TABLE 1.
Chinese botanical drugs and their wound healing activities.
| Botanical drug and Source | Family | Extract/component/product | Experimental model | Dose and route of administration | Wound healing activity and potential mechanism | Reference |
|---|---|---|---|---|---|---|
| Angelicae dahuricae radix [Angelica dahurica (Hoffm.) Benth. and Hook.f. ex Franch. and Sav. or Angelica dahurica var. formosana (H.Boissieu) Yen] | Apiaceae | 70% ethanol extract | Diabetic rats with full-thickness wound | 1.2 g/kg once daily by oral gavage | Promoted diabetic wound closure via inducing angiogenesis and granulation tissue formation | Zhang et al. (2017b) |
| db/db mice with full-thickness wound | 1.8 g/kg once daily by oral gavage | Reduced wound area, increased in neovascularization, increased PDGF-β expression, and capillary formation | Guo et al. (2020) | |||
| Human umbilical vein endothelial cells (HUVECs) | 10–400 μg/ml | Induced cell proliferation, migration, and tube formation via the activation of ERK1/2, Akt, eNOS. Increased NO production and the expression of VEGF. | Zhang et al. (2017b) | |||
| HUVECs | 50–300 μg/ml | Promoted angiogenesis of HUVECs via activation of the HIF-1α/PDGF-β pathway | Guo et al. (2020) | |||
| Angelicae sinensis radix [Angelica sinensis (Oliv.) Diels] | Apiaceae | Extract containing 60% polysaccharide | HUVECs | 11.1–100 μg/ml | Stimulated the proliferation and migration of HUVECs via the activation of the JNK 1/2 and p38 signal pathways | Lam et al. (2008) |
| — | Zebrafish embryos | 50–400 μg/ml | Increased in angiogenic phenotype in subintestinal vessels | Lam et al. (2008) | ||
| SBD.4 | db/db mice with full-thickness wound and human skin grafted on SCID mice with full-thickness wound | Topically applied SBD.4 (2 mg per wound) in 2% carboxymethyl cellulose | In db/db mice, SBD.4 stimulated wound healing with complete remodeling of the wounds. In SCID mice, SBD.4 increased granulation tissue formation and assisted in the remodeling of wounds | Zhao et al. (2006) | ||
| SBD.4 (1%)-nanosilver hydrocolloid dressing | Chronic ulcer patients | External application | All patients’ wounds healed at the end of the treatment (day 30) | Zhao et al. (2012) | ||
| Astragali radix [Astragalus mongholicus Bunge] | Fabaceae | Formononetin | Mice with full-thickness wound | Formononetin (50 μM) was injected into dermis nearby wound | Accelerated wound-closure rate | Huh et al. (2011) |
| — | HUVECs | 0.1–50 μM | Promoted endothelial repair via the regulation of Egr-1 through the ERK and p38 MAPK pathways | — | ||
| Astragaloside IV (AS-IV) | Diabetic mice with full thickness wound | 10 μL AS-IV (100 mM) once daily by local delivery | Narrower wounds gaping and augmented re-epithelialization | Luo et al. (2016) | ||
| APS2-1 (polysaccharide) | Human skin fibroblasts | 1, 5, and 25 μg/ml | Promoted cell proliferation and migration | Zhao et al. (2017) | ||
| — | Scalded mice model | Topically applied 0.5 g ointment (containing 1.55% APS2-1) | Accelerated wound healing via reducing inflammatory response and promoting the expression of TGF-β1, bFGF, and EGF. | Zhao et al. (2017) | ||
| Draconis sanguis [Calamus draco Willd.] | Arecaceae | Dracorhodin perchlorate (DP) | Rats with full-thickness wound | Topical applied DP ointment (200 μg of DP DMSO solution mixed with 16 g of Vaseline) | Reduced inflammation via inhibiting IL-1α and TNF-α secretion. Increased VEGF and TGF expression, and collagen deposition | Jiang et al. (2017) |
| HaCaT keratinocytes | 1 μg/ml and 2 μg/ml | Promoted the wound healing of HaCaT keratinocytes via β-catenin, ERK, p38 MAPK, and AKT pathways | Lu et al. (2021) | |||
| HUVECs under high-glucose stimulation | 7.5 μM | Promoted the angiogenesis via the activation of the Ras/MAPK pathway | Li et al. (2016a) | |||
