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    Body protective compound-157 enhances alkali-burn wound healing in vivo and promotes proliferation, migration, and angiogenesis in vitro. Huang Tonglie,Zhang Kuo,Sun Lijuan,Xue Xiaochang,Zhang Cun,Shu Zhen,Mu Nan,Gu Jintao,Zhang Wangqian,Wang Yukun,Zhang Yingqi,Zhang Wei Drug design, development and therapy Chemical burns take up a high proportion of burns admissions and can penetrate deep into tissues. Various reagents have been applied in the treatment of skin chemical burns; however, no optimal reagent for skin chemical burns currently exists. The present study investigated the effect of topical body protective compound (BPC)-157 treatment on skin wound healing, using an alkali burn rat model. Topical treatment with BPC-157 was shown to accelerate wound closure following an alkali burn. Histological examination of skin sections with hematoxylin-eosin and Masson staining showed better granulation tissue formation, reepithelialization, dermal remodeling, and a higher extent of collagen deposition when compared to the model control group on the 18th day postwounding. BPC-157 could promote vascular endothelial growth factor expression in wounded skin tissues. Furthermore, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and cell cycle analysis demonstrated that BPC-157 enhanced the proliferation of human umbilical vein endothelial cells (HUVECs). Transwell assay and wound healing assay showed that BPC-157 significantly promoted migration of HUVECs. We also observed that BPC-157 upregulated the expression of VEGF-a and accelerated vascular tube formation in vitro. Moreover, further studies suggested that BPC-157 regulated the phosphorylation level of extracellular signal-regulated kinases 1 and 2 (ERK1/2) as well as its downstream targets, including c-Fos, c-Jun, and Egr-1, which are key molecules involved in cell growth, migration, and angiogenesis. Altogether, our results indicated that BPC-157 treatment may accelerate wound healing in a model of alkali burn-induced skin injury. The therapeutic mechanism may be associated with accelerated granulation tissue formation, reepithelialization, dermal remodeling, and collagen deposition through ERK1/2 signaling pathway. 10.2147/DDDT.S82030
    Topical application of substance P promotes wound healing in streptozotocin-induced diabetic rats. Kant Vinay,Kumar Dinesh,Kumar Dhirendra,Prasad Raju,Gopal Anu,Pathak Nitya N,Kumar Pawan,Tandan Surender K Cytokine Substance P (SP) is known to stimulate angiogenesis, fibroblasts proliferation and expressions of cytokines and growth factors involved in wound healing. However, SP level reduces in dermis in diabetics and, hence, it was hypothesized that exogenously applied SP could be helpful in improving wound healing in diabetic rats. Excision skin wound was created on the back of diabetic rats and rats were divided into three groups i.e. (i) saline-, (ii) gel- and (iii) SP-treated. Normal saline, pluronic gel and SP (10(-6)M) in gel were topically applied once daily for 19days. SP treatment significantly increased the wound closure, levels of interleukin-10, and expressions of vascular endothelial growth factor, transforming growth factor-beta1, heme oxygenase-1 and endothelial nitric oxide synthase, whereas it significantly decreased the expression of tumor necrosis factor-alpha, interleukin-1beta and matrix metalloproteinases-9 in the granulation/healing tissue. The inflammatory cells were present for long time in normal saline-treated group. Histological evaluation revealed better extracellular matrix formation with marked fibroblast proliferation and collagen deposition in SP-treated group. Early epithelial layer formation, increased microvessel density and greater growth associated protein-43 positive nerve fibers were also evidenced in SP-treated group. In conclusion, SP treatment markedly accelerated cutaneous wound healing in diabetic rats. 10.1016/j.cyto.2014.12.015
    Bitter Melon Extract Promotes Granulation Tissue Growth and Angiogenesis in the Diabetic Wound. Singh Rekha,Garcia-Gomez Ignacio,Gudehithlu Krishnamurthy P,Singh Ashok K Advances in skin & wound care OBJECTIVE:Bitter melon is a plant fruit that has been shown to exert a hypoglycemic effect when used systemically in patients with diabetes. This study was designed to investigate the topical effect of bitter melon on diabetic wounds using the wound chamber model in rats. DESIGN:Two bilateral wound chambers were implanted subcutaneously in the thoracic-lumbar region of male Sprague-Dawley rats. Diabetes was induced with streptozotocin 7 days after implantation of wound chambers. After 24 hours of induction of diabetes, aqueous extract of bitter melon was injected into 1 wound chamber, and saline (0.9% sodium chloride solution) was injected into the contralateral chamber once daily for 3 days. Wound fluid was collected on day 4 for analysis, following which rats were euthanized. The granulation tissue encapsulating the wound chamber was removed and processed for histology. Controls included diabetic rats with wound chambers injected with saline (instead of bitter melon) and nondiabetic rats with wound chambers injected with bitter melon. RESULTS:In rats with diabetes, wound granulation tissue treated with bitter melon was well formed, with distinct cellular layers, whereas the saline-treated granulation tissue showed a severe loss of tissue organization and blood vessels. Moreover, the bitter melon treatment increased angiogenesis in the diabetic granulation tissue, marked by abundant microvessels and large blood vessels. In nondiabetic rats, no differences in wound granulation tissues were observed between saline- and bitter melon-treated groups. Bitter melon treatment had no effect on systemic blood glucose levels or insulin receptor substrate 1, suggesting that its stimulatory effect on diabetic granulation tissue was not due to alteration of systemic blood glucose levels. CONCLUSIONS:When applied locally to diabetic wounds, bitter melon extract prevents regression of granulation tissue and blood vessels, thus accelerating and improving wound healing. 10.1097/01.ASW.0000504758.86737.76
