Excessive mitochondrial fission in myocardial ischemia/reperfusion injury: Pathophysiological relevance and potential cardioprotective modulation by plant-derived interventions and electroacupuncture

Table 1 Chemically defined plant-derived compounds associated with mitochondrial fusion-fission regulation in myocardial ischemia/reperfusion injury and related experimental models

Compound	Chemical class	Major plant source	Experimental model	Study groups	Sample size and design	Dosage, administration route, and regimen	Main findings	Evidence strength	Ref.
Ginsenoside Rg1	Triterpenoid saponin	Panax ginseng C.A. Mey (Araliaceae; Ginseng Radix et Rhizoma)	H9c2 H/R (3 hours/3 hours)	Ctrl; H/R; H/R + Rg1	3 independent experiments; R/B: NR	3.125, 6.25, 12.5 μmol/L; MEC NR; pretreated for 24 hours before H/R	Cell viability 66.86% ± 2.655% vs 54.39% ± 0.6338% (H/R; 12.5 μmol/L; mean ± SEM). ↑: MFN2, GDH activity, intracellular glutamate, cell viability, ATP, ΔΨm. ↓: Mitochondrial fragmentation, LDH, CK, ROS, Bax/Bcl-2	C; MFN2 siRNA; Pre (C): Clinical window untested	Dong et al[53]
Ginsenoside Rg1	Triterpenoid saponin	Panax ginseng C.A. Mey (Araliaceae; Ginseng Radix et Rhizoma)	HL-1 H/R (6 hours/2 hours)	Ctrl; H/R; H/R + Rg1; H/R + Rg1 + siNotch1	n = 6 (viability/LDH), 3 (protein assays); R/B: NR	200 μmol/L; MEC NR; added at hypoxia onset and maintained throughout H/R	↑: Notch1, MFN1, ΔΨm, ATP, cell viability. ↓: MFN2, LDH, cytosolic ROS	C; Notch1 siRNA; Isch (C): Clinical window untested	Zhang et al[54]
Ginsenoside Rg5	Triterpenoid saponin	Panax ginseng C.A. Mey (Araliaceae; Ginseng Radix et Rhizoma)	ICR mice, ISO-induced ischemic injury; NRVMs challenged with PA (100 μmol/L, 2 hours), with or without subsequent H/R (4 hours/1 hour)	In vivo: Sham; ISO; ISO + Rg5; TMZ + ISO. In vitro: Ctrl; PA; Rg5 + PA; H/R; PA + H/R; Rg5 + PA + H/R	In vivo: n = 4 (localization), 3-6 (TUNEL). Cells: 3 independent experiments; R/B: NR	In vivo: 50 mg/kg; MED NR; oral; administered 1 hour before ISO on 2 consecutive days. In vitro: 10 μmol/L; MEC NR; pretreated for 0.5 hours before PA	In vivo: ↑: Mitochondrial HK II, and Akt; ↓: Mitochondrial Drp1 recruitment. In vitro: PA model: ↑: P-Akt, mitochondrial HK II, p-Drp1(Ser637), ΔΨm; ↓: Mitochondrial Drp1 recruitment, mPTP opening, ROS, mitochondrial fragmentation. PA + H/R model: ↑: ATP; ↓: Cyt c release, ROS, cell death	C, E; Akt/Drp1 siRNA (cells); Pre: Post-onset untested	Yang et al[55]
Ginsenoside Rc	Triterpenoid saponin	Panax ginseng C.A. Mey (Araliaceae; Ginseng Radix et Rhizoma)	SD rat LAD I/R (2 hours/6 hours); H9c2 H/R (time NR)	In vivo: Sham; I/R; Rc + I/R. In vitro: Ctrl; H/R; Rc + H/R	In vivo: n = 5 (infarct); R: Yes; B: NR	In vivo: 10 mg/kg; MED NR; administered for 14 days before I/R; route and frequency NR. In vitro: 2.5 μmol/L, 5 μmol/L, 10 μmol/L; MEC NR; pretreated for 48 hours before H/R	In vivo: ↑: SIRT1, ETC complex III/IV activities; ↓: Infarct size. In vitro: ↑: SIRT1, ETC complex I-III protein levels, ATP, Bcl-2/Bax; ↓: PGC-1α acetylation, Cyt c	A, C; SIRT1 perturbation (cells); Pre: Post-onset untested	Huang et al[56]
