Sodium Tanshinone IIA Sulfonate Research Articles

Sodium tanshinone IIA sulfonate protects against hyperhomocysteine-induced vascular endothelial injury via activation of NNMT/SIRT1-mediated NRF2/HO-1 and AKT/MAPKs signaling in human umbilical vascular endothelial cells

Homocysteine (Hcy) is one of the independent risk factors of cardiovascular disease. Sodium tanshinone IIA sulfonate (STS) is a hydrophilic derivate of tanshinone IIA which is the main active constitute of Chinese Materia Medica Salviae Miltiorrhizae Radix et Rhizoma, and exhibits multiple pharmacological activities. However, whether STS could prevent from Hcy-induced endothelial cell injury is unknown.We found that STS dramatically reversed Hcy-induced cell death concentration dependently in human umbilical vascular endothelial cells (HUVECs). STS ameliorated the endothelial cell cycle progression, proliferation and cell migratory function impaired by Hcy, which might be co-related to the inhibition of intracellular oxidative stress and mitochondrial dysfunction. STS also elevated the phosphorylation of AKT and MAPKs and protein expression of sirtuin1 (SIRT1), NRF2 and HO-1 which were suppressed by Hcy. The protective effect of STS against Hcy-induced endothelial cell toxicity was partially attenuated by PI3K, AKT, MEK, ERK, SIRT1, NRF2 and HO-1 inhibitors. Besides, knockdown of SIRT1 by its siRNA dramatically decreased the endothelial protective effect of STS accompanied with suppression of SIRT1, NRF2, HO-1 and phosphorylated AKT. The activation of AKT or NRF2 partially reversed SIRT1-knockdown impaired cyto-protective effect of STS against Hcy-induced cell injury. Furthermore, STS prevented from Hcy-induced intracellular nicotinamide N-methyltransferase (NNMT) reduction along with elevation of intracellular methylnicotinamide (MNA), and MNA enhanced STS protecting against Hcy induced endothelial death. Knockdown of NNMT reduced the protective effect of STS against Hcy induced endothelial cell injury.Collectively, STS presented potent endothelial protective effect against Hcy and the underlying molecular mechanisms were involved in the suppression of intracellular oxidative stress and mitochondria dysfunction by activation of AKT/MAPKs, SIRT1/NRF2/HO-1 and NNMT/MNA signaling pathways.

Sodium Tanshinone IIA Sulfonate Inhibits Vascular Endothelial Cell Pyroptosis via the AMPK Signaling Pathway in Atherosclerosis.

Atherosclerosis (AS) is the underlying cause of cardiovascular events. Endothelial cell mitochondrial damage and pyroptosis are important factors contributing to AS. Changes in internal mitochondrial conformation and increase in reactive oxygen species (ROS) lead to the disruption of mitochondrial energy metabolism, activation of the NLRP3 inflammasome and pyroptosis, which in turn affect atherogenesis by impairing endothelial function. AMPK is a core player in the regulation of cellular metabolism, not only by regulating mitochondrial homeostasis but also by regulating cellular inflammatory responses. Sodium tanshinone IIA sulfonate (STS), a water-soluble derivative of tanshinone IIA, has significant antioxidant and anti-inflammatory effects, and roles in cardiovascular protection. In this study, we investigated whether STS plays a protective role in AS by regulating endothelial cell mitochondrial function and pyroptosis through an AMPK-dependent mitochondrial pathway. Male ApoE-/- mice and HUVECs were used for the experiments. We found that STS treatment largely abrogated the upregulation of key proteins in aortic vessel wall plaques and typical pyroptosis signaling in ApoE-/- mice fed a western diet, consequently enhancing pAMPK expression, plaque stabilization, and anti-inflammatory responses. Consistently, STS pretreatment inhibited cholesterol crystallization (CC) -induced cell pyroptosis and activated pAMPK expression. In vitro, using HUVECs, we further found that STS treatment ameliorated mitochondrial ROS caused by CC, as evidenced by the finding that STS inhibited mitochondrial damage caused by CC. The improvement of endothelial cell mitochondrial function by STS is blocked by dorsomorphin (AMPK inhibitor). Consistently, the blockade of endothelial cell pyroptosis by STS is disrupted by dorsomorphin. Our results suggest that STS enhances maintenance of mitochondrial homeostasis and inhibits mitochondrial ROS overproduction via AMPK, thereby improving endothelial cell pyroptosis during AS.