    Negative-Pressure Wound Therapy Promotes Wound Healing by Enhancing Angiogenesis Through Suppression of NLRX1 via miR-195 Upregulation. Liu Yu,Tang Ningning,Cao Ke,Wang Shaohua,Tang Sijie,Su Honghui,Zhou Jianda The international journal of lower extremity wounds Negative-pressure wound therapy (NPWT) is one of the most advanced therapeutic methods in the treatment of various hard-to-heal acute and refractory chronic wounds. Recent emerging evidence points to a role of the microRNA-mediated regulation of angiogenesis in ischemic tissues, and a series of microRNAs associated with angiogenesis have been successively identified. In this study, we found that miR-195 expression was significantly upregulated and the microvessel density (MVD) was increased in granulation tissue collected 7 days after NPWT compared with those in the pre-NPWT tissue. Moreover, the expression of NLRX1, the potential target gene of miR-195, was down-regulated in post-NPWT compared with that in pre-NPWT tissue. Significant negative correlations were detected between miR-195 and NLRX1 expression levels ( r = -.856, P < .001) and between NLRX1 expression and MVD ( r = -.618, P < .05), whereas miR-195 expression was positively correlated with MVD in the granulation tissue ( r = .630, P < .05). In summary, NPWT may suppress NLRX1 expression through the upregulation of miR-195 expression, thus efficaciously promoting angiogenesis in the granulation tissue to enhance wound healing. 10.1177/1534734618794856
    Type II Collagen from Cartilage of Promotes Wound Healing in Human Dermal Fibroblasts and in Mouse Skin. Lai Ching-Shu,Tu Chun-Wei,Kuo Hsing-Chun,Sun Pei-Pei,Tsai Mei-Ling Marine drugs Type II collagen is an important component of cartilage; however, little is known about its effect on skin wound healing. In this study, type II collagen was extracted from the cartilage of and its effect on in vitro and in vivo wound healing was compared to type I collagen derived from tilapia skin. Sturgeon cartilage collagen (SCC) was composed of α1 chains and with a thermal denaturation (T) at 22.5 and melting temperature (T) at 72.5 °C. Coating SCC potentiated proliferation, migration, and invasion of human dermal fibroblast adult (HDFa) cells. Furthermore, SCC upregulated the gene expression of extracellular matrix (ECM) components (col Iα1, col IIIα1, elastin, and Has2) and epithelial-mesenchymal transition (EMT) molecules (N-cadherin, Snail, and MMP-1) in HDFa. Pretreatment with Akt and mitogen-activated protein kinase (MAPK) inhibitors significantly attenuated the HDFa invasion caused by SCC. In mice, the application of SCC on dorsal wounds effectively facilitated wound healing as evidenced by 40-59% wound contraction, whereas the untreated wounds were 18%. We observed that SCC reduced inflammation, promoted granulation, tissue formation, and ECM deposition, as well as re-epithelialization in skin wounds. In addition, SCC markedly upregulated the production of growth factors in the dermis, and dermal and subcutaneous white adipose tissue; in contrast, the administration of tilapia skin collagen (TSC) characterized by typical type I collagen was mainly expressed in the epidermis. Collectively, these findings indicate SCC accelerated wound healing by targeting fibroblast in vitro and in vivo. 10.3390/md18100511
    Notoginsenoside Ft1 Promotes Fibroblast Proliferation via PI3K/Akt/mTOR Signaling Pathway and Benefits Wound Healing in Genetically Diabetic Mice. Zhang Eryun,Gao Bo,Yang Li,Wu Xiaojun,Wang Zhengtao The Journal of pharmacology and experimental therapeutics Wound healing requires the essential participation of fibroblasts, which is impaired in diabetic foot ulcers (DFU). Notoginsenoside Ft1 (Ft1), a saponin from Panax notoginseng, can enhance platelet aggregation by activating signaling network mediated through P2Y12 and induce proliferation, migration, and tube formation in cultured human umbilical vein endothelial cells. However, whether it can accelerate fibroblast proliferation and benefit wound healing, especially DFU, has not been elucidated. In the present study on human dermal fibroblast HDF-a, Ft1 increased cell proliferation and collagen production via PI3K/Akt/mTOR signaling pathway. On the excisional wound splinting model established on db/db diabetic mouse, topical application of Ft1 significantly shortened the wound closure time by 5.1 days in contrast with phosphate-buffered saline (PBS) treatment (15.8 versus 20.9 days). Meanwhile, Ft1 increased the rate of re-epithelialization and the amount of granulation tissue at day 7 and day 14. The molecule also enhanced mRNA expressions of COL1A1, COL3A1, transforming growth factor (TGF)-β1 and TGF-β3 and fibronectin, the genes that contributed to collagen expression, fibroblast proliferation, and consequent scar formation. Moreover, Ft1 facilitated the neovascularization accompanied with elevated vascular endothelial growth factor, platelet-derived growth factor, and fibroblast growth factor at either mRNA or protein levels and alleviated the inflammation of infiltrated monocytes indicated by reduced tumor necrosis factor-α and interleukin-6 mRNA expressions in the diabetic wounds. Altogether, these results indicated that Ft1 might accelerate diabetic wound healing by orchestrating multiple processes, including promoting fibroblast proliferation, enhancing angiogenesis, and attenuating inflammatory response, which provided a great potential application of it in clinics for patients with DFU. 10.1124/jpet.115.229369