Calenduloside E	Triterpenoid saponin	Aralia elata (Miq) Seem (Araliaceae; NR)	SD rat LAD I/R (30 minutes/48 hours); H9c2 H/R (6 hours/reoxygenation duration NR)	In vivo: Sham, Sham + CE, I/R, I/R + CE. In vitro: Ctrl, H/R, H/R + CE	In vivo: n = 6 (cardiac). Cells: 3 independent experiments; R: Yes (rats); B: NR	In vivo: 15 mg/kg/day; MED NR; gavage for 3 days; last dose 60 minutes before ligation. In vitro: 1 μmol/L, 2 μmol/L, 4 μmol/L, 8 μmol/L; MEC NR; pretreated for 4 hours before hypoxia	In vivo: ↑: MFN2, OPA1, p-AMPK/AMPK, ATP, EF, FS; ↓: Drp1, cTnI, infarct size, Cyt c release, mitochondrial Bax translocation. In vitro: ↑: MFN2, OPA1, p-AMPK/AMPK, ATP, cell viability; ↓: Drp1, Fis1, cleaved caspase-3, cleaved PARP, LDH	A, C; OPA1 siRNA/AMPK blockade (C); Pre: Post-onset untested	Wang et al[60]
Notoginsenoside R1	Triterpenoid saponin	Panax notoginseng (Burkill) F.H. Chen (Araliaceae; Notoginseng Radix et Rhizoma)	H9c2 H/R (6 hours/2 hours)	Ctrl; Ctrl + NGR1; H/R; H/R + NGR1	n = 8 (viability), 6 (LDH); R/B: NR	25 μmol/L; MEC NR; pretreated for 2 hours before H/R and maintained throughout H/R	↑: OPA1, MFN1/2, PGC-1α, NRF1, NRF2, ATP, ETC complexes I-V activity, cell viability. ↓: Drp1, Fis1, mPTP opening, ΔΨm depolarization, ROS, LDH, PINK1, Parkin, BNIP3	C; Assoc.; Pre (C): Clinical window untested	Xu et al[59]
Astragalosidic acid (LS-102)	Triterpenoid saponin derivative	As astragaloside IV derivative; parent compound from Astragalus membranaceus (Fisch) Bunge (Fabaceae; Astragali Radix)	SD rat LAD I/R (30 minutes/90 minutes); H9c2 H/R (12 hours/2 hours)	Sham; I/R; I/R + LS-102; positive control (verapamil). In vitro: Ctrl; H/R; H/R + LS-102	In vivo: n = 6 (infarct), 8-10 (arrhythmia); R: Yes; B: NR	In vivo: 2.5 mg/kg, 5 mg/kg, 10 mg/kg; MED NR; gavage; administered 30 minutes before LAD ligation. In vitro: 0.3125 μmol/L, 0.625 μmol/L, 1.25 μmol/L; MEC NR; pretreated for 24 hours before H/R	VT/VF incidence 10% (1/10) vs 88% (7/8) (I/R; 10 mg/kg). In vivo: ↑: P-PI3K, p-Akt; ↓: Infarct size, CK, LDH In vitro: ↑: P-Drp1(Ser637), p-PI3K, p-Akt, p-GSK-3β(Ser9), ATP, SOD, ΔΨm, Bcl-2/Bax ratio; ↓: P-Drp1(Ser616), CK, LDH, Ca2+ overload, ROS, Cyt c	A, C; PI3K/Akt blockade; Pre: Post-onset untested	Chen et al[58]
Vitexin	Flavonoid glycoside	Crataegus pinnatifida Bunge (Rosaceae; Crataegi Fructus)	SD rat Langendorff I/R (30 minutes/30 minutes); H9c2 H/R (5 hours/2 hours)	Shared (ex vivo/in vitro): Vehicle control; I/R (H/R); VT + I/R (H/R)	Ex vivo: n = 6 (cardiac); cells: n = 4 (protein); R: Yes (both); B: NR	Ex vivo: 10 μmol/L in perfusate; MED NR; perfused for 20 minutes before ischemia and during 30-minute reperfusion. In vitro: 10 μmol/L; MEC NR; pretreated for 2 hours before H/R	Ex vivo: ↑: MFN2, Bcl-2/Bax ratio; ↓: Mitochondrial Drp1, Epac1, Rap1, cytosolic Cyt c, cleaved caspase-3/9, infarct size. In vitro: ↑: MFN2, ΔΨm; ↓: Mitochondrial Drp1, ROS, Epac1, Rap1, NOX4, mitochondrial Bax, cleaved caspase-3/9	B, C; Epac agonist/inhibitor; Pre+Rep (B): Rep-only untested; Pre (C)	Yang et al[67]