EEF‐2K knockdown synergizes with STS treatment to inhibit cell proliferation, migration, and invasion via the TG2/ERK pathway in A549 cells

Emerging research has suggested the anticancer potential of tanshinone IIA, the bioactive ingredient isolated from the traditional Chinese herb Salvia miltiorrhiza. However, the molecular mechanism of sodium tanshinone IIA sulfonate (STS) antilung cancer effect is not very clear. In this study, our purpose is to investigate the roles of STS and elongation factor-2 kinase (eEF-2K) in regulating the proliferation, migration, and invasion of A549 cells and explore the implicated pathways. We found that STS suppressed A549 cell survival and proliferation in a time- and xdose-dependent manner. Knockdown of eEF-2K and treatment with STS synergistically exerted antiproliferative, -migratory, and -invasive effects on A549 cells. These effects were caused by attenuation of the extracellular signal-regulated kinase(ERK) pathway via inhibition of tissue transglutaminase (TG2). In summary, the inhibition of eEF-2K synergizes with STS treatment, exerting anticancer effects on lung adenocarcinoma cells through the TG2/ERK signaling pathway, which provides a potential therapeutic target for treating lung adenocarcinoma.

Traditional Chinese medicine injections with activating blood circulation, equivalent effect of anticoagulation or antiplatelet, for acute myocardial infarction: A protocol for the systematic review and meta-analysis of randomized clinical trials.

BackgroundIn spite of a growing number in the use of percutaneous coronary intervention (PCI) in China, the mortality of acute myocardial infarction (AMI) has not decreased. Traditional Chinese medicine injections for Activating Blood Circulation (TCMi-ABC), equivalent effect of anticoagulation or antiplatelet, are widely used in China; however, the improvement of fatality towards AMI is unclear. Therefore, we intend to conduct a systematic review and meta-analysis to evaluate the efficacy and safety of TCMi-ABC in treatment with AMI.MethodsBased on the “National Medical Products Administration of China,” TCMi-ABC with AMI treatment indication will be selected, including Danhong injection, Sodium Tanshinone IIA Sulfonate injection, Danshen Chuanxiongqin injection, and Puerarin injection. Randomized controlled studies will be searched from as follows: PubMed, Embase, the CENTRAL in Cochrane Library, Chinese Biomedical Literature Database (SinoMed), China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), and Wanfang Data Knowledge Service Platform. Two researchers will work independently on literature selection, data extraction, and quality assessment. The outcomes focus on the effects of TCMi-ABC on fatality of patients with AMI in hospitalization and in the long term, the incidence of malignant arrhythmia, left ventricular ejection fraction, and adverse events. RevMan 5.4.1 software was used for mate analysis.ResultsThis study will conduct a comprehensive literature search and provide a systematic synthesis of current published data to explore the efficacy and safety of TCMi-ABC for AMI.ConclusionThis study will provide high-quality evidence for treatment of AMI with TCMi-ABC in terms of efficacy and safety, which may help clinicians make a better complementary treatment schedule of patients with AMI.

The regulatory effect of pulmonary lymphatic drainage on silicosis fibrosis

Silicosis is a fibrotic disease caused by long-term inhalation of SiO2 particles that currently has no effective treatment. Earlier studies have suggested that pulmonary lymphatic vessels play a key role in the transport of silica but have not address the long-term effects of altered pulmonary lymphatic drainage on silicosis. Here, we investigated the impact of impaired pulmonary lymphatic drainage on silicosis. In the past, lymphatic drainage disorders were established mainly through the use of VEGF inhibitors. For the first time, we established a model of pulmonary lymphatic drainage disorder by ligating the thoracic duct in rats. Impaired pulmonary lymphatic drainage was found to aggravate inflammation and oxidative damage in silicosis rats and accelerate silicosis progression. Next, we investigated the effect of pulmonary lymphatic drainage on silicosis. We have demonstrated the effect of sodium tanshinone IIA sulfonate(STS) on lymphangiogenesis, which revealed that STS promotes lymphangiogenesis and can delay inflammation, oxidative damage, and fibrosis progression in silicosis rats by promoting the pulmonary lymphatic drainage response, and this effect is mediated by the VEGFR-3/PI3K/AKT signaling pathway. These findings suggest that pulmonary lymphogenesis plays an important role in silicosis pathogenesis, and targeted intervention in pulmonary lymphangiogenesis may be a potential strategy for treating of silicosis in the future.

