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Novel Natural Compounds as Wound Healing Agents

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 31715

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Special Issue Editors

Dr. Mansour Sobeh

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Mohammed VI Polytechnic University (UM6P), Lot 660, Hay Moulay Rachid, Ben Guerir 43150, Morocco
Interests: natural product chemistry; metabolomics; functional foods; agro-waste valorization
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Mona F. Mahmoud

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Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
Interests: medicinal and aromatic plant; anti-inflammatory; antidiabetic; wound healing; ulcer

Dr. Daria Maria Monti

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Department of Chemical Sciences, University of Naples Federico II, 80126 Naples, Italy
Interests: microalgae; antioxidant activity; antitumor activity; skin UV protection; nanoparticles; ferritin nanocages; anticancer metallodrugs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The skin is one of the most important organs in the body because it protects it from environmental hazards. A complicated dynamic wound-healing mechanism is launched immediately after a skin injury by a complex sequence of cellular, molecular, and biochemical processes with a signaling cascade. Successful healing depends on the immune system as a key player in re-establishing homeostasis following tissue injury through the collaborative efforts of numerous proangiogenic cells, such as fibroblasts, leukocytes, monocytes, macrophages, endothelial cells, and epidermal cells, as well as a series of cross-cascade reactions such as hemostasis, inflammation, proliferation, and remodeling to promote cell differentiation, extracellular matrix synthesis, and extracellular matrix synthesis.

Chronic wounds are wounds that have progressed into a condition of pathological inflammation rather than healing normally. In type 2 diabetic mellitus (DM) patients, delayed foot wound healing is a prominent consequence linked to hyperglycemia, and these wounds can lead to foot ulcers. Debridement of necrotic tissue, use of topical antibiotics to limit infection, and application of a wound dressing (e.g., films, fibers, hydrogels) are all common treatments for chronic wounds. However, finding out a drug with potent wound-healing properties and fewer side effects still needed.

Thus, studies investigating the beneficial effects of herbal extract as well as individual secondary metabolites on wound healing in silico, in vitro, and in vivo, along with the involved molecular mechanisms, will be a subject of interest for this Special Issue.

Dr. Mansour Sobeh
Prof. Dr. Mona F. Mahmoud
Dr. Daria Maria Monti
Guest Editors

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Keywords

natural products
wound healing
diabetic foot ulcer
fibroblasts
skin remodeling
photoprotection
cosmeceuticals
elastase inhibitory activity

Published Papers (10 papers)

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Research

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19 pages, 3914 KiB

Open AccessArticle

Extraction Optimization, Antioxidant, Cosmeceutical and Wound Healing Potential of Echinacea purpurea Glycerolic Extracts

by Petar Ciganović, Lejsa Jakupović, Plamen Momchev, Laura Nižić Nodilo, Anita Hafner and Marijana Zovko Končić

Molecules 2023, 28(3), 1177; https://doi.org/10.3390/molecules28031177 - 25 Jan 2023

Cited by 8 | Viewed by 1974

Abstract

Echinacea purpurea is a plant with immunomodulating properties, often used in topical preparations for treatment of small superficial wounds. In the presented study, the best conditions for ultrasound-assisted extraction of caffeic acid derivatives (caftaric and cichoric acid) (TPA-opt extract), as well as the conditions best suited for preparation of the extract with high radical scavenging activity (RSA-opt extract), from E. purpurea aerial parts were determined. A Box–Behnken design based on glycerol content (%, w/w), temperature (°C), ultrasonication power (W) and time (min) as independent variables was performed. Antioxidant, antiaging and wound healing effects of the two prepared extracts were evaluated. The results demonstrate that glycerol extraction is a fast and efficient method for preparation of the extracts with excellent radical scavenging, Fe²⁺ chelating and antioxidant abilities. Furthermore, the extracts demonstrated notable collagenase, elastase and tyrosinase inhibitory activity, indicating their antiaging properties. Well-pronounced hyaluronidase-inhibitory activities, with IC₅₀ values lower than 30 μL extract/mL, as well as the ability to promote scratch closure in HaCaT keratinocyte monolayers, even in concentrations as low as 2.5 μL extract/mL (for RSA-opt), demonstrate promising wound healing effects of E. purpurea. The fact that the investigated extracts were prepared using glycerol, a non-toxic and environmentally friendly solvent, widely used in cosmetics, makes them suitable for direct use in specialized cosmeceutical formulations. Full article

