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. 2023 Jun 2;9(6):e16919. doi: 10.1016/j.heliyon.2023.e16919

Table 2.

Prospective biological targets for natural products to manage heart-related diseases.

No Source(s) Compound or extract(s) Mechanism of action(s) Experimental model(s) Key findings Refs
1 Rhizoma coptidis Berberine (BBR) Induces the mitophagy-mediated HIF-1a/BNIP3 pathway

  • •An In vivo using rats subjected to MI/R surgery

  • •An In vitro study in rat embryonic myocardium-derived cells H9C2

  • •BBR exhibited protective effects by inducing cardiomyocyte proliferation, inhibiting cardiomyocyte apoptosis, and activating the mitophagy-mediated HIF-1a/BNIP3 pathway.

  • •CK-MB, LDH, and AST levels in all treated I/R groups with BBR at 300 mg/kg once a day for three consecutive days significantly decreased compared with untreated I/R groups.

 [323]

  • •Activates the AK2/STAT3 signaling pathway

  • •Diminishs ER stress-induced apoptosis

  • •Administration of BBR several days before the cardiac injury was able to alleviate MI/R injury by activation of JAK2/STAT3 signaling.

  • •Activation of JAK2/STAT3 prevented mitochondrial oxidative damage induced by myocardial ischemia.

  • •BBR at 50 μmol/L significantly reduced SIR-induced cell apoptosis, oxidative stress, and ER stress in H9C2 cells.

 [318]
Modulating AMPK activity in both non-ischemic areas and risk areas of the heart

  • •An In vivo using rats subjected to MI/R surgery

  • •An In vitro Isolated heart perfusion

  • •IR group treated with BBR exhibited rate of death (%), premature betas (times), last time of VF(s), and last time of VT(s) were significantly decreased compared with the untreated IR group with values of 10, 108.5 ± 14.1, 5.1 ± 1.7, and 4.1 ± 1.1, respectively.

  • •In addition, infark size (IS) at risk area and Left Ventricular area in the group treated with BBR 100 mg/kg were significantly different from the untreated IR group.

  • •BBR significantly decreased AMPK protein concentration and the ratio of ADP/ATP and AMP/ATP in AAR. Conversely, BBR significantly increased AMPK protein concentration and the ratio of ADP/ATP and AMP/ATP in NIA compared with controls.

 [41]

  • An in vivo study using ischemia-reperfusion injury in a rat model of type 2 diabetes

  • •DMIR, diabetic ischemia-reperfusion group, treated with BBR exhibited rate of death (%), premature betas (times), last time of VF(s), and last time of VT(s) were dramatically different from untreated DMIR.

  • •BBR treatment enhanced AMPK activity and the ratio of ADP/ATP and AMP/ATP in non-ischemic areas.

  • •Pretreatment with BBR stimulated protein kinase B (AKT) phosphorylation and suppressed glycogen synthase kinase 3b (GSK3b) activity in non-ischemic areas.

 [40]
2 Aralia elata Total saponins of Aralia elata (Miq) Seem (AS) Modulate contractile function and intracellular calcium via activation PKCε phosphorylation

  • •An in vitro study using isolated rat ventricular myocytes

  • •An in vivo study in dog models

 AS showed positive effects in treating myocardial ischemia/reperfusion injury by exerting its mechanism to improve coronary blood flow, decrease oxygen consumption and heart workload with several actions, maintain the contraction and relaxation of myocytes, and activate PKCε, a Ca2þ-independent PKC isoform. [284]
Inhibit endoplasmic reticulum stress-related apoptosis An in vivo study in myocardial I/R injury rats

  • •AS significantly reversed the pathological progress of myocardium, minimized infarct size, recovered the activities of Ca2+-Mg2+ -ATPase, Na + -K + -ATPase, sarcoplasmic reticulum Ca2+-ATPases (SERCA), and calcineurin (CaN).

  • •Bcl-2 as anti-apoptotic was increased to prevent Bax oligomerization.

