• CD40‐AKT pathway
• endometrial carcinoma
• salvianolic acid A

• Female
• Humans
• Salvia miltiorrhiza/chemistry
• Animals
• Proto-Oncogene Proteins c-akt/metabolism
• Signal Transduction/drug effects
• NF-kappa B/metabolism
• Cell Line, Tumor
• Mice
• Endometrial Neoplasms/drug therapy
• Endometrial Neoplasms/pathology
• Endometrial Neoplasms/metabolism
• Cell Proliferation/drug effects
• CD40 Antigens/metabolism
• CD40 Antigens/genetics
• Apoptosis/drug effects
• Caffeic Acids/pharmacology
• Caffeic Acids/therapeutic use
• Xenograft Model Antitumor Assays
• Lactates/pharmacology
• Lactates/therapeutic use
• Cell Movement/drug effects
• Mice, Nude
• Disease Progression
• Mice, Inbred BALB C
• Cell Survival/drug effects

• FRG-24-046-FC Macau University of Science and Technology Research Fund

• a long-term synaptic depression
• acute ischemic stroke
• middle cerebral artery occlusion (MCAO)
• neuroprotective
• photothrombosis
• salvianolic acid a

• Animals
• Neuroprotective Agents/pharmacology
• Neuroprotective Agents/therapeutic use
• Male
• Rats
• Mice
• Long-Term Synaptic Depression/drug effects
• Caffeic Acids/pharmacology
• Caffeic Acids/therapeutic use
• Disease Models, Animal
• Lactates/pharmacology
• Lactates/therapeutic use
• Rats, Sprague-Dawley
• Mice, Inbred C57BL
• Neuroprotection/drug effects
• Infarction, Middle Cerebral Artery/drug therapy
• Stroke/drug therapy

• Caffeic acid (PubChem CID 689043)
• Clinical applications
• Danshensu (PubChem CID 11600642)
• Ischemic stroke
• Lithospermic acid (PubChem CID 6441498)
• Molecular mechanisms
• Pathogenesis
• Protocatechualdehyde (PubChem CID 8768)
• Protocatechuic acid (PubChem CID 72)
• Rosmarinic acid (PubChem CID 5281792)
• Salvia miltiorrhiza
• Salvianolic acids
• Salvianolic acids A, B, C, D, E, and Y (PubChem CIDs 5281793, 11629084, 13991590, 75412558, 86278266, 97182154)

• Humans
• Animals
• Ischemic Stroke/drug therapy
• Ischemic Stroke/metabolism
• Polyphenols/therapeutic use
• Polyphenols/pharmacology
• Alkenes/therapeutic use
• Alkenes/pharmacology
• Neuroprotective Agents/therapeutic use
• Neuroprotective Agents/pharmacology
• Salvia miltiorrhiza/chemistry

• STING
• Salvianolic acid A
• Skin damage
• UVB

• Ultraviolet Rays/adverse effects
• Membrane Proteins/metabolism
• Membrane Proteins/genetics
• Animals
• Signal Transduction/drug effects
• Keratinocytes/drug effects
• Keratinocytes/radiation effects
• Skin/drug effects
• Skin/pathology
• Skin/radiation effects
• Nucleotidyltransferases/metabolism
• Caffeic Acids/pharmacology
• Humans
• Mice
• Macrophages/drug effects
• Macrophages/immunology
• Mice, Inbred C57BL
• Skin Aging/drug effects
• Skin Aging/radiation effects
• DNA Damage/drug effects
• Interferon Regulatory Factor-3/metabolism
• Female
• RAW 264.7 Cells
• Lactates

• Activity evaluation
• Hypoxia
• Natural products
• Online stacking
• Prolyl hydroxylase domain 2

• Humans
• Biological Products/pharmacology
• Electrophoresis, Capillary/methods
• Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists & inhibitors
• Ketoglutaric Acids/analysis

• Blood-brain barrier
• Brain-targeted liposomes
• Ischemic stroke
• Neuroprotective effect
• Salvianolic acid A