Tanshinone IIA protects against chronic obstructive pulmonary disease via exosome‑shuttled miR‑486‑5p

Chronic obstructive pulmonary disease (COPD) is one of the major causes of death worldwide today, and its related morbidity has been predicted to show an increase in subsequent years. Recent studies have shown that Danshen, a Chinese herbal medicine, is a potential drug in the treatment of inflammation-related lung diseases. COPD was induced in this study using cigarette smoke (CS) exposure plus intranasal inhalation of lipopolysaccharide to ascertain whether the main pharmacological component from Danshen, tanshinone IIA (TIIA), and its water soluble form, sodium tanshinone IIA sulfonate (STS), protect against the development of COPD. The weight, lung function, hematoxylin and eosin staining, and Masson Trichrome determinations revealed that TIIA inhalation attenuated lung dysfunction in COPD mice induced by cigarette smoke and lipopolysaccharide exposure. In addition, exosomes derived from TIIA-treated COPD mice exerted similar protective effects against COPD, suggesting that TIIA may protect against COPD through exosome-shuttled signals. miR-486-5p was found to be a key molecule in mediating the protective effects of exosomes derived from TIIA-treated COPD mice using miRNA sequencing and cellular screening. Treatment of COPD mice with an agomiR of miR-486-5p protected lung function in COPD mice, and treatment of COPD mice with an antagomir of miR-486-5p abolished the protective effects of TIIA. Moreover, luciferase activity reporter assay, RT-qPCR, and western blot analyses showed that miR-486-5p exerted protective effects against COPD via targeting phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1). These results suggest that STS protects against COPD through upregulation of miR-486-5p, and that TIIA or miR-486-5p is a potential drug for the treatment of COPD.

The crosstalk signals of Sodium Tanshinone ⅡA Sulfonate in rats with cerebral ischemic stroke: Insights from proteomics

BackgroundStroke could cause long-term disability, even mortality around the world. Recently, Sodium tanshinone IIA sulfonate (STS), identified from Salvia miltiorrhiza Bunge and was found to have unique efficiency in clinical practice as a potential therapeutic agent for ischemic cerebral infarction. However, systematic investigation about the biological mechanism is still lacking. Herein, we utilized high-throughput proteomics approach to identify the underlying targets for the treatment of STS in stroke. MethodsWe investigated the effect of STS on stroke outcomes on rat model of the Middle Cerebral Artery Occlusion and Reperfusion (MCAO/R), assessing by Z-Longa score, infarct volume and HE staining. Pharmacoproteomic profiling of ischemic penumbra in cortical (IPC) was performed using DIA-based label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) technique. Bioinformatics analysis was processed for further investigation. The expression of core proteins was semi-quantified by DIA, and the major protein correlating with stroke was examined using parallel reaction monitoring (PRM). ResultsRats in the MCAO/R group showed neurological function deterioration, which was improved by STS. There were 423 differentially expressed proteins (DEPs) in IPC being detected and quantified in both the sham group and the MCAO/R group. Meanwhile, 285 proteins were significantly changed in the STS treated group, compared to the MCAO/R model. Protein-protein interaction (PPI) network, pathway and biological function enrichment were processed for the DEPs across each two groups, the results of which were integrated for analysis. Alb, mTOR, Dync1h1, Stxbp1, Cltc, and Sptan1 were contained as the core proteins. Altered molecules were discovered to be enriched in 18 signal pathways such as phosphatidylinositol signaling system, PI3K/AKT signal pathway and HIF-1 signal pathway. The results also showed the correlation with sleep disturbances and depression post-stroke. ConclusionsWe concluded that STS could prevent penumbra from progressively ongoing damage and improve neurological deficits in MCAO/R model rats. The intersected pathways and protein networks predicted by proteomics might provide much more detailed information for the therapeutic mechanisms of STS in the treatment of CIS.

