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Skin wound healing is a critical and complex biological process after trauma. This process is activated by signaling pathways of both epithelial and nonepithelial cells, which release a myriad of different cytokines and growth factors. Hepatocyte growth factor (HGF) is a cytokine known to play multiple roles during the various stages of wound healing. This study evaluated the benefits of HGF on reepithelialization during wound healing and investigated its mechanisms of action. Gross and histological results showed that HGF significantly accelerated reepithelialization in diabetic (DB) rats. HGF increased the expressions of the cell adhesion molecules ß1-integrin and the cytoskeleton remodeling protein integrin-linked kinase (ILK) in epidermal cells in vivo and in vitro. Silencing of ILK gene expression by RNA interference reduced expression of ß1-integrin, ILK, and c-met in epidermal cells, concomitantly decreasing the proliferation and migration ability of epidermal cells. ß1-Integrin can be an important maker of poorly differentiated epidermal cells. Therefore, these data demonstrate that epidermal cells become poorly differentiated state and regained some characteristics of epidermal stem cells under the role of HGF after wound. Taken together, the results provide evidence that HGF can accelerate reepithelialization in skin wound healing by dedifferentiation of epidermal cells in a manner related to the ß1-integrin/ILK pathway. [ABSTRACT FROM AUTHOR]

In this study, the toxicity effects on circulatory system and respiratory system, and the acute toxicity test of recombinant neorudin (EPR-hirudin, EH) in cynomolgus monkeys were evaluated to provide reference information for clinical studies. Eighteen cynomolgus monkeys were randomly divided into three groups for single intravenous administration of 3, 30 mg/kg EH and normal saline, respectively. The changes of respiratory frequency, respiratory intensity, blood pressure and electrocardiogram before and after administration were recorded. In acute toxicity test, six cynomolgus monkeys were intravenously received EH at a single dose of 171, 257, 385, 578, 867 and 1300 mg/kg respectively. The vital signs, hematology, serum biochemistry, coagulation indexes and electrocardiogram indexes of the animals were determined before administration and on the 7th and 14th day after administration. As the results showed that there were no significant abnormal changes in respiratory frequency, respiratory intensity, blood pressure or electrocardiogram in cynomolgus monkeys after receiving EH at 3 mg/kg and 30 mg/kg, and there was no statistical difference between the treated groups and normal saline group. In the acute toxicity test, no significant abnormalities were observed in vital signs, hematology, serum biochemistry, coagulation indexes and electrocardiogram indexes of six cynomolgus monkeys at day 7 and 14 after EH administration. Furthermore, autopsies of all cynomolgus monkeys showed no abnormalities. The results of toxicokinetics showed that AUClast of the drug increased in proportion to the EH dose in the range of 171-578 mg/kg, and increased in over proportion to the EH dose in the range of 578-1300 mg/kg. The variation of Cmax was basically consistent with AUClast. In a sum, A single intravenous injection of 3 and 30 mg/kg of EH did not affect the circulatory system and respiratory system in cynomolgus monkeys and the maximum tolerated dose of EH in cynomolgus monkey is over 1300 mg/kg (equivalent to 619-1300 times of the proposed clinical equivalent dose).

Skin wound healing is a critical and complex biological process after trauma. This process is activated by signaling pathways of both epithelial and nonepithelial cells, which release a myriad of different cytokines and growth factors. Hepatocyte growth factor (HGF) is a cytokine known to play multiple roles during the various stages of wound healing. This study evaluated the benefits of HGF on reepithelialization during wound healing and investigated its mechanisms of action. Gross and histological results showed that HGF significantly accelerated reepithelialization in diabetic (DB) rats. HGF increased the expressions of the cell adhesion molecules β1-integrin and the cytoskeleton remodeling protein integrin-linked kinase (ILK) in epidermal cells in vivo and in vitro. Silencing of ILK gene expression by RNA interference reduced expression of β1-integrin, ILK, and c-met in epidermal cells, concomitantly decreasing the proliferation and migration ability of epidermal cells. β1-Integrin can be an important maker of poorly differentiated epidermal cells. Therefore, these data demonstrate that epidermal cells become poorly differentiated state and regained some characteristics of epidermal stem cells under the role of HGF after wound. Taken together, the results provide evidence that HGF can accelerate reepithelialization in skin wound healing by dedifferentiation of epidermal cells in a manner related to the β1-integrin/ILK pathway.

Aim: To investigate the role of hepatopoietin Cn (HPPCn) in apoptosis of hepatocellular carcinoma (HCC) cells and its mechanism., Methods: Two human HCC cell lines, SMMC7721 and HepG2, were used in this study. Immunostaining, Western blotting and enzyme linked immunosorbent assay were conducted to identify the expression of HPPCn and the existence of an autocrine loop of HPPCn/HPPCn receptor in SMMC7721 and HepG2. Apoptotic cells were detected using