• Animals
• Liposomes
• Ischemic Stroke/drug therapy
• Male
• Caffeic Acids/administration & dosage
• Caffeic Acids/chemistry
• Caffeic Acids/pharmacology
• Blood-Brain Barrier/drug effects
• Blood-Brain Barrier/metabolism
• Receptor, IGF Type 1/metabolism
• Mice
• Lactates/administration & dosage
• Lactates/chemistry
• Infarction, Middle Cerebral Artery/drug therapy
• Drug Delivery Systems/methods
• Rats, Sprague-Dawley
• Rats
• Brain/metabolism
• Brain/drug effects

• inflammaging
• inflammation
• oxidative stress
• phenolic composition
• senescence

• UIDB/04539/2020 Fundação para a Ciência e Tecnologia
• UIDP/04539/2020 Fundação para a Ciência e Tecnologia
• LA/P/0058/2020 Fundação para a Ciência e Tecnologia

• Atherosclerosis
• Inflammation
• Macrophage
• Salvianolic acid A
• Secretory GRP78

• Mice
• Animals
• Endothelial Cells/metabolism
• Endoplasmic Reticulum Chaperone BiP
• Lipopolysaccharides
• RNA, Long Noncoding
• Atherosclerosis/drug therapy
• Inflammation

• aging
• essential oil
• hydrodistillation residual water
• inflammatory mediators
• phytochemical composition

• UIDB/04539/2020 Fundação para a Ciência e Tecnologia
• UIDP/04539/2020 Fundação para a Ciência e Tecnologia
• LA/P/0058/2020 Fundação para a Ciência e Tecnologia

Disseminated intravascular coagulation (DIC) is a syndrome characterized by coagulopathy, microthrombus, and multiple organ failure. The complement system in DIC is overactivated, and the functions of complement and coagulation pathways are closely related. Our previous screening revealed that salvianolic acid A (SAA) has anti-complement activity. The hyper-activated complement system was involved in the lipopolysaccharide (LPS) induced DIC in rats. The effects of SAA anti-complement action on LPS-induced DIC in rats were investigated.

The complement activity of the classical pathway and alternative pathway was detected through an in vitro hemolysis assay. The binding sites of SAA and complement C3b were predicted by molecular docking. LPS-induced disseminated coagulation experiments were performed on male Wistar rats to assess coagulation function, complement activity, inflammation, biochemistry, blood routine, fibrinolysis, and survival.

SAA had an anti-complement activity in vivo and in vitro and inhibited the complement activation in the classical and alternative pathway of complement. The infusion of LPS into the rats impaired the coagulation function, increased the plasma inflammatory cytokine level, complemented activation, reduced the clotting factor levels, fibrinogen, and platelets, damaged renal, liver, and lung functions, and led to a high mortality rate (85%). SAA treatment of rats inhibited complement activation and attenuated the significant increase in D-dimer, interleukin-6, alanine aminotransferase, and creatinine. It ameliorated the decrease in plasma levels of fibrinogen and platelets and reversed the decline in activity of protein C and antithrombin III. The treatment reduced kidney, liver, and lung damage, and significantly improved the survival rate of rats (46.2 and 78.6% for the low- and high-dose groups, respectively).

SAA reduced LPS-induced DIC by inhibiting complement activation. It has considerable potential in DIC treatment.

Salvianic acid A (SAA), as the main bioactive component of the traditional Chinese herb Salvia miltiorrhiza, has important application value in the treatment of cardiovascular diseases. In this study, a two-step bioprocess for the preparation of SAA from l-DOPA was developed. In the first step, l-DOPA was transformed to 3,4-dihydroxyphenylalanine (DHPPA) using engineered Escherichia coli cells expressing membrane-bound L-amino acid deaminase from Proteus vulgaris. After that, the unpurified DHPPA was directly converted into SAA by permeabilized recombinant E. coli cells co-expressing d-lactate dehydrogenase from Pediococcus acidilactici and formate dehydrogenase from Mycobacterium vaccae N10. Under optimized conditions, 48.3 mM of SAA could be prepared from 50 mM of l-DOPA, with a yield of 96.6%. Therefore, the bioprocess developed here was not only environmentally friendly, but also exhibited excellent production efficiency and, thus, is promising for industrial SAA production.

