Table 1.
Mechanisms of Chinese herbal medicine active ingredients regulating endoplasmic reticulum stress (ERS).
| Active ingredients | Chemical formula | Mechanism and effect | The disease of myocardial injury | Experimental model | Dose | Refs. |
|---|---|---|---|---|---|---|
| Anisodamine | C17H23NO4 | ↓GRP78, CHOP, Cleaved Caspase-3 | Myocardial injury after cardiac arrest and resuscitation in rats | Cardiac and I/R injury and arrest Wistar rats (in vivo) | 10 mg/kg | [69] |
| Apigenin-7-O-β-d-(-6″-p-coumaroyl)-glucopyranoside | C30H26O12 | ↓PERK, p-PERK, eIF2α, p-eIF2α, CHOP, Bax, Cleaved Caspase-3, ↑Bcl-2, p-AMPK, AMPK, | Myocardial hypoxia-reperfusion injury | Myocardial ischemia/reperfusion injury isolated heart of adult SD rats (in vivo) Hypoxia/Reoxygenation injury in primary neonatal rat cardiomyocytes (in vitro) |
4 μM | [70] |
| Araloside C | C53H84O23 | ↓PERK, eIF2α, ATF6, CHOP, Caspase-12, ↑HSP90 | Myocardial hypoxia-reperfusion injury | Hypoxia/Reoxygenation injury in H9c2 cardiomyocytes | 12.5 μM | [71] |
| Astragaloside IV | C41H68O14 | ↓p-eIF2α, CHOP, Caspase-3, Caspase-9, ROS, ↑Bcl-2 | Myocardial hypoxia-reperfusion injury | Hypoxia/Reoxygenation injury in H9c2 cardiomyocytes (in vitro) | 50, 10, 5, 1 and 0.5 μM |
[72] |
| Atractylenolide Ⅲ | C15H20O3 | ↓GRP78, Caspase-12, Caspase-3, Ca2+ | Myocardial hypoxia-reperfusion injury | Hypoxia/Reoxygenation injury in H9c2 cardiomyocytes (in vitro) | 15, 30 and 60 μM | [73] |
| Berberine | C20H18NO4]+ | ↓ PERK, eIF2α, ATF4, CHOP | Myocardial hypoxia-reperfusion injury | Myocardial I/R injured in SD rats (in vivo) Hypoxia/Reoxygenation injury in H9c2 cardiomyocytes (in vitro) |
200 mg/kg/d for 2 week; 50 μM | [74] |
| Crocin | C44H64O24 | ↓GRP78, Caspase 3, Bax, miR-34a, ↑SIRT1, Nrf2, HO-1 | Myocardial hypoxia-reperfusion injury | I/R-induced left ventricular dysfunction and infarct in C57BL/6 mice (in vivo) Hypoxia/Reoxygenation injury in primary neonatal mouse cardiomyocytes (in vitro) |
50 mg/kg/d for 1 week; 10 μM | [75] |
| Elatoside C | C46H74O16 | ↓GRP78, CHOP, Caspase-12, JNK | Myocardial hypoxia-reperfusion injury | Hypoxia/Reoxygenation injury in H9c2 cardiomyocytes (in vitro) | 25 μM | [76] |
| Grape seed proanthocyanidins | C30H26O13 | ↓GRP78, CHOP, eIF2α, p-PERK | Myocardial hypoxia-reperfusion injury | Hypoxia/Reoxygenation injury in H9c2 cardiomyocytes (in vitro) | 50, 100 and 200 μM | [77] |
| Gypenoside | C47H80O17 | ↓CHOP, GRP78, CHOP, Caspase-12, PERK, eIF2α, ATF4 ↑PI3K, Akt, p-GSK3β | Myocardial hypoxia-reperfusion injury; coronary heart diseases | Myocardial I/R injured in Wistar rats (in vivo) Hypoxia/Reoxygenation injury in H9c2 cardiomyocytes (in vitro) |
200 mg/kg for 1 week | [78] |
| Gypenoside XVII | C48H82O18 | ↓GRP78, PERK, IRE1, P-JNK, CHOP, Bad, BAX, Caspase-12, p38-MAPK pathway ↑Bcl-2, PI3K/Akt pathway | Myocardial hypoxia-reperfusion injury | Hypoxia/Reoxygenation injury in H9c2 cardiomyocytes (in vitro) | 5, 10 and 20 μM | [79] |
| Luteolin | C15H10O6 | ↓GRP78, p-eIF2α, IRE1α, XBP-1, ATF6, CHOP, Bax, Caspase-3, ↑Bcl-2 | Myocardial hypoxia-reperfusion injury | Hypoxia/Reoxygenation injury in H9c2 cardiomyocytes (in vitro) | 10 μM | [80] |
