidative stress were measured using an ELISA while activity of the p38 MAPK pathway was assessed using Western blot analysis. Results. Compared with the control group, needle puncture significantly decreased IVD volume and T-2 weighted MR signal intensity, confirming disc degeneration. These alterations were significantly attenuated by treatment with 10 or 20 mg/kg STS. Lower COL2 and aggrecan and higher MMP-3/13, IL-1β, IL-6, and TNF-α levels in the IDD group were substantially reversed by STS. In addition, treatment with STS increased antioxidative enzyme activity and decreased levels of oxidative stress induced by needle puncture. Furthermore, STS inhibited the p38 MAPK pathway in the rat model of IDD. Conclusions. STS ameliorated injury-induced intervertebral disc degeneration and displayed anti-inflammatory and antioxidative properties in a rat model of IDD, possibly via inhibition of the p38 MAPK signaling pathway.

Sodium Tanshinone IIA Sulfonate Promotes Spinal Cord Injury Repair by Inhibiting BSCB Disruption In Vitro and In Vivo

Background:Spinal cord injury (SCI) leads to microvascular damage and the destruction of blood spinal cord barrier (BSCB), which progresses to secondary injuries like apoptosis and necrosis of neurons and glia, culminating in permanent neurological deficits. BSCB restoration is the primary goal of SCI therapy, although very few drugs can repair the damaged barrier structure and permeability. Sodium tanshinone IIA sulfonate (STS) is commonly used to treat cardiovascular disease. We found that STS restored BSCB integrity and promoted microvessel recovery 7 days after SCI in a mouse model. However, the therapeutic effects of STS on damaged BSCB in the early stage of SCI remained uncertain. Methods: we exposed spinal cord microvascular endothelial cells (SCMECs) to H2O2 and treated them with different doses of STS. The mice received intraperitoneal injection of STS after SCI in vivo model. Spinal cord tissue was taken 1 and 3d post-SCI. HE, Nissl staining, BSCB permeability, and the expression levels of tight junction (TJ) and adherens junction (AJ), MMP2, MMP9, NeuN, and C-caspase-3 were analyzed.Results: In addition to protecting the cells from H2O2-induced apoptosis, STS also reduced cellular permeability. In the in vivo model of SCI as well, STS reduced BSCB permeability, relieved tissue edema and hemorrhage, suppressed MMPs activation and prevented TJ and AJ the loss of proteins. Conclusions:Our findings indicate that STS treatment promotes SCI recovery, and should be investigated further as a drug candidate against traumatic SCI.