Sodium Tanshinone IIA Sulfonate as a Potent IDO1/TDO2 Dual Inhibitor Enhances Anti-PD1 Therapy for Colorectal Cancer in Mice.

Although the antitumor efficacy of immune checkpoint blockade (ICB) has been proved in colorectal cancer (CRC), the results are unsatisfactory, presumably owing to the presence of tryptophan metabolism enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2). However, only a few dual inhibitors for IDO1 and TDO2 have been reported. Here, we discovered that sodium tanshinone IIA sulfonate (STS), a sulfonate derived from tanshinone IIA (TSN), reduced the enzymatic activities of IDO1 and TDO2 with a half inhibitory concentration (IC50) of less than 10 μM using enzymatic assays for natural product screening. In IDO1- or TDO2- overexpressing cell lines, STS decreased kynurenine (kyn) synthesis. STS also reduced the percentage of forkhead box P3 (FOXP3) T cells in lymphocytes from the mouse spleen cocultured with CT26. In vivo, STS suppressed tumor growth and enhanced the antitumor effect of the programmed cell death 1 (PD1) antibody. Compared with anti-PD1 (α-PD1) monotherapy, combined with STS had lower level of plasma kynurenine. Immunofluorescence assay suggested that STS decreased the number of FOXP3+ T cells and increased the number of CD8+ T cells in tumors. Flow cytometry analysis of immune cells in tumor tissues demonstrated an increase in the percentage of tumor-infiltrating CD8+ T cells. According to our findings, STS acts as an immunotherapy agent in CRC by inhibiting both IDO1 and TDO2.

Sodium tanshinone IIA sulfonate enhances the BMP9-BMPR2-Smad1/5/9 signaling pathway in rat pulmonary microvascular endothelial cells and human embryonic stem cell–derived endothelial cells

BackgroundRecent studies have demonstrated the beneficial effects of STS in treating pulmonary hypertension by inhibiting the pulmonary vascular remodeling and suppressing the abnormally elevated proliferation and migration of PASMCs. However, the roles of STS on pulmonary vascular endothelium remain largely known. MethodsIn this study, we investigated the effects and mechanisms of STS on pulmonary vascular endothelial dysfunction by using a chronic hypoxia-induced pulmonary hypertension (HPH) rat model, as well as in primarily cultured rat PMVECs and human ESC-ECs cell models. ResultsFirstly, a 21-day treatment of STS significantly prevents the disease development of HPH by normalizing the right ventricular systolic pressure and right ventricular hypertrophy, improving the cardiac output. Then, STS treatment markedly inhibits the hypoxia-induced medial wall thickening of the distal intrapulmonary arteries. Notably, STS significantly inhibits the hypoxia-induced apoptosis in both the pulmonary endothelium of HPH rats and primarily cultured PMVECs, through the stabilization of BMPR2 protein and protection of the diminished BMP9-BMPR2-Smad1/5/9 signaling pathway. In mechanism, STS treatment retrieves the hypoxic downregulation of BMPR2 by stabilizing the BMPR2 protein, inhibiting the BMPR2 protein degradation via lysosome system, and promoting the plasma membrane localization of BMPR2, all of which together reinforcing the BMP9-induced signaling transduction in both PMVECs and human ESC-ECs. However, these effects are absent in hESC-ECs expressing heterozygous dysfunctional BMPR2 protein (BMPR2+/R899X). ConclusionSTS may exert anti-apoptotic roles, at least partially, via induction of the BMP9-BMPR2-Smad1/5/9 signaling transduction in pulmonary endothelium and PMVECs.

Sodium Tanshinone IIA Sulfonate Improves Adverse Ventricular Remodeling Post-MI by Reducing Myocardial Necrosis, Modulating Inflammation, and Promoting Angiogenesis.