  • •The expression of GRP78, C/EBP homologous protein (CHOP) was decreased, the subsequent biomarker oxidative stress (MDA) was reduced, and SOD was increased.

 [285]
Activate PI3K/Akt pathway and inhibition of MAPKs family An in vivo study using lipopolysaccharide-induced cardiac dysfunction mice

  • •In immunohistochemistry, the infiltrated leukocytes significantly decreased in myocytes mice treated with AS 140 mg/kg BW compared with untreated mice. It correlated with reducing TNF-α, interleukin (IL)-1b, and IL-6 levels and preventing NF-kB activation.

  • •LDH, CK, AST, and cTnI were decreased in treated mice.

  • •ROS level was reduced as a result of downregulating LPS-mediated NOX2 expression.

  • •The other mechanism of AS in treat LPS-induced cardiac dysfunction is significantly activated PI3K/Akt signaling pathway and inhibition of MAPKs family.

 [43]
Elatoside C

  • •Activates the STAT3 pathways

  • •Reduces ER stress-associated apoptosis

 An in vitro study in hypoxia/reoxygenation (H/R)- induced H9c2 cardiomyocyte injury

  • •Elatoside C significantly protected H/R-induced cell death by maintaining cell viability, stabilizing mitochondrial membrane potential, reducing mitochondrial ROS, and suppressing apoptotic cardiomyocytes.

  • •On the other hand, apoptosis markers such as GRP78, CHOP, Caspase-12, and JNK were greatly suppressed. These data were supported by increasing STAT3 phosphorylation and an increase of Bcl2/Bax ratio.

 [283]
3 Brassica oleracea var. capitata rubra Anthocyanin

  • •Antioxidant

  • •Cardioprotective

 An in vivo study using atherogenic (ATH) diet-induced hypercholesterolemia and related cardiac in rats

  • •CK, CK-MB, and LDH in groups treated with anthocyanin-rich red cabbage extract at a dose of 100 mg/kg BW a day for eight weeks were significantly different from the untreated ATH group with levels of 54.17 ± 8.09, 82.50 ± 9.28, 98.10 ± 9.31 U/L, respectively.

  • •In addition, MDA level was 9.00 ± 0.66, and SOD and CAT levels were 30.89 ± 1.45, 7.88 ± 0.19 U min−1 mg−1 protein, respectively. All of these parameters were significantly different from untreated ATH groups.

 [226]
4 Songling Xuemaikang Capsule (SXC) (Puerariae thomsoni, Pinus massonana, and powdered nacre) Songling Xuemaikang Capsule (SXC) Inhibits of cardiac hypertrophy via CaMKIIδ and ERK1/2 pathways

  • •An in vivo study using an iso-induced cardiac remodeling model in rats

  • •An in vitro study using H9C2 rat cardiomyocytes

  • •SXC suppressed the expression of CaMKIIδ, and the phosphorylation of ERK1/2, leading to inhibiting expression of GATA4 protein in the nucleus and brain natriuretic peptide in serum.

  • •Moreover, left ventricular diastolic posterior wall thickness in the SXC group was significantly decreased.

  • •The cardiac hypertrophy indicator HW/BW was decreased at dose-dependently.

 [209]
5 Beta vulgaris Betanin Sentrin-specific protease −2 (SENP2) inhibitor An in-silico study (PDB ID: 1TH0) Betanin showed low toxicity, high binding energy, and hydrogen bonds to the SENP2 active site with low RMSD. [255]
6 Wuwei Yuganzi San (WYS) Sennoside D, quercetin, and procyanidin B-5,3’-O-gallate Inhibiting of several crucial protein targets of CHD such as, ADAM17, AKR1C2, ALB, AKT1, and ADH1C An in-silico study using AutoDock Vina software The compounds showed binding affinity to protein targets, approximately < -10 kcal/mol, offered the promising therapeutic CHD. [311]
7 Allium sativum, Peganum harmala, and Berberis vulgaris Ethanol extract from A.sativum and P. harmala, and Methanol extract from B. vulgaris Restoration of left ventricular remodeling, decreasing hs-CRP and NT-ProBNP An in vivo study using isoproterenol-induced heart failure in rats

  • •Treatment ISO rats using A. sativum, P. harmala, and B. vulgaris exhibited heart weight/Body weight significantly different from ISO untreated rats.

