Use of Plant and Herb Derived Medicine for Therapeutic Usage in Cardiology
2. History of Plant- and Herb-Derived Medicine and Their Usage in Cardiology
3. Cardiovascular Diseases
3.3. Ischemia Reperfusion Injury
4. Introduction of Plant and Herb Derived Medicine
4.1. Anti-Inflammatory and Antioxidant Roles of Plant and Herb Derived Medicine
- Vanillyl alcohol (VA), one of the main phenolic components in plants, is also an active ingredient in Gastrodia elata Blume, which had been used as a traditional medicine for centuries . Using fertilized brown Leghorn eggs, Jung and colleagues (2008) discovered that VA can be synthesized from the reduction of vanillin, a commonly used aromatic compound. A study has shown that vanillin, also an active component in G. elata, has anti-inflammatory, anti-angiogenic, and anti-nociceptive properties. VA also significantly inhibits the chick chorioallantoic membrane (CAM) angiogenesis, which involves growing new blood vessels from pre-existing vessels . Angiogenesis can cause various conditions, such as metastasis, CVDs, and inflammatory diseases. Down-regulation of angiogenesis could prevent neoplastic growth and inflammation.
- Curcumin, which is derived from turmeric, consists of antioxidative, anti-apoptotic, and anti-inflammatory properties. It also protects against MI and endothelial injury . Using adult male mouse cardiomyocytes, Wang and colleagues (2017) discovered a novel monocarbonyl curcumin analog, Y20, which has immense curative ability in cardiac injury caused by obesity through anti-inflammatory pathways, portrayed by decreased TNF-α, IL-6, IL-1, and COX-2 (cyclooxygenase-2) levels. Reduction of pro-inflammatory cytokines and COX-2 levels shows that Y20 has a promising therapeutic potential for cardioprotection in obese patients. Moreover, it was found that curcumin downregulates the levels of inflammatory cytokines through inhibition of Egr-1(early growth response-1) in the ischemic heart, which corresponds to reduced TNF-α and IL-6 levels and reduced ischemic injury. Results from Wang and colleagues (2017) suggest that curcumin illustrates anti-inflammatory properties beneficial for the heart via inhibition of pro-inflammatory cytokines, phagocytic cell adhesion and infiltration, and immunocyte activity.
- Yi-Qi-Fu-Mai (YQFM) is a Chinese herbal medicine, composed of ginseng Radix Et Rhizoma Rubra (the root of Panax ginseng C.A.Mey.), Ophiopogonis Radix (the root of Ophiopogon japonicas (L.f) Ker-Gawl), and Schisandrae Chinensis Fructus (the fructus of Schisandra chinensis (Turcz.) Baill) [29,30]. YQFM successfully suppressed the inflammatory expressions and significantly enhanced myocardial contractility, blood-vessel expansion, anti-lipid peroxidation, and anti-inflammatory effects of the male rats . Another study showed that certain bioactive compounds from Ginseng Radix Et Rhizoma Rubra, specifically ginsenoside Rb1, Rg1, and Rg3, can inactivate via NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) inactivation and suppress the cytokines. . Ginsenosides also contributes to anti-inflammatory activities. Among the many types of ginsenoside compounds, ginsenoside Ro was classified as the new NF-kB inhibitor . Treating the rats with chronic heart failure (CHF) using YQFM helped to preserve myocardial function, reduce myocardial necrosis, improve cardiac microstructure, decrease brain natriuretic peptide (BNP) levels and relieve inflammation stress. These findings suggest that YQFM exhibits cardioprotective effects in rats with CHF.
- Xanthone is derived from G. acuta, which is a herb that belongs to the Gentianella genus of Gentianaceae family . G. acuta can be found in Ewenki medicinal plants in northeast China. Dosage of 400 mg/kg improved heart functions, diminished the oxidative stress of myocardial cells, increased the release of antioxidant enzymes, and prevented mitochondrial dysfunction and myocardial apoptosis against acute IRI. Xanthones also mitigated the release of lactate dehydrogenase (LDH). The levels of LDH and creatine kinase (CK) in the xanthone group were significantly reduced compared with the IRI group (p < 0.05). LDH and CK are endoenzymes that are released into the bloodstream during the reperfusion once myocardial cells are degenerated. Therefore, the severity of myocardial damage can be indirectly measured by observing the levels of LDH and CK.
- Luteolin is mainly derived from flavonoid that not only inhibits tumor development and inflammation, but also suppresses CVD . Luteolin possesses antioxidative, anti-tumor, and anti-inflammatory properties. It also mitigates oxidative stress of the ischemia induced rats through heme oxygenase-1 (HO-1), an integral membrane protein in the smooth endoplasmic reticulum. It is regulated via transcription factors, particularly NF-E2-related factor 2 (Nrf2), which regulates a pathway that promotes cytoprotective effects against oxidative stress. Another way that luteolin blocks oxidative stress is via attenuation of TNF-α levels through NOX4, an isoform of NADPH oxidase for NOX4 expression leads to ROS generation . Luo and colleagues (2017) concluded that luteolin prevents coronary artery disease (CAD), heart failure, and atherosclerosis. Although there has not been a cardiovascular clinical research using luteolin, Luo and colleagues (2017) concluded from an open-label pilot study that 10 mg/kg may become the standard dosage of safety in future CVD studies.