    Amniotic Epithelial Cells Accelerate Diabetic Wound Healing by Modulating Inflammation and Promoting Neovascularization. Zheng Yongjun,Zheng Shiqing,Fan Xiaoming,Li Li,Xiao Yongqiang,Luo Pengfei,Liu Yingying,Wang Li,Cui Zhenci,He Fei,Liu Yuhuan,Xiao Shichu,Xia Zhaofan Stem cells international Human amniotic epithelial cells (hAECs) are nontumorigenic, highly abundant, and low immunogenic and possess multipotent differentiation ability, which make them become ideal alternative stem cell source for regenerative medicine. Previous studies have demonstrated the therapeutic potential of hAECs in many tissue repairs. However, the therapeutic effect of hAECs on diabetic wound healing is still unknown. In this study, we injected hAECs intradermally around the full-thickness excisional skin wounds of db/db mice and found that hAECs significantly accelerated diabetic wound healing and granulation tissue formation. To explore the underlying mechanisms, we measured inflammation and neovascularization in diabetic wounds. hAECs could modulate macrophage phenotype toward M2 macrophage, promote switch from proinflammatory status to prohealing status of wounds, and increase capillary density in diabetic wounds. Furthermore, we found that the hAEC-conditioned medium promoted macrophage polarization toward M2 phenotype and facilitated migration, proliferation, and tube formation of endothelial cells through in vitro experiments. Taken together, we first reported that hAECs could promote diabetic wound healing, at least partially, through paracrine effects to regulate inflammation and promote neovascularization. 10.1155/2018/1082076
    [Effect of Qufu Shengji ointment(QFSJO) on promoting the healing of infectious wounds]. Zhang Lei,Li Chao-Ding,Shen Jin-Hu,Yang Liu-Zhong,Wang Jian-Wei,Zhang Zhen,Luo Zhong-Wei,Cheng Fei Zhongguo gu shang = China journal of orthopaedics and traumatology OBJECTIVE:To explore the clinical effect of Qufu Shengji ointment(QFSJO) in promoting the wound healing after trauma. METHODS:From January 2014 to June 2018, 60 patients with soft tissue injury, skin defect and wound infection caused by violent trauma were admitted, including 32 males and 28 females, aged from 18 to 65 years, with an average age of 41.3 years. Among them, 30 patients were treated with QFSJO (QFSJO group) and 30 patients were treated with normal saline iodophor (control group). The reduction rate of wound area, the days of decayed flesh, the time of new epithelium and the recovery rate of 28 days after dressing change were compared between the two groups. RESULTS:In the QFSJO group, after using large dose of QFSJO, the pus of the wound increased, the granulation grew, and the new epithelium appeared on the edge of the wound, showing a rapid healing phenomenon. The wound healing rate of QFSJO group was higher than that of the control group at all time points, and the time of decaying flesh and new epithelium appeared in QFSJO group was earlier than that of the control group. The recovery rate of QFSJO group was significantly higher than that of the control group(<0.05). All the patients were followed up, and the duration ranged form 6 to 12 months, with an average of 9.4 months. The exposed areas of bone and teadon were covered well. The vital signs of the two groups were stable and no adverse reactions occurred. CONCLUSIONS:QFSJO can promote the growth of granulation tissue, promote the production of new skin, and accelerate the healing of infectious wound after trauma. 10.3969/j.issn.1003-0034.2019.12.015
    Effects of Periploca forrestii Schltr on wound healing by Src meditated Mek/Erk and PI3K/Akt signals. Li Jinsong,Chen Lei,Xu Jian,Xie Zijian,Xu Yunhui,Jiang Pan,Duan Bingjing,Huang Xiaoxian,Feng Feng,Liu Wenyuan Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Periploca forrestii Schltr. (PF) is a traditional folk medicine in China that has been used widely for treating rheumatoid arthritis and traumatic injuries for a long history. Previously, we have roughly demonstrated that the ethanol extract of PF possessed in vitro wound healing potential, and more in depth research deserves to be conducted. AIM OF THE STUDY:The present study is aiming to fully evaluate the wound healing activity of PF in vitro and in vivo, clarify the mechanism of actions and the primary constituents responsible for wound healing. MATERIALS AND METHODS:The total extract of Periploca forrestii Schltr. (EPF) and its fraction (65% ethanol fraction, EPFE65) were obtained and evaluated on in vitro wound healing properties using mouse dermal fibroblasts (L929). Cell proliferation was tested by MTT and EdU assay, confirmed by cell cycle analysis, cell migration was evaluated by scratch and transwell assay and collagen production was also determined. Then EPFE65 was tested on in vivo wound healing activity using the excision rat models. The wounded skin of rats was topically applied with 0.1% EPFE65 once daily for 6 days with hydrogel as the carrier and the recombinant bovine basic fibroblast growth factor hydrogel (rbFGF) as positive control. Histopathology of the wounded skin on day 6 and day 12 was studied via hematoxylin and eosin (HE) staining. The expression of phosphorylation of Src, Akt and Erk1/2 was determined after the treatment with EPFE65 by western blot. In order to figure out whether the activation of Src, Akt and Erk1/2 was directly in conjunction with wound healing process promoted by EPFE65, cell proliferation and migration were tested in the presence of three inhibitors of Src, Akt and Erk1/2. Finally, the chemical composition of the effective fraction EPFE65 was analyzed by HPLC-Q-TOF-MS/MS. RESULTS:In vitro experiments suggested that EPFE65 was comparable to EPF that had potent effect on promoting L929 fibroblasts proliferation, migration and increasing collagen production. 