• biocatalysis
• biological engineering
• l-DOPA
• membrane-bound l-amino acid deaminases
• molecular biology
• salvianic acid A

• Biocatalysis
• Escherichia coli/genetics
• Formate Dehydrogenases
• Levodopa
• Phenylpyruvic Acids

• Chinese herb medicine
• Clozapine
• cardiotoxicity
• salvianolic acid A
• zebrafish embryos

Retinal degeneration (RD) is a serious, irreversible, and blinding eye disease, which seriously affects the visual function and quality of life of patients. At present, there is no effective method to treat RD. The final outcome of its development is photoreceptor cell oxidation and apoptosis. Therefore, looking for safe, convenient, and effective antioxidant therapy is still the key research field of Rd. In this study, the mice model of RD was induced by N-methyl-N-nitrosourea (MNU) in vivo to explore the therapeutic effect and mechanism of salvianolic acids (Sal A) on RD. In vitro, the protective effect of Sal A on MNU injured 661 W cell line of mouse retina photoreceptor cone cells was investigated preliminarily.

Male C57BL/6 mice (7–8 weeks old) received a single intraperitoneal injection (ip) of 60 mg/kg MNU or vehicle control. Treatment groups then received Sal-A 0.5 mg/kg and 1.0 mg/kg via daily intravenous injections. On day 7, functional and morphological examinations were performed, including photopic and scotopic electroretinography (ERG) and hematological analyses to observe functional changes and damage to the outer nuclear layer (ONL). On the 3rd and 7th days, the levels of superoxide dismutase (SOD) activity and malondialdehyde (MDA) content were determined. The expression of retinal Bax, Bcl-2, and caspase-3 was quantified by Western blot and RT-PCR assays. 661 W strain of mice retinal photoreceptor cone cells were cultured in vitro and treated with 1 µm MNU. The cells in the treatment group were given 50 μM Sal A as an intervention. The growth of 661 W cells was observed and recorded under an inverted light microscope, and the activity of cells was detected by the MTT method.

Sal A treatment was effective against MNU-induced RD in mice at both 0.5 mg/kg/d and 1.0 mg/kg/d doses, and the protective effect was dose-dependent. Sal A can alleviate MNU-mediated alterations to retinal ERG activity and can support maintenance of the thickness of the ONL layer. Sal A treatment increases the expression of retinal SOD and reduces the lipid peroxidation product MDA, suggesting that its protective effect is related to the oxidation resistance. It can offset changes to the expression of apoptotic factors in the retina caused by MNU treatment. Sal A mitigates MNU-mediated damage to cultured mice photoreceptor cone cells 661 W in vitro.

Sal A alleviates the damage caused by MNU to retinal photoreceptor cells in vivo and in vivo, and its protective effect is related to its antioxidant and antiapoptotic activities.

A cardioprotective effect of salvianolic acid A (SalA) has been described, but it is unknown whether SalA can protect cardiomyocytes against doxorubicin (Dox)-induced cardiotoxicity. This study aimed to investigate whether SalA could inhibit Dox-induced apoptosis in H9C2 cells and to uncover the potential mechanism.

H9C2 cardiomyocytes exposed to Dox were treated with SalA or not, and then cell viability, apoptosis, and the expression of nuclear factor-κB (NF-κB) signaling were detected by Cell Counting Kit-8, TUNEL staining, and western blot assays, respectively. Nuclear factor kappa B subunit 1 (NFKB1) was overexpressed in H9C2 cells, and then alterations in cell viability and apoptosis in H9C2 cells co-treated with Dox and SalA were investigated.