- Many plants with antioxidant properties contain flavonoid. To evaluate its importance, Jiang and colleagues (2004) extracted flavonoids from Dracocephalum moldavica L. (DML) . DML is derived from herbs native to Central Asia. In Xinjiang, China, it is renowned for its medicinal properties in treating stomach and liver diseases, headaches, and congestion. Jiang and colleagues (2004) discovered that the total flavonoids pretreatment significantly reduced the LDH and CK release in rat hearts. To determine the mechanism of flavonoid on cardioprotection, the malondialdehyde (MDA) level, superoxide dismutase (SOD) activity and the ratio of glutathione/glutathione disulfide (GSH/GSSG) were examined in myocardial tissues. In the total flavonoids pretreatment groups, the MDA level decreased considerably while SOD activity and the ratio of GSH/GSSG heightened relative to the group with IRI. Therefore, it was concluded that the total flavonoids attenuate ischemic reperfusion induced enzyme release and one of the mechanisms of the cardioprotection of DML includes antioxidant effects.
- Grape seed procyanidin extract (GSPE) is a naturally derived compound that possess anti-inflammatory, anti-carcinogenic, and antioxidant characteristics . Data show that GSPE prevents the changes of histopathology and biomarkers in heart, kidney, and liver tissues of the mice exposed to TiO2 nanoparticles (NPs); grape seed procyanidin extract prevents the majority of tissue and molecular damage resulting from NP treatment. The protective effect of GSPE may be due to its strong antioxidative activities which are related to the activated Nrf2 and GSPE’s down-regulated genes, including NAD(P)H dehydrogenase[quinine] 1 (NQO1), glutamate-cysteine ligase catalytic subunit (GCLC), and HO-1. Nrf2 expression led to an increase in the oxidative stress and inflammation. The expression of Nrf2 also amplified the damage on the kidneys, which is correlated with induced protein expression of NQO1 and HO-1; expressions of GCLC and HO-1 are associated with increased ROS generation [36,37]. The effect of GSPE has proven beneficial to especially hypercholestrolmeic patients as it has become a renowned herbal supplement for treating CVD.
- 3,3′-diindolylmethane (DIM) is a plant alkaloid synthesized via hydrolysis of indolylmethyl glucosinolate (glucobrassicin) . To investigate DIM’s antioxidant properties, oxidative stress was induced by doxorubicin (DOX), an antibiotic pertained in anthracycline group that causes DNA intercalation between the base pairs of normal DNA. DIM significantly mitigated DOX-induced oxidative stress by reducing levels of free radicals and lipid peroxidation and increasing the level of reduced glutathione and the activity of antioxidant enzymes. The evaluation of cardiac tissues corroborated the chemoprotective effects of DIM. DIM significantly ameliorated DOX-induced damages, including clastogenicity, apoptosis, and myeloid hyperplasia in bone marrow niche.
4.2. Anti-Hypertensive Role of Plant and Herb Derived Medicine
- The traditional Mexican medicine incorporates plants, for instance B. simaruba, J. spicigera, and S. lepidophylla, as anti-hypertensive therapies . These medicinal plants have shown beneficial effects on male rats with glucose-induced hypertension. B. simaruba is characterized by negative chronotropic effects (decrease heart rate), long-term hypotension induced by one oral administration of the extract and vasodilating properties that protect the endothelium. B. simaruba also has proanthocyanidins, which improve the endothelial function through vascular endothelial NO synthase activation, thus explaining the vascular protecting effect. J. spicigera includes eucalyptol as one of its main ingredients, which promotes vascular smooth muscle relaxation and creates anti-hypertensive effects. S. lepidophylla promotes diuresis and includes biflavonoids, which could also produce anti-hypertensive effects.
- Qishenyiqi (QSYQ) is a Chinese traditional medicine that was often used to treat CHD and CHF . It is composed of six Chinese herbs: Radix Astragali Mongolica, Salvia miltiorrhiza bunge, Flos Lonicerae, Poria, Radix Aconiti Lateralis Preparata, and Radix Glycyrrhizae. Qiu and colleagues (2014) used cardiac tissues from miniature pigs and discovered that QSYQ had improved heart function in pigs with CHF. QSYQ can ameliorate and remodel any abnormal enlargement in myocardium by inhibiting the Angiotensin II (Ang II) expression in LAD (left anterior descending coronary) of rats. Ang II is one of the main peptides in the renin-angiotensin system. Ang II biological effects include blood vessel contraction, fibrinolysis inhibition, and tissue fibrosis promotion. QSYQ can diminish these effects by reducing apoptosis and decreasing the level of TNF-α and active caspase-3. Caspase-3 plays an important role as a substrate of apoptosis and has been used as a sign of irreversible apoptosis. In addition to apoptosis-induced biological effects, caspase-3 can also shear the muscle fibers cells α-actin and troponin T, and α-actin and muscle fiber rupture further reduce contractile function.