| Lycopene | C40H56 | ↓CHOP, GRP78, ATF6, eIF2α, sXBP-1, Bax/Bcl-2, | Myocardial hypoxia-reperfusion injury | Hypoxia/Reoxygenation injury in primary neonatal rat cardiomyocytes (in vitro) | 5 μM | [81] |
| Notoginsenoside R1 | C47H80O18 | ↓Calnexin, BiP, CHOP, Caspase-3, ↑RyR2 | Myocardial hypoxia-reperfusion injury | Hypoxia/Reoxygenation injury in H9c2 cardiomyocytes, HL-1 cells, and primary cultured neonatal cardiomyocytes from Sprague–Dawley rats (in vitro) | 20, 40, 80 and 100μg/mL | [82] |
| Panax quinquefolium saponin | − | ↓GRP78, Calreticulin, CHOP, Bax, ↑Bcl-2 | Myocardial infarction | Acute myocardial infarction in SD rats (in vivo) | 50 and 100 mg/kg for 4 week | [83] |
| Piperine | C17H19NO3 | ↓GRP78, CHOP, Caspase-12, BiP, ↑p-PI3K, p-AKT | Myocardial ischemia/reperfusion injury | Hypoxia/Reoxygenation injury in primary neonatal rat cardiomyocytes from Sprague-Dawley (in vitro) | 20 μM | [84] |
| Protocatechualdehyde | C7H6O3 | ↓eIF2α, p-eIF2α, Ero1-Lα, PERK, CHOP, BiP, IRE1α, ATF6, Caspase-3, BAX, HIF-1α, ↑Bcl-2 | Myocardial ischemia/reperfusion injury | Oxygen-glucose deprivation/reoxygenation in H9c2 cardiomyocytes, and primary neonatal rat cardiomyocytes from Sprague Dawley (in vitro) | 5 μM | [85] |
| Quercetin | C15H10O7 | ↓PERK, CHOP, Caspase-12, ↑SIRT1, TMBIM6 | Myocardial ischemia/reperfusion injury | Hypoxia/reoxygenation in H9c2 cardiomyocytes (in vitro) | 150 mg/L | [86] |
| Salidroside | C14H20O7 | ↓p-PERK, p-eIF2α, CHOP, p-PERK, ↑AMPK | Myocardial ischemia/reperfusion injury | Myocardial ischemia in SD rats (in vivo) I/R injury in H9c2 cardiomyocytes (in vitro) |
40 mg/kg; 10 μM | [87] |
| Sulforaphane | C6H11NOS2 | ↓GRP78, CHOP, caspase-12, SIRT1, PERK, eIF2α, ↑Bcl-2 | Myocardial ischemia/reperfusion injury | Ischemia/reperfusion injury in H9c2 cardiomyocytes (in vitro) | 0.1–5 μM | [89] |
| Tanshinone IIA | C19H18O3 | ↓GRP78, CHOP, Caspase-12, ↑miR-133 | Myocardial injury | Tunicamycinc induced injury in primary neonatal rat cardiomyocytes (in vitro) | 10 μM | [90] |
| Tournefolic acid B | C17H12O6 | ↓CHOP, Caspase-12, JNK↑SOD、CAT, GSH-Px, p-PI3K, p-AKT, Bcl-2/Bax ratio | Myocardial ischemia/reperfusion injury | Hypoxia/reoxygenation injury in H9c2 cardiomyocytes (in vitro) | 0.5, 1 and 2 μM | [91] |
| Baicalin | C21H18O11 | ↓CHOP, ↑eNOS, NO | Clotrimazole-induced apoptosis in cardiomyocytes | Hypoxia/Reoxygenation injury in primary neonatal rat cardiomyocytes from SD rats (in vitro) | 12.5, 25 and 50 μM | [92] |
| Barbaloin | C21H22O9 | ↓GRP78, CHOP, PERK, p-PERK, ATF4, Caspase-12, Caspase-3, CNPY2 | Myocardial I/R injured in SD rats (in vivo) | 20 mg/kg/d for 1 week | [93] | |
| Berberine | C20H18NO4 | ↓CHOP, Caspase-12, Caspase-3 ↑Bcl-2/Bax ratio | Cardiac remodeling of heart failure after myocardial infarction | Myocardial infarction in Wistar rats (in vivo) | 20 mg/kg for 4 week | [94] |
| Echinacoside | C35H46O20 | ↓GRP78, P–I/REα, p-PERK, ATF6, CHOP, NADPH, ROS | Heart failure | Isoprenaline (ISO)-induced HF rats (in vivo) Isoprenaline (ISO)-induced primary cardiomyocytes of neonatal from Sprague–Dawley rats (in vitro) |
10 mg/kg/d for 2 week | [95] |
