Table 3.

Summary of cardioprotective effects exerted by terpenophenolic compounds published between 2017 and 2022.

Terpenophenolics	Terpenophenolics Subclasses	Study Design	Dose	Findings	Conclusion	References
Bakuchiol	Meroterpenoids	In vivo & in vitro; C57BL6 male mice (20–25 g) & H9c2 cells	60 mg/kg/day; 2, 5, 10 μM	-Bakuchiol inhibited the synthesis of fibrosis-associated protein in diabetic myocardium by reducing gene expression of α-SMA and Smad3. -Bakuchiol ameliorated oxidative stress in diabetic myocardium by increasing SOD, and GSH-Px. -Bakuchiol attenuated cardiomyocyte apoptosis in high glucose-treated H9c2 cells by decreasing TUNEL-positive nuclei and apoptotic ratio.	Protective effect of bakuchiol in limiting the synthesis fibrosis, preventing oxidative damage and cell death in diabetic myocardium may be via the SIRT1 and Nrf2 signalling pathway.	[42]
		In vivo & in vitro; C57BL/6J mice & NRCM cells	10 mg/kg/day; 1, 5, 10 μM	-Bakuchiol ameliorated the cardiomyocyte hypertrophy by reducing gene expression of ANP, BNP and β-MHC and inhibited the enlargement of cardiomyocytes in NRCM. -Bakuchiol ameliorated the cardiomyocyte fibrosis and inflammatory responses by reducing gene expression of collagen 1 & 3 and CGTF, protein and gene expression of TNF-α, IL-6 and MCP-1. -Bakuchiol treatment showed no significant difference in the fraction of apoptotic cells compared to the control group.	Bakuchiol exerts antihypertrophy effects by modulating synthesis of fibrosis and inflammatory responses may be via the NF-κB pathway.	[43]
Ferruginol	Diterpenoids	In vivo; Wistar rats	50 mg/kg/day	-Ferruginol attenuated cardiac injury in myocardial infarction by reducing cTnT, cTnI, CK, CK-MB. -Ferruginol ameliorated oxidative damage in myocardial infarction by reducing malondialdehyde and improving SOD, GPx, CAT and GSH. -Ferruginol attenuated inflammation in myocardial infarction by limiting the secretion of TNF-α, IL-6, and NF-κB.	Cardioprotective effect of ferruginol against myocardial infarction via modulation of inflammatory response and upregulation of antioxidant enzymes.	[44]
		In vivo & in vitro; C57BL/6 mice (20 ± 2) & H9c2 cells	20 mg/kg/day; 0.1 μM	-Ferruginol attenuated the reduced ejection fraction and fractional shortening induced by DOX treatment. -Ferruginol ameliorated the tissue injury marker by reducing the level of LDH and CK-MB caused by DOX treatment. -DOX caused the increase of ROS production, while ferruginol mitigated it. -TUNEL assay demonstrated that DOX caused increasing in apoptotic cells meanwhile ferruginol alleviated the progression of apoptosis.	The cardioprotective action of ferruginol is proven by preserving the mitochondrial from the production of ROS, limiting damage to heart function and attenuating the apoptotic process, possibly via the SIRT1 pathway that mediates mitochondrial biogenesis and fatty acid oxidation.	[45]
Carnosic Acid	Diterpenoids	In vivo; C57BL/6 mice	0.02%	-Carnosic acid diminished the gene expression of adipocyte differentiation and fat accumulation in white adipose tissue by reducing aP2, PPAR-γ and LPL. -Carnosic acid ameliorated inflammation in white adipose tissue by reducing TNF-α, and IL-6. -Carnosic acid reduced the size of abdominal fat adipocytes.	Carnosic acid exhibit antiobesity effect by improving hormone homeostasis and reduced genes expression of liver lipogenesis possibly via the PPAR-γ pathway.	[46]
		In vivo; C57BL/6 mice	50 mg/kg	-Carnosic acid alleviates cardiac hypertrophy by reducing gene expression ANP, BNP, and β-MHC and limiting the enlargement of the cardiomyocyte area. -Carnosic acid attenuated the development of cardiac fibrosis by reducing gene expression of Col 1 & 3, CTGF and α-SMA. -Carnosic acid suppressed the oxidative damage by increasing the SOD level and decreasing the MDA level and NAPDH activity. Protein and gene expression of NOX 2 & 4 are also reduced by carnosic acid. -Carnosic acid inhibited myocardial apoptosis by upregulating Bcl-2 and downregulating Bax and caspase-3.	Cardioprotective of carnosic acid against myocardial remodelling by modulation oxidative stress and apoptosis via the AKT/GSK3β/NOX 4 signalling pathway.	[47]
		In vivo & in vitro; C57BL/6 mice & H9c2 cells	5 mg/kg; 10 μM	-Carnosic acid ameliorated cardiac injury in cardiotoxicity rats by reducing CK-MB and remarkably preventing the enlargement of cardiomyocytes. -Carnosic acid attenuated the myocardial hypertrophy in cardiotoxicity rats by reducing the gene expression of ANP, BNP and β-MHC. -Carnosic acid mitigated the oxidative damage in cardiotoxicity rats by upregulating the antioxidant enzymes; SOD, CAT and GSH and downregulating the lipid peroxidation (MDA). -Carnosic acid suppressed inflammation in cardiotoxicity rats by reducing protein expression of p-NF-κB, IL-1β and IL-18. -Carnosic acid inhibited myocardial apoptosis and autophagy in cardiotoxicity rats by upregulating Bcl-2 and downregulating caspase-3. Autophagy associated-molecules; LC3BII, ATG-5, and ATG-7 suppressed by carnosic acid.	Carnosic acid protects the heart against toxicity by suppression of oxidative damage, inflammation, apoptosis, and autophagy.	[48]