| NIH/3T3 fibroblasts | 0.5–4 μg/ml | Promoted fibroblast proliferation through the activation of the ERK-CREB and PI3K/Akt/mTOR pathways | Liu et al. (2019) | |||
| Notoginseng Radix et Rhizoma [Panax notoginseng (Burkill) F.H.Chen] | Araliaceae | Notoginsenoside R1 | HUVECs | 10 μg/ml | Stimulated the proliferation of HUVECs and enhanced its ability of tube formation | Yang et al. (2016) |
| Ginsenoside Rg1 | Excision diabetic foot ulcer | 150 mg/kg (i.p.) | Accelerated wound healing in diabetic ulcer through NO pathway via miR-23a | Cai et al. (2019) | ||
| Notoginsenoside Ft1 | HUVECs | 0.25–10 μM | Stimulated angiogenesis via HIF-1α-mediated VEGF expression, with PI3K/AKT and Raf/MEK/ERK concurrently participating | Shen et al. (2012) | ||
| — | Excisional wound in db/db mice | Topically applied 15 μL solution (6.7 mg/ml) once daily | Promoted the neovascularization accompanied with increased VEGF, PDGF, and FGF at either mRNA or protein levels. Reduced inflammation via downregulating TNF-α and IL-6 expressions | Zhang et al. (2016a) | ||
| Ginsenoside Rb1 | A rat model of second-degree burn injury | Topical application of ointment at the dose of 1.25, 2.5, or 5 g/kg | Accelerated burn wound healing via upregulating FGF-2/PDGF-BB/PDGFR-β gene and protein expressions | Zhang et al. (2021) | ||
| 20(S)-Protopanaxadiol | Excisional wound splinting model in db/db mice | Topically applied of 15 μL solution (0.6, 6 and 60 mg/ml) once daily | Enhanced angiogenesis via HIF-1α-mediated VEGF expression by the activation of p70S6K via PI3K/Akt/mTOR and Raf/MEK/ERK signaling pathways | Zhang et al. (2017a) | ||
| Arnebiae Radix [Arnebia euchroma (Royle ex Benth.) I.M.Johnst., Arnebia guttata Bunge or Lithospermum erythrorhizon Siebold and Zucc.] | Boraginaceae | A/S-based ointment | Dogs with full-thickness skin defect on forelimb | Topically applied a thin layer of the ointment | Promoted wound angiogenesis, collagen production, and epithelialization | Karayannopoulou et al. (2011) |
| Shikonin | Human gingival fibroblasts | 1 and 10 μM | Promoted fibroblast proliferation and migration via ERK 1/2 signaling pathway | Imai et al. (2019) | ||
| Human keratinocytes and HDFs | 1 μM | Promoted cell proliferation and showed anti-inflammatory activity via inhibiting the NF-κB signaling pathway | Yan et al. (2015) | |||
| Bletillae Rhizoma [Bletilla striata (Thunb.) Rchb.f.] | Orchidaceae | Polysaccharides | Mice with full-thickness wound | 12.5%-crosslinked polysaccharides hydrogel topically applied | Reduced inflammatory cells, decreased TNF-α, and increased EGF secretion in polysaccharides-treated wounds | Luo et al. (2010) |
| Diabetic mice with full-thickness wound | 5% polysaccharides solution (50 μL) treatment once daily | Accelerated wound healing, suppressed macrophage infiltration, promoted angiogenesis via inhibiting the high glucose-activated NLRP3 inflammasome | Zhao et al. (2021) | |||
| Rhei Radix et Rhizoma [Rheum palmatum L., Rheum tanguticum (Maxim. ex Regel) Balf. or Rheum officinale Baill.] | Polygonaceae | Emodin | Rats with full-thickness wound | Topically applied at the dose of 100–400 μg/ml | Enhanced cutaneous wound healing via regulating the Smads-mediated TGF-β1 signaling pathway | Tang et al. (2007) |
| Rehmanniae Radix [Rehmannia glutinosa (Gaertn.) DC.] | Orobanchaceae | Aqueous extract | Diabetic foot ulcer rat model | Topically applied at the dose of 1.85 g/kg | Better developed scars and epithelialization, and improved formation of capillaries with enhanced VEGF expression | Lau et al. (2009b) |
| Norviburtinal | Zebrafish embryo model | 50 μg/ml | An increase in capillary sprouts formation in SIV. | Liu et al. (2011) | ||
