紫草属缓解炎症反应促进伤口愈合

Shikonin is the major bioactive component extracted from the roots of Lithospermum erythrorhizon which is also known as "Zicao" in Traditional Chinese Medicine (TCM). Recent studies have shown that shikonin demonstrates various bioactivities related to the treatment of cancer, inflammation, and wound healing. This review aimed to provide an updated summary of recent studies on shikonin. Firstly, many studies have demonstrated that shikonin exerts strong anticancer effects on various types of cancer by inhibiting cell proliferation and migration, inducing apoptosis, autophagy, and necroptosis. Shikonin also triggers Reactive Oxygen Species (ROS) generation, suppressing exosome release, and activate anti-tumor immunity in multiple molecular mechanisms. Examples of these effects include modulating the PI3 K/AKT/mTOR and MAPKs signaling; inhibiting the activation of TrxR1, PKM2, RIP1/3, Src, and FAK; and regulating the expression of ERP57, MMPs, ATF2, C-MYC, miR-128, and GRP78 (Bip). Next, the anti-inflammatory and wound-healing properties of shikonin were also reviewed. Furthermore, several studies focusing on shikonin derivatives were reviewed, and these showed that, with modification to the naphthazarin ring or side chain, some shikonin derivatives display stronger anticancer activity and lower toxicity than shikonin itself. Our findings suggest that shikonin and its derivatives could serve as potential novel drug for the treatment of cancer and inflammation.

… Several early in vivo animal studies tested Shikonin and its derivatives for wound healing. Hayashi’s experiments on rats were performed with Shikonin, acetylshikonin [52-54], the …

BACKGROUND The emergence of antibiotic resistance over the past decade has made the treatment of Staphylococcus aureus infection difficult. Burn wounds infected with methicillin-resistant S. aureus (MRSA) can cause mortality in animals. Shikonin (SH) has been reported to possess antimicrobial and anti-inflammatory properties, and is also responsible for the process of wound healing. However, the pharmacological mechanism of its wound healing process remains poorly comprehended, hence the probable mechanism deserves further investigation. PURPOSE The current study was designed to develop a novel SH-liposome with improved anti-MRSA effect and to detect its beneficial wound healing effects. STUDY DESIGN In vitro antibacterial tests and in vivo infected wound healing test were conducted. METHODS SH-liposome was produced by the film formation method, and the characteristics were measured using a laser particle size analyzer, transmission electron microscopy, and the dialysis method. Additionally, in vitro antibacterial tests were conducted to investigate the antibacterial effects and the relative mechanism of SH-liposome. Furthermore, the therapeutic effects and bioactivity of SH-liposome in MRSA infected burn wounds were investigated in rats. Sixty-four male Sprague Dawley rats (250 ± 10 g) were randomly divided into four groups, including Group I (control group); Group II (model group); Group III (SH-liposome group) and Group IV (Arnebia oil® group), and the drug treatments were applied topically twice daily for 21 days. Further, full thickness skin biopsies at different periods were collected aseptically to evaluate tissue cytokines, recognize flora, observe histopathological changes, and determine the mechanism underlying the wound healing effects of SH-liposome. The data were analyzed via one-way analysis of variance (ANOVA) and Duncan's multiple range test. RESULTS The results showed that SH-liposome was successful with a drug load of 4.6 ± 0.17%. Moreover, SH-liposome showed a sustained-release behavior and improved antibacterial ability in a dose-dependent manner. For the possible antibacterial mechanism, we observed that SH-liposome achieved antibacterial activity by damaging the integrity of bacterial cell wall and membrane to further disturb the physiological activities of S. aureus. In addition, SH-liposome facilitated wound healing by inhibiting bacterial activities to control infection, regulating the I-κBα/NFκB-p65 pathway to alleviate inflammation, and directly promoting repair in burn wounds. CONCLUSION In conclusion, SH-liposome showed an antibacterial effect against S. aureus, promoted effective healing of infected burn wounds; hence, it could be used as an alternative therapy for drug-resistant infections.

Currently, skin injuries have a serious impact on people’s lives and socio-economic stress. Shikonin, a naphthoquinone compound derived from the root of the traditional Chinese medicine Shikonin, has favorable biological activities such as anti-inflammatory, antibacterial, immunomodulatory, anticancer, and wound-healing-promoting pharmacological activities. It has been reported that Shikonin can be used for repairing skin diseases due to its wide range of pharmacological effects. Moreover, the antimicrobial activity of Shikonin can play a great role in food and can also reduce the number of pathogenic bacteria in food. This paper summarizes the research on the pharmacological effects of Shikonin in recent years, as well as research on the mechanism of action of Shikonin in the treatment of certain skin diseases, to provide certain theoretical references for the clinical application of Shikonin, and also to provides research ideas for the investigation of the mechanism of action of Shikonin in other skin diseases.

Shikonin, a major component of Lithospermum erythrorhizon, exerts anti‐inflammatory and antibacterial effects and expedites wound healing. This study aims to evaluate the anti‐inflammatory and antioxidant activities of shikonin in a Sprague–Dawley rat model and cell models using fibroblast and endothelial cells.

Although various pharmacological activities of the shikonins have been documented, understanding the hierarchical regulation of these diverse bioactivities at the genome level is unsubstantiated. In this study, through cross examination between transcriptome and microRNA array analyses, we predicted that topical treatment of shikonin in vivo affects epithelial-mesenchymal transition (EMT) and the expression of related microRNAs, including 200a, 200b, 200c, 141, 205, and 429 microRNAs, in mouse skin tissues. In situ immunohistological analyses further demonstrated that specific EMT regulatory molecules are enhanced in shikonin-treated epidermal tissues. RT-PCR analyses subsequently confirmed that shikonin treatment downregulated expression of microRNA-205 and other members of the 200 family microRNAs. Further, expression of two RNA targets of the 200 family microRNAs in EMT regulation, Sip1 (Zeb2) and Tcf8 (Zeb1), was consistently upregulated by shikonin treatment. Enhancement of these EMT activities was also detected in shikonin-treated wounds, which repaired faster than controls. These results suggest that topical treatment with shikonin can confer a potent stimulatory effect on EMT and suppress the expression of the associated microRNAs in skin wound healing. Collectively, these cellular and molecular data provide further evidence in support of our previous findings on the specific pharmacological effects of shikonin in wound healing and immune modulation.