Vitexin	Flavonoid glycoside	Crataegus pinnatifida Bunge (Rosaceae; Crataegi Fructus)	SD rat Langendorff I/R (30 minutes/30 minutes); H9c2 H/R (5 hours/1 hour)	Ex vivo: Ctrl; I/R; I/R + VT. In vitro: Ctrl; H/R; H/R + VT	Ex vivo: n = 5-6 (infarct), 6-7 (function); R: Yes (hearts/cells); B: NR	Ex vivo: 1 μmol/L, 3 μmol/L, 10 μmol/L in perfusate; MED NR; perfused for 20 minutes before I/R. In vitro: 1 μmol/L, 3 μmol/L, 10 μmol/L, 30 μmol/L; MEC NR; pretreated for 2 hours before H/R	Ex vivo: ↑: MFN2, COX IV, CF, Bcl-2/Bax ratio; ↓: Mitochondrial Drp1, NOX4, cytosolic Cyt c, cleaved caspase-3/9, infarct size, LDH. In vitro: ↑: MFN2, ATP, ΔΨm; ↓: Mitochondrial Drp1, LDH, cleaved caspase-3/9, ROS	B, C; Assoc; Pre: Post-onset untested	Xue et al[68]
Berberine	Isoquinoline alkaloid	Coptis chinensis Franch (Ranunculaceae; Coptidis Rhizoma)	SD rats ISO-induced injury; H9c2 CoCl2 hypoxia-mimetic injury	In vivo: Vehicle; ISO; ISO + BBR. In vitro: Ctrl; CoCl2; CoCl2 + BBR	In vivo: n = 6 (serum), 3 (protein); cells: n = 3; R: Yes (rats); B: NR	In vivo: 100 mg/kg/day; MED NR; gavage for 14 days before ISO. In vitro: 2.5 μmol/L; MEC NR; pretreated for 24 hours before CoCl2 exposure	In vivo: ↑: MFN2 (mRNA), ATP, Beclin 1, p62, p-AMPK, p-Akt, LKB1, p-Drp1/Drp1; ↓: LDH, CK. In vitro: ↑: Drp1, Beclin 1, p62, p-AMPK, p-Akt, LKB1; ↓: ROS, LDH	E; Assoc; Pre: Post-onset untested	Yang et al[71]
Gastrodin	Phenolic glycoside	Gastrodia elata Blume (Orchidaceae; Gastrodiae Rhizoma)	H9c2 H2O2 oxidative injury (400 μmol/L, 3 hours); additional I/R-like injury (9 hours/3 hours)	H2O2 model: Ctrl; H2O2; GAS + H2O2. I/R-like model: Ctrl; I/R-like; GAS + I/R-like	3 independent experiments; R/B: NR	20 μmol/L, 50 μmol/L, 100 μmol/L; MEC NR; pretreated for 4 hours before injury induction	H2O2 model: ↑: MFN2 and OPA1 mRNA; ↓: Fis1 mRNA, mitochondrial fragmentation, ROS. NRF2-siRNA blunted protection in the H2O2 model; GAS did not significantly alter Drp1 mRNA	C, E; NRF2 siRNA (E); Pre (C,E): Clinical window untested	Cheng et al[62]
Rhein	Anthracenecarboxylic acid	Rheum palmatum L (Polygonaceae; Rhei Radix et Rhizoma)	SD rat LAD-ligation AMI; H9c2 hypoxia 12 hours	Sham; AMI; AMI + rhein; AMI + mdivi-1. In vitro: Ctrl; hypoxia; hypoxia + rhein	In vivo: n = 5 (serum), 3 (TUNEL/protein); R: Yes; B: NR	In vivo: 90 mg/kg; MED NR; gavage for 8 weeks before AMI; frequency NR. In vitro: 1 μg/mL; MEC NR; pretreated for 1 hour before hypoxia	Myocardial TUNEL-positive cells ≈ 15% vs > 30% (AMI; author-reported approximations). Shared (in vivo/in vitro): ↑: OPA1, Beclin 1, PINK1, Parkin, LC3-II/LC3-I; ↓: Drp1, Bax/Bcl-2, cleaved caspase-3. In vivo only: ↓: CK, CK-MB, cTnT, LDH, infarct size	D, E; mdivi-1 comparator; Pre: Post-onset untested	Li et al[73]
Salidroside	Phenylethanoid glycoside	Rhodiola rosea L (Crassulaceae; Rhodiolae roseae Rhizoma et Radix)	SD rat LAD I/R (30 minutes/2 hours); H9c2 H/R (9 hours/6 hours)	In vivo: Sham; I/R; I/R + Sal; I/R + Sal + compound C. In vitro: Ctrl; H/R; H/R + Sal; H/R + Sal + AMPK siRNA	In vivo: n = 6 (infarct/function); R: Yes (rats/cells); B: NR	In vivo: 40 mg/kg; MED NR; administered i.v. 5 minutes before ischemia. In vitro: 10 μmol/L; MEC NR; pretreated for 30 minutes before hypoxia	In vivo: ↑: MFN2, OPA1, p-AMPK/AMPK, ATP, Bcl-2; ↓: P-Drp1(Ser616), Fis1, CHOP, infarct size, LDH, CK, cleaved caspase-3, Bax. In vitro: ↑: P-AMPK/AMPK, Bcl-2; ↓: P-Drp1(Ser616), LDH, CK, CHOP, cleaved caspase-3, Bax	A, C; AMPK blockade/siRNA (C); Pre: Post-onset untested	Tian et al[64]