SalA (2, 10, and 50 μM) had no effect on H9C2 cell viability, while Dox reduced cell viability in a concentration-dependent manner. In addition, SalA rescued Dox-decreased cell viability. Dox also triggered apoptosis as evidenced by an increased ratio of TUNEL-positive cells, enhanced expression of pro-apoptotic proteins, and reduced expression of anti-apoptotic protein BCL-2, which were all partially blocked by SalA co-treatment. The proteins involved in NF-κB signaling including IκBα, IKKα, IKKβ, and p65 were activated by Dox but inactivated by SalA co-treatment. Moreover, Dox increased NFKB1 mRNA and nuclear expression, which was blocked by SalA. NFKB1 could bind to plasmacytoma variant translocation 1 (PVT1) and upregulate PVT1 expression. Mechanistically, the overexpression of NFKB1 blocked the inhibitory effect of SalA on Dox-induced cell viability impairment and apoptosis.

We demonstrated that SalA may exert a protective effect against Dox-induced H9C2 injury and apoptosis via inhibition of NFKB1 expression, thereby downregulating lncRNA PVT1.

• adenosine monophosphate activated protein kinase
• lipotoxicity
• non-alcoholic fatty liver disease
• salvianolic acid A
• sirtuin 1

Salvia miltiorrhiza (Danshen), as an important traditional Chinese medicinal plant, has been used in China for the treatment of cardiovascular diseases for hundreds of years. Salvianolic acids (salvianolic acid A and salvianolic acid B) as the most abundant water-soluble component extracted from Salvia miltiorrhiza have attracted more and more attention from cardiovascular scientists due to its comprehensive cardiovascular actions. In vivo and in vitro studies have rendered salvianolic acid an excellent drug candidate for the treatment and prevention of cardiovascular diseases. In this review, we surveyed the protective effects of salvianolic acid A and salvianolic acid B against cardiovascular diseases and the pharmacological basis, providing a strong scientific rationale for elucidating the important role of Salvia miltiorrhiza in cardiovascular therapy. More importantly, we also hope to provide new inspiration and perspectives on the development and innovation of small-molecule cardiovascular drugs based on salvianolic acid.

• Invasion
• MMP-2
• Migration
• Nasopharyngeal carcinoma
• Salvianolic acid A

• Antineoplastic Agents/pharmacology
• Caffeic Acids/pharmacology
• Cell Line, Tumor
• Cell Movement/drug effects
• Humans
• Lactates/pharmacology
• MAP Kinase Signaling System/drug effects
• Matrix Metalloproteinase 2/genetics
• Matrix Metalloproteinase 2/metabolism
• Matrix Metalloproteinase Inhibitors/pharmacology
• Nasopharyngeal Neoplasms/drug therapy
• Nasopharyngeal Neoplasms/metabolism
• Neoplasm Invasiveness

Platelets in patients with type 2 diabetes mellitus (DM2) are characterized by increased activation and aggregation, which tends to be associated with a high morbidity and mortality due to cardiovascular disease (CVD). Moreover, a large proportion of DM2 patients show an inadequate response to standard antiplatelet treatments, contributing to recurrent cardiovascular events. In our previous study, we indicated that Salvianolic acid A (SAA) presents an antiplatelet effect in healthy volunteers. However, whether it can inhibit “activated platelets” with a pathologic status has not been explored. Therefore, this study was designed to investigate the antiplatelet effect of SAA and its diabetic complication-related difference in DM2.

Forty patients diagnosed with DM2 from January 2018 to April 2018 were recruited. Fibrinogen-binding (PAC-1) and P-selectin (CD62p) flow cytometry reagents were measured under resting and stimulated conditions by flow cytometry, while agonist-induced platelet aggregation was conducted by light transmission aggregometry. Before all these measurements were conducted, all platelet samples were preincubated with a vehicle or SAA for 10 min. Additionally, the diabetic complication-related difference in the antiplatelet effect of SAA was further studied in enrolled patients.

The expressions of PAC-1 and CD62p were elevated in DM2, as well as the maximal platelet aggregation. In addition, SAA decreased the expressions of PAC-1 and CD62p, which were enhanced by ADP and thrombin (all P < 0.01). It also reduced the platelet aggregation induced by ADP (P < 0.001) and thrombin (P < 0.05). Comparing the antiplatelet effect of SAA on DM2, with and without diabetic complications, no statistically significant difference was found (all P > 0.05).

