TABLE 3.
Studies regarding the pharmacological effects of the active constituents or extract from Danshen-Shanzha Formula (DSF).
| Constituent/Extract | Source | Model | Effects/mechanisms | References |
|---|---|---|---|---|
| Vascular actions | ||||
| Tanshinone I | Danshen | Human vascular smooth muscle cells (Ang II stimulated) | Inhibit VSMC proliferation without inducing apoptosis; prevent IGF-1R/PI3K signaling activation | Wu et al. (2019a) |
| Dihydrotanshinone I | Danshen | ApoE−/− mice (high-cholesterol/high-fat diet fed); RAW264.7 macrophages (LPS/ZVAD stimulated) | Inhibit macrophages necroptosis; enhance plaque stability | Zhao et al. (2021) |
| Tanshinone IIA | Danshen | Human vascular smooth muscle cells (high-glucose stimulated) | Inhibit VSMC proliferation and migration; regulate miR-21-5p/TPM1 signaling | Jia et al. (2019a) |
| Cryptotanshinone | Danshen | ApoE−/− mice (high-cholesterol diet fed); Human umbilical vein endothelial cells (oxLDL stimulated) | Attenuate plaque formation; enhance plaque stability; inhibit NADPH oxidase subunit 4-mediated ROS generation and activation of NF-κB | Liu et al. (2015) |
| Danshensu | Danshen | Rats (methionine-rich diet fed) | Reduce serum homocysteine; inhibited TNF-α and ICAM-1 expression in arterial endothelia; suppress alterations of serum endothelin and NO levels | Yang et al. (2010) |
| Shanzha extract (WS®1442) | Danshen | Human umbilical vein endothelial cells (thrombin stimulated) | Inhibit detrimental effects of thrombin on adherens junctions, the F-actin cytoskeleton, and the contractile apparatus; block the calcium/PKC/RhoA signaling and activate the cAMP/Epac/Rap1 signaling | Bubik et al. (2012) |
| Shanzha extract | Danshen | ApoE−/− mice (high-fat diet fed) | Stabilize unstable plaques; regulate inflammatory and apoptotic signaling | Wang et al. (2019) |
| Danshen and Shanzha extract (SC121) | DSF | Human umbilical vein endothelial cells (oxLDL stimulated); RAW264.7 macrophages (oxLDL stimulated) | Alleviate macrophages and endothelial cells damage; inhibit foam cell formation; reduce ROS level | Zhang et al. (2016) |
| Danshen and Shanzha extract | DSF | Rats (high-fat diet fed) | Increase serum nitric oxide and 6-keto-prostaglandin F1α level; decrease serum endothelin and thromboxane B2 level | Zhang et al. (2019) |
| Anti-hyperlipidemic actions | ||||
| Danshen and Shanzha extract | DSF | Rats (vitamin D3 stimulated plus high-fat diet fed) | Decrease serum steroid indices; elevate high-density lipoprotein cholesterols level | Zhang et al., 2013b; Zhang, 2013 |
| Shanzha extract | Shanzha | Rats (vitamin D3 and ovalbumin stimulated plus high-fat diet fed) | Improve lipid metabolism; alleviate inflammatory cytokine responses | Zhang et al. (2013a) |
| Tanshinone IIA | Danshen | ApoE−/− mice (high-fat diet fed); THP-1 cells and mouse peritoneal macrophages (apoA-I stimulated) | Promote cholesterol efflux; meliorates lipid accumulation; increase reverse cholesterol transport; regulate omentin-1/ABCA1 signaling | Tan et al. (2019) |
| Cryptotanshinone | Danshen | 3T3-L1 murine pre-adipocytes | Reduce lipid accumulation; inhibit the phosphorylation of STAT3 | Rahman et al. (2016) |
| Salvianolic acid B | Danshen | Rats (high-fat diet fed) | Regulates the expression of mRNA, circRNA and lncRNA which involved in the insulin resistance pathway, IL-17 signaling and B cell receptor signaling | An et al. (2019) |
| db/db Mice | Decrease serum triglyceride and free fatty acid levels; regulate AMPK signaling | Huang et al., 2016 | ||
| Salvianolic acid A | Danshen | Rats (high-fat diet fed); C3H10T1/2 cells | Attenuate weight gain and lipid accumulation; regulate AMPK signaling | Lai et al. (2021) |
| Flavonoids | Shanzha | Mice (PM2.5 exposure) | Increase fatty acid uptake; decrease lipid export; balance the hepatic triacylglycerol levels | Gu et al. (2023) |
| Shanzha extract | Shanzha | Rats (high-fat diet fed) | Restore the metabolic abnormality; regulate bio-oxidation along with metabolism of energy, amino acid and lipid pathways | Zeng et al. (2021a) |
| Anti-inflammatory actions | ||||