Selected models, groups and findings are shown; ↑/↓ denote increases/decreases. Minimum effective dose/minimum effective concentration require dose-response support; otherwise not reported. Botanical names and medicinal parts follow authoritative databases and pharmacopoeial/European Medicines Agency monographs. Evidence strength summarizes model directness, mechanistic tests and timing relevance. Model categories: A: In vivo myocardial ischemia/reperfusion (I/R) in an intact animal; B: Isolated-heart I/R without intact systemic context; C: Cellular hypoxia/reoxygenation (R) or oxygen-glucose deprivation/R surrogates; D: Permanent myocardial ischemia/myocardial infarction (MI) without reperfusion; E: Other injury models. A/B directly model cardiac I/R; C models cellular components; D/E provide indirect evidence. Categories are not overall evidence-quality ranks. Assoc: No targeted causal test; named perturbations support the tested pathway, not necessarily fission mediation; comparators do not establish necessity. Pre: Before injury (post-onset initiation untested); Isch: During ischemia; Rep: At/after reperfusion onset. Acute-treatment relevance depends on start time, model, route and exposure; Pre + Rep does not establish Rep-only efficacy. Post-MI: After non-reperfused MI (post-infarction recovery). Cellular timing does not establish clinical windows; timing relevance does not establish clinical efficacy. Sample sizes are endpoint-specific and per group unless independent experiments are specified; cellular n retains the reported replication unit. Only explicitly reported outcome values are shown; graph estimates are excluded. ≈ denotes an approximation stated by the source authors; dispersion is retained as reported. R: Randomization; B: Reported blinding stage; yes: Reported; NR: Not reported; H/R: Hypoxia/reoxygenation; SEM: Standard error of the mean; MFN1/2: Mitofusin 1/2; GDH: Glutamate dehydrogenase; ATP: Adenosine triphosphate; ΔΨm: Mitochondrial membrane potential; LDH: Lactate dehydrogenase; CK: Creatine kinase; ROS: Reactive oxygen species; Bax/Bcl-2: Bcl-2-associated X protein to B-cell lymphoma 2; ISO: Isoproterenol; NRVMs: Neonatal rat ventricular myocytes; PA: Palmitic acid; TMZ: Trimetazidine; HK II: Hexokinase II; Akt: Protein kinase B; Drp1: Dynamin-related protein 1; mPTP: Mitochondrial permeability transition pore; Cyt c: Cytochrome c; LAD: Left anterior descending coronary artery; I/R: Ischemia/reperfusion; SIRT1: Sirtuin 1; ETC: Electron transport chain; PGC-1α: Peroxisome proliferator-activated receptor-γ coactivator 1α; CE: Calenduloside E; OPA1: Optic atrophy 1; AMPK: AMP-activated protein kinase; EF: Ejection fraction; FS: Fractional shortening; cTnI: Cardiac troponin I; PARP: Poly(adenosine