Diabetic wounds are typically chronic wounds and the healing process is limited by problems such as high blood glucose levels, bacterial infections, and other issues that make wound healing difficult. Designing drug-loaded wound dressings is an effective way to promote diabetic wound healing. In this study, we developed an SA/PVA nanofiber (SPS) containing Shikonin (SK) for the treatment of diabetic wounds. The prepared nanofibers were uniform in diameter, had good hydrophilicity and high water vapor permeability, and effectively promoted gas exchange between the wound site and the outside world. The results of in vitro experiments showed that SPS was effective in antimicrobial, antioxidant, and biocompatible. In vivo tests showed that the wound healing rate of mice treated with SPS reached 85.5 %. Immunohistochemical staining results showed that SPS was involved in the diabetic wound healing process through the up-regulation of growth factors (CD31, HIF-1α) and the down-regulation of inflammatory factors (CD68). Western blotting experiments showed that SPS attenuated the inflammation through the inhibition of the IκBα/NF-κB signaling pathway. These results suggest that SPS is a promising candidate for future clinical application of chronic wound dressings.

Diabetes is an endocrine disorder characterized by abnormally elevated blood glucose levels. Diabetic patients often exhibit impaired wound healing capabilities, particularly in the lower limbs, which is one of the numerous complications of diabetes. This is a significant factor leading to recurrent inflammation, disability, and even amputation. The primary objective of this study is to explore the mechanism by which shikonin accelerates diabetic wound healing by modulating macrophage phenotypes, particularly its role in the MAPK signaling pathway. To this end, we used a diabetic rat model and analyzed the effects of shikonin on the wound healing process and macrophage polarization in both in vivo and in vitro experiments. Additionally, we used immunofluorescence staining and Western blot techniques to detect the expression levels of macrophage polarization markers and proteins related to the MAPK signaling pathway. The results verify that shikonin significantly accelerated wound healing in diabetic rats and inhibited the polarization of M1 macrophages, reducing the expression of pro-inflammatory factors, while promoting the polarization of M2 macrophages, increasing the expression of anti-inflammatory factors. This process was accompanied by the regulation of the MAPK signaling pathway, indicating that shikonin accelerates diabetic wound healing by regulating the MAPK signaling pathway to inhibit the inflammatory phenotype of macrophages, showing significant clinical application prospects.

… have been attributed to shikonin, eg wound healing, enhanced … action for shikonin lead us to hypothesize that shikonin is an … broad spectrum of shikonin biological and pharmacological …

Burns are a significant public health issue worldwide, resulting in prolonged hospitalization, disfigurement, disability and, in severe cases, death. Among them, deep second-degree burns are often accompanied by bacterial infections, insufficient blood flow, excessive skin fibroblasts proliferation and collagen deposition, all of which contribute to poor wound healing and scarring following recovery. In this study, SNP/MCNs-SKN-chitosan-β-glycerophosphate hydrogel (MSSH), a hydrogel composed of a temperature-sensitive chitosan-β-glycerophosphate hydrogel matrix (CGH), mesoporous carbon nanospheres (MCNs), nitric oxide (NO) donor sodium nitroprusside (SNP) and anti-scarring substance shikonin (SKN), is intended for use as a biomedical material. In vitro tests have revealed that MSSH has broad-spectrum antibacterial abilities and releases NO in response to near-infrared (NIR) laser to promote angiogenesis. Notably, MSSH can inhibit excessive proliferation of fibroblasts and effectively reduce scarring caused by deep second-degree burns, as demonstrated by in vitro and in vivo tests.

… and skin wounds. However, the effect of shikonin on intestinal wound healing is unknown… Using an in vitro model for wound healing, we observed that shikonin enhances cell …

… wound-healing activity. The extract was found to contain a dimer of alkannin/shikonin; studies on wound-healing … wound-healing potential; hence the compound was evaluated for its …

Wound healing is a complicated biological process, which involves interactions of multiple cell types, various growth factors, their mediators and the extracellular matrix proteins. In this study, we evaluated the effects of shikonin analogue 93/637 (SA), derived from the plant <i>Arnebia nobilis</i>, on normal and hydrocortisone-induced impaired healing in full thickness cutaneous punch wounds in rats. SA (0.1%) was applied topically daily as an ointment in polyethylene glycol base on wounds. SA treatment significantly accelerated healing of wounds, as measured by wound contraction compared to controls in hydrocortisone-impaired animals. SA treatment promoted formation of granulation tissue including cell migration and neovascularization, collagenization and reepithelialization. The expression of basic fibroblast growth factor (bFGF) was higher as revealed by immunohistochemistry in treated wounds compared to controls. However, the expression of transforming growth factor-β<sub>1</sub> was not affected by SA treatment. Since bFGF is known to accelerate wound healing, the increased expression of bFGF by SA may be partly responsible for the enhancement of wound healing. These studies suggest that SA could be further studied for clinical use to enhance wound healing.

Diabetic foot ulcers (DFUs) exhibit impaired healing due to disrupted macrophage polarization, wherein persistent hyperglycemia inhibits the critical M1‐to‐M2 phenotypic transition, sustaining a pro‐inflammatory microenvironment. This investigation elucidates the therapeutic potential of L‐shikonin (L‐SK), a bioactive phytochemical derived from comfrey with established immunomodulatory properties. In a streptozotocin‐induced diabetic murine model, L‐SK treatment significantly enhanced wound closure through coordinated anti‐inflammatory effects (downregulation of CD86 and tumor necrosis factor‐α) and pro‐regenerative outcomes (increased collagen deposition and CD31‐mediated angiogenesis). At the molecular level, L‐SK administration facilitated macrophage polarization towards the regenerative M2 phenotype (upregulated CD163 expression) while activating the pivotal Janus Kinase/phosphatidylinositol‐3‐kinase/protein kinase B/vascular endothelial growth factor (JAK/PI3K/AKT/VEGF) signaling cascade, as evidenced by enhanced phosphorylation of AKT and PI3K alongside elevated VEGF production. Complementary in vitro studies using human monocytic leukemia cells‐derived macrophages confirmed these mechanistic findings, demonstrating consistent modulation of macrophage differentiation markers and secretory profiles. These results position L‐SK as a multifaceted therapeutic agent capable of concurrently addressing the immunological and vascular deficiencies characteristic of DFUs, through its dual capacity for macrophage phenotype reprogramming and angiogenic pathway activation. The study provides compelling preclinical evidence for L‐SK's potential application in diabetic wound management strategies.