| Danshen extract | Danshen | ApoE−/− mice | Decrease serum lipid levels; inhibit inflammatory responses via TLR4/NF-κB signaling | Wu et al. (2023b) |
| Salvianolic acid A | Danshen | Zucker diabetic fatty rats (vitamin D3 stimulated plus high-fat diet fed) | Decrease hemoglobin A1C level; ameliorate serum disrupted lipid profiles; decrease serum hypersensitive C-reactive protein level; inhibit NLRP3 inflammatory and NF-κB signaling | Ma et al. (2020) |
| Salvianolic acid B | Danshen | LDLR−/− mice; RAW264.7 cells (LPS stimulated/oxLDL stimulated) | Decrease serum lipids levels; attenuate inflammatory cytokines; attenuate phosphorylation of MAPK/NF-κB singalongs | Zhang et al. (2022) |
| Tanshinones | Danshen | THP-1 macrophages (LPS stimulated | Inhibit the expression of TNF-α, IL-1β, and IL-8 | Ma et al. (2016) |
| Cryptotanshinone | Danshen | Mice (LPS stimulated); bone marrow-derived macrophages (LPS stimulated) | Inhibit NLRP3 inflammasome activation; blocks Ca2+ signaling; attenuate caspase-1 activation and IL-1β secretion | Liu et al. (2021b) |
| Tanshinone IIA | Danshen | ApoE−/− mice (high-fat diet fed); Mouse B6 macrophages (oxLDL stimulated) | Attenuate NLRP3 inflammasome activation; downregulate IL-1β and NLRP3 expression; decrease LOX-1 and CD36 expression; inhibite NF-κB activation | Wen et al. (2021b) |
| ApoE−/− mice (porphyromonas gingivalis infected) | Inhibit inflammatory mediators’ secretion; downregulate miR-146b and miR-155 expressions | Xuan et al. (2017) | ||
| ApoE−/− mice (high-fat diet fed); human umbilical vein endothelial cells (oxLDL stimulated) | Attenuate buildup of plaque and the accumulation of lipids; reduce vascular inflammatory factors levels; regulate COX-2/TNF-α/NF-κB signaling | Ma et al. (2023) | ||
| Shanzha extract | Shanzha | ARPE-19 cells (high glucose stimulated) | Alleviate inflammatory, oxidative and apoptotic damages; regulate AMPK/SIRT1/NF-κB signaling and miR34a/SIRT1/p53 signaling | Liu et al. (2021c) |
| Quercetins | Shanzha | ApoE−/− mice (high-fat diet fed); RAW264.7 cells (oxLDL stimulated) | Alleviate atherosclerotic lesions and reduce lipid retention; alleviate cellular steatosis and IL-1β secretion; suppress NLRP3 inflammasome activation; modulate galectin-3-NLR family | Li et al. (2021) |
| Hyperoside | Shanzha | MOVAS-1 cells (TNF-α stimulated) | Inhibit VCAM-1 expression; suppresses monocyte adhesion; suppress activation of p38 MAPK, ERK1/2, JNK, and NF-κB | Jang et al. (2018) |
| Anti-apoptosis and autophagy promoting actions | ||||
| Danshen extract | Danshen | ApoE−/− mice (high-fat diet fed); human umbilical vein endothelial cells (oxLDL stimulated) | Attenuate formation of atherosclerotic plaque; inhibited foam cell formation and increase autophagic activity; inhibit cell proliferation and induce autophagy flux | Ko et al. (2020) |
| Salvianolic acid B | Danshen | RAW264.7 macrophages (cholesterol crystals stimulated) | Reduce apoptosis and proinflammatory cytokines levels; improves autophagic dysfunction; inhibit the Akt/mTOR signaling | Sun et al. (2021a) |
| Tanshinone IIA | Danshen | ApoE−/− mice (high-fat diet fed); RAW264.7 cells (oxLDL stimulated) | Attenuate lipid accumulation and promote autophagy; regulate miR-214-3p/ATG16L1 axis; facilitate MAPK/mTOR signal-mediated autophagy | Qian et al. (2023) |
| Quercetin | Shanzha | RAW264.7 cells (oxLDL stimulated) | Inhibit the formation of foam cells; delay senescence; regulate mammalian sterile 20-like kinase 1 mediated autophagy | Cao et al. (2019a) |
| ApoE−/− mice | Enhance autophagy; upregulate P21 and P53 expression | Cao et al. (2019b) | ||
| Hypericin | Shanzha | Mice (left anterior descending ligated) | Activate autophagy; inhibit NLRP1 inflammatory pathway | Yang et al. (2021b) |
| Mice (high-fat diet fed) | Increase glucose and lipid metabolism; induce lipophagy; facilitate degradation of lipid droplets; regulate CDK6-TFEB signaling | Cheng et al., 2023 | ||
| Cardiac protective actions | ||||
| Tanshinone IIA | Danshen | Rats (left anterior descending ligated) | Reduce the expression of collagen families, ameliorate myocardial fibrosis and cardiac dysfunction; regulate Nox4 signaling | Chen et al. (2021) |