The present study demonstrated that SAA can inhibit platelet activation and aggregation in patients with DM2, and the inhibition did not abate for the existence of diabetic complications.

• CD62p
• Maximal platelet aggregation
• PAC-1
• Salvianolic acid a
• Type 2 diabetes mellitus

• apoptosis
• inflammation
• ischemia-reperfusion
• liver
• salvianolic acid-A
• toll-like receptor 4

Background: Liver fibrosis occurs due to chronic liver disease due to multiple pathophysiological causes. The main causes for this condition are chronic alcohol abuse, nonalcoholic steatohepatitis, and infection due to hepatitis C virus. Currently, there is more and more information available about the molecular as well as cellular mechanisms, which play a role in the advancement of liver fibrosis. However, there is still no effective therapy against it.

Purpose: In order to find an effective treatment against liver fibrosis, our study explored whether salvianolic acid A (SA-A), a traditional Chinese medicine extracted from the plant Danshen, could effectively inhibit the liver fibrosis, which is induced by CCl₄ in vivo.

Methods: The effects of SA-A were evaluated by assessing the parameters related to liver fibrosis such as body weight, histological changes, and biochemical parameters. Thereafter, the related protein or gene levels of P13K/AKT/mTOR, Bcl-2/Bax and caspase-3/cleaved caspase-3 signaling pathways were determined by western blotting, real-time PCR or immunohistochemistry staining.

Results: According to the results of our study, SA-A could reduce liver fibrosis by inhibiting liver function, liver fibrosis index, collagen deposition, and improving the degree of liver fibrosis in rats. Mechanistically, the PI3K/AKT/mTOR signaling cascade was inhibited by SA-A to prevent the stimulation of hepatic stellate cell, as well as the synthesis of extracellular matrix, and regulated Bcl-2/Bax and caspase-3/cleaved caspase-3 signaling pathways to prevent hepatocyte apoptosis.

Conclusion: The novel findings of this study suggested that SA-A could reduce liver fibrosis and the molecular mechanisms behind it are closely associated with the regulation of PI3K/AKT/mTOR, Bcl-2/Bax and caspase-3/cleaved caspase-3 signaling pathways.

• AKT/mTOR
• Bcl-2/Bax
• caspase-3/cleaved caspase-3
• liver fibrosis
• salvianolic acid A

• Alzheimer’s disease
• Amyloid β plaques
• Autophagy
• Danshen
• Mitochondrial dysfunction
• Neurofibrillary tangles

Salvianolic acid A (SAA) is a bioactive polyphenol extracted from Salviae miltiorrhizae Bunge, which possesses a variety of pharmacological activities. In our previous study, we have demonstrated that SAA effectively attenuates kidney injury and inflammation in an established animal model of 5/6 nephrectomized (5/6Nx) rats. However, there has been limited research regarding the antioxidative effects of SAA on chronic kidney disease (CKD). Here, we examined the antioxidative effects and underlying mechanisms of SAA in 5/6Nx rats. The rats were injected with SAA (2.5, 5, and 10 mg·kg⁻¹·d⁻¹, ip) for 28 days. Biochemical, flow cytometry, and Western blot analyses showed that SAA significantly increased the activities of total superoxide dismutase (T-SOD), glutathione peroxidase (GPx), and catalase (CAT) and lowered the levels of malondialdehyde (MDA), reactive oxygen species (ROS), and NADPH oxidase 4 (NOX-4) in a dose-dependent manner in 5/6Nx rats and in H₂O₂-induced HK-2 cells in vitro. Moreover, SAA enhanced the activation of the protein kinase B/glycogen synthase kinase-3β/nuclear factor-erythroid-2-related factor 2 (Akt/GSK-3β/Nrf2) signaling pathway in a dose-dependent manner and subsequently increased the expression of heme oxygenase-1 (HO-1) in the kidney of 5/6Nx rats, which were consistent with those obtained in H₂O₂-induced HK-2 cells in vitro shown by Western blot analysis. Furthermore, SAA significantly increased the expression of intranuclear Nrf2 and HO-1 proteins compared to HK-2 cells stimulated by LPS on the one hand, which can be enhanced by QNZ to some extent; on the other hand, SAA significantly lowered the expression of p-NF-κB p65 and ICAM-1 proteins compared to HK-2 cells stimulated by H₂O₂, which can be abrogated by ML385 to some extent. In conclusion, our results demonstrated that SAA effectively protects the kidney against oxidative stress in 5/6Nx rats. One of the pivotal mechanisms for the protective effects of SAA on kidney injury was mainly related with its antioxidative roles by activating the Akt/GSK-3β/Nrf2 signaling pathway and inhibiting the NF-κB signaling pathway.