Shiunko ointment is composed of five ingredients including Lithospermi Radix (LR), Angelicae Gigantis Radix, sesame seed oil, beeswax, and swine oil. It is externally applied as a treatment for a wide range of skin conditions such as eczema, psoriasis, hair loss, burns, topical wounds, and atopic dermatitis. Deoxyshikonin is the major angiogenic compound extracted from LR. In this study, we investigated the efficacy of LR extract and deoxyshikonin on impaired wound healing in streptozotocin (STZ)-induced diabetic mice. Treatment with LR extract elevated tube formation in human umbilical vein endothelial cells (HUVECs) and exerted antioxidant activity. An open skin wound was produced on the backs of diabetic mice and was then topically treated with deoxyshikonin or vehicle. In addition, deoxyshikonin promoted tube formation in high glucose conditions exposed to HUVECs, and which may be regulated by increased VEGFR2 expression and phosphorylation of Akt and p38. Our results demonstrate that deoxyshikonin application promoted wound repair in STZ-induced diabetic mice. Collectively, these data suggest that deoxyshikonin is an active ingredient of LR, thereby contributing to wound healing in patients with diabetes.

… Herein, we successfully prepared Lithospermum erythrorhizon-derived … inflammation model in vitro and detect the expression of inflammatory factors to evaluate the anti-inflammatory …

Wound healing is a critical process in tissue repair following injury, and traditional herbal therapies have long been utilized to facilitate this process. This review delves into the mechanistic understanding of the significant contribution of pharmacologically demonstrated natural products in wound healing. Natural products, often perceived as complex yet safely consumed compared to synthetic chemicals, play a crucial role in enhancing the wound‐healing process. Drawing upon a comprehensive search strategy utilizing databases such as PubMed, Scopus, Web of Science, and Google Scholar, this review synthesizes evidence on the role of natural products in wound healing. While the exact pharmacological mechanisms of secondary metabolites in wound healing remain to be fully elucidated, compounds from alkaloids, phenols, terpenes, and other sources are explored here to delineate their specific roles in wound repair. Each phytochemical group exerts distinct actions in tissue repair, with some displaying multifaceted roles in various pathways, potentially enhancing their therapeutic value, supported by reported safety profiles. Additionally, these compounds exhibit promise in the prevention of keloids and scars. Their potential alongside economic feasibility may propel them towards pharmaceutical product development. Several isolated compounds, including chlorogenic acid, thymol, and eugenol from natural sources, are undergoing investigation in clinical trials, with many reaching advanced stages. This review provides mechanistic insights into the significant role of pharmacologically demonstrated natural products in wound healing processes.

Alkannin-based pharmaceutical formulations for improving wound healing have been on the market for several years. However, detailed molecular mechanisms of their action have yet to be elucidated. Here, we investigated the potential roles of AAN-II in improving the healing of pressure-induced venous ulcers using a rabbit model generated by combining deep vein thrombosis with a local skin defect/local skin defect. The extent of healing was evaluated using hematoxylin and eosin (HE) or vimentin staining. Rabbit skin fibroblasts were cultured for AAN-II treatment or TGFB1-sgRNA lentivirus transfection. ELISA was used to evaluate the levels of various cytokines, including IL-1β, IL-4, IL-6, TNF-α, VEGF, bFGF, TGF-β and PDGF. The protein levels of TGF-β sensors, including TGF-β, Smad7 and phosphor-Smad3, and total Smad3, were assayed via western blotting after TGF-β knockout or AAN-II treatment. The results show that, for this model, AAN-II facilitates ulcer healing by suppressing the development of inflammation and promoting fibroblast proliferation and secretion of proangiogenic factors. AAN-II enhances the activation of the TGF-β1-Smad3 signaling pathway during skin ulcer healing. In addition, the results demonstrate that AAN-II and TGF-β have synergistic effects on ulcer healing. Our findings indicate that AAN-II can promote healing of pressure-induced venous skin ulcers via activation of TGF-β-Smad3 signaling in fibroblast cells and provide evidence that could be used in the development of more effective treatments.

… of alkannin and shikonin derivatives. Additionally, several ointments containing alkannin and … prepared and evaluated for their effectiveness on wound healing. In recent years, research …

Abstract The aim of this study was to investigate the potential of novel electrospun fiber mats loaded with alkannin and shikonin (A/S) derivatives, using as carrier a highly biocompatible, bio-derived, eco-friendly polymer such as poly[(R)-3-hydroxybutyric acid] (PHB). PHB fibers containing a mixture of A/S derivatives at different ratios were successfully fabricated via electrospinning. Αs evidenced by scanning electron microscopy, the fibers formed a bead-free mesh with average diameters from 1.25 to 1.47 μm. Spectroscopic measurements suggest that electrospinning marginally increases the amorphous content of the predominantly crystalline PHB in the fibers, while a significant drug amount lies near the fiber surface for samples of high total A/S content. All scaffolds displayed satisfactory characteristics, with the lower concentrations of A/S mixture-loaded PHB fiber mats achieving higher porosity, water uptake ratios, and entrapment efficiencies. The in vitro dissolution studies revealed that all samples released more than 70% of the encapsulated drug after 72 h. All PHB scaffolds tested by cell viability assay were proven non-toxic for Hs27 fibroblasts, with the 0.15 wt.% sample favoring cell attachment, spreading onto the scaffold surface, as well as cell proliferation. Finally, the antimicrobial activity of PHB meshes loaded with A/S mixture was documented for Staphylococcus epidermidis and S. aureus.