diphosphate-ribose) polymerase; NGR1: Notoginsenoside R1; NRF1: Nuclear respiratory factor 1; NRF2: Nuclear factor erythroid 2-related factor 2; PINK1: Phosphatase and tensin homolog-induced kinase 1; BNIP3: B-cell lymphoma 2/adenovirus early region 1B 19-kDa-interacting protein 3; VT/VF: Ventricular tachycardia/ventricular fibrillation; PI3K: Phosphoinositide 3-kinase; GSK-3β: Glycogen synthase kinase 3β; SOD: Superoxide dismutase; Epac1: Exchange protein directly activated by cyclic adenosine monophosphate 1; NOX4: NADPH oxidase 4; BBR: Berberine; LKB1: Liver kinase B1; GAS: Gastrodin; AMI: Acute myocardial infarction; LC3-II: Light chain 3-II; CK-MB: Creatine kinase-MB; cTnT: Cardiac troponin T; Fis1: Mitochondrial fission 1 protein; CHOP: CCAAT/enhancer-binding protein homologous protein.

Table 2 Experimental evidence for plant-derived interventions and electroacupuncture associated with mitochondrial fusion-fission-related changes in myocardial ischemia/reperfusion injury and related experimental models

Intervention type	Intervention	Composition or acupoints	Experimental model	Study groups	Sample size and design	Dosage, administration route, and regimen	Main findings	Evidence strength	Ref.
Defined combination	GRS	Ginsenoside Rb1 + ruscogenin + schisandrin (ratio: 6:0.75:6)	In vivo: ICR mice LAD I/R (30 minutes/24 hours). In vitro: H9c2 H/R (6 hours/6 hours; 2-hour reoxygenation for Drp1 and 1-hour for AMPK assays); NRVMs H/R (12 hours/12 hours)	In vivo: Sham; I/R; GRS + I/R; positive control (captopril). In vitro: Ctrl; H/R; GRS + H/R	In vivo: n = 6 (cardiac); R: Yes; B: Surgery	In vivo: 6.4 mg/kg, 12.8 mg/kg, 19.2 mg/kg; MED NR; administered i.p. within 10 minutes after reperfusion onset. In vitro: 0.1 μg/mL, 1 μg/mL, 10 μg/mL; MEC NR; added at hypoxia onset and maintained throughout H/R	In vivo: ↑: EF; ↓: Infarct size. In vivo/in vitro: ↑: Bcl-2/Bax ratio; ↓: P-Drp1(Ser616), LDH, caspase-3. In vivo/in vitro: ↑: P-AMPK	A, C; AMPK siRNA (C); Early Rep (A): Potential acute relevance; Isch (C)	Li et al[80]
PBM (injection)	Shenmai Injection	Aqueous extracts from Panax ginseng C.A. Mey (Araliaceae; Ginseng Radix et Rhizoma) and Ophiopogon japonicus (Thunb) Ker Gawl (Asparagaceae; Ophiopogonis Radix)	In vivo: SD rat MI model (LAD ligation). In vitro: H9c2 H/R (12 hours/2 hours)	In vivo: Sham; MI; MI + SMI; positive control (valsartan). In vitro: Ctrl; H/R; SMI + H/R	In vivo: n = 8 (EF/FS), 3 (infarct); R: Yes; B: Echocardiography	In vivo: 0.38 mL/kg; MED NR; post-MI treatment; SMI route/frequency NR (28-day protocol). In vitro: 1 μL/mL, 2.5 μL/mL, 5 μL/mL; MEC NR; pretreated for 24 hours before H/R	In vivo: ↑: EF, FS; ↓: Infarct size. In vitro: ↑: MFN1/2 and OPA1 mRNA, Parkin, Beclin 1, LC3-II/LC3-I, ΔΨm; ↓: Drp1 and Fis1 mRNA, mitochondrial fragmentation, cytosolic Ca2+ overload, mPTP opening	C, D; Assoc; Post-MI (D): Recovery; Pre (C)	Yu et al[74]