• 5/6 nephrectomized rat
• LPS-induced HK-2 cell
• NF-κB
• chronic kidney disease; inflammation
• p38 MAPK
• salvianolic acid A

• Animals
• Caffeic Acids/therapeutic use
• I-kappa B Proteins/metabolism
• Kidney/pathology
• Lactates/therapeutic use
• MAP Kinase Signaling System/drug effects
• Male
• Rats, Sprague-Dawley
• Renal Insufficiency, Chronic/pathology
• Renal Insufficiency, Chronic/prevention & control
• Transcription Factor RelA/metabolism
• p38 Mitogen-Activated Protein Kinases/metabolism

• Atherosclerosis
• Cardiac hypertrophy
• Cardiovascular diseases
• Coronary artery disease
• Danhong injection
• Danshensu (PubChem CID: 11600642)
• Ferulic acid (PubChem CID: 445858)
• Hydroxysafflor yellow A (PubChem CID: 6443665)
• Protocatechuic aldehyde (PubChem CID: 8768)
• Rosmarinic acid (PubChem CID: 5281792)
• Salvianolic acid A (PubChem CID: 5281793)
• Salvianolic acid B (PubChem CID: 11629084)
• Salvianolic acid D (PubChem CID: 75412558)
• Stroke

• ConA
• Liver injury
• NF-κB
• Protopanaxitriol

• Blood brain barrier
• Ischemia
• MCAO
• MMP-9
• NF-κB
• Salvianolic acid A

• Animals
• Anti-Inflammatory Agents/administration & dosage
• Blood-Brain Barrier/drug effects
• Blood-Brain Barrier/enzymology
• Blood-Brain Barrier/immunology
• Brain
• Brain Ischemia/drug therapy
• Brain Ischemia/enzymology
• Brain Ischemia/genetics
• Caffeic Acids/administration & dosage
• Drugs, Chinese Herbal/administration & dosage
• Humans
• Lactates/administration & dosage
• Male
• Matrix Metalloproteinase 9/genetics
• Matrix Metalloproteinase 9/metabolism
• Rats
• Rats, Sprague-Dawley
• Reperfusion Injury/enzymology
• Reperfusion Injury/genetics
• Reperfusion Injury/immunology
• Reperfusion Injury/prevention & control
• Salvia miltiorrhiza/chemistry
• Tissue Inhibitor of Metalloproteinase-1/genetics
• Tissue Inhibitor of Metalloproteinase-1/metabolism
• Transcription Factor RelA/genetics
• Transcription Factor RelA/immunology

• Salvia miltiorrhiza Bunge
• dextran sodium sulphate
• gut microbiota
• inflammatory bowel disease
• salvianolic acid A

• Animals
• Caffeic Acids/chemistry
• Caffeic Acids/therapeutic use
• Colitis/chemically induced
• Colitis/prevention & control
• Cytokines/genetics
• Cytokines/metabolism
• Dextran Sulfate/toxicity
• Drugs, Chinese Herbal/therapeutic use
• Gene Expression Regulation/drug effects
• Inflammation/metabolism
• Lactates/chemistry
• Lactates/therapeutic use
• Male
• Molecular Structure
• Random Allocation
• Rats
• Rats, Sprague-Dawley
• Salvia miltiorrhiza/chemistry