0.1% EPFE65 hydrogel also exhibited significant effect on promoting wound healing in rats. The wound closure was significantly faster in EPFE65 and positive rbFGF group than that in negative control group since the third day post wounding (p < 0.05). Specifically, on day10-12, the wounds in EPFE65 and rbFGF group were almost healed as the wound areas diminished into 13.3-5.3% and 7.7-4.0%, while the wound in control group was still apparent with 36.8-22.1% wound area. HE staining demonstrated that EPFE65 and rbFGF group could advance re-epithelialization in the early days and promote the transition of granulation tissue into complete dermis tissue with more skin appendages resembling those of normal skin in the last days. Western blot results suggested that the active fraction EPFE65 could increase the phosphorylation of Src, Akt and Erk1/2 in both dose-dependent and time-dependent manner, whereas Akt and Erk1/2 phosphorylation caused by EPFE65 could be abolished by Src inhibition. Inhibition experiments confirmed that the activation of Src, Akt and Erk1/2 were involved in cell proliferation and migration. All of these demonstrated that EPFE65 promoted wound healing at least in part via Src mediated Mek/Erk and PI3K/Akt signaling pathways. Analysis of chemical composition of EPFE65 revealed that cardiac glycosides were major components in EPFE65, among which periplocin showed effectiveness on promoting fibroblasts proliferation indicating that cardiac glycosides in EPFE65 maybe the active compounds responsible for wound healing. CONCLUSION:The present study confirmed that EPFE65, ethanol extract of Periploca forrestii Schltr. could accelerate wound healing in vitro and in vivo through Src meditated Mek/Erk and PI3K/Akt signaling pathways. 10.1016/j.jep.2019.03.046
    Direct conversion of injury-site myeloid cells to fibroblast-like cells of granulation tissue. Sinha Mithun,Sen Chandan K,Singh Kanhaiya,Das Amitava,Ghatak Subhadip,Rhea Brian,Blackstone Britani,Powell Heather M,Khanna Savita,Roy Sashwati Nature communications Inflammation, following injury, induces cellular plasticity as an inherent component of physiological tissue repair. The dominant fate of wound macrophages is unclear and debated. Here we show that two-thirds of all granulation tissue fibroblasts, otherwise known to be of mesenchymal origin, are derived from myeloid cells which are likely to be wound macrophages. Conversion of myeloid to fibroblast-like cells is impaired in diabetic wounds. In cross-talk between keratinocytes and myeloid cells, miR-21 packaged in extracellular vesicles (EV) is required for cell conversion. EV from wound fluid of healing chronic wound patients is rich in miR-21 and causes cell conversion more effectively compared to that by fluid from non-healing patients. Impaired conversion in diabetic wound tissue is rescued by targeted nanoparticle-based delivery of miR-21 to macrophages. This work introduces a paradigm wherein myeloid cells are recognized as a major source of fibroblast-like cells in the granulation tissue. 10.1038/s41467-018-03208-w
    Cultured Human Epidermis Combined With Meshed Skin Autografts Accelerates Epithelialization and Granulation Tissue Formation in a Rat Model. Sakamoto Michiharu,Morimoto Naoki,Inoie Masukazu,Takahagi Miki,Ogino Shuichi,Jinno Chizuru,Suzuki Shigehiko Annals of plastic surgery INTRODUCTION:As the take rate of cultured epidermal autografts in burn wound treatment is variable, widely expanded meshed auto skin grafts are often used in combination with cultured epidermal autograft to increase the take rate and achieve definitive wound coverage. However, a long time (3-4 weeks) required to prepare a cultured epidermis sheet is a disadvantage. Allogeneic cultured epidermis can be prepared in advance and cryopreserved to be used in combination with auto meshed skin grafts for treating third-degree burns. Nevertheless, the human cultured epidermis (hCE) has not been proved to accelerate wound healing after meshed skin grafting. Here, we investigated the effect of hCE on wound healing in a rat model of meshed skin grafting. MATERIALS AND METHODS:Human cultured epidermis was prepared from human neonatal foreskin and assessed by the release of growth factors into the culture medium using enzyme-linked immunosorbent assay. Skin wounds were inflicted on male F344 rats and treated by the application of widely meshed (6:1 ratio) autogenous skin grafts with or without hCE (n = 8 rats per group). Wound area, neoepithelium length, granulation tissue formation, and neovascularization were evaluated on day 7 postgrafting. RESULTS:Human cultured epidermis secreted IL-1α, Basic fibroblast growth factor, platelet-derived growth factor-AA, TGF-α, TGF-β1, and vascular endothelial growth factor in vitro. In rats, hCE accelerated wound closure (P = 0.003), neoepithelium growth (P = 0.019), and granulation tissue formation (P = 0.043), and increased the number of capillaries (P = 0.0003) and gross neovascularization area (P = 0.008) compared with the control group. CONCLUSIONS:The application of hCE with meshed grafts promoted wound closure, possibly via secretion of growth factors critical for cell proliferation and migration, suggesting that hCE can enhance the healing effect of widely expanded skin autografts. 10.1097/SAP.0000000000001058