PBM (injection)	Guanxinning Injection	Extracts of Salvia miltiorrhiza Bunge (Lamiaceae; Salviae Miltiorrhizae Radix et Rhizoma) and Ligusticum chuanxiong Hort (Apiaceae; Chuanxiong Rhizoma)	Wistar rat LAD I/R (30 minutes/60 minutes) in a CRF background	Sham; CRF; I/R; CRF + I/R + IPost; CRF + I/R + IPost + GXN; CRF + I/R	n = 15 (allocated); R: Yes; B: NR	Administered i.v. 10 minutes after ischemia onset; dose NR; MED NR	AN/AAR: 0.17 ± 0.09 (GXN + IPost), 0.39 ± 0.07 (CRF + I/R), 0.29 ± 0.07 (IPost); mean ± SD. GXN + IPost vs CRF + I/R: ↑: MFN1, OPA1; ↓: Drp1, cTnT, CK-MB. GXN + IPost vs IPost alone: ↑: MFN1, OPA1; ↓: CK-MB	A; Assoc; Isch + IPost: Potential acute relevance (combined)	Wang et al[75]
PBM (capsule)	Shuangshen Ningxin Formula	Extracts of Panax ginseng C.A. Mey (Araliaceae; Ginseng Radix et Rhizoma) + Salvia miltiorrhiza Bunge (Lamiaceae; Salviae Miltiorrhizae Radix et Rhizoma) + Corydalis yanhusuo W.T.Wang ex Z.Y.Su & C.Y.Wu (Papaveraceae; Corydalis Rhizoma)	In vivo: SD rat LAD I/R (45 minutes/24 hours). In vitro: CMECs OGD/R (4 hours/2 hours)	In vivo: Sham; I/R; SSNX + I/R. In vitro: Ctrl; OGD/R; SSNX + OGD/R	In vivo: n = 6 (EF); cells: n = 6 (viability); R: Yes (rats); B: NR	In vivo: 45 mg/kg/day, 90 mg/kg/day, 180 mg/kg/day; MED NR; gavage for 7 days before I/R. In vitro: 25 μg/mL; MEC NR; added before OGD; lead time NR	In vivo: ↑: EF. In vivo/in vitro: ↓: NR4A1, Mff, Drp1, HK II, Cyt c, caspase-9	A, C; NR4A1 inhibitor comparator (C); Pre: Post-onset untested	Liu et al[83]
Botanical decoction	Taohong Siwu Decoction	Prunus persica (L) Batsch (Rosaceae; Persicae Semen) + Carthamus tinctorius L (Asteraceae; Carthami Flos) + Angelica sinensis (Oliv) Diels (Apiaceae; Angelicae Sinensis Radix) + Paeonia lactiflora Pall (Paeoniaceae; Paeoniae Radix Alba) + Ligusticum chuanxiong Hort (Apiaceae; Chuanxiong Rhizoma) + Rehmannia glutinosa (Gaertn) Libosch ex DC (Orobanchaceae; Rehmanniae Radix Praeparata)	SD rat MI (LAD ligation)	MI; THSWD + MI	n = 13 (allocated); R: Yes; B: Echocardiography	1 mL/day; MED NR; gavage for 4 weeks, starting 2 days after MI (reported concentration 1.13 g/mL)	4-week: ↓ LVESV; EF/FS differences NS. ↑: P-Akt/Akt. ↓: Fis1, mitochondrial ROS; LC3B: No statistically significant change	D; Assoc; Post-MI: Recovery	Luo et al[82]
PBM (pill)	Qishen Yiqi Dripping Pill	Astragalus membranaceus (Fisch) Bunge (Fabaceae; Astragali Radix) + Salvia miltiorrhiza Bunge (Lamiaceae; Salviae Miltiorrhizae Radix et Rhizoma) + Dalbergia odorifera T.C.Chen (Fabaceae; Dalbergiae Odoriferae Lignum) + Panax notoginseng (Burkill) F.H. Chen (Araliaceae; Notoginseng Radix et Rhizoma)	ICR male mice MI (LAD ligation)	Sham; MI; QSYQ + MI; positive control (enalapril)	n = 6 (LVEF); R: Yes; B: H&E assessment	12 mg/kg/day, 35 mg/kg/day, 105 mg/kg/day; MED NR; gavage for 14 days after MI	↑: LVEF, MFN2, L-OPA1/S-OPA1, PGC-1α, TFAM, NRF1. ↓: P-Drp1(Ser616)/Drp1	D; Assoc; Post-MI: Recovery	Wu et al[79]