(This article belongs to the Special Issue Novel Natural Compounds as Wound Healing Agents)

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13 pages, 1394 KiB

Open AccessArticle

Cupressus arizonica Greene: Phytochemical Profile and Cosmeceutical and Dermatological Properties of Its Leaf Extracts

by Nora Tawfeek, Eman Fikry, Ismail Mahdi, Melvin Adhiambo Ochieng, Widad Ben Bakrim, Noamane Taarji, Mona F. Mahmoud and Mansour Sobeh

Molecules 2023, 28(3), 1036; https://doi.org/10.3390/molecules28031036 - 20 Jan 2023

Cited by 17 | Viewed by 2188

Abstract

For many decades, natural resources have traditionally been employed in skin care. Here, we explored the phytochemical profile of the aqueous and ethanolic leaf extracts of Cupressus arizonica Greene and assessed their antioxidant, antiaging and antibacterial activities in vitro. Liquid chromatography–mass spectrometry (LC-MS/MS) analysis led to the tentative identification of 67 compounds consisting mainly of phenolic and fatty acids, diterpene acids, proanthocyanidins and flavonoid and biflavonoid glycosides. The aqueous extract demonstrated substantial in vitro antioxidant potential at FRAP and DPPH assays and inhibited the four target enzymes (collagenase, elastase, tyrosinase, and hyaluronidase) engaged in skin remodeling and aging with IC₅₀ values close to those of the standard drugs. Moreover, the aqueous extract at 25 mg/mL suppressed biofilm formation by Pseudomonas aeruginosa, a bacterial pathogen causing common skin manifestations, and decreased its swarming and swimming motilities. In conclusion, C. arizonica leaves can be considered a promising candidate for potential application in skin aging. Full article

(This article belongs to the Special Issue Novel Natural Compounds as Wound Healing Agents)

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14 pages, 1892 KiB

Open AccessFeature PaperArticle

Effect of Chicken Egg White-Derived Peptide and Hydrolysates on Abnormal Skin Pigmentation during Wound Recovery

by Pei-Gee Yap, Chee-Yuen Gan, Idanawati Naharudin and Tin-Wui Wong

Molecules 2023, 28(1), 92; https://doi.org/10.3390/molecules28010092 - 22 Dec 2022

Cited by 1 | Viewed by 1585

Abstract

Abnormal skin pigmentation commonly occurs during the wound healing process due to the overproduction of melanin. Chicken egg white (CEW) has long been used to improve skin health. Previous published works had found CEW proteins house bioactive peptides that inhibit tyrosinase, the key enzyme of melanogenesis. The current study aimed to evaluate the anti-pigmentation potential and mechanism of the CEW-derived peptide (GYSLGNWVCAAK) and hydrolysates (CEWH_mono and CEWH_di), using a cell-based model. All of these peptide and hydrolysates inhibited intracellular tyrosinase activity and melanin level up to 45.39 ± 1.31 and 70.01 ± 1.00%, respectively. GYSLGNWVCAAK and CEWH_di reduced intracellular cAMP levels by 13.38 ± 3.65 and 14.55 ± 2.82%, respectively; however, CEWH_mono did not affect cAMP level. Moreover, the hydrolysates downregulated the mRNA expression of melanogenesis-related genes, such as Mitf, Tyr, Trp-1 and Trp-2, but GYSLGNWVCAAK only suppressed Tyr gene expression. Downregulation of the genes may lower the catalytic activities and/or affect the structural stability of TYR, TRP-1 and TRP-2; thus, impeding melanogenesis to cause an anti-pigmentation effect in the cell. Outcomes from the current study could serve as the starting point to understand the underlying complex, multifaceted melanogenesis regulatory mechanism at the cellular level. Full article