| Acteoside | HDFs | 6.3–100 µM | The activation of proMMP-2 along with an increase in MT1-MMP expression through a PI3K signal pathway | Nan et al. (2018) | ||
| Salviae Miltiorrhizae Radix et Rhizoma [Salvia miltiorrhiza Bunge] | Lamiaceae | Nonalcoholic solution produced with a 1:3 dry herb/menstruum ratio | Rats with burn wound | Orally administered at the dose of 1 g/kg/day for 14 days | Decreased the amount of necrosis in burn wounds | Irmak et al. (2018) |
| Cryptotanshinone | db/db mice with excisional wound | 300 mg/kg/d by gavage for 16 days | Accelerated wound closure and increased re-epithelialization and granulation tissue formation | Song et al. (2020) | ||
| Danshensu and salvianolic acid B | Detroit 551 human normal fibroblasts | 25–200 μM and 0.1 mM | Increased cell proliferation (25–200 µM) and promoted collagen synthesis (0.1 mM) | Chen et al. (2014) | ||
| Llilii Bulbus [Lilium lancifolium Thunb., Lilium brownii var. viridulum Baker or Lilium pumilum Redouté] | Liliaceae | Steroidal glycoside 1 and 2 | 3T3 murine fibroblasts | 5 µM | Induced production of NO and increased mRNA level of TGF-β Type I receptor, which played important roles in early wound healing | Esposito et al. (2013) |
| Steroidal glycoside 1 | Primary human dermal fibroblasts | 5 µM | Downregulated gene expression of inflammatory, chemokine, and tissue remodeling, upregulate ECM and cell adhesion related genes to regulate basic functions of cells in wound healing | Di et al. (2020) | ||
| Glycyrrhizae Radix et Rhizoma [Glycyrrhiza uralensis Fisch. ex DC., Glycyrrhiza inflata Batalin or Glycyrrhiza glabra L.] | Fabaceae | Collagen sponge loaded with 72 µg soluble polysaccharide in microcapsule | Rat trauma model | Topically applied | Increased the content of hydroxyproline, promoted the proliferation of capillaries and fibroblasts, and increased number of microvessels in wound site through activating the expression of p-STAT3 and VEGF and upregulating the tanscription levels of VEGF mRNA and miRNA-21 genes | Hao et al. (2020) |
| Isoliquiritin | Zebrafish skin wound model | 100 or 200 μg/ml | Promoted inflammation response and facilitated angiogenesis | Liu et al. (2020) | ||
| Zingiberis Rhizoma Recens [Zingiber officinale Roscoe] | Zingiberaceae | 10-shogaol | Human normal epidermal keratinocytes and dermal fibroblasts | 2 and 10 µM | Enhanced the production of TGF-β, PDGF-αβ, and VEGF. | Chen et al. (2012a) |
| 6-dehydrogingerdione | Fibroblasts | 2 and 10 µM | Upregrulated the production of growth factor, and accelerated cellular proliferation, and migration through blocking the MAPK pathway by supressing c-Jun protein levels and ERK phosphorylation | Chen et al. (2013a) | ||
| Lonicerae Japonicae Flos [Lonicera japonica Thunb.] | Caprifoliaceae | 95% ethanol extract | Rat excision wound model | 10% (w/w) extract ointment topically applied | Promoted wound healing, elevated the production of IL-10, and suppressed the production of TNF-α and IL-6 | Chen et al. (2012b) |
| Portulacae Herba [Portulaca oleracea L.] | Portulacaceae | Fresh plant homogenate | Mouse excision wound model | A single dose of 50 mg or a twice dose of 25 mg topically applied | Stimulated wound contraction and increased the strength of wound | Rashed et al. (2003) |
| Hippophae rhamnoides L | Elaeagnaceae | Leaves extract | Rats with full-thickness wound | 1% aqueous extract prepared in propylene glycol topically applied twice daily | Reduced wound area and increased the hydroxyproline and protein contents in wounds | Gupta et al. (2005) |
| Rats with burn wound | 5% extract prepared in petroleum jelly topically applied twice daily for 7 days | Faster reduction in the wound area, increased collagen synthesis, promoted angiogenesis, and increased levels of antioxidants in wounds | Upadhyay et al. (2011) | |||