• salvia miltiorrhiza burge
• danshen
• cardiovascular diseases
• herbal medicine
• traditional chinese medicine

• Animals
• Cardiotonic Agents/therapeutic use
• Cardiovascular Diseases/drug therapy
• Cardiovascular Diseases/physiopathology
• Drug Synergism
• Drugs, Chinese Herbal/therapeutic use
• Endothelial Cells/drug effects
• Fibrinolytic Agents/therapeutic use
• Humans
• Muscle, Smooth, Vascular/drug effects
• Myocytes, Smooth Muscle/drug effects
• Salvia miltiorrhiza

• Inflammatory reaction
• Ischemia/reperfusion injury
• Platelet activation
• Reperfusion recovery
• Salvianolic acid A

Age-related macular degeneration is closely related to lipid oxidation, while relationship between OX-LDL and choroidal neovascularization is unclear. Recently, cylindromatosis is proved to regulate angiogenesis. However, its role in CNV progression remained unclear. Salvianolic acid A is widely used in vascular diseases. We investigated the relationship between OX-LDL and CNV and explore antineovascularization mechanism of Sal A.

C57BL6/J mice were randomized into four groups and injected with PBS or OX-LDL, together with Sal A for one week. CNV was induced by laser; CNV severity was analyzed by fundus fluorescein angiography, H&E staining, and choroid flat mount after 1 week. In in vitro experiments, ARPE-19 and HUVECs were cultured with OX-LDL (with or without Sal A) for 48 hours. Angiogenic proteins, cell junction integrity, and tube formation were measured. CYLD siRNA and specific inhibitors were used to explore mechanisms of CYLD in promoting OX-LDL-induced CNV progression.

OX-LDL promoted laser-induced CNV volume by increasing VEGF, PDGF, and CYLD levels. Sal A antagonized OX-LDL effects and restrained CNV progression by decreasing VEGF/PDGF/CYLD, increasing antiangiostatin levels, and promoting P62-CYLD-TRAF6 interaction.

We demonstrated oxidation damage exacerbates CNV progression, and Sal A could be a clinical therapeutic reagent to exudative AMD.

• Blood-spinal cord barrier
• Heme oxygenase-1
• Salvianolic acid A
• Spinal cord injury
• Tight junction

• Cdk5, doublecortin
• Glycogen synthase kinase 3 (GSK3)
• Ischemic stroke
• Salvianolic acid A (SalA)
• β-catenin

• Animals
• Anti-Inflammatory Agents, Non-Steroidal/pharmacology
• Antioxidants/pharmacology
• Apoptosis/drug effects
• Blood-Brain Barrier/drug effects
• Brain Ischemia/drug therapy
• Brain Ischemia/genetics
• Brain Ischemia/mortality
• Brain Ischemia/pathology
• Brain-Derived Neurotrophic Factor/genetics
• Brain-Derived Neurotrophic Factor/metabolism
• Caffeic Acids/pharmacology
• Cyclin-Dependent Kinase 5/genetics
• Cyclin-Dependent Kinase 5/metabolism
• Disease Models, Animal
• Doublecortin Domain Proteins
• Doublecortin Protein
• Drug Administration Schedule
• Gene Expression Regulation
• Glycogen Synthase Kinase 3 beta/genetics
• Glycogen Synthase Kinase 3 beta/metabolism
• Injections, Intravenous
• Lactates/pharmacology
• Male
• Mice
• Mice, Inbred ICR
• Microtubule-Associated Proteins/genetics
• Microtubule-Associated Proteins/metabolism
• Neurogenesis/drug effects
• Neuropeptides/genetics
• Neuropeptides/metabolism
• Proto-Oncogene Proteins c-bcl-2/genetics
• Proto-Oncogene Proteins c-bcl-2/metabolism
• Reperfusion Injury/drug therapy
• Reperfusion Injury/genetics
• Reperfusion Injury/mortality
• Reperfusion Injury/pathology
• Signal Transduction
• Stroke/drug therapy
• Stroke/genetics
• Stroke/mortality
• Stroke/pathology
• Survival Analysis
• Transcription Factor RelA/genetics
• Transcription Factor RelA/metabolism
• beta Catenin/genetics
• beta Catenin/metabolism