(This article belongs to the Special Issue Novel Natural Compounds as Wound Healing Agents)

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15 pages, 4549 KiB

Open AccessArticle

Euodia daniellii Hemsl. Extract and Its Active Component Hesperidin Accelerate Cutaneous Wound Healing via Activation of Wnt/β-Catenin Signaling Pathway

by Minguen Yoon, Seol Hwa Seo, Seonghwi Choi, Gyoonhee Han and Kang-Yell Choi

Molecules 2022, 27(20), 7134; https://doi.org/10.3390/molecules27207134 - 21 Oct 2022

Cited by 3 | Viewed by 1545

Abstract

The activation of the Wnt/β-catenin signaling pathway plays a key role in the wound-healing process through tissue regeneration. The extract of Euodia daniellii Hemsl. (E. daniellii), a member of the Rutaceae family, activates the Wnt/β-catenin signaling pathway. However, the function of E. daniellii in wound healing has not yet been elucidated. We performed a migration assay to determine the wound-healing effect of E. daniellii extract in vitro using human keratinocytes and dermal fibroblast. In addition, a mouse acute wound model was used to investigate the cutaneous wound-healing effect of E. daniellii extract in vivo and confirm the potential mechanism. E. daniellii extract enhanced the migration of human keratinocytes and dermal fibroblasts via the activation of the Wnt/β-catenin pathway. Moreover, the E. daniellii extract increased the levels of keratin 14, PCNA, collagen I, and α-SMA, with nuclei accumulation of β-catenin in vitro. E. daniellii extract also efficiently accelerated re-epithelialization and stimulated wound healing in vivo. Furthermore, we confirmed that hesperidin, one of the components of E. daniellii, efficiently accelerated the migration of human keratinocytes and dermal fibroblasts, as well as wound healing in vivo via the activation of the Wnt/β-catenin pathway. Overall, E. daniellii extract and its active component, hesperidin, have potential to be used as therapeutic agents for wound healing. Full article

(This article belongs to the Special Issue Novel Natural Compounds as Wound Healing Agents)

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27 pages, 12614 KiB

Open AccessArticle

The Potential of Corchorus olitorius Seeds Buccal Films for Treatment of Recurrent Minor Aphthous Ulcerations in Human Volunteers

by Nourhan Hisham Shady, Abdullah H. Altemani, Faisal H. Altemani, Sherif A. Maher, Mahmoud A. Elrehany, Entesar Ali Saber, Ahmed M. Badawi, Fatma Mohamed Abd El-Mordy, Nada M. Mohamed, Mohammed A. S. Abourehab, Ahmed M. Sayed, Usama Ramadan Abdelmohsen and Soad A. Mohamad

Molecules 2022, 27(20), 7020; https://doi.org/10.3390/molecules27207020 - 18 Oct 2022

Cited by 6 | Viewed by 2092

Abstract

Aphthous ulcers are very common disorders among different age groups and are very noxious and painful. The incidence of aphthous ulcer recurrence is very high and it may even last for a maximum of 6 days and usually, patients cannot stand its pain. This study aims to prepare a buccoadhesive fast dissolving film containing Corchorus olitorius seed extract to treat recurrent minor aphthous ulceration (RMAU) in addition to clinical experiments on human volunteers. An excision wound model was used to assess the in vivo wound healing potential of Corchorus olitorius L. seed extract, with a focus on wound healing molecular targets such as TGF-, TNF-, and IL-1. In addition, metabolomic profiling using HR-LCMS for the crude extract of Corchorus olitorius seeds was explored. Moreover, molecular docking experiments were performed to elucidate the binding confirmation of the isolated compounds with three molecular targets (TNF-α, IL-1β, and GSK3). Additionally, the in vitro antioxidant potential of C. olitorius seed extract using both H₂O₂ and superoxide radical scavenging activity was examined. Clinical experiments on human volunteers revealed the efficiency of the prepared C. olitorius seeds buccal fast dissolving film (CoBFDF) in relieving pain and wound healing of RMAU. Moreover, the wound healing results revealed that C. olitorius seed extract enhanced wound closure rates (p ≤ 0.001), elevated TGF-β levels and significantly downregulated TNF-α and IL-1β in comparison to the Mebo-treated group. The phenotypical results were supported by biochemical and histopathological findings, while metabolomic profiling using HR-LCMS for the crude extract of Corchorus olitorius seeds yielded a total of 21 compounds belonging to diverse chemical classes. Finally, this study highlights the potential of C. olitorius seed extract in wound repair uncovering the most probable mechanisms of action using in silico analysis. Full article