Alkanna tinctoria (L.) Tausch, is a Mediterranean herb that belongs to Boraginaceae family. It is a valuable medicinal plant with various pharmacological properties. The roots of A. tinctoria contain bioactive naphthoquinones, primarily alkannin and shikonin, along with their derivatives, which exhibit notable antimicrobial, anti-inflammatory, and wound-healing activities. Modern research has shown many traditional applications while discovering new therapeutic potentials, particularly in cancer treatment and diabetic wound management. The plant's rich phytochemical profile includes terpenoids, flavonoids, and phenolic compounds that contribute to its antioxidant and anti-inflammatory properties. Recent innovations in drug delivery systems, such as chitosan-based nanoparticles and electrospun nanofibers, have enhanced the efficacy of A. tinctoria extracts in wound healing applications. The plant also shows promise in cosmeceuticals due to its UV-protective and anti-aging properties. Despite these benefits, safety concerns exist regarding trace amounts of pyrrolizidine alkaloids, necessitating careful consideration in systemic applications. Advanced analytical techniques have enabled detailed characterization of bioactive compounds and their mechanisms of action. The usage of A. tinctoria in modern therapeutic applications represents a successful bridge between traditional medicine and contemporary pharmaceutical research, though additional clinical studies are needed to fully establish its therapeutic efficacy

Abstract Several plant preparations and extracts are used in folk medicine for treatment of topical wounds. Yet the validity of their use as well as the mechanism has not been ascertained in well-designed experimental settings. The wound healing activity of a topical hexane extract of Alkanna strigosa roots (HEASR) in excision and incision wound models in rats was evaluated. The pro-healing activity was assessed by the rate of wound contraction & wet granulation tissue weight and tensile strength in the excision and incision models, respectively. The active components of HEASR were isolated. Finally, the antimicrobial activity against five microorganisms; namely Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Bacillus subtilis and Candida albicans were assessed for both crude extract and pure compounds. The HEASR increased the weight of wet granulation tissue per wound area and tensile strength of wounds, and showed antimicrobial activity against Gram-positive bacteria and C. albicans. The pure compounds were alkanin & shikonin and showed remarkable activity against S. aureus, E. coli and B. subtilis. The results document the beneficial effect of A. strigosa extract and its pure compounds for treating the supurative excision as well as the incision wounds.

Alkanna tinctoria, called as Alkanet, is considered as a perennial plant (family: Boraginaceae). The plant is well-known for its large quantity of naphthoquinone enantiomers, specifically Alkannin and Shikonin (A/S). These compounds offer various pharmaceutical applications and find use in cosmetics, food supplements, and natural dyes. A search was conducted on the online databases Scopus, Science Direct, PubMed, Web of Science, and Google Scholar using the following keywords including traditional applications, phytochemical compositions, alkannin, shikonin, endangered species, wound healing, ulcer, and toxicity about A. tinctoria. Shikonin known for a coloured pigment that has been isolated from A.tinctoria has several potential effects as an anti-inflammatory, anticancer agent and in the management of wound healing. However, several obstacles prevent them from reaching their full potential. Sustainable production is a significant obstacle; relying on plant sources raises worries about supply and environmental impact, which necessitates the use of alternate technologies such as plant tissue culture or microbial biosynthesis. Also, possible side effects and toxicity need to be fully studied to make sure they are safe for people to use. The current manuscript describes the isolation, biosynthesis, patents filed, clinical trials, toxicity studies, and various novel formulations containing A/S.

… mixture of alkannins/shikonins (A/S), bioactive molecules isolated from the roots of Alkanna tinctoria, which comprise the active pharmaceutical ingredients of the strong wound healing …

… wound healing agents, alkannins/shikonins (A/S), for wound healing … hydrogel scaffolds with a mixture of alkannins/shikonins. A/S … and proliferative phases of wound healing, as well as …

… alkannin and to eluci— date the expression of CD antigen and histological changes on the proliferation of granulation tissue in rats. Shikonin and alkannin … and alkannin accelerate the …

… This study investigates the effect of Arnebia euchroma root ointment on wound healing and … -hemorrhoidectomy wound care has demonstrated significant improvement in wound healing …

Rosmarinic acid is a well-known natural antioxidant and anti-inflammatory compound, and it is one of the polyphenolic compounds found in comfrey plants. Comfrey root also contains allantoin, which helps with new skin regeneration. This study aimed to investigate the healing and skin regeneration process of skin wounds in Wistar rats using creams based on comfrey extract and to correlate the results with active compounds in the extract. The obtained results showed that comfrey root is rich in bioactive compounds, including allantoin, salvianolic acid, and rosmarinic acid, which are known for their great free radical scavenging activity, and the high antioxidant activity of the extract may be mainly due to these compounds. The obtained extract has an antimicrobial effect on Staphylococcus aureus (1530.76/382.69), Escherichia coli (6123.01/6123.01), and Pseudomonas aeruginosa (6123.01/6123.01). The macroscopic evaluation and the histological analysis of the skin defects 14 days after the intervention showed faster healing and complete healing in the skin excisions treated with oil-in-water cream with 20% extract of comfrey as the active ingredient.

With around 34 recognized species, Symphytum genus (comfrey) has a noteworthy position within the Boraginaceae family. Comfrey species have been empirically used since ancient times as wound-healing and skin-regenerating agents in ulcers, wounds, bone fractures, and rheumatic complaints. This review aims to provide a thorough examination of recent scientific advances and challenges within the Symphytum genus, covering data published between 2013 and 2023. It delivers an updated overview of the taxonomy, ethnopharmacological uses, chemical composition, and pharmacological activities of the genus. Special emphasis is put on molecular identification methods for species taxonomy, emerging extraction technologies for comfrey phytochemicals, metabolomics techniques for mapping chemical complexity, modern bioassay platforms revealing its poly-pharmacology, formulation strategies, and remediation approaches for removal of toxic pyrrolizidine alkaloids (PAs). For instance, recent metabolomic studies employing advanced spectro-chromatographic techniques have revealed a diverse chemical composition of comfrey plants, including polysaccharides, allantoin, benzoic and cinnamic acid derivatives, flavonoids, fatty acids, and unsaturated necine-structure-based PAs. The mechanisms underlying their anti-inflammatory, analgesic, wound-healing, anti-irritant, and osteo-regenerative properties were targeted in modern pharmacological setups. Thus, key compounds like allantoin, rosmarinic acid, globoidnans A and B, rabdosiin, and comfreyn A, have been identified as significant contributors to the anti-inflammatory and wound-healing effects of Symphytum-derived preparations. Despite their well-established clinical use, concerns about PAs-induced toxicity have prompted the development of novel PA remediation strategies, enabling the production of comfrey extracts with enhanced safety profiles that can meet the regulatory standards imposed by authorities.