Myocardial infarction (MI) leads to pathological cardiac remodeling and heart failure. Sodium tanshinone IIA sulfonate (STS) shows to possess therapeutic potential. The present study aimed to explore the potential role of STS in ventricular remodeling post-MI. 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. 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. STS improved pathological remodeling post-MI, and the associated therapeutic effects may be a result of a decrease in myocardial necrosis, modulation of inflammation, and an increase in angiogenesis.

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, AD transgenic mouse model (APP/PS1) was used to explore the potential mechanism of STS against AD. Morris water maze and Y-maze tests showed that administration of STS improved learning and memory abilities of APP/PS1 mice. STS reduced the levels of reactive oxygen species and malondialdehyde, while improved the activity of superoxide dismutase in both hippocampus and cortex in APP/PS1 mice. STS inhibited the activity of acetylcholinesterase, while improved the activity of choline acetyltransferase in APP/PS1 mice. In addition, STS elevated the protein expressions of neurotrophic factors and synapse-related proteins in both the hippocampus and cortex in APP/PS1 mice. At last, STS improved the protein expressions of glucose transporter 1 (GLUT1) and low-density lipoprotein receptor-related protein 1 (LRP1). These results indicated that the potential mechanism of STS on AD might be related to Aβ transportation function via GLUT1/LRP1 pathway. HIGHLIGHTS: STS improves cognitive impairment of APP/PS1 mice. STS ameliorates the oxidative stress damage and improves the cholinergic system. STS protects against neuronal dysfunction and enhances the synaptic plasticity. STS mediates the Aβ transportation of BMECs.

Tetramethylpyrazine Stalls Lesional Progression via Inducing Senescence in Mouse with Induced Deep Endometriosis

So far, the pressing need for the development of non-hormonal therapeutics for endometriosis has been unfulfilled. In light of the evidence that platelets play important roles in the development of endometriosis and that tetramethylpyrazine has therapeutic potential, we tested the hypothesis that tetramethylpyrazine can induce cellular senescence in endometriotic lesions, hindering fibrogenesis in mice with induced deep endometriosis and that the combined use of tetramethylpyrazine and sodium tanshinone IIA sulfonate may have a synergistic effect. We induced deep endometriosis in 32 female Balb/C mice, and then randomly divided mice into equal-sized four groups: low- and high-dose tetramethylpyrazine, low-dose tetramethylpyrazine plus low-dose tanshinone IIA sulfonate and inert vehicle control. After two weeks of treatment, their lesion tissues were removed and procured. All lesions were weighed, and lesion fibrosis was quantitated by Masson trichrome staining. In addition, cellular senescence in lesions was evaluated by senescence-associated β-galactosidase, along with immunohistochemistry analyses of p53, Salvador 1, cellular communication network factor 1, hyaluronan synthase 2, surviving and granulocyte-macrophage colony stimulating factor and other markers. We found that tetramethylpyrazine treatment significantly decreased lesion weight, arrested lesional progression and ameliorated pain behaviour ostensibly via inducing senescence by p53 activation, and induction of Salvador 1 and cellular communication network factor 1 while suppressing hyaluronan synthase 2, survivin and granulocyte-macrophage colony stimulating factor, resulting in increased apoptosis and reduced lesional infiltration of alternatively activated macrophages. Tetramethylpyrazine treatment also significantly reduced the plasma concentration of P-selectin and hyaluronic acid, possibly leading to reduced lesional platelet aggregation. Thus, we conclude that tetramethylpyrazine holds the promise as therapeutics for treating endometriosis, but the tetramethylpyrazine plus tanshinone IIA sulfonate did not further enhance the therapeutic effect. These results further underscore the notion that induced senescence may play an antifibrotic role in endometriosis, and activating the senescence pathway, through treatment with tetramethylpyrazine or other similar drugs, may be a novel avenue for treating endometriosis.