Endothelin-1 (ET-1) autocrine and paracrine signaling modulate cell proliferation of tumor cells by activating its receptors, endothelin A receptor (ET_AR) and endothelin B receptor (ET_BR). Dysregulation of ET_AR activation promotes tumor development and progression. The potential of ET_AR antagonists and the dual-ET_AR and ET_BR antagonists as therapeutic approaches are under preclinical and clinical studies. Salvianolic acid A (Sal A) is a hydrophilic polyphenolic derivative isolated from Salvia miltiorrhiza Bunge (Danshen), which has been reported as an anti-cancer and cardio-protective herbal medicine. In this study, we demonstrate that Sal A inhibits ET_AR activation induced by ET-1 in both recombinant and endogenous ET_AR expression cell lines. The IC₅₀ values were determined as 5.7 µM in the HEK293/ET_AR cell line and 3.14 µM in HeLa cells, respectively. Furthermore, our results showed that Sal A suppressed cell proliferation and extended the doubling times of multiple cancer cells, including HeLa, DU145, H1975, and A549 cell lines. In addition, Sal A inhibited proliferation of DU145 cell lines stimulated by exogenous ET-1 treatment. Moreover, the cytotoxicity and cardio-toxicity of Sal A were assessed in human umbilical vein endothelial cells (HUVEC) and Human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), which proved that Sal A demonstrates no cytotoxicity or cardiotoxicity. Collectively, our findings indicate that Sal A is a novel anti-cancer candidate through targeting ET_AR.

• Salvianolic acid A
• antagonist
• anticancer
• cardiotoxicity
• endothelin A receptor

• IκB kinase
• NF-κB
• lipopolysaccharide
• nitric oxide
• prostaglandin E2
• spironolactone
• tumor necrosis factor-α

• NF-κB
• UPLC/Q-TOF
• inflammation
• optimization
• response surface methodology

• Induced pluripotent stem cells
• Middle cerebral artery occlusion
• Neural stem cells
• Neuronal differentiation
• Salvia miltiorrhiza

• Animals
• Cell Differentiation/drug effects
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Female
• Gene Expression Regulation/drug effects
• Induced Pluripotent Stem Cells/cytology
• Induced Pluripotent Stem Cells/drug effects
• Infarction, Middle Cerebral Artery
• Mice
• Microtubule-Associated Proteins/genetics
• Neural Stem Cells/cytology
• Neural Stem Cells/drug effects
• Plant Extracts/administration & dosage
• Plant Extracts/pharmacology
• Rats
• Rats, Sprague-Dawley
• Recovery of Function/drug effects
• Reverse Transcriptase Polymerase Chain Reaction
• Salvia miltiorrhiza/chemistry
• Time Factors

• Age-related macular degeneration
• Akt/mTOR
• Free radicals
• HO-1
• Nrf2
• Oxidative stress
• Salvianolic acid A

• Animals
• Apoptosis/drug effects
• Caffeic Acids/administration & dosage
• Heme Oxygenase-1/metabolism
• Lactates/administration & dosage
• Macular Degeneration/drug therapy
• Macular Degeneration/genetics
• Macular Degeneration/pathology
• Mechanistic Target of Rapamycin Complex 1
• Membrane Proteins/metabolism
• Multiprotein Complexes/metabolism
• NF-E2-Related Factor 2/metabolism
• Oxidative Stress/drug effects
• Proto-Oncogene Proteins c-akt/metabolism
• Reactive Oxygen Species/metabolism
• Retinal Pigment Epithelium/drug effects
• Signal Transduction/drug effects
• TOR Serine-Threonine Kinases/metabolism