    Human mesenchymal stem cells-conditioned medium improves diabetic wound healing mainly through modulating fibroblast behaviors. Saheli Mona,Bayat Mohammad,Ganji Rasoul,Hendudari Farzane,Kheirjou Raziyeh,Pakzad Mohammad,Najar Baran,Piryaei Abbas Archives of dermatological research Fibroblast plays a key role in wound healing, and the advantages of mesenchymal stem cells (MSC) secretome in wound healing have previously been reported. In the present study, we investigated the impact of human bone marrow MSC-conditioned media (CM) on skin wound healing in diabetic rats and found that some improvements occurred mainly through fibroblast functions. Then, we scrutinized the impact of MSC-CM treatment on fibroblast cellular behavior by culturing human dermal fibroblasts (HDFs) in a high-glucose (HG) medium, as an in vitro diabetic model. In vivo findings revealed significant improvements in some healing kinetics of diabetic wound which received MSC-CM. Particularly, MSC-CM-treated diabetic wounds reached considerably higher percentages of wound closure. Also, the granulation tissue of these wound had less pronounced inflammatory response, better tissue remodeling, and more vascularization compared with non-treated diabetic ones. Gene expression analyses indicated that MSC-CM treatment leads to upregulation of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) genes. In addition, a significantly higher cell viability/proliferation, migration, and bFGF gene expression were observed when MSC-CM was used to treat HDFs in HG culture media. Based on these findings, it is suggested that MSC-CM could promote wound repair and skin regeneration, in some major processes, via improvement of cellular behaviors of fibroblasts in the diabetic microenvironment. The beneficial advantages of mesenchymal stem cells-conditioned media on fibroblast cellular behaviors and wound healing may lead to establish a novel approach as an alternative therapeutic procedure to cure chronic wounds in diabetic conditions. 10.1007/s00403-019-02016-6
    A hypoxia response element in the Vegfa promoter is required for basal Vegfa expression in skin and for optimal granulation tissue formation during wound healing in mice. Ciarlillo Domenic,Celeste Christophe,Carmeliet Peter,Boerboom Derek,Theoret Christine PloS one Hypoxia in skin wounds is thought to contribute to healing through the induction of hypoxia inducible factor-1 (HIF-1). Although HIF-1 can regulate the expression of vascular endothelial growth factor A (Vegfa), whether hypoxia and HIF-1 are required to induce Vegfa expression in the context of wound healing is unknown. To test this hypothesis, we evaluated Vegfa expression and wound healing in mutant mice that lack a functional HIF-1 binding site in the Vegfa promoter. Full-thickness excisional wounds were made using a biopsy punch, left to heal by second intention, and granulation tissue isolated on a time course during healing. mRNA levels of Vegfa and its target genes platelet-derived growth factors B (Pdgfb) and stromal cell-derived factor-1 (Sdf1) were measured by RT-qPCR, and HIF-1alpha and VEGFA protein levels measured by immunoblotting. Lower levels of Vegfa, Pdgf1 and Sdf1 mRNA were found in intact skin of mutant mice relative to wild-type controls (n = 6 mice/genotype), whereas levels in granulation tissue during wound healing were unaltered. VEGFA protein levels were also lower in intact skin of the mutant versus the wild-type mice. Decreased Vegfa mRNA levels in skin of mutant mice could not be attributed to decreased HIF-1alpha protein expression, and were therefore a consequence of the loss of HIF-1 responsiveness of the Vegfa promoter. Comparative histologic analyses of healing wounds in mutant and wild-type mice (n = 8 mice/genotype) revealed significant defects in granulation tissue in the mutant mice, both in terms of quantity and capillary density, although epithelialization and healing rates were unaltered. We conclude that HIF-1 is not a major regulator of Vegfa expression during wound healing; rather, it serves to maintain basal levels of expression of Vegfa and its target genes in intact skin, which are required for optimal granulation tissue formation in response to wounding. 10.1371/journal.pone.0180586
    Hydrocellular foam dressings promote wound healing associated with decrease in inflammation in rat periwound skin and granulation tissue, compared with hydrocolloid dressings. Yamane Takumi,Nakagami Gojiro,Yoshino Sawako,Shimura Mari,Kitamura Aya,Kobayashi-Hattori Kazuo,Oishi Yuichi,Nishijima Yoshimi,Minematsu Takeo,Sanada Hiromi Bioscience, biotechnology, and biochemistry The effects of modern dressings on inflammation, which represent the earliest phase of wound healing, are poorly understood. We investigated the effects of modern hydrocellular foam dressings (HCFs) on wound healing and on the gene expression levels of the inflammatory markers--interleukin (IL)-1β, IL-6, and IL-10--in rat periwound skin and granulation tissue by quantitative reverse transcription-polymerase chain reaction. HCF absorbed significantly higher volume of water than hydrocolloid dressing (HCD) and increased the contraction of wounds. Polymorphonuclear neutrophils were massively infiltrated to the wound edge and boarded between granulation and dermis in the HCD group. IL-1β, IL-6, and IL-10 mRNA levels were significantly decreased in the periwound skin around the wounds and granulation tissue covered with HCF. These findings suggest that HCF may promote wound healing along with decrease in inflammation by reducing gene expression levels of IL-1β, IL-6, and IL-10. 10.1080/09168451.2014.968088