The present work evaluates wound healing activity of leaves extracts of Symphytum officinale L. (comfrey) incorporated in three pharmaceutical formulations. Wound healing activity of comfrey was determined by qualitative and quantitative histological analysis of open wound in rat model, using allantoin as positive control. Three topical formulations, carbomer gel, glycero-alcoholic solution and O/W emulsion (soft lotion) were compared. The histological analysis of the healing process shows significant differences in treatment, particularly on its intensity and rate. The results indicate that emulsion containing both extracts, commercial and prepared, induced the largest and furthest repair of damaged tissue. This could be evidenced from day 3 to 28 by increase in collagen deposition from 40% to 240% and reduction on cellular inflammatory infiltrate from 3% to 46%. However, 8% prepared extract in emulsion presented the best efficacy. This work clearly demonstrates that comfrey leaves have a wound healing activity. The O/W emulsion showed to be the vehicle most effective to induce healing activity, particularly with extracts obtained from comfrey leaves collected in Minas Gerais state in Brazil. It shows the best efficacy to control the inflammatory process and to induce collagen deposition at 8% concentration.

Introduction: An accelerated healing of superficial wounds was demonstrated in clinical trials with a topical comfrey preparation (Symphytum × uplandicum Nyman). The effect has previously not been examined in skin models. Methods: An established in vitro model of epidermal cells with the typical strata was used for the observation of effects of applied substances on skin regeneration. Damage corresponding to a typical abrasion was created on day 1 by punching an opening into the epidermal fine structure down to the stratum basale. Samples were either untreated (controls) or exposed to comfrey cream on days 2, 3, 5, and 6. Tissue samples were taken for light and electron microscopy on days 1, 4, and 7. Results and Conclusions: Application of comfrey cream led to a quicker regeneration of skin cells and to an earlier differentiation of the cells towards a normal fine structure with a visible distinction of epidermal strata, keratin, and corneocyte formation within 4–7 days. The study covered the early days of skin regeneration and confirms the benefits observed in published clinical trials and non-interventional studies in patients with abrasions.

Any injury to the body, including damage to the skin's outer layer and impairment of its normal structure and function, is referred to as a wound. Since the beginning of time, people have recognized the crucial nature of wound healing, and significant resources have been used to create cutting-edge wound dressings made of the best materials possible for quick and effective recovery. A vital part of this healing process is played by medicinal herbs. Many studies conducted recently have focused on developing novel wound dressings that contain infusions from medicinal plants or their purified active components, providing viable substitutes for conventional dressings. Several investigations have looked into how various herbal remedies aid in the healing of wounds. This article intends to explain and examine the molecular components of wound healing that are aided by natural plant-based products. The remedies made from herbs participate in various phases of wound healing and work through a variety of processes. Certain herbal medications also increase the formation of important factors that are involved in re-epithelialization, angiogenesis, granulation tissue development, and collagen fiber deposition, such as transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF). encouraging anti-inflammatory in nature and antioxidant qualities at different stages of the wound-healing process. The field of herbal medicine and other natural products are used in traditional and alternative medicine to treat wounds. These methods have various benefits over conventional treatments, such as enhanced efficacy owing to different ways in which they work action, antibacterial qualities, and long-term safety when using wound dressings.

… wounds were produced by the application of cantharidin dressings. These wounds were then treated with either comfrey … The regeneration of damaged skin was examined in the OECD …

BackgroundDrugs of plant origin such as Arnica montana, Calendula officinalis or Hypericum perforatum have been frequently used to promote wound healing. While their effect on wound healing using preparations at pharmacological concentrations was supported by several in vitro and clinical studies, investigations of herbal homeopathic remedies on wound healing process are rare. The objective of this study was to investigate the effect of a commercial low potency homeopathic remedy Similasan® Arnica plus Spray on wound closure in a controlled, blind trial in vitro.MethodsWe investigated the effect of an ethanolic preparation composed of equal parts of Arnica montana 4x, Calendula officinalis 4x, Hypericum perforatum 4x and Symphytum officinale 6x (0712–2), its succussed hydroalcoholic solvent (0712–1) and unsuccussed solvent (0712–3) on NIH 3T3 fibroblasts. Cell viability was determined by WST-1 assay, cell growth using BrdU uptake, cell migration by chemotaxis assay and wound closure by CytoSelect ™Wound Healing Assay Kit which generated a defined “wound field”. All assays were performed in three independent controlled experiments.ResultsNone of the three substances affected cell viability and none showed a stimulating effect on cell proliferation. Preparation (0712–2) exerted a stimulating effect on fibroblast migration (31.9%) vs 14.7% with succussed solvent (0712–1) at 1:100 dilutions (p < 0.001). Unsuccussed solvent (0712–3) had no influence on cell migration (6.3%; p > 0.05). Preparation (0712–2) at a dilution of 1:100 promoted in vitro wound closure by 59.5% and differed significantly (p < 0.001) from succussed solvent (0712–1), which caused 22.1% wound closure.ConclusionResults of this study showed that the low potency homeopathic remedy (0712–2) exerted in vitro wound closure potential in NIH 3T3 fibroblasts. This effect resulted from stimulation of fibroblasts motility rather than of their mitosis.

… of the comfrey root extract is to stimulate the tissue regeneration, … The key constituents of the comfrey root extract responsible … Remarkable activity of the comfrey root in wound healing is …

Under normal circumstances, wound healing can be summarized as three processes. These include inflammation, proliferation, and remodeling. The vast majority of wounds heal rapidly; however, a large percentage of nonhealing wounds have still not been studied significantly. The factors affecting wound nonhealing are complex and diverse, and identifying an effective solution from nature becomes a key goal of research. This study aimed to highlight and review the mechanisms and targets of natural products (NPs) for treating nonhealing wounds. The results of relevant studies have shown that the effects of NPs are associated with PI3K-AKT, P38MAPK, fibroblast growth factor, MAPK, and ERK signaling pathways and involve tumor growth factor (TNF), vascular endothelial growth factor, TNF-α, interleukin-1β, and expression of other cytokines and proteins. The 25 NPs that contribute to wound healing were systematically summarized by an inductive collation of the six major classes of compounds, including saponins, polyphenols, flavonoids, anthraquinones, polysaccharides, and others, which will further direct the attention to the active components of NPs and provide research ideas for further development of new products for wound healing.

