Combination of Adrenomedullin with Its Binding Protein Accelerates Cutaneous Wound Healing

Idrovo, Juan Pablo; Yang, Weng Lang; Jacob, Asha; Ajakaiye, Michael A.; Cheyuo, Cletus; Wang, Zhimin; Prince, José M.; Nicastro, Jeffrey; Coppa, Gene F.; Wang, Ping

doi:10.1371/journal.pone.0120225

Cited by 19 publications

(10 citation statements)

References 43 publications

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“…Acute cutaneous wounds caused by trauma can become chronic non-healing wounds in patients with diabetes mellitus 21. Although numerous therapeutic attempts have been made to accelerate the healing process of diabetic wounds, the optimal treatment strategies are still being developed.…”

Section: Discussionmentioning

confidence: 99%

Exosomes Derived from Human Endothelial Progenitor Cells Accelerate Cutaneous Wound Healing by Promoting Angiogenesis Through Erk1/2 Signaling

Zhang¹,

Chen²,

Hu³

et al. 2016

Int. J. Biol. Sci.

219

187

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Chronic skin wounds represent one of the most common and disabling complications of diabetes. Endothelial progenitor cells (EPCs) are precursors of endothelial cells and can enhance diabetic wound repair by facilitating neovascularization. Recent studies indicate that the transplanted cells exert therapeutic effects primarily via a paracrine mechanism and exosomes are an important paracrine factor that can be directly used as therapeutic agents for regenerative medicine. However, application of exosomes in diabetic wound repair has been rarely reported. In this study, we demonstrated that the exosomes derived from human umbilical cord blood-derived EPCs (EPC-Exos) possessed robust pro-angiogenic and wound healing effects in streptozotocin-induced diabetic rats. By using a series of in vitro functional assays, we found that EPC-Exos could be incorporated into endothelial cells and significantly enhance endothelial cells' proliferation, migration, and angiogenic tubule formation. Moreover, microarray analyses indicated that exosomes treatment markedly altered the expression of a class of genes involved in Erk1/2 signaling pathway. It was further confirmed with functional study that this signaling process was the critical mediator during the exosomes-induced angiogenic responses of endothelial cells. Therefore, EPC-Exos are able to stimulate angiogenic activities of endothelial cells by activating Erk1/2 signaling, which finally facilitates cutaneous wound repair and regeneration.

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Section: Discussionmentioning

confidence: 99%

Exosomes Derived from Human Endothelial Progenitor Cells Accelerate Cutaneous Wound Healing by Promoting Angiogenesis Through Erk1/2 Signaling

Zhang¹,

Chen²,

Hu³

et al. 2016

Int. J. Biol. Sci.

219

187

View full text Add to dashboard Cite

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“…The wound area was traced on a transparency film every other day until day 14 and wound closure was calculated using NIH ImageJ software. The wound closure rate was calculated according to the following formula as described previously (17): wound closure rate (%) = [(Area day 0 -Area day n )/Area day 0 ] x100; where Area day 0 is the initial wound area on day 0 and the Area day n is the area on day 'n' after wounding.…”

Section: Methodsmentioning

confidence: 99%

“…Total RNA was extracted from the skin tissues using TRIzol reagent (Invitrogen, Carlsbad, CA, USA) and reverse transcribed into cDNA and subjected to RT-qPCR using the ∆∆Cq method with primers specific for mouse TNF-α. The PCR reaction was carried out as described previously (17). The levels were normalized against those of mouse β-actin.…”

Section: Methodsmentioning

confidence: 99%

A deficiency in cold-inducible RNA-binding protein accelerates the inflammation phase and improves wound healing