    A Novel Composite Biomaterial Made of Jellyfish and Porcine Collagens Accelerates Dermal Wound Healing by Enhancing Reepithelization and Granulation Tissue Formation in Mice. Sumiyoshi Hideaki,Nakao Sachie,Endo Hitoshi,Yanagawa Takayo,Nakano Yasuhiro,Okamura Yosuke,Kawaguchi Akira T,Inagaki Yutaka Advances in wound care Impaired dermal wound healing represents a major medical issue in today's aging populations. Granulation tissue formation in the dermis and reepithelization of the epidermis are both important and necessary for proper wound healing. Although a number of artificial dermal grafts have been used to treat full-thickness dermal loss in humans, they do not induce reepithelization of the wound, requiring subsequent epithelial transplantation. In the present study, we sought a novel biomaterial that accelerates the wound healing process. We prepared a composite biomaterial made of jellyfish and porcine collagens and developed a hybrid-type dermal graft that composed of the upper layer film and the lower layer sponge made of this composite biomaterial. Its effect on dermal wound healing was examined using a full-thickness excisional wound model. Structural properties of the dermal graft and histological features of the regenerating skin tissue were characterized by electron microscopic observation and immunohistological examination, respectively. The composite biomaterial film stimulated migration of keratinocytes, leading to prompt reepithelization. The regenerating epithelium consisted of two distinct cell populations: keratin 5-positive basal keratinocytes and more differentiated cells expressing tight junction proteins such as claudin-1 and occludin. At the same time, the sponge made of the composite biomaterial possessed a significantly enlarged intrinsic space and enhanced infiltration of inflammatory cells and fibroblasts, accelerating granulation tissue formation. This newly developed composite biomaterial may serve as a dermal graft that accelerates wound healing in various pathological conditions. We have developed a novel dermal graft composed of jellyfish and porcine collagens that remarkably accelerates the wound healing process. 10.1089/wound.2019.1014
    Fibroblast growth factor 2 dimer with superagonist in vitro activity improves granulation tissue formation during wound healing. Decker Caitlin G,Wang Yu,Paluck Samantha J,Shen Lu,Loo Joseph A,Levine Alex J,Miller Lloyd S,Maynard Heather D Biomaterials Site-specific chemical dimerization of fibroblast growth factor 2 (FGF2) with the optimal linker length resulted in a FGF2 homodimer with improved granulation tissue formation and blood vessel formation at exceptionally low concentrations. Homodimers of FGF2 were synthesized through site-specific linkages to both ends of different molecular weight poly(ethylene glycols) (PEGs). The optimal linker length was determined by screening dimer-induced metabolic activity of human dermal fibroblasts and found to be that closest to the inter-cysteine distance, 70 Å, corresponding to 2 kDa PEG. A straightforward analysis of the kinetics of second ligand binding as a function of tether length showed that, as the polymerization index (the number of monomer repeat units in the polymer, N) of the tether decreases, the mean time for second ligand capture decreases as ∼N(3/2), leading to an enhancement of the number of doubly bound ligands in steady-state for a given (tethered) ligand concentration. FGF2-PEG2k-FGF2 induced greater fibroblast metabolic activity than FGF2 alone, all other dimers, and all monoconjugates, at each concentration tested, with the greatest difference observed at low (0.1 ng/mL) concentration. FGF2-PEG2k-FGF2 further exhibited superior activity compared to FGF2 for both metabolic activity and migration in human umbilical vein endothelial cells, as well as improved angiogenesis in a coculture model in vitro. Efficacy in an in vivo wound healing model was assessed in diabetic mice. FGF2-PEG2k-FGF2 increased granulation tissue and blood vessel density in the wound bed compared to FGF2. The results suggest that this rationally designed construct may be useful for improving the fibroblast matrix formation and angiogenesis in chronic wound healing. 10.1016/j.biomaterials.2015.12.003
    Vascular endothelial growth factor receptor 1 (VEGFR1) tyrosine kinase signaling facilitates granulation tissue formation with recruitment of VEGFR1 cells from bone marrow. Park Keiichi,Amano Hideki,Ito Yoshiya,Mastui Yoshio,Kamata Mariko,Yamazaki Yasuharu,Takeda Akira,Shibuya Masabumi,Majima Masataka Anatomical science international Vascular endothelial growth factor (VEGF)-A facilitates wound healing. VEGF-A binds to VEGF receptor 1 (VEGFR1) and VEGFR2 and induces wound healing through the receptor's tyrosine kinase (TK) domain. During blood flow recovery and lung regeneration, expression of VEGFR1 is elevated. However, the precise mechanism of wound healing, especially granulation formation on VEGFR1, is not well understood. We hypothesized that VEGFR1-TK signaling induces wound healing by promoting granulation tissue formation. A surgical sponge implantation model was made by implanting a sponge disk into dorsal subcutaneous tissue of mice. Granulation formation was estimated from the weight of the sponge and the granulation area from the immunohistochemical analysis of collagen I. The expression of fibroblast markers was estimated from the expression of transforming growth factor-beta (TGF-β) and cellular fibroblast growth factor-2 (FGF-2) using real-time PCR (polymerase chain reaction) and from the immunohistochemical analysis of S100A4. VEGFR1 TK knockout (TK) mice exhibited suppressed granulation tissue formation compared to that in wild-type (WT) mice. Expression of FGF-2, TGF-β, and VEGF-A was significantly suppressed in VEGFR1 TK mice, and the accumulation of VEGFR1 cells in granulation tissue was reduced in VEGFR1 TK mice compared to that in WT mice. The numbers of VEGFR1 cells and S100A4 cells derived from bone marrow (BM) were higher in WT mice transplanted with green fluorescent protein (GFP) transgenic WT BM than in VEGFR1 TK mice transplanted with GFP transgenic VEGFR1 TK BM. These results indicated that VEGFR1-TK signaling induced the accumulation of BM-derived VEGFR1 cells expressing F4/80 and S100A4 and contributed to granulation formation around the surgically implanted sponge area in a mouse model. 10.1007/s12565-017-0424-8