… indeed facilitate wound healing and … comfrey extract ointment on healing of superficial wounds was published [12]. Shortly thereafter, a clinical documentation of the effects of a comfrey …

… for wounds, the indications for which it was also perceived to be most effective. Comfrey was … Allantoin stimulates the regeneration of connective tissue, bone and cartilage [18]. Animal …

Shikonin, an active ingredient of Lithospermum erythrorhizon, exerts anti-inflammatory and antibacterial effects, and promotes wound healing. We investigated whether shikonin stimulated gingival tissue wound healing in human gingival fibroblasts (hGF). In addition, we evaluated the effects of shikonin on the mitogen-activated protein kinase (MAPK) signaling pathway, which has an important role in wound healing. hGF were subjected to primary culture using gingiva collected from patients. The cells were exposed to/treated with Shikonin at concentrations ranging from 0.01 to 100 μM. The optimal concentration was determined by cell proliferation and migration assays. Type I collagen and fibronectin synthesis, the gene expression of vascular endothelial growth factor (VEGF) and FN, and the phosphorylation of Extracellular signal-regulated kinase (ERK) 1/2 were investigated. Identical experiments were performed in the presence of PD98059 our data suggest, a specific ERK 1/2 inhibitor. Shikonin significantly promoted hGF proliferation and migration. Shikonin (1 µM) was chosen as the optimal concentration. Shikonin promoted type I collagen and FN synthesis, increased VEGF and FN expression, and induced ERK 1/2 phosphorylation. These changes were partially suppressed by PD98059. In conclusion, Shikonin promoted the proliferation, migration, type I collagen and FN synthesis, and expression of VEGF and FN via ERK 1/2 signaling pathway in hGFs. Therefore, shikonin may promote periodontal tissue wound healing.

Hypertrophic scarring/hypertrophic scars (HS) is a highly prevalent condition following burns and trauma wounds. Numerous studies have demonstrated that transforming growth factor-β1 (TGF-β1) plays an essential role in the wound healing process by regulating cell differentiation, collagen production and extracellular matrix degradation. The increased expression of TGF-β1 is believed to result in the formation of HS. Shikonin (SHI), an active component extracted from the Chinese herb, Radix Arnebiae, has previously been found to downregulate the expression of TGF-β1 in keratinocyte/fibroblast co-culture conditioned medium. In view of this, in this study, we aimed to further investigate the effects of SHI on TGF-β1-stimulated hypertrophic scar-derived human skin fibroblasts (HSFs) and examined the underlying mechanisms. Cell viability and proliferation were measured using alamarBlue and CyQUANT assays. The total amount of collagen and cell contraction were examined using Sirius red staining and the cell contraction assay kit. Gene expression and signalling pathway activation were detected using reverse transcription-quantitative polymerase chain reaction and western blot analysis. Our results revealed that SHI reduced TGF-β1-induced collagen production through the ERK/Smad signalling pathway and attenuated TGF-β1-induced cell contraction by downregulating α-smooth muscle actin (αSMA) expression in the HSFs. The data from this study provide evidence supporting the potential use of SHI as a novel treatment for HS.

… four shikonin derivatives deoxyshikonin, acetyl shikonin, 3-hydroxy-isovaleryl shikonin and 5,8-O-dimethyl acetyl shikonin … They suggested that the accelerative effect on proliferation of …

ABSTRACT Purpose: To investigate the Shikonin (SHI) induce autophagy of hypertrophic scar-derived fibroblasts (HSFs) and the mechanism of which in repairing hypertrophic scar. Methods: This study showed that SHI induced autophagy from HSFs and repaired skin scars through the AMPK/mTOR pathway. Alamar Blue and Sirius red were used to identify cell activity and collagen. Electron microscopy, label-free quantitative proteomic analysis, fluorescence and other methods were used to identify autophagy. The differences in the expression of autophagy and AMPK/mTOR pathway-related proteins after SHI treatment were quantitatively analyzed by Western blots. A quantitative real-time polymerase chain reaction assay was used to detect the expression of LC3, AMPK and ULK after adding chloroquine (CQ) autophagy inhibitor. Results: After treatment with SHI for 24 hours, it was found that the viability of HSFs was significantly reduced, the protein expression of LC3-II/LC3-I and Beclin1 increased, while the protein expression of P62 decreased. The expression of phosphorylated AMPK increased and expression of phosphorylated mTOR decreased. After the use of CQ, the cell autophagy caused by SHI was blocked. The key genes LC3 and P62 were then reexamined by immunohistochemistry using a porcine full-thickness burn hypertrophic scar model, and the results verified that SHI could induce autophagy in vivo. Conclusions: These findings suggested that SHI promoted autophagy of HSFs cells, and the potential mechanism may be related to the AMPK/mTOR signal pathway, which provided new insights for the treatment of hypertrophic scars.

Impaired growth factor production, angiogenic response, macrophage function, and collagen accumulation have been shown to delay wound healing. Delayed wound healing is a debilitating complication of diabetes that leads to significant morbidity. In this study, curcumin and Lithospermi radix (LR) extract, which are used in traditional Chinese herbal medicine, were added within nanofibrous membranes to improve wound healing in a streptozotocin (STZ)-induced diabetic rat model. Gelatin-based nanofibers, which were constructed with curcumin and LR extract at a flow rate of 0.1 mL/hour and an applied voltage of 20 kV, were electrospun onto chitosan scaffolds to produce bilayer nanofibrous scaffolds (GC/L/C). The wounds treated with GC/L/C exhibited a higher recovery rate and transforming growth factor-beta (TGF-β) expression in Western blot assays. The decreased levels of pro-inflammatory markers, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), provided evidence for the anti-inflammatory effects of GC/L/C treatment. Chronic wounds treated with GC/L/C achieved better performance with a 58 ± 7% increase in recovery rate on the seventh day. Based on its anti-inflammatory and wound-healing effects, the GC/L/C bilayer nanofibrous scaffolds can be potential materials for chronic wound treatment.