Sodium tanshinone ⅡA sulfonate injection as adjunctive therapy for the treatment of heart failure: A systematic review and meta-analysis

BackgroundSodium tanshinone ⅡA sulfonate (STS) injection has been widely used to treat heart failure over the past years in China. However, to the best of our knowledge, neither systematic review nor meta-analysis on the efficacy of STS injection as adjunctive therapy for heart failure has been reported. ObjectiveThe aim of this study is to summarize relevant evidence from the published randomized controlled trials (RCTs) to evaluate the efficacy of STS injection as adjunctive therapy for heart failure. MethodsRCTs on STS injection as adjunctive therapy for the treatment of heart failure were screened from China National Knowledge Infrastructure (CNKI), Wanfang Database, Sino-Med, PubMed, Google Scholar, Medline, China Science and Technology Journal Database (VIP), Chinese Biomedical Literature Database, Cochrane Library, Embase and Chinese Science Citation Database until July 2021. Two authors independently performed the literature searching, data extraction, and quality evaluation. The meta-analysis was carried out by RevMan 5.3. Based on the methodological quality, years of publication, and sample size of the included RCTs, sensitivity analysis and subgroup analysis were investigated. ResultsFourteen RCTs with a total of 1368 patients were identified in this study. Results from this meta-analysis showed that STS injection as adjunctive therapy was superior to western medicine alone for the treatment of heart failure in improving the total effective rate (RR = 1.23; 95% CI, 1.17 to 1.29; p < 0.00001) and the left ventricular ejection fraction (LVEF; MD = 6.34; 95% CI 5.25 to 7.43; p < 0.00001), meanwhile reducing the left ventricular end-diastolic diameter (LVEDD; MD = -4.79; 95% CI, -6.44 to -3.15; p < 0.00001), left ventricular end-systolic dimension (LVESD; MD = -3.98; 95% CI, -5.79 to -2.17; p < 0.0001) and brain natriuretic peptide (BNP; MD = -118.75; 95% CI, -175.36 to -62.15; p < 0.0001). ConclusionsThis study indicated that STS injection as adjunctive therapy seemed to be more effective than western medicine alone in treating heart failure. However, due to the poor methodological quality of the included RCTs, further well-designed RCTs are required to confirm the efficacy of STS injection.

Sodium tanshinone IIA sulfonate promotes spinal cord injury repair by inhibiting blood spinal cord barrier disruption in vitro and in vivo.

Spinal cord injury (SCI) leads to microvascular damage and the destruction of the blood spinal cord barrier (BSCB), which can progress into secondary injuries, such as 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 damaged barrier structure and permeability. Sodium tanshinone IIA sulfonate (STS) is commonly used to treat cardiovascular disease. However, the therapeutic effects of STS on damaged BSCB during the early stage of SCI remain uncertain. Therefore, we exposed spinal cord microvascular endothelial cells to H2 O2 and treated them with different doses of STS. In addition to protecting the cells from H2 O2 -induced apoptosis, STS also reduced cellular permeability. In the in vivo model of SCI, STS reduced BSCB permeability, relieved tissue edema and hemorrhage, suppressed MMP activation and prevented the loss of tight junction and adherens junction proteins. Our findings indicate that STS treatment promotes SCI recovery, and should be investigated further as a drug candidate against traumatic SCI.

Traditional Herbal Medicine Discovery for the Treatment and Prevention of Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is characterized by pulmonary artery remodeling that may subsequently culminate in right heart failure and premature death. Although there are currently both non-pharmacological (lung transplantation, etc.) and pharmacological (Sildenafil, Bosentan, and new oral drugs on trial) therapies available, PAH remains a serious and fatal pulmonary disease. As a unique medical treatment, traditional herbal medicine (THM) treatment has gradually exerted its advantages in treating PAH worldwide through a multi-level and multi-target approach. Additionally, the potential mechanisms of THM were deciphered, including suppression of proliferation and apoptosis of pulmonary artery smooth muscle cells, controlling the processes of inflammation and oxidative stress, and regulating vasoconstriction and ion channels. In this review, the effects and mechanisms of the frequently studied compound THM, single herbal preparations, and multiple active components from THM are comprehensively summarized, as well as their related mechanisms on several classical preclinical PAH models. It is worth mentioning that sodium tanshinone IIA sulfonate sodium and tetramethylpyrazine are under clinical trials and are considered the most promoting medicines for PAH treatment. Last, reverse pharmacology, a strategy to discover THM or THM-derived components, has also been proposed here for PAH. This review discusses the current state of THM, their working mechanisms against PAH, and prospects of reverse pharmacology, which are expected to facilitate the natural anti-PAH medicine discovery and development and its bench-to-bedside transformation.