(This article belongs to the Special Issue Novel Natural Compounds as Wound Healing Agents)

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24 pages, 5478 KiB

Open AccessArticle

Synthesis and Characterization of Silver Nanoparticles from Rhizophora apiculata and Studies on Their Wound Healing, Antioxidant, Anti-Inflammatory, and Cytotoxic Activity

by Saeed Ali Alsareii, Abdulrahman Manaa Alamri, Mansour Yousef AlAsmari, Mohammed A. Bawahab, Mater H. Mahnashi, Ibrahim Ahmed Shaikh, Arun K. Shettar, Joy H. Hoskeri and Vijay Kumbar

Molecules 2022, 27(19), 6306; https://doi.org/10.3390/molecules27196306 - 24 Sep 2022

Cited by 14 | Viewed by 2756

Abstract

Silver nanoparticles (AgNPs) have recently gained interest in the medical field because of their biological features. The present study aimed at screening Rhizophora apiculata secondary metabolites, quantifying their flavonoids and total phenolics content, green synthesis and characterization of R. apiculata silver nanoparticles. In addition, an assessment of in vitro cytotoxic, antioxidant, anti-inflammatory and wound healing activity of R. apiculata and its synthesized AgNPs was carried out. The powdered plant material (leaves) was subjected to Soxhlet extraction to obtain R. apiculata aqueous extract. The R. apiculata extract was used as a reducing agent in synthesizing AgNPs from silver nitrate. The synthesized AgNPs were characterized by UV-Vis, SEM-EDX, XRD, FTIR, particle size analyzer and zeta potential. Further aqueous leaf extract of R. apiculata and AgNPs was subjected for in vitro antioxidant, anti-inflammatory, wound healing and cytotoxic activity against A375 (Skin cancer), A549 (Lung cancer), and KB-3-1 (Oral cancer) cell lines. All experiments were repeated three times (n = 3), and the results were given as the mean ± SEM. The flavonoids and total phenolics content in R. apiculata extract were 44.18 ± 0.086 mg/g of quercetin and 53.24 ± 0.028 mg/g of gallic acid, respectively. SEM analysis revealed R. apiculata AgNPs with diameters ranging from 35 to 100 nm. XRD confirmed that the synthesized silver nanoparticles were crystalline in nature. The cytotoxicity cell viability assay revealed that the AgNPs were less toxic (IC₅₀ 105.5 µg/mL) compared to the R. apiculata extract (IC₅₀ 47.47 µg/mL) against the non-cancerous fibroblast L929 cell line. Antioxidant, anti-inflammatory, and cytotoxicity tests revealed that AgNPs had significantly more activity than the plant extract. The AgNPs inhibited protein denaturation by a mean percentage of 71.65%, which was equivalent to the standard anti-inflammatory medication diclofenac (94.24%). The AgNPs showed considerable cytotoxic effect, and the percentage of cell viability against skin cancer, lung cancer, and oral cancer cell lines was 31.84%, 56.09% and 22.59%, respectively. R. apiculata AgNPs demonstrated stronger cell migration and percentage of wound closure (82.79%) compared to the plant extract (75.23%). The overall results revealed that R. apiculata AgNPs exhibited potential antioxidant, anti-inflammatory, wound healing, and cytotoxic properties. In future, R. apiculata should be further explored to unmask its therapeutic potential and the mechanistic pathways of AgNPs should be studied in detail in in vivo animal models. Full article

(This article belongs to the Special Issue Novel Natural Compounds as Wound Healing Agents)