… Chronic diabetic wounds are characterized by persistent inflammation and impaired … derived from Lithospermum erythrorhizon, to achieve controlled drug release and multifunctional …

DFU is a common complication of DM that has shown an increasing trend over previous decades. In total, it is estimated that 15% of patients with diabetes will suffer from DFU during their lifetime. To compare wound outcome, limb salvage, healing time of diabetes related foot ulcers. and cost effectiveness in terms of usage of hospital resources and numbers and easiness of dressings between Lithospermum erythrorhizon dressings and standard moist wound therapy (SMWT) in management of diabetic foot ulcers. This is a prospective observational study involving 34 patients with active diabetic foot ulcers, in a high-volume tertiary referral vascular center. They were divided into 2 groups: 17 patients (group A) were prescribed SMWD and the other 17 patients (group B) received Lithospermum erythrorhizon wound dressing. Study Period: 6 months from September 2022 to March 2023. Analyzing the results of our study, we suggest that Lithospermum erythrorhizon wound dressing has a definitive role in promotion of proliferation of granulation tissue, reduction in the wound size, and rapid clearing of bacterial load. Our data demonstrates that Lithospermum erythrorhizon wound dressings decrease the wound depth more effectively than saline gauze dressings over the first 8 weeks of therapy. It is suggested that Lithospermum erythrorhizon wound dressing is a cost-effective, easy to use and patient- friendly method of treating diabetic foot ulcers which helps in early closure of wounds, preventing complications and hence promising a better outcome. Application of Lithospermum erythrorhizon wound dressing over wound bed increases the effectiveness of local circulation, which assists in the proliferation of granulation tissue and epithelialization. We have also found that the patients on Lithospermum erythrorhizon wound dressing therapy had earlier complete granulation.

The management of skin wound healing problems is a public health issue in which traditional herbal medicines could play a determining role. Kampo medicine, with three traditionally used ointments, provides interesting solutions for these dermatological issues. These ointments named Shiunkō, Chuōkō, and Shinsen taitsukō all have in common a lipophilic base of sesame oil and beeswax from which herbal crude drugs are extracted according to several possible manufacturing protocols. This review article brings together existing data on metabolites involved in the complex wound healing process. Among them are representatives of the botanical genera Angelica, Lithospermum, Curcuma, Phellodendron, Paeonia, Rheum, Rehmannia, Scrophularia, or Cinnamomum. Kampo provides numerous metabolites of interest, whose content in crude drugs is very sensitive to different biotic and abiotic factors and to the different extraction protocols used for these ointments. If Kampo medicine is known for its singular standardization, ointments are not well known, and research on these lipophilic formulas has not been developed due to the analytical difficulties encountered in biological and metabolomic analysis. Further research considering the complexities of these unique herbal ointments could contribute to a rationalization of Kampo’s therapeutic uses for wound healing.

The aim of this study was to observe the curative effect and mechanism of Shengji Yuhong ointment in the healing of chronic ulcer of lower limbs. 400 patients were equally divided into treatment group and control group. The treatment group was covered with a piece of Shengji Yuhong ointment gauze, while the control group was covered with a piece of Vaseline gauze. Both groups changed dressings every other day for 4 weeks. On the 3rd, 7th, 14th, 21st, and 28th days of treatment, the reduction rate of wound area and the growth of wound granulation were observed and the levels of hydroxyproline and hemoglobin in wound granulation tissue were measured. The total effective rate was 99.00% in the treatment group and 71.00% in the control group. The treatment group was significantly better than the control group (P < .01). The ulcer area reduction rate of the treatment group was significantly higher than that of the control group (P < .01). The scores of ulcer depth, granulation color, and coverage area on the 7th, 14th, 21st, and 28th days after treatment in the treatment group were significantly lower than those before treatment (P < .05). After treatment, the levels of hydroxyproline and hemoglobin in granulation tissue of wounds in both groups were significantly higher than those before treatment (P < .01), and the levels in the treatment group were significantly higher than those in the control group (P < .01). Shengji Yuhong ointment can improve the healing rate of chronic ulcer of lower limbs.

… Of these five herbal plants in our study, Lithospermi radix (the root of Lithospermum … of Aloe vera on the healing of dermal wounds in diabetic rats, J Ethnopharmacol 59:195À201, 1998. …

BACKGROUND Necrotizing fasciitis (NF) of the lower leg is a severe, potentially fatal aggressive infection. Untimely treatment frequently leads to amputation or even life-threatening outcomes. CASE PRESENTATION This case report presents a limb-salvage and life-saving strategy integrating Traditional Chinese Medicine (TCM) and Western medicine in a 93-year-old male patient with lower extremity necrotizing fasciitis who refused amputation. The integrated treatment plan included: early surgical incision with debridement, nose ring drainage, broad-spectrum antibiotics, and symptomatic supportive therapy. Local wound irrigation was performed with rhubarb-licorice decoction, supplemented by topical galla chinensis paste application and oral administration of Si-Miao-Yong-An Decoction and Siwu Decoction. During the intermediate phase, limited additional debridement was performed, followed by local chymotrypsin and lithospermum gauze application. After optimal wound bed preparation, split-thickness stamp skin grafting was performed. Postoperatively, Vaseline gauze and lithospermum gauze were applied alternately with intermittent closed drainage. The oral TCM regimen was subsequently adjusted to Buzhong Yiqi Decoction. CONCLUSION This integrative approach effectively addressed infection control, systemic inflammation, and tissue regeneration, demonstrating its potential as a limb-preserving alternative for NF patients when standard surgery is contraindicated or declined. Further studies are warranted to validate these findings.

Wound healing properties of plant extracts that contain the naphthoquinone natural products alkannin (1) and shikonin (2) have been known for many centuries. More recently, the biological properties of 1, 2, and related derivatives have been demonstrated experimentally, and their production both by cell cultures and chemical synthesis has been studied extensively.