| Seed oil | Rats with burn wound | Co-administered by two routes at the dose of 2.5 ml/kg (p.o.) and 200 µL (topical) for 7 days | Increased expression of MMP-2 and 9, collagen III and VEGF in granulation tissue | Upadhyay et al. (2009) | ||
| Sheep with 3rd degree flame burns | 20 ml seed oil topically applied | Shorter complete epithelization time | Ito et al. (2014) | |||
| Urtica dioica L | Urticaceae | Crude saponins extract | Rats with full-thickness wound | 20% saponins extract was prepared in vaseline and topically applied once daily | Promoted the wound healing with shorten heal time | Razika et al. (2017) |
| Dried leaves extract | Rats with full-thickness wound | 10% extract dissolved in glycerol topically applied on the wound at the dose of 50 µL/mm2 | Accelerated wound healing with fast wound closure and improved hydroxyproline content | Zouari Bouassida et al. (2017) | ||
| Periploca forrestii Schltr | Apocynaceae | 65% ethanol eluted fraction (EPFE65) derived from macroporous resin column | Rats with full-thickness wound and mouse fibroblasts | 50 μg/ml for in vitro studies and 0.1% EPFE65 hydrogel for animal studies | Promoted wound healing via enhancing the re-epithelialization, promoting fibroblast proliferation, migration, and stimulating the collagen synthesis | Li et al. (2019a) |
| Periplocin | Rats with full-thickness wound and mouse fibroblasts | 5–20 μg/ml | Promoted wound healing via the activation of Src/Erk and PI3K/Akt signaling pathways | Chen et al. (2019) | ||
| Streptocaulon juventas (Lour.) Merr | Apocynaceae | Ethanol extract | Mice with full-thickness wound | Topically applied at the dose of 100 mg/kg/day | Promoted wound healing via inducing the fibroblast proliferation and angiogenesis, and inhibiting the inflammation | Nguyen et al. (2017) |
| Carthamus tinctorius L | Asteraceae | Hydroxysafflor yellow A | HUVECs and human epithelial keratinocytes | 0.4, 0.8 and 1.6 mM | Enhance keratinocytes migration in a dose-dependent manner (0.4–1.6 mM). Increased the tube formation of HUVECs at 0.4 mM | Gao et al. (2018) |
| Splinted excisional wound model in diabetic rats | 0.2 mg locally applied once daily | Promoted wound closure and elevated the levels of VEGF and TGF-β1 in treated wounds | Gao et al. (2018) | |||
| Reynoutria japonica Houtt | Polygonaceae | 20% or 40% ethanol extract or 60% acetone extract | Human gingival fibroblasts (HGFs) | 50 μg/ml | Stimulated cell proliferation, migration, and collagen III synthesis | Nawrot-Hadzik et al. (2021) |
| Artemisia annua L | Asteraceae | Artemisia annua L.-containing nanofibers | Mouse fibroblasts | Fibroblasts were seeded onto the dressing | Encouraged the attachment, spreading, and proliferation of the fibroblast cells | Mirbehbahani et al. (2020) |
| Acorus calamus L | Acoraceae | 80% ethanol extract of dried leaves | Rats with excision or incision wound | 20% or 40% ointment topically applied once daily | Accelerated wound closure, less inflammatory cells, and higher collagen in treated wounds | Jain et al. (2010) |
| 70% ethanol extract of rhizome | Rats with excision wound | 40 mg/kg topically applied once daily | Increased the levels of collagen, hexosamical, and uronic acid in treated wounds | Ponrasu et al. (2014) | ||
| Triticum aestivum L | Poaceae | Exosomes | HDFs, HUVECs, human keratinocytes | 30–200 μg/ml | Promoted cell proliferation and migration at 30–200 μg/ml. Increased tube formation in HUVECs and promoted collagen synthesis in HDFs at 200 μg/ml | Sahin et al. (2019) |
| A small peptide (YDWPGGRN) | Rats with full thickness wound | Topically applied 20 μL peptide (250 μM) | Stimulated angiogenesis and collagen production in wounds | Sui et al. (2020) |