  • •Furthermore, extracts exhibited therapeutic effects by decreasing left ventricular end-diastolic/systolic diameters (LVED/Sd), NT-ProBNP and hs-CRP values, and increasing the ejection fractions.

 [134]
8 Terminalia arjuna (Roxb.) Lyophilized aqueous extract of stem bark The extract modulated ERK/Akt, ER stress marker Grp78, and epigenetic regulator HDAC5. An in vivo study using isoproterenol-induced cardiac hypertrophy in rats

  • •Down- and up-regulation of several proteins by isoproterenol was remarkably restored by the extract.

  • •The other markers of cardiac hypertrophy, such as, heart-to-body weight ratio, interventricular septal and left ventricular posterior wall diameters, β-MHC, Sk.α Actin-1, BNP, and TGF-β2 were greatly restored.

  • •The extract modulated ERK/Akt, ER stress marker Grp78, and epigenetic regulator HDAC5 and reversed to baseline.

 [147]
9 Radix salviae Milthiorrhizae Salvianic acid A (SAA) as a water-soluble fraction Inhibite L-type calcium channels and decreasing myocardial contractility An in vivo study using iso-induced myocardial ischemia injury in rats Low and high doses of SAA inhibited cell shortening by 33.48 ± 0.75%, significantly reduced CK and LDH levels, inhibited L-type calcium channels in a dose-dependent manner, and histopathology of rat hearts were in normal structures. [248]
10 Cissampelos pareira Ethanol extract from root Antioxidant activity and ameliorating calcineurin activity An in vivo study using isoproterenol-induced cardiac dysfunction in rats

  • •Co-treatment CIS 200 mg/kg BW daily for 30 days proposed cardioprotective effects by regulating several cardiac dysfunction markers. LDH and TBARS levels significantly decreased at 437.65 ± 22.12 U/L and 7.52 ± 0.27 μM/L, respectively. In contrast, The GSH was increased at a 3.11 ± 0.11 μM/L level. In addition, NO, HW/BW, and calcineurin activity were lowered.

  • •Antioxidant enzymes, such as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione-S-transferase (GST) levels were significantly enhanced compared to untreated rats.

 [244]
11 Salvia miltiorrhiza Salvia miltiorrhiza hydrophilic extract (SMHE) Antioxidant activity A clinical study in diabetic patients with chronic heart disease (CHD)

  • •After treatment with SMHE 5 g twice daily for 60 days, GSH levels, SOD, and GSSG-R activities in patients were significantly higher than in the placebo group.

  • •In contrast, the malondialdehyde (MDA) level in the treatment group was significantly lower than in the placebo group on the 30th day.

 [211]
12 Phyllanthus tenellus pino- cembrin-7-O-[3′′-O-galloyl-4′′,6′′-(S)-hexahydroxydiphenoyl]- α-D-glucose (P7OG) Inhibit platelet aggregation, vasorelaxation, protection vascular disorders An in vitro study using G-6-P, vascular reactivity, aggregation platelet assays. P7OG greatly inhibited glucose-6-phosphatase, ADP, collagen with IC50 at 17.20, 26, 61 μM, respectively. In addition, P7OG showed remarkably inhibition effect on the G-6-Pase (83%) assayed in intact microsomes. [73]
13 Abies alba Silver fir trunk extract (SFTE) Antiarrhythmia, vasoralaxan, antioxidant An in vivo study using ischemic-reperfused isolated heart rats SFTE significantly decreased lactate dehydrogenase (LDH) release rate, increased coronary flow rate, and restored arrhythmias duration by 80%, compared to untreated group during the reperfusion period. [65]