Topical application of HA-g-TEMPO accelerates the acute wound healing via reducing reactive oxygen species (ROS) and promoting angiogenesis.

During the occurring of cutaneous trauma, increasing oxidative stress response in wound site retards the progress of proliferation phase, impeding sequent efficient wound repair. At the same time, high-quality healing also requires adequate new blood vessels in order to furnish the wound site with a nutrient and oxygen-sufficient environment. Here we synthesized a novel hyaluronic acid (HA) material modified with a peroxidation inhibitor 2,2,6,6-tetramethylpiperidinyloxy (ATEMPO) for prevention of excessive reactive oxygen species (ROS) and promotion of angiogenesis after full-thickness skin excision in rats. Amines in ATEMPO attaching with carbonyls in HA chains was fabricated through N-acylation. The HA-g-TEMPO exerted a ROS-scavenging and angiogenesis-promoting function in vitro. In acute wound rat model, the wound closure efficacy was significantly improved to almost 55% at day 6 in comparison to 49% of HA, and wound sites in initial wound phase was also narrowed down sharply. Moreover, initially formed blood vessels were found in wound sites, further proved the angiogenesis-promoting function of HA-g-TEMPO. More interestingly, wound sites demonstrated an exciting regenerative healing effect which was characterized by marked skin appendages as well as reduced scarring. Therefore, this strategy showed a promising future that could be considered as a reliable and effective method to cutaneous wound healing.

Co-delivery of deferoxamine and hydroxysafflor yellow A to accelerate diabetic wound healing via enhanced angiogenesis.

Nonhealing chronic wounds on foot induced by diabetes is a complicated pathologic process. They are mainly caused by impaired neovascularization, neuropathy, and excessive inflammation. A strategy, which can accelerate the vessel network formation as well as inhibit inflammatory response at the same time, makes it possible for effective diabetic ulcers treatment. Co-delivery of multiple drugs with complementary bioactivity offers a strategy to properly treat diabetic wound. We previously demonstrated that hydroxysafflor yellow A (HSYA) could accelerate diabetic wound healing through promoting angiogenesis and reducing inflammatory response. In order to further enhance blood vessel formation, a pro-angiogenic molecular called deferoxamine (DFO) was topically co-administrated with HSYA. The in vitro results showed that the combination of DFO and HSYA exerted synergistic effect on enhancing angiogenesis by upregulation of hypoxia inducible factor-1 alpha (HIF-1α) expression. The interpenetrating polymer networks hydrogels, characterized by good breathability and water absorption, were designed for co-loading of DFO and HSYA aiming to recruit angiogenesis relative cells and upgrade wound healing in vivo. Both DFO and HSYA in hydrogel have achieved sustained release. The in vivo studies indicated that HSYA/DFO hydrogel could accelerate diabetic wound healing. With a high expression of Hif-1α which is similar to that of normal tissue. The noninvasive US/PA imaging revealed that the wound could be recovered completely with abundant blood perfusion in dermis after given HSYA/DFO hydrogel for 28 days. In conclusion, combination of pro-angiogenic small molecule DFO and HSYA in hydrogel provides a promising strategy to productively promote diabetic wound healing as well as better the repair quality.

Topical application of Hydroxysafflor Yellow A accelerates the wound healing in streptozotocin induced T1DM rats.

To investigate the effects of Hydroxysafflor Yellow A (HSYA), which is derived from safflower, on the proliferation, migration and angiogenesis of cells in vitro and its potential efficacy in vivo when topically applied to a diabetic wound. Human umbilical vein endothelial cells (HUVECs) and mouse macrophage cells (RAW264.7) were used to evaluate angiogenesis and anti-inflammatory activities, respectively. The influence of HSYA on the wound scratch assay was investigated in keratinocytes. A splinted excisional wound model in rats with TIDM induced by streptozotocin was used to assess the effects of wound healing. Collagen disposition and secretion of vascular growth factors (VEGF) as well as transforming growth factor-ß1 (TGF-ß1) were evaluated by an ELISA assay and histological staining. The in vitro results showed that HSYA could significantly enhance both the neovascularization of HUVECs and the migration of keratinocytes. It showed the significant inhibitory effect on nitric oxide production, indicating the anti-inflammatory activity of HSYA. In vivo, the topical application of HSYA significantly enhanced the wound closure rate, and the time to complete wound closure was 17 days, whereas 30 days were needed with PBS treatment. Further, treatment with HSYA exhibited significant granulation tissue formation with higher collagen content, re-epithelialization and angiogenesis according to Masson's trichrome staining evaluation, VEGE and TGF-ß1 ELISA measurement. In conclusion, HSYA application could be considered a promising therapeutic strategy for treating chronic non-healing diabetic foot ulcers.