| Ophiopogonin D | C44H70O16 | ↓Bip, Bax, Perk、ATF4, Caspase-12, CHOP | Heart failure | Isoprenaline (ISO)-induced cardiac hypertrophy injury in H9c2 cardiomyocytes (in vitro) | 10 μM | [96] |
| Resveratrol | C14H12O3 | ↓GRP78, GRP94, CHOP, ↑Bcl-2/Bax ratio | Cardiac hypertrophy | Isoprenaline (ISO)-induced cardiac hypertrophy injury in H9c2 cardiomyocytes (in vitro) | 50 μM | [97] |
| 1, 8-cineole | C10H18O | ↓GRP78, PERK, ATF4, CHOP, ROS, Bcl-2/Bax ratio, p-Caspase 3 | Heart failure | Isoprenaline (ISO)-induced cardiac hypertrophy injury in H9c2 cardiomyocytes (in vitro) | 10, 15, 20, 25, 30, 35 and 40 μM; 120, 60 and 30 mg/kg/d for 4 week | [98] |
| Astragalus polysaccharides | C10H7ClN2O2S | ↓ATF6, PERK, CHOP | Diabetic cardiomyopathy | Streptozotocin-induced type 1 diabetic ratsl (in vivo) High Glucose (HG)-Induced H9c2 cardiomyocytes (in vitro) |
1 g/kg/d for 16 week; 0.8 mg/mL | [99] |
| Beta carotene | C40H56 | ↓ROS, Bax, ATF4, GRP78, CHOP, Beclin 1, p62, LC3II/LC3I ratio, ↑Bcl-2, p-PI3K, p-AKT, p-mTOR, SOD, GSH-Px | Diabetic cardiomyopathy | Advanced glycation end products-induced H9c2 cardiomyocytes (in vitro) | 40 μM | [100] |
| Berberine | C20H18NO4]+ | ↓XBP1, ↑AMPK, p-eNOS | Diabetes-Associated Endothelial Dysfunction | High-fat diet and streptozotocin induced diabetes in C57BL/6 J mice (in vivo) High sugar or clindamycin-treated HUVECs cell (in vitro) |
11.3, 14.5, 12.2 and 1 μM | [101] |
| Curcumin | C21H20O6 | ↓GRP78, CHOP, Caspase 3, BAX, | Diabetic cardiomyopathy | Palmitate treated H9c2 cardiomyocytes (in vitro) | 10 μM | [102]. |
| Curcumin | C21H20O6 | ↓p-PERK, p-eIF2α, and ATF4, ↑LC3-II | Lipotoxic cardiomyopathy | Palmitate treated H9c2 cardiomyocytes (in vitro) | 100 μM | [103] |
| Linderalactone | C15H16O3 | ↓ATF6, p-ERK, p-JNK, p38, CHOP, MAPKs | Diabetic cardiomyopathy | Streptozotocin-induced type 1 diabetes in C57BL/6 J mice (in vivo) | 2.5 or 5 mg/kg for 5 week | [104] |
| Mangiferin | C19H18O11 | ↓GRP78, CHOP, TXNIP, NLRP3, Caspase-3,↑AMPK, NO | Endothelial dysfunction induced by diabetes | High sugar treated EA.hy926 cells (in vitro) | 10 μM | [105] |
| Resveratrol | C14H12O3 | ↓PERK, eIF2α, ATF6, CHOP, IRE1α, JNK, ↑SIRT1 | Diabetic cardiomyopathy | Streptozotocin-induced diabetes in Sprague–Dawley rats (in vivo) High sugar treated H9c2 cardiomyocytes (in vitro) |
10 μM | [106] |
| Tanshinone IIA | C19H18O3 | ↓GRP78, ATF4, ATF6, XBP-1s, P-eIF2α, CHOP, ↑SIRT1, | Diabetic cardiomyopathy | High-sugar, high-fat diet induces diabetes in C57BL/6 J mice (in vivo) High sugar treated primary neonatal rat cardiomyocytes from C57BL/6 J mouse (in vitro) |
10, 50 and 250 mg/kg/day for 14 week; 1.5 and 6.25 μM | [107] |
| Black tea | − | ↓ATF3, ATF6, p-eIF2α, ROS | Hypertension-associated endothelial dysfunction | Angiotensin II (Ang II)-induced hypertension in Sprague–Dawley rats (in vivo) | 15 mg/kg/day for 2 week | [108] |
| Berberine | C20H18NO4]+ | ↓AFT3, ATF4, XBP1, COX2, ROS, ↑AMPK | Spontaneously hypertensive | carotid artery tissue of Spontaneously hypertensive rats (in vivo) | 1 μM | [109] |
| Nobiletin | C21H22O8 | ↓GRP78, GRP94, CHOP, Caspase-3 | Renal vascular hypertension and left ventricular remodeling | Renal vascular hypertensive Wistar rats (in vivo) | 100 mg/kg/d for 4 week | [110] |