PBM (capsule)	Danqi Soft Capsule	50% Panax notoginseng (Burkill) F.H. Chen (Araliaceae; Notoginseng Radix et Rhizoma) + 50% Salvia miltiorrhiza Bunge (Lamiaceae; Salviae Miltiorrhizae Radix et Rhizoma)	In vivo: SD rat LAD I/R (30 minutes/24 hours). In vitro: H9c2 H2O2 injury	In vivo: Sham; I/R; DQ + I/R. In vitro: Ctrl; H2O2; DQ + H2O2	In vivo: n = 4 (infarct), 6 (serum); R: Yes; B: Histology scoring	In vivo: 0.6 g/kg/day, 1.2 g/kg/day; MED NR; gavage for 5 days before I/R. In vitro: 300 mg/mL, 600 mg/mL; MEC NR; pretreated for 2.5 hours before H2O2 exposure	In vivo: ↑: Bcl-2; ↓: Infarct size, p-CaMKII, p-Drp1(Ser616), cTnT, LDH, cleaved caspase-3, Bax. In vitro: ↑: Bcl-2, ΔΨm; ↓: P-CaMKII, p-Drp1(Ser616), ROS, Cyt c, cleaved caspase-3, caspase-3/8/9 activities, Bax, mPTP opening	A, E; Assoc; Pre: Post-onset untested	Yang et al[76]
PBM (pill)	Tongmai Yangxin Pill	Multiple constituents, including Rehmannia glutinosa (Gaertn.) Libosch ex DC (Orobanchaceae; Rehmanniae Radix) + Spatholobus suberectus Dunn (Fabaceae; Spatholobi Caulis) + Ophiopogon japonicus (Thunb) Ker Gawl (Asparagaceae; Ophiopogonis Radix) + Glycyrrhiza uralensis Fisch ex DC (Fabaceae; Glycyrrhizae Radix et Rhizoma) + Reynoutria multiflora (Thunb) Moldenke (Polygonaceae; Polygoni Multiflori Radix Praeparata) + Schisandra chinensis (Turcz) Baill (Schisandraceae; Schisandrae Chinensis Fructus) + Codonopsis pilosula (Franch) Nannf (Campanulaceae; Codonopsis Radix) + Ziziphus jujuba Mill (Rhamnaceae; Jujubae Fructus) + Cinnamomum cassia (L) J.Presl (Lauraceae; Cinnamomi Ramulus) + Asini Corii Colla + Mauremydis Carapax et Plastrum	In vivo: SD rat LAD I/R (30 minutes/120 minutes). In vitro: H9c2 H/R (6 hours/24 hours)	In vivo: Sham; I/R; TMYX + I/R (1/2/4 g/kg); positive control (raloxifene). In vitro: Ctrl; H/R; TMYX + H/R	In vivo: n = 9 (EF), 3 (infarct), 8 (serum); R: Yes; B: NR	In vivo: 1 g/kg/day, 2 g/kg/day, 4 g/kg/day; MED NR; gavage for 7 days after I/R establishment per Methods; pretreatment wording elsewhere is inconsistent. In vitro: 100 μg/mL; MEC NR; timing NR	In vivo: ↑: EF, MFN1/2; ↓: Drp1, Fis1, ROS, CK-MB, cTnI, LDH. In vitro: ↑: ERα, PGC-1α, ATP, ΔΨm; ↓: ROS, Bax and caspase-3 mRNA	A, C; ERα siRNA (C); timing inconsistent (A): Relevance unclear; NR (C)	Yu et al[84]
Electroacupuncture	Electroacupuncture pretreatment	Acupoints: PC6 + ST36 + CV4	SD rat LAD I/R (30 minutes/120 minutes)	Sham; I/R; EA + I/R; EA + compound C + I/R; EA + ML385 + I/R	n = 3 (ROS/SOD/MDA), 6 (protein); R: Yes; B: NR	EA: 20 minutes/day for 7 days before I/R (2 Hz, 1 mA); inhibitors administered i.p. 30 minutes before model induction	Cardiac function and infarct size were not assessed. ↑: SOD, AMPK, NRF2. ↓: Drp1, Mff, Fis1, ROS, MDA, mitochondrial structural damage	A; AMPK/NRF2 blockade; Pre: Post-onset untested	Zhang et al[86]

Selected models, groups and findings are shown; ↑/↓ denote increases/decreases. Minimum effective dose/minimum effective concentration require dose-response support; otherwise not reported. Botanical names and medicinal parts follow authoritative databases and pharmacopoeial/European Medicines Agency monographs. Evidence strength summarizes model directness, mechanistic tests and timing relevance. Model categories: A: In vivo myocardial ischemia/reperfusion (I/R) in an intact animal; B: Isolated-heart I/R without intact systemic context; C: Cellular hypoxia/reoxygenation (R) or oxygen-glucose deprivation/R surrogates; D: Permanent myocardial ischemia/myocardial infarction (MI) without reperfusion; E: Other injury models. A/B directly model cardiac I/R; C models cellular components; D/E provide indirect evidence. Categories are not overall evidence-quality ranks. Assoc: No targeted causal test; named perturbations support the tested pathway, not necessarily fission mediation; comparators do not establish necessity. Pre: Before injury (post-onset initiation untested); Isch: During ischemia; Rep: At/after reperfusion onset. Acute-treatment relevance depends on start time, model, route and exposure; Pre + Rep does not establish Rep-only efficacy. Post-MI: After non-reperfused MI (post-infarction recovery). Cellular timing does not establish clinical windows; timing relevance does not establish clinical efficacy. Sample sizes are endpoint-specific and per group unless independent experiments are specified; cellular n retains the reported replication unit. Only explicitly reported outcome values are shown; graph estimates are excluded. ≈ denotes an approximation stated by the source authors; dispersion is retained as reported. Tongmai Yangxin Pill timing is inconsistently reported in Yu et al[84], precluding a firm timing-relevance assessment. R: Randomization; B: Reported blinding stage; yes: Reported; NR: Not reported; GRS: Ginsenoside Rb1-ruscogenin-schisandrin combination; LAD: Left anterior descending coronary artery; I/R: Ischemia/reperfusion; H/R: Hypoxia/reoxygenation; Drp1: Dynamin-related protein 1; AMPK: AMP-activated protein kinase; NRVMs: Neonatal rat ventricular myocytes; MED: Minimum effective dose; MEC: Minimum effective concentration; EF: Ejection fraction; Bcl-2/Bax: B-cell lymphoma 2 to Bcl-2-associated X protein; LDH: Lactate dehydrogenase; AMPK: AMP-activated protein kinase; PBM: Proprietary botanical medicine; MI: Myocardial infarction; LAD: Left anterior descending coronary artery; SMI: Shenmai Injection; FS: Fractional shortening; LC3-II: Light chain 3-II; ΔΨm: Mitochondrial membrane potential; Fis1: Mitochondrial fission 1 protein; mPTP: Mitochondrial permeability transition pore; CRF: Chronic renal failure; GXN: Guanxinning Injection; MFN1: Mitofusin 1; OPA1: Optic atrophy 1; cTnT: Cardiac troponin T; CK-MB: Creatine kinase-MB; CMECs: Cardiac microvascular endothelial cells; OGD/R: Oxygen-glucose deprivation/reoxygenation; SSNX: Shuangshen Ningxin Formula; NR4A1: Nuclear receptor subfamily 4 group A member 1; Mff: Mitochondrial fission factor; HK II: Hexokinase II; Cyt c: Cytochrome c; THSWD: Taohong Siwu Decoction; LVESV: Left ventricular end-systolic volume; ROS: Reactive oxygen species; Akt: Protein kinase B; QSYQ: Qishen Yiqi Dripping Pill; LVEF: Left ventricular ejection fraction; PGC-1α: Peroxisome proliferator-activated receptor-γ coactivator 1α; TFAM: Mitochondrial transcription factor A; DQ: Danqi Soft Capsule; TMYX: Tongmai Yangxin Pill; cTnI: Cardiac troponin I; ERα: Estrogen receptor α; PC6: Pericardium 6, Neiguan; ST36: Stomach 36, Zusanli; CV4: Conception vessel 4, Guanyuan; EA: Electroacupuncture; SOD: Superoxide dismutase; MDA: Malondialdehyde; NRF2: Nuclear factor erythroid 2-related factor 2.