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21 pages, 4887 KiB

Open AccessArticle

Cinnamaldehyde-Based Self-Nanoemulsion (CA-SNEDDS) Accelerates Wound Healing and Exerts Antimicrobial, Antioxidant, and Anti-Inflammatory Effects in Rats’ Skin Burn Model

by Kamal A. Qureshi, Salman A. A. Mohammed, Omar Khan, Hussein M. Ali, Mahmoud Z. El-Readi and Hamdoon A. Mohammed

Molecules 2022, 27(16), 5225; https://doi.org/10.3390/molecules27165225 - 16 Aug 2022

Cited by 21 | Viewed by 2228

Abstract

Cinnamaldehyde, the main phytoconstituent of the cinnamon oil, has been reported for its potential wound healing activity, associated to its antimicrobial and anti-inflammatory effects. In this study, we are reporting on the cinnamaldehyde-based self-nanoemulsifying drug delivery system (CA-SNEDDS), which was prepared and evaluated for its antimicrobial, antioxidant, anti-inflammatory, and wound healing potential using the rat third-degree skin injury model. The parameters, i.e., skin healing, proinflammatory, and oxidative/antioxidant markers, were evaluated after 3 weeks of treatment regimens with CA-SNEDDS. Twenty rats were divided randomly into negative control (untreated), SNEDDS control, silver sulfadiazine cream positive control (SS), and CA-SNEDDS groups. An aluminum cylinder (120 °C, 10-s duration) was used to induce 3rd-degree skin burns (1-inch square diameter each) on the rat’s dorsum. At the end of the experiment, skin biopsies were collected for biochemical analysis. The significantly reduced wound size in CA-SNEDDS compared to the negative group was observed. CA-SNEDDS-treated and SS-treated groups demonstrated significantly increased antioxidant biomarkers, i.e., superoxide dismutase (SOD) and catalase (CAT), and a significant reduction in the inflammatory marker, i.e., NAP-3, compared to the negative group. Compared to SNEDDS, CA-SNEDDS exhibited a substantial antimicrobial activity against all the tested organisms at the given dosage of 20 µL/disc. Among all the tested microorganisms, MRSA and S. typhimurium were the most susceptible bacteria, with an inhibition zone diameter (IZD) of 17.0 ± 0.3 mm and 19.0 ± 0.9 mm, respectively. CA-SNEDDS also exhibited strong antifungal activity against C. albicans and A. niger, with IZD of 35.0 ± 0.5 mm and 34.0 ± 0.5 mm, respectively. MIC and MBC of CA-SNEDDS for the tested bacteria ranged from 3.125 to 6.25 µL/mL and 6.25 to 12.5 µL/mL, respectively, while the MIC and MBC for C. albicans and A. niger were 1.56 µL/mL and 3.125 µL/mL, respectively. The MBIC and MBEC of CA-SNEDDS were also very significant for the tested bacteria and ranged from 6.25 to 12.5 µL/mL and 12.5 to 25.0 µL/mL, respectively, while the MBIC and MBEC for C. albicans and A. niger were 3.125 µL/mL and 6.25 µL/mL, respectively. Thus, the results indicated that CA-SNEDDS exhibited significant wound healing properties, which appeared to be attributed to the formulation’s antimicrobial, antioxidant, and anti-inflammatory effects. Full article

(This article belongs to the Special Issue Novel Natural Compounds as Wound Healing Agents)

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13 pages, 3157 KiB

Open AccessArticle

Anti-Phototoxicity Effect of Phenolic Compounds from Acetone Extract of Entada phaseoloides Leaves via Activation of COX-2 and iNOS in Human Epidermal Keratinocytes

by Yanisa Mittraphab, Yhiya Amen, Maki Nagata, Masako Matsumoto, Dongmei Wang and Kuniyoshi Shimizu

Molecules 2022, 27(2), 440; https://doi.org/10.3390/molecules27020440 - 10 Jan 2022