- Guanxin Danshen Formulation (GXDSF) is a Chinese herbal medicine that is comprised of Salviae miltiorrhizae Radix et Rhizoma, Notoginseng Radix et Rhizoma, and Dalbergiae odoriferae Lignum . Deng and colleagues (2017) confirmed the effects of GXDSF on myocardial ischemia reperfusion injury-induced left ventricular remodeling (MIRI-LVR) rats, indicating that GXDSF has a cardioprotective effect on CVD. They also discovered that the GXDSF treated group had lower levels and increased ratio of collagen I and (p < 0.05), suggesting that GXDSF exhibits some anti-fibrosis effects. Collagen subtypes I and III are the main constituents in interstitial collagens that influence cardiac function. More importantly, measuring the collagen III/I ratio helps to determine the effectiveness of GXDSF . In addition, the GXDSF-treated group had lower fibrosis conditions, suggesting that GXDSF can inhibit ventricular fibrosis in the mouse heart.
- Ethanolic extract from the root bark of Ulmus macrocarpa (RBUM) has been used as an Chinese traditional medicine for treating inflammation, edema, mastitis, gastric cancer . RBUM’s active ingredients include procyanidin oligomers, which are a subclass of flavonoids that include catechin oligomers, a natural phenolic antioxidant that protects against cadmium nephrotoxicity . The procyanidin oligomers have shown antioxidant, anti-inflammatory, and anti-hypertensive properties; procyanidin oligomers are present in several plants, such as grapeseed. Oh and colleagues (2008) discovered that oral administration of 100 mg/kg RBUM decreased the systolic blood pressure in spontaneously hypertensive male rats by approximately 20 mmHg, compared to the vehicle treated group. The anti-hypertensive effect of RBUM may be due to its ability to recover structural and functional changes of the vascular endothelium in SHR (spontaneously hypertensive rats) .
5. Synergistic Effects of Nanoparticles Combined with Plant and Herb Derived Medicine
- Total flavonoid extract from Dracocephalum moldavica L. (TFDM) is composed of Dracocephalum moldavica L., a plant in the Labiatae family. TFDM is known to have cardioprotective qualities against CHD, HTN and atherosclerosis . The specific agent that is accountable for its pharmacological effect comes from the flavonoid extract from the plant. Despite its beneficial pharmacological properties, like many flavonoids, TFDM has low solubility and bioavailability. In order to maximize its cardioprotective benefits, solid lipid nanoparticles (SLNs) were incorporated. SLNs are taken into intestinal epithelial cells of male rats after lipolysis and improve the bioavailability and solubility of TFDM. It was found that TFDM-SLN, compared to just TFDM, had a 5.72% increase in its drug release as well as significantly decreasing the MI size and improving myocardium integrity. TFDM-SLN also reduced the amount of IL-1β and TNF-α, illustrating an anti-inflammatory trait.
- Selenium-incorporated guar gum (GG) NPs have also shown cardioprotective activities regarding IRI . Selenium is a powerful antioxidant that has low toxicity. Furthermore, selenium NPs have shown exceptional bioactivity and bioavailability and even less toxicity than sodium selenite, the dietary form of selenium. GG is an easily attainable polysaccharide from the Cyamopsis tetragonoloba seed. GG is a good source of fiber and assists in lowering cholesterol levels. To enhance its cardioprotective properties, selenium incorporated guar gum (SGG) NPs were made to examine its antioxidant properties. When compared to guar gum nanoparticle (GGN) and selenium NP used independently, SGG NP illustrated improved antioxidant properties such as enhanced reducing power, metal chelation abilities as well as hydroxyl radical scavenging effects in rat cardiomyoblasts (H9c2). Furthermore, SGG portrayed considerable protective traits in IRI in H9c2 cells through its antioxidant characteristics.
- PVAX, or copolyoxalate containing VA, is made up of H2O2-targeting peroxalate ester linkages covalently bonded to the backbone, incorporated with VA [48,49,50]. VA, as previously mentioned, is from Gastrodia elata Blume, an herbal factor commonly used for ischemic injury and CVDs; VA is known for its antioxidant and anti-inflammatory activities. VA and peroxalate ester bond together; together they are excellent H2O2 scavengers that prevent ROS production synergistically in male rats. PVAX’s anti-inflammatory characteristics were conveyed by the reduction of pro-inflammtory cytokines and MI size. It also illustrated reduction of NOX2 and NOX4, which consequently assist in lowering ROS generation after IRI.
Conflicts of Interest
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Koo, Y.E.; Song, J.; Bae, S. Use of Plant and Herb Derived Medicine for Therapeutic Usage in Cardiology. Medicines 2018, 5, 38. https://doi.org/10.3390/medicines5020038
Koo YE, Song J, Bae S. Use of Plant and Herb Derived Medicine for Therapeutic Usage in Cardiology. Medicines. 2018; 5(2):38. https://doi.org/10.3390/medicines5020038Chicago/Turabian Style
Koo, Ye Eun, Jiwon Song, and Soochan Bae. 2018. "Use of Plant and Herb Derived Medicine for Therapeutic Usage in Cardiology" Medicines 5, no. 2: 38. https://doi.org/10.3390/medicines5020038