Carnosol	Diterpenoids	In vitro; H9c2 cells	5, 10, 20 μM	-Carnosol ameliorated inflammation in H9c2 cells by reducing protein and gene expression of TNF-α, IL-1β, IL-6 and COX-2.	The protective effect of carnosol against inflammation in the cardiomyoblasts may be via the NF-κB signalling pathway.	[49]
		In vitro; MAPC cells	0.2 μM	-Carnosol inhibited the production of ROS and apoptosis by downregulating caspase-3 activity. -Carnosol limit oxidative damage by upregulating the antioxidant enzyme, GSH, GST, and CAT and protein expression of Nrf-2.	Carnosol promotes vascular health by regulating redox status and downregulating inflammation and apoptosis.	[50]
Carvacrol	Monoterpenoids	In vivo & in vitro; Wistar rats & NRCM cells	25, 50, 100 mg/kg; 0.6 mM	-Carvacrol significantly reduced the infarct volume in myocardial I/R injury rats and suggested that it was dose-dependent. -Carvacrol alleviated the lipid peroxidation marker, MDA in myocardial I/R injury rats. -Carvacrol attenuated the apoptosis protein in mitochondrial injury induced by I/R by upregulating Bcl-2 protein levels and downregulating Bax and cleaved-caspase protein levels.	Carvacrol was found to possess cardioprotective properties, which may be related to its antioxidant and antiapoptotic properties in myocardial I/R injury through activation of MAPK/ERK and Akt-eNOS signalling pathways.	[51]
		In vivo; Wistar rats	5, 10, 25, 50 mg/kg	-Carvacrol improved the MAP in the myocardial hypertrophy group in a dose-dependent manner. -Carvacrol ameliorates apoptosis in myocardial hypertrophy by upregulating gene expression of Bcl-xL and Bcl-2 and downregulating Bad.	Protective effect of carvacrol against myocardial hypertrophy by improving blood pressure and inhibiting apoptosis via regulation of the Bcl-2 family protein.	[52]
Thymol	Monoterpenoids	In vivo; Wistar rats	24 mg/kg	-Thymol attenuated the lipid profile in hypercholesterolemic rats by improving total cholesterol and oxidized LDL. -Thymol mitigated oxidative damage by upregulating the antioxidant enzymes; GSH-Px and TAC and limiting the lipid peroxidation. -Thymol ameliorated apoptosis in hypercholesterolemic rats by reducing protein expression of caspase-3 and phospho-p38 and upregulating Bcl-2 protein.	Thymol preserves carotid tissue by reducing apoptosis and inflammation, which may be a result of its direct antioxidant properties.	[53]
		In vivo; Albino Wistar rats	15, 30, 60 mg/kg	-Thymol ameliorated cardiac injury in myocardial infarction rats by reducing CK levels and improving cardiomyocyte structure in a dose-dependent manner. -Thymol attenuated oxidative damage in myocardial infarction rats by upregulating antioxidant enzyme GSH and limiting the lipid peroxidation. -Thymol mitigated inflammation in myocardial infarction rats by reducing protein expression of NF-κB and IL-1β in a dose-dependent manner. -Thymol attenuated apoptosis in myocardial infarction rats by reducing protein expression of caspase-3 and enhancing Bcl-2 protein.	Thymol has been revealed to have a cardioprotective effect against myocardial infarction via modulating oxidative stress, inflammation, and apoptosis.	[54]
Hinokitiol	Monoterpenoids	In vitro; SEVC4-10 cells and A7r5 cells	4, 12 μM	-Hinokitiol mitigated the inflammation-induced cell adhesion molecules in SEVC4-10 cells by reducing protein expression of E-selectin, sICAM-1, and sVCAM-1. -Hinokitiol inhibited the promotion of atherosclerosis by reducing protein expression of MMP-2 and MMP-9.	Hinokitiol exerts a protective effect against atherosclerosis through modulating cell adhesion molecules and members of the matrix metalloproteinase (MMP) family.	[55]
		In vitro; AC16 cells	20 μM	-Hinokitiol mitigated autophagy flux in cardiomyocytes from oxidative damage by decreasing LC3B-II/I ration, enhancing p62 protein and reducing Beclin-1 protein. -Hinokitiol attenuated apoptosis in cardiomyocytes from oxidative damage by upregulating protein expression of p21. -Molecular docking of hinokitiol found that it inhibited the GSK3β signalling pathway through its phosphorylated at the Ser9 site.	Hinokitiol protects cardiomyocytes from oxidative damage by regulating apoptosis and autophagy, probably through the GSK3β signalling pathway.	[56]