Cited by 8 | Viewed by 2038

Abstract

The extract from Entada phaseoloides was employed as active ingredients of natural origin into cosmetic products, while the components analysis was barely reported. Using LC-DAD-MS/qTOF analysis, eleven compounds (1–11) were proposed or identified from acetone extract of E. phaseoloides leaves (AE). Among them, six phenolic compounds, protocatechuic acid (2), 4-hydroxybenzoic acid (3), luteolin-7-O-β-d-glucoside (5), cirsimaritin (6), dihydrokaempferol (9), and apigenin (10), were isolated by various chromatographic techniques. Protocatechuic acid (2), epicatechin (4), and kaempferol (11) at a concentration 100 μM increased the HaCaT cells viability of the UVB-irradiated cell without any cytotoxicity effect and reduced the expression of COX-2 and iNOS inflammation gene. Moreover, compounds 2 and 4 could have potent effects on cell migration during wound closure. These results suggest that compounds 2, 4, and 11 from AE have anti-photoaging properties and could be employed in pharmaceutical and cosmeceutical products. Full article

(This article belongs to the Special Issue Novel Natural Compounds as Wound Healing Agents)

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Review

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18 pages, 2024 KiB

Open AccessReview

Wound Healing Properties of Natural Products: Mechanisms of Action

by Marilyn S. Criollo-Mendoza, Laura A. Contreras-Angulo, Nayely Leyva-López, Erick P. Gutiérrez-Grijalva, Luis Alfonso Jiménez-Ortega and J. Basilio Heredia

Molecules 2023, 28(2), 598; https://doi.org/10.3390/molecules28020598 - 6 Jan 2023

Cited by 26 | Viewed by 5823

Abstract

A wound is the loss of the normal integrity, structure, and functions of the skin due to a physical, chemical, or mechanical agent. Wound repair consists of an orderly and complex process divided into four phases: coagulation, inflammation, proliferation, and remodeling. The potential of natural products in the treatment of wounds has been reported in numerous studies, emphasizing those with antioxidant, anti-inflammatory, and antimicrobial properties, e.g., alkaloids, saponins, terpenes, essential oils, and polyphenols from different plant sources, since these compounds can interact in the various stages of the wound healing process. This review addresses the most current in vitro and in vivo studies on the wound healing potential of natural products, as well as the main mechanisms involved in this activity. We observed sufficient evidence of the activity of these compounds in the treatment of wounds; however, we also found that there is no consensus on the effective concentrations in which the natural products exert this activity. For this reason, it is important to work on establishing optimal treatment doses, as well as an appropriate route of administration. In addition, more research should be carried out to discover the possible side effects and the behavior of natural products in clinical trials. Full article

(This article belongs to the Special Issue Novel Natural Compounds as Wound Healing Agents)

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30 pages, 1846 KiB

Open AccessReview

Phytochemistry and Biological Activity of Medicinal Plants in Wound Healing: An Overview of Current Research

by Stefania Vitale, Sara Colanero, Martina Placidi, Giovanna Di Emidio, Carla Tatone, Fernanda Amicarelli and Anna Maria D’Alessandro

Molecules 2022, 27(11), 3566; https://doi.org/10.3390/molecules27113566 - 1 Jun 2022

Cited by 34 | Viewed by 7654

Abstract

Wound healing is a complicated process, and the effective management of wounds is a major challenge. Natural herbal remedies have now become fundamental for the management of skin disorders and the treatment of skin infections due to the side effects of modern medicine and lower price for herbal products. The aim of the present study is to summarize the most recent in vitro, in vivo, and clinical studies on major herbal preparations, their phytochemical constituents, and new formulations for wound management. Research reveals that several herbal medicaments have marked activity in the management of wounds and that this activity is ascribed to flavonoids, alkaloids, saponins, and phenolic compounds. These phytochemicals can act at different stages of the process by means of various mechanisms, including anti-inflammatory, antimicrobial, antioxidant, collagen synthesis stimulating, cell proliferation, and angiogenic effects. The application of natural compounds using nanotechnology systems may provide significant improvement in the efficacy of wound treatments. Increasing the clinical use of these therapies would require safety assessment in clinical trials. Full article

(This article belongs to the Special Issue Novel Natural Compounds as Wound Healing Agents)

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