| Paeonol | C9H10O3 | ↓GRP78, ATF6, eIF2α, ROS, ↑AMPK, PPARδ, NO | Atherosclerosis | Tunicamycin induced C57BJ/6 J and PPARδ wild type (WT) mouse aortas (in vivo) Tunicamycin-induced human umbilical vein endothelial cells, H5V cells (in vitro) |
0.1 μM | [111] |
| Pterostilbene | C16H16O3 | ↓PERK, eIF2α, ATF4, CHOP, ↑SIRT1 | Atherosclerosis | TNF-α- induced H9c2 cells (in vitro) | 0.1, 0.5, or 1 μM | [112] |
| Curcumin | C21H20O6 | ↓GRP78, CHOP, cTn-I, Ang II, ↑Bcl-2 | Heat-stress-induced cardiac injury | Heat stress exposure C57BL/6 J mice (in vivo) | 50, 100 and 200 mg/kg/day for 4 week | [113] |
| Rosa canina L, methanolic extract | − | ↓p-PERK, p-eIF2α, CHOP, Caspase 8 | Heat-stress-induced cardiac injury | Heat stress exposure Wistar rats (in vivo) | 500/1000 mg/mL | [114] |
| Ursolic acid | C30H48O3 | ↓p-PERK, p-eIF2α, CHOP, ↑Mcl-1 | Heat stress | Heat stress exposure ICR rats (in vivo) | 20 or 40 mg/kg | [115] |
| Panax quinquefolium saponin | − | ↓Erk1/2, CaMKII, HDAC4, CK-MB, cTnT, IMA, ↑AMPK | Cardiac remodeling induced by simulated microgravity | Unloading induced cardiac remodeling SD rats (in vivo) | 200 mg/kg/d for 8 week | [116] |
| Astaxanthin | C40H52O4 | ↓GRP78, p-PERK, p-eIF2α, ATF4, ATF6, p-IRE1, XBP-1, CHOP, Caspase-12 | Alcoholic cardiomyopathy | Ethanol induced Alcoholic cardiomyopathy in C57BL/6 J mice (in vivo) Ethanol treated H9c2 cardiomyocytes and primary cardiomyocytes (in vitro) |
20 mg/kg/d for 8 week; 10 μM | [117] |
GRP78: glucose regulated protein78; CHOP: C/EBP homologous protein; I/R: ischemia/reperfusion; PERK: protein kinase RNA (PKR)-like endoplasmic reticulum (ER) kinase; eIF2α: eukaryotic translation initiation factor 2α; Bcl-2: BCL2 apoptosis regulator; AMPK: 5′ adenosine monophosphate-activated protein kinase; SD rats: Sprague-Dawley rats; ATF6: activating transcription factor 6; HSP90: heat shock protein 90 alpha family class A member 1; ROS: reactive oxygen species; ATF: activating transcription factor; SIRT1: silencing information regulator 1; Nrf2: nuclear factor erythroid-2-related factor 2; HO-1: heme oxygenase 1; JNK: c-Jun N-terminal kinase; RyR2: type 2 ranibodin receptor; Bip: binding-immunoglobulin protein; HIF-1α: hypoxia inducible factor 1 subunit alpha; TMBIM6: transmembrane BAX inhibitor-1 motif-containing 6; CNPY2: cardiomyocyte-specific protein canopy homolog 2; NADPH: nicotinamide adenine dinucleotide phosphate oxidase; LC3II: microtubule associated protein 1 light chain 3 beta; XBP1: X-box-binding protein 1; MAPK: mitogen-activated protein kinase; TXNIP: thioredoxin interacting protein; NLRP3: NLR family fyrin domain containing 3; eNOS: endothelial-type nitric oxide synthase; HUVECs: human umbilical vein endothelial cells; NO: nitric oxide; ATF3: activating transcription factor 3; COX2: cyclooxygenase-2; PPARδ: peroxisome proliferator activated receptor gamma; cTn-I: cardiac troponin I; TNF-α: tumor necrosis factor-α; Ang II: angiotensin II; Mcl-1: MCL1 apoptosis regulator, BCL2 family member; GRP94: glucose regulatory protein94; HDAC4: histone deacetylase 4; CK-MB: creatine kinase-MB; cTnT: cardiac trophoblast protein T; CaMKII: Ca2+/calmodulin-dependent protein kinase II; IMA: ischemia-modified albumin; −: no data.