| Mice (left anterior descending ligated) | Reduce the release of inflammatory cytokines; inhibit cell apoptosis; promote angiogenesis | Wu et al. (2019b) | ||
| Protocatechuic aldehyde | Danshen | Rats (isoproterenol stimulated); neonatal rat cardiomyocytes (isoproterenol stimulated) | Downregulate hypertrophic gene markers; reduce cardiomyocyte cross-sectional area and collagen level; inhibit the JAK2/STAT3 signaling | Fang et al. (2018) |
| Rats (isoproterenol stimulated); neonatal rat cardiomyocytes (oxygen/glucose deprived; hydrogen peroxide stimulated) | Reduce lipid peroxidation and DNA damage; prevented cell apoptosis; protect cell survival; regulate PKM2/β-catenin/TCF4 signaling | Wu et al. (2021) | ||
| Salvianolate | Danshen | Rats (left anterior descending ligated); neonatal rat cardiomyocytes (Ang II stimulated) | Improve cardiomyocyte remodeling; downregulate the expression of β-MHC, reduce nuclear NFATc3 translocation; downregulation of CaNA subunit expression; inhibit CaN activity | Chen et al. (2022) |
| Shanzha extract | Shanzha | Rats (isoproterenol stimulated) | Decrease myocardial enzyme indexes level; Decrease blood liquid indexes level | Ao et al. (2020) |
| Cerebral Protective Actions | ||||
| Danshen and Shanzha extract | DSF | Rats (Rose Bengal injected and cold-light source irradiated) | Regulate vascular endothelial functions and inflammatory factors; regulate protein expression of vWF, VCAM-1, and ICAM-1; downregulate gene expression of ICAM-1 | Ding et al. (2020) |
| Danshen extract | Danshen | Rats (middle carotid artery occluded) | Inhibit thrombosis formation and platelet aggregation; activate PLC/PKC signaling | Fei et al. (2017) |
| Salvianolic acid A | Danshen | Rats (middle cerebral artery occluded); human brain microvascular endothelial cells (oxygen/glucose deprived) | Improve neurological deficits, intracerebral hemorrhage, BBB disruption, and vascular endothelial dysfunction; suppress degradation of tight junction proteins; blocked the activation of the Src signaling | Liu et al. (2021a) |
| Vitexin | Shanzha | Mice (common carotid artery ligated); primary cortical neuronal cells (oxygen/glucose deprived) | Alleviate neurological impairment; decrease cerebral infarct volume; mitigate neuronal damage, inhibit phosphorylation of Ca2+/Calmodulin-dependent protein kinase II; decrease protein expressions of NF-κB and cleaved caspase-3 levels | Min et al. (2017) |
Abbreviations: Ang II, Angiotensin II; ApoE, Apolipoprotein E; ABCA1, ATP-binding cassette transporter A1; AMPK, AMP-activated protein kinase; Akt, v-Akt Murine Thymoma Viral Oncogene; BBB, Blood-brain barrier; COX-2, Cyclooxygenase-2; cAMP/Epac/Rap1, Cyclic adenosine monophosphate/exchange protein directly activated by cAMP/repressor activator protein 1; CDK6, Cyclin-dependent kinase 6; ERK, Extracellular signal-regulated kinase; IGF-1R/PI3K, insulin-like growth factor 1 receptor/phosphatidylinositol 3-kinase; IL-17, Interleukin-17; JNK, c-Jun N-terminal kinase; JAK2, Janus kinase 2; LPS, lipopolysaccharide; MAPK, Mitogen-activated protein kinase; MOVAS-1, Mouse vascular smooth muscle cell line 1; mTOR, mammalian target of rapamycin; NLRP3, Nucleotide oligomerization domain-like receptor protein 3; NF-κB, Nuclear Factor-κB; NFATc3, Nuclear factor of activated T cells cytoplasmic 3; Nox4, Nicotinamide adenine dinucleotide phosphate oxidase 4; oxLDL, Oxidized low-density lipoprotein; PM2.5, Particulate matter 2.5; P21, Cyclin-dependent kinase inhibitor 1; PLC/PKC, phospholipase C/protein kinase C; PKM2/β-catenin/TCF4, pyruvate kinase isoform M2/β-catenin/T cell factor 4; RhoA, Ras homolog gene family member A; ROS, reactive oxygen species; STAT3, Signal transducer and activator of transcription 3; TFEB, Transcription factor EB; THP-1, human leukemic monocyte; TLR4, Toll-like receptor 4; TNF-α, tumour necrosis factor alpha; TPM1, tropomyosin 1; VSMC, vascular smooth muscle cell; VCAM-1, Vascular cell adhesion molecule-1; vWF, Von Willebrand factor.