Abstract Serious consequences including septicemia and amputations can result from complex wounds, which is a serious healthcare concern. In addition, there are currently only a few choices for management, which justifies the search for novel, highly effective wound-healing medications. This research work was aimed at fabricating chitosan-based Alkanna tinctoria and Mupirocin nanoparticles by ionic gelation technique for burn wound management. Preliminary studies were conducted, and the prepared nanoparticles were characterized by various techniques that involve, high-performance liquid chromatography for the detection of components in A. tinctoria root extract, ATR-FTIR, particle size, zeta potential, percent drug content (DC%), percent entrapment efficiency (EE%), scanning electron microscopy, and transmission electron microscopy (TEM) for surface morphology. The optimized formulation CS-AT-MU-NPs3 shows a particle size of 340.8 ± 34.46 nm and positive zeta potential 27.3 ± 3.10 mV. In vitro drug release study was also performed, which demonstrated improved and controlled release of the drug from the nanoparticles. The CS-AT-MU-NPs3 exhibited a maximum release up to 92.61% (AT) and 88.35% (MU). Antibacterial and antifungal activities of the formulation were also accessed by utilizing the agar well diffusion technique. The combination of AT and MU in chitosan-based nanoparticles was significantly effective against bacterial and fungal strains like Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans as compared to other formulations. The skin irritation study was also conducted, which shows that the prepared formulation did not cause any observable changes to the skin in terms of inflammation, erythema, edema, or any other symptoms associated with skin irritation. All the chitosan-based nanoparticles showed almost 75% reduction in wound contraction, while the optimized formulation CS-AT-MU-NPs3 showed complete wound healing on the 15th day. Based on the results, it can be assumed that chitosan-based nanoparticles containing A. tinctoria and Mupirocin demonstrated good wound healing and could be used to effectively manage burn wounds of any description.

Abstract Natural products’ inflammatory and antioxidant properties have crucial roles in tissue repair and regeneration. This study aimed to investigate HPLC analysis, antioxidant activity, and wound-healing effect of Echium amoenum (EA) on rats. The EA was analysed for the determination of shikonin a derivative of naphthoquinone. In the wound healing assessment, forty Wistar rats were divided into five groups that were receiving the cream base, normal saline (NS), 1% silver sulfadiazine (SSD), and 5 and 10% EA cream (EAC). Shikonin was found in the EA extract. The average wound area on the 10th day was 0.71 ± 0.01, 0.86 ± 0.13, 0.58 ± 0.08, 0.53 ± 0.03 and 0.43 ± 0.04 cm2 for the cream base, NS, SSD, and 5 and 10% EAC, respectively. The collagen fibres were well formed and horizontally oriented in 5 and 10% EAC groups compared to other groups. EA cream was an effective treatment for wound healing in comparison with SSD. Graphical Abstract

BackgroundA prospective, randomized, placebo-controlled clinical trial was conducted to compare the healing effectiveness of Alkanna tinctoria (L.) Tausch (Boraginaceae) with standard dressing on wound healing at the donor site after removal of the skin graft.MethodsEnrolled patients were randomly allocated to receive topicalA. tinctoria extract ointment (20%) or standard dressing (dressing with base ointment) daily. Wound healing was assessed using the Bates-Jenson assessment tool at the 2nd and 4th weeks after intervention.ResultsDecreases in wound score were significantly greater in the A. tinctoria group compared with the placebo group (P <0.05). The surface areas of graft donor sites in the A. tinctoria group were significantly reduced as compared with the control group at day 28 of the intervention (P < 0.05). The proportion of patients in the A. tinctoria group achieving complete wound healing within 2 to 4 weeks was 50% and 96.66%, respectively, significantly higher than in patients receiving standard care: 0% and 23.3%, respectively.ConclusionsThis clinical study showed that A. tinctoria dressing accelerates wound healing after graft harvesting.Trial registrationIRCT ID: IRCT201511165781N2.

Background: Shikonin (SHK) possesses extensive pharmacological effects including antimicrobial and anti‐inflammatory properties for diabetic wound (DW), while its molecular mechanism remains to be clarified. In this study, we investigated the potential mechanisms of SHK in treating DW by combining network pharmacology and in vitro experiments.

Introduction The management and prevention of hypertrophic scars present significant challenges in clinical medicine. The development of hypertrophic scars primarily results from angiogenesis, localized inflammatory responses, and the excessive deposition of collagen during the wound healing process. Given the practical requirements for clinical applications, the development of a multifunctional dressing that exhibits synergistic effects and adapts to wounds of diverse shapes is of paramount importance. Hydrogels have emerged as promising biomaterials in dermatological applications due to their excellent biocompatibility, injectability, and strong adhesion. Shikonin (SHI), a compound derived from traditional Chinese medicine, exhibits anti-inflammatory and antioxidant properties that facilitate wound healing. It is posited that SHI possesses diverse pharmacological potential for the prevention and treatment of scars. Methods Based on these characteristics, this study developed a methacrylated gelatin (GelMA) dressing incorporated with shikonin. In vitro experiments were conducted to evaluate the material properties and biocompatibility of SHI-GelMA. Concurrently, an in vivo rabbit ear model was established to assess the efficacy of SHI-GelMA in inhibiting scar hyperplasia through treatment and subsequent observation. Results By utilizing GelMA’s superior biological properties, the dressing enhances the therapeutic efficacy of SHI on hypertrophic scars while addressing challenges related to drug release kinetics. In vitro experiments demonstrated that the SHI-GelMA dressing exhibits favorable biocompatibility. Importantly, both in vitro and in vivo studies consistently indicated that SHI-GelMA synergistically prevents and inhibits hypertrophic scar formation through SHI's principal anti-inflammatory, anti-angiogenic, and anti-fibrotic mechanisms. Discussion In summary, we have successfully developed a functional wound dressing that incorporates the diverse bioactivities of SHI, offering novel materials and strategies for the synergistic prevention and treatment of hypertrophic scars.

… Wound healing has a close relationship with angiogenesis. Angiogenesis is a complex process involving basement membrane dissolution, endothelial cell proliferation and migration, …

… healing, although we could not rule out the roles of other ingredients on wound healing. … Study of the accelerating effect of Shikonin and Alkannin on the proliferation of granulation …