    Transgenic mice overexpressing CD109 in the epidermis display decreased inflammation and granulation tissue and improved collagen architecture during wound healing. Vorstenbosch Joshua,Gallant-Behm Corrie,Trzeciak Alissa,Roy Stéphane,Mustoe Thomas,Philip Anie Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society Transforming growth factor-β (TGF-β) is a multifunctional growth factor involved in all aspects of wound healing. TGF-β accelerates wound healing, but an excess of its presence at the wound site has been implicated in pathological scar formation. Our group has recently identified CD109, a glycophosphatidylinositol-anchored protein, as a novel TGF-β coreceptor and inhibitor of TGF-β signaling in vitro. To determine the effects of CD109 in vivo on wound healing, we generated transgenic mice overexpressing CD109 in the epidermis. In excisional wounds, we show that CD109 transgenic mice display markedly reduced macrophage and neutrophil recruitment, granulation tissue area, and decreased Smad2 and Smad3 phosphorylation, whereas wound closure remains unaffected as compared with wild-type littermates. Futhermore, we demonstrate that the expression of the proinflammatory cytokines interleukin-1α and monocyte chemoattractant protein-1, and extracellular matrix components is markedly decreased during wound healing in CD109 transgenic mice. In incisional wounds, CD109 transgenic mice show improved dermal architecture, whereas the tensile strength of the wound remains unchanged. Taken together, our findings demonstrate that CD109 overexpression in the epidermis reduces inflammation and granulation tissue area and improves collagen organization in vivo. 10.1111/wrr.12023
    Moxibustion Promotes Formation of Granulation in Wound Healing Process through Induction of Transforming Growth Factor-β in Rats. Kawanami Hiroshi,Kawahata Hirohisa,Mori Hiroko-Miyuki,Aoki Motokuni Chinese journal of integrative medicine OBJECTIVE:To examine the effect of moxibustion on the wound healing process and its mechanism using a rat wound model. METHODS:Sixty male Sprague-Dawley rats were randomly divided into a sham-treated group (n=30, wound surgery only) and a moxibustion group (n=30, wound treated with moxibustion). Circular full-thickness skin wounds were produced in rats. Moxibustion was applied to the edge of wound and was continued on alternating days till 14 days after surgery, followed by measurement of wound size. Expression of collagens, prolyl-4-hydroxylase (P4H) and transforming growth factor-β (TGF-β) were evaluated by histochemical study and real-time polymerase chain reaction. RESULTS:The size of the wound lesion was significantly reduced in rats treated with moxibustion as compared to that in sham-treated rats at 4-10 days after wounding (P<0.01). Moxibustion stimulated mRNA expression of collagens at 4 days (P<0.01), but not at 7 days, accompanied by enhanced proliferation of P4H-positive fibroblasts. Of importance, expression of TGF-β in tissue from the wound lesion treated with moxibustion was significantly increased as compared to that in sham-treated rats at 4 days (P<0.01 or P<0.05), but not at 7 days. CONCLUSIONS:The treatment with moxibustion promoted the wound healing process in the early phase through proliferation of fibroblasts and rapid formation of granulation, possibly mediated by induction of TGF-β which is a key molecule in the physiological process of wound healing. Moxibustion can be expected to be effective as complementary treatment for intractable ulcers. 10.1007/s11655-019-3083-x
    [Effects of arnebia root oil on wound healing of rats with full-thickness skin defect and the related mechanism]. Shen J Y,Ma Q,Yang Z B,Gong J J,Wu Y S Zhonghua shao shang za zhi = Zhonghua shaoshang zazhi = Chinese journal of burns To observe the effects of arnebia root oil on wound healing of rats with full-thickness skin defect, and to explore the related mechanism. Eighty SD rats were divided into arnebia root oil group and control group according to the random number table, with 40 rats in each group, then full-thickness skin wounds with area of 3 cm×3 cm were inflicted on the back of each rat. Wounds of rats in arnebia root oil group and control group were treated with sterile medical gauze and bandage package infiltrated with arnebia root oil gauze or Vaseline gauze, respectively, with dressing change of once every two days. On post injury day (PID) 3, 7, 14, and 21, 10 rats in each group were sacrificed respectively for general observation and calculation of wound healing rate. The tissue samples of unhealed wound were collected for observation of histomorphological change with HE staining, observation of expressions of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) with immunohistochemical staining, and determination of mRNA expressions of VEGF and bFGF with real time fluorescent quantitive reverse transcription polymerase chain reaction. Data were processed with analysis of variance of factorial design, test, and Bonferroni correction. (1) On PID 3, there were a few secretions in wounds of rats in the two groups. On PID 7, there were fewer secretions and more granulation tissue in wounds of rats in arnebia root oil group, while there were more secretions and less granulation tissue in wounds of rats in control group. On PID 14, most of the wounds of rats in arnebia root oil group were healed and there was much red granulation tissue in unhealed wounds, while part of wounds of rats in control group was healed and there were a few secretions and less granulation tissue in unhealed wounds. On PID 21, wounds of rats in arnebia root oil group were basically healed, while there were still some unhealed wounds of rats in control group. (2) On PID 3 and 7, the wound healing rates of rats in arnebia root oil group were (39±5)% and (46±4)% respectively, which were close to (34±3)% and (44±4)% of rats in control