Traditional Chinese Medicine Injections Combined With Antihypertensive Drugs for Hypertensive Nephropathy: A Network Meta-Analysis.

Background: Hypertension, a risk factor for cardiovascular events, is often associated with chronic kidney disease. This is called hypertensive nephropathy (HN), which negatively affects physical fitness and body mass, leading to economic burden. Traditional Chinese medicine injections (TCMIs) are common traditional Chinese-patent medicine preparations in China. There was a lack of evidence to prove which TCMIs combine with ADs (TCMIs+ADs) may be a therapeutic option for HN. Thus, we systematically reviewed the efficacy and safety of various TCMIs + ADs in patients with HN. Methods: We conducted a comprehensive search of PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, and VIP information resource integration service platform databases for relevant Chinese- and English-language randomized controlled trials (RCTs) published from database inception until May 2021. Literature screening, data extraction, and quality assessment was performed by two reviewers independently but using the same criteria. We performed the effect modeling to analyze the data for all outcomes and ranked each intervention using the P-score. Furthermore, sensitivity analysis, meta-regression, and funnel plots were used to test the stability, heterogeneity, and publication bias, respectively. Results: We included 69 RCTs with 6373 patients and including six TCMIs + ADs. Network analysis indicated that the ginkgo leaf extract and dipyridamole combined with ADs (GLED + ADs) was the most efficacious in terms of 24-h urinary protein excretion [mean difference (MD) = −0.70, 95% confidence interval (CI): −0.82 to −0.58; P-score = 1] and systolic blood pressure (MD = −12.95, 95% CI: −21.03 to −4.88; P-score = 0.88), whereas the salvianolate combined with ADs (SA + ADs) showed the highest effectiveness for diastolic blood pressure (MD = −6.88, 95% CI: −10.55 to −3.21; P-score = 0.9). Based on the combined P-score of network meta-analysis results (88% and 85.26%) and sensitivity analysis results (72% and 71.54%), the biplots showed that the GLED + ADs was the most efficacious intervention in all TCMIs + ADs for primary outcomes, followed by the SA + ADs and sodium tanshinone IIA sulfonate combined with ADs (STS + ADs). There was no significant difference in terms of safety between TCMIs + ADs and ADs alone. Conclusion: Of all the TCMIs + ADs, GLED + ADs, SA + ADs, and STS + ADs may demonstrate a higher efficacy than ADs alone for HN. Weighing with the potential benefits and limitations in methodology, potential heterogeneity and outcomes, we should use various TCMIs with caution in clinical practice. Nevertheless, additional high-quality RCTs are warranted and future research should focus on the clinical value of core outcomes to confirm the effectiveness and safety of TCMIs for HN. Systematic Review Registration: clinicaltrials.gov, identifier CRD42020205358

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 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 protein levels (complexes I-IV) in CSE-stimulated A549 cells. The protective effects of STS were associated with SIRT1 upregulation, because 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.

Prevention of endotoxin-induced cardiomyopathy using sodium tanshinone IIA sulfonate: Involvement of augmented autophagy and NLRP3 inflammasome suppression

Increasing evidence indicates that patients or experimental animals exposure to endotoxin (lipopolysaccharides, LPS) exert deleterious cardiac functions that greatly contribute to morbidity and mortality. The pathophysiologic processes, including NLRP3 inflammasome overactivation and cardiac inflammatory injury, are complicated. Sodium tanshinone IIA sulfonate (STS), a water-soluble derivative of tanshinone IIA, is a naturally occurring compound extracted from Salvia miltiorrhiza and has anti-inflammatory and cardioprotective properties. In this study we examined the effect of STS on endotoxin-induced cardiomyopathy and investigated the underlying mechanisms. An endotoxemic mouse model was established by injecting LPS (10 mg/kg). Different doses of STS were administered intraperitoneally (5, 10, or 50 mg/kg) at different time points (2/12 h, 4/12 h, and 8/12 h) after LPS challenge to assess its effect on survival of mice with endotoxemia. In parallel, cardiac function, myocardial inflammatory cytokines, cardiomyocyte pyroptosis and autophagy were evaluated to determine the extent of myocardial damage due to sepsis in the presence and absence of STS at the optimal dose (10 mg/kg) and time-point (2/12 h). The results demonstrated that STS increased the survival rates, improved the compromised cardiac function and reduced myocardial inflammatory injury associated with enhanced autophagy and mitigated NLRP3 inflammasome activation. Moreover, inhibiting of autophagy or blocking the AMPK pathway reversed STS-elicited prevention of cardiomyopathy and activated the NLRP3 inflammasome in endotoxemic mice. Collectively, our study demonstrates that STS attenuates endotoxemia-induced mortality and cardiomyopathy, which may be associated with promotion of autophagy and inhibition of NLRP3 inflammasome overactivation.