Evidence based anti-osteoporosis effects of Periplaneta americana L on osteoblasts, osteoclasts, vascular endothelial cells and bone marrow derived mesenchymal stem cells.

BACKGROUND: Kangfuxin (KFX) is the ethanol extract of Periplaneta americana L, which has been widely used in the Traditional Chinese Medicine for the repair and regeneration of injured organ and tissues with long history. This study is to investigate the influence of KFX in the various cellular activities and evaluate the anti-osteoporosis potential of KFX. METHODS: The influence of the KFX in the cellular activities, including: 1) migration, osteocalcin secretion of osteoblasts; 2) apoptosis of osteoclasts; 3) migration and tube formation of human umbilical vein endothelial cell (HUVEC); and 4) proliferation, cell cycle regulation and migration of bone marrow mesenchymal stem cells (BMSCs), were investigated systematically. RESULTS: KFX was shown to significantly 1) Promote of the migration of osteoblasts, HUVEC, and BMSCs; 2) Increase the secretion of osteocalcin and mineralization of osteoblasts; 3) Accelerate the apoptosis of osteoclasts; 4) Stimulate the proliferation and regulate the cell cycle of BMSCs. CONCLUSION: Taken together, these results provide the evidence for the osteogenesis, anti-osteoporosis and angiogenesis effects of KFX, with the mechanism of activating the bone formation through stimulating the osteoblasts and HUVECs, as well as inhibiting the bone absorption by inhibiting the osteoclasts activities. The KFX was definitely shown a promising bone turnover agent with great potential for anti-osteoporosis treatment.

Capsaicin-loaded nanolipoidal carriers for topical application: design, characterization, and in vitro/in vivo evaluation.

Capsaicin has been used in clinical applications for the treatment of pain disorders and inflammatory diseases. Given the strong pungency and high oil/water partition coefficient of capsaicin, capsaicin-loaded nanolipoidal carriers (NLCs) were designed to increase permeation and achieve the analgesic, anti-inflammatory effect with lower skin irritation. Capsaicin-loaded NLCs were prepared and later optimized by the Box-Behnken design. The physicochemical characterizations, morphology, and encapsulation of the capsaicin-loaded NLCs were subsequently confirmed. Capsaicin-loaded NLCs and capsaicin-loaded NLCs gel exhibited sustained release and no cytotoxicity properties. Also, they could significantly enhance the penetration amount, permeation flux, and skin retention amounts of capsaicin due to the application of NLCs. To study the topical permeation mechanism of capsaicin, 3,3'-dioctadecyloxacarbocyanine perchlorate (Dio) was used as a fluorescent dye. Dio-loaded NLCs and Dio-loaded NLCs gel could effectively deliver Dio up to a skin depth of 260 and 210 µm, respectively, primarily through the appendage route on the basis of version skin sections compared with Dio solution, which only delivered Dio up to 150 µm. In vivo therapeutic experiments demonstrated that capsaicin-loaded NLCs and capsaicin-loaded NLCs gel could improve the pain threshold in a dose-dependent manner and inhibit inflammation, primarily by reducing the prostaglandin E2 levels in the tissue compared with capsaicin cream and capsaicin solution. Meanwhile, skin irritation was reduced, indicating that application of NLCs could decrease the irritation caused by capsaicin. Overall, NLCs may be a potential carrier for topical delivery of capsaicin for useful pain and inflammation therapy.

[Research progress on the animal models and treatment strategies of diabetic foot ulcer].

The suitable experimental animal model is important in research of pathogenesis and therapeutic strategies of diabetic foot ulcer, and the murine model is the most commonly used one at present. It can be divided into two types: the animal model simulating pathological conditions and the model simulating clinical symptoms. This article reviews the current research progress on the mechanisms of diabetic ulcer pathogenesis, and relevant treatment strategies, including the inhibition of matrix metalloproteinases (MMPs) expression, promotion of angiogenesis and anti-inflammatory therapy.