Idrovo

Jacob

Yang

et al. 2016

International Journal of Molecular Medicine

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Chronic or non-healing wounds are a major concern in clinical practice and these wounds are mostly associated with diabetes, and venous and pressure ulcers. Wound healing is a complex process involving overlapping phases and the primary phase in this complex cascade is the inflammatory state. While inflammation is necessary for wound healing, a prolonged inflammatory phase leads to impaired healing. Cold-inducible RNA-binding protein (CIRP) belongs to a family of cold-shock proteins that are expressed in high levels under stress conditions. Recently, we demonstrated that a deficiency in CIRP led to decreased inflammation and mortality in an experimental model of hemorrhagic shock. Thus, we hypothesized that a deficiency in CIRP would accelerate the inflammatory phase and lead to an improvement in cutaneous wound healing. In this study, to examine this hypothesis, a full-thickness wound was created on the dorsum of wild-type (WT) and CIRP-/- mice. The wound size was measured every other day for 14 days. The wound area was significantly decreased in the CIRP-/- mice by day 9 and continued to decrease until day 14 compared to the WT mice. In a separate cohort, mice were sacrificed on days 3 and 7 after wounding and the skin tissues were harvested for histological analysis and RNA measurements. On day 3, the mRNA expression of tumor necrossis factor (TNF)-α in the skin tissues was increased by 16-fold in the WT mice, whereas these levels were increased by 65-fold in the CIRP-/- mice. Of note on day 7, while the levels of TNF-α remained high in the WT mice, these levels were significantly decreased in the CIRP-/- mice. The histological analysis of the wounded skin tissue indicated an improvement as early as day 3 in the CIRP-/- mice, whereas in the WT mice, infiltrated immune cells were still present on day 7. On day 7 in the CIRP-/- mice, Gr-1 expression was low and CD31 expression was high, whereas in the WT mice, Gr-1 expression was high and CD31 expression was low, indicating that the CIRP-/- mice have already moved into the angiogenesis and tissue formation phase, whereas the WT mice were still in the inflammatory state. These data collectively suggest that a deficiency in CIRP accelerates the wound healing process.

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“…Adrenomedullin topically delivered in a sustained-release ointment formation significantly improved wound closure in pressure ulcer patients through acceleration of granulation tissue formation and enhanced neovascularization (Harada et al, 2011). In addition, when used in a combination treatment with its binding protein adrenomedullin also promoted faster wound repair in a rat model of cutaneous healing (Idrovo et al, 2015). Endothelial cell-specific endothelin-1 knockout mice exhibited faster wound healing rates and attenuated fibrosis (Makino et al, 2014) and the role of endothelin-1 in promoting fibrosis is well documented (Rodriguez-Pascual et al, 2014).…”

Section: Alpha-melanocyte-stimulating Hormone (A-msh)mentioning

confidence: 99%

Autonomic nerve dysfunction and impaired diabetic wound healing: The role of neuropeptides

Theocharidis

Veves

2020

Autonomic Neuroscience

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Lower extremity ulcerations represent a major complication in diabetes mellitus and involve multiple physiological factors that lead to impairment of wound healing. Neuropeptides are neuromodulators implicated in various processes including diabetic wound healing. Diabetes causes autonomic and small sensory nerve fibers neuropathy as well as inflammatory dysregulation, which manifest with decreased neuropeptide expression and a disproportion in pro-and anti-inflammatory cytokine response. Therefore to fully understand the contribution of autonomic nerve dysfunction in diabetic wound healing it is crucial to explore the implication of neuropeptides. Here, we will discuss recent studies elucidating the role of specific neuropeptides in wound healing.

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Combination of Adrenomedullin with Its Binding Protein Accelerates Cutaneous Wound Healing

Cited by 19 publications

References 43 publications

Exosomes Derived from Human Endothelial Progenitor Cells Accelerate Cutaneous Wound Healing by Promoting Angiogenesis Through Erk1/2 Signaling

Exosomes Derived from Human Endothelial Progenitor Cells Accelerate Cutaneous Wound Healing by Promoting Angiogenesis Through Erk1/2 Signaling

A deficiency in cold-inducible RNA-binding protein accelerates the inflammation phase and improves wound healing

Autonomic nerve dysfunction and impaired diabetic wound healing: The role of neuropeptides

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