group (with values respectively 0.807 and 0.481, values above 0.05). On PID 14 and 21, the wound healing rates of rats in arnebia root oil group were (76±4)% and (90±3)% respectively, which were significantly higher than (60±6)% and (73±5)% of rats in control group (with values respectively 2.308 and 3.072, <0.05 or <0.01). (3) On PID 3, 7, and 14, granulation tissue, fibroblasts, and nascent capillaries in unhealed wound tissue of rats in the two groups both gradually increased, and more ranulation tissue, fibroblasts, and nascent capillaries were seen in unhealed wound tissue of rats in arnebia root oil group. On PID 21, granulation tissue, fibroblasts, and nascent capillaries in unhealed wound tissue of rats in the two groups both gradually decreased. (4) On PID 3, 7, and 14, the numbers of VEGF positive cells and bFGF positive cells in unhealed wound tissue of rats in the two groups both gradually increased; there were more VEGF positive cells and bFGF positive cells in unhealed wound tissue of rats in arnebia root oil group than those in control group. On PID 21, positive expressions of VEGF and bFGF both decreased in unhealed wound tissue of rats in the two groups. (5) On PID 3, 7, and 14, mRNA expressions of VEGF in unhealed wound tissue of rats in arnebia root oil group were higher than those of control group (with values from 2.967 to 4.173, values below 0.01). On PID 21, mRNA expression of VEGF in unhealed wound tissue of rats in arnebia root oil group was lower than that of control group (=-4.786, <0.001). From PID 3 to 21, mRNA expressions of bFGF in unhealed wound tissue of rats in arnebia root oil group were higher than those of control group (with values from 2.326 to 4.702, <0.05 or <0.01). Arnebia root oil can promote wound healing of rats with full-thickness skin defect, which may relate to increasing expressions of VEGF and bFGF. 10.3760/cma.j.issn.1009-2587.2017.09.008
    A systematic review of Calendula officinalis extract for wound healing. Givol Or,Kornhaber Rachel,Visentin Denis,Cleary Michelle,Haik Josef,Harats Moti Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society Use of complementary and alternative medicine for wound healing is influencing mainstream medical practice. This systematic review evaluates the role of Calendula officinalis flower extract as monotherapy compared to control for wound healing in vivo. Searches were conducted in PubMed, EMBASE, Cochrane Central Register of Controlled Trials, CINAHL, and Scopus (up to April 2018) with 14 studies meeting the inclusion criteria, comprising 7 animal experiments and 7 clinical trials. Findings from the review on acute wound healing showed faster resolution of the inflammation phase with increased production of granulation tissue in the test groups treated with extract. These findings were consistent in five animal studies and one randomized clinical trial. Chronic wound healing studies were varied. Two clinical control studies on venous ulcers demonstrated decreased ulcer surface area compared to controls. Another randomized clinical trial demonstrated no improvement for the calendula group in diabetic leg ulcer healing. Burn healing similarly showed mixed results. Two animal studies demonstrated a prophylactic effect for the administration of calendula extract prior to burn injury. A randomized clinical trial of patients suffering from partial to full thickness burns demonstrated no benefit for topical application of calendula extract compared to controls. Two randomized clinical trials assessed the potential for extract to prevent acute post radiation dermatitis, with one study showing improvements compared to trolamine, while the other found no improvement compared to aqua gel cream. Animal studies provide moderate evidence for improved recovery from the inflammation phase and increased production of granulation tissue in calendula extract treatment groups. This review identified some evidence for the beneficial effects of C. officinalis extract for wound healing, consistent with its role in traditional medicine. There is a need for larger, well-designed randomized control trials to assess the effect of calendula on wound healing including complications. 10.1111/wrr.12737
    Root extractive from benefits in wound healing of anal fistula through up-regulation of collagen genes in human skin fibroblasts. Yang Dong,Xu Jun-Hua,Shi Ren-Jie Bioscience reports Wound healing is the main problem in the therapy of anal fistula (AF). root has been traditionally used as an agent to soak sutures in operation of AF patients, but its function in wound healing remains largely unclear. The aim of the present study was to illuminate mechanisms of root treatment on AF. In the present study, 60 AF patients after surgery were randomly divided into two groups, external applied with or without the extractive. Wound healing times were compared and granulation tissues were collected. , we constructed damaged human skin fibroblasts (HSFs) with the treatment of (10 μg/ml). Cell Count Kit-8 (CCK-8) and flow cytometry analysis were used to determine the effects of root extractive on cell viability, cell cycle and apoptosis of damaged HSFs. Furthermore, protein levels of , matrix metalloproteinase (MMP)-3 () and signalling pathways were investigated both and Results showed that root extractive greatly shortens the wound healing time in AF patients. In granulation tissues and HSFs, treatment with the extractive significantly elevated the expressions of and , while reduced the expression of Further detection presented that signalling was activated after the stimulation of extractive in HSFs. Our study demonstrated that extractive from root could effectively improve wound healing in patients with AF via the up-regulation of fibroblast proliferation and expressions of and . 10.1042/BSR20170182