Sodium tanshinone IIA sulfonate ameliorates cerebral ischemic injury through regulation of angiogenesis.

Vascular remodeling and neuroprotection are two major adaptable methods for treating ischemic stroke. Edaravone is a protective agent for the treatment of stroke and was used as a positive control in the present study. Sodium tanshinone IIA sulfonate (STS) has demonstrated therapeutic clinical effects in cerebral infarction in China, while its mechanisms of action in ischemic stroke have remained elusive. The angiogenesis and neuroprotective effects of STS were evaluated in a rat model induced by middle cerebral artery occlusion and 3 days of reperfusion. When used at the same dose, the magnitude of the therapeutic effect of STS was similar to that of edaravone in terms of decreased blood-brain barrier damage as indicated by reduced Evans blue leakage, improved neurological deficits, alleviated cerebral edema and inhibition of histopathological changes caused by ischemia/reperfusion. The TUNEL assay demonstrated that the ability of STS to inhibit neuronal apoptosis was equivalent to that of edaravone. Immunofluorescence detection of CD31 and α-smooth muscle actin indicated that the vascular density was significantly reduced in the vehicle group compared with that in the sham operation group, STS increased the microvessel density in the ischemic area. Furthermore, in the vehicle group the protein expression of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR) as determined by fluorescence microscopy and immunohistochemistry was significantly reduced compared with that in the sham group. However, STS promoted their expression compared to the vehicle group respectively, and increaed the mRNA expression of VEGF, VEGFR, CD31 and angiopoietin-1 as determined by reverse transcription-quantitative PCR, but these changes were not significant or not present for edaravone apart from Ang-1. In conclusion, STS protected against ischemic brain injury by promoting angiogenesis in ischemic areas and inhibiting neuronal apoptosis. These results provide a potential treatment for stroke recovery.

Network Meta-analysis of clinical efficacy of Chinese herbal injection in adjuvant treatment of unstable angina pectoris

The present study evaluated the curative efficacy of Chinese herbal injection on unstable angina pectoris( UAP) by network Meta-analysis. The databases,including Pub Med,Cochrane Library,Web of Science,CNKI,CBM,VIP and Wanfang were searched for randomized controlled trial( RCT) of Chinese herbal injection in the treatment of UAP. All researchers independently screened the articles,extracted the data and evaluated the quality. Open BUGS and Stata were employed for the analysis of the trials that met the quality standards. Fifty-eight studies were finally included in this study,involving 20 intervention measures. In terms of the effective rate,16 injections such as Dengzhan Xixin Injection,Xuesaitong Injection and Danshen Injection combined with western medicine exhibited significant efficacy. In terms of ECG,Puerarin Injection,Ginkgo Leaf Extract and Dipyridamole Injection( GDI),Breviscapine Injection combined with western medicine were superior to western medicine. In terms of the reduction of the angina attack times,Sodium Tanshinone ⅡASulfonate Injection,GDI and Dazhu Hongjingtian Injection combined with western medicine showed better effects than western medicine. In terms of shortening the angina duration,Shenmai Injection combined with western medicine was superior to western medicine. As revealed by the results,Dengzhan Xixin Injection,Xuesaitong Injection,Danshen Injection,Breviscapine Injection,Danshen Ligustrazine Injection combined with western medicine displayed prominent curative efficacy,which were recommended for clinical application. Meanwhile,appropriate intervention measures should be selected according to individual conditions. Limited by the quality of the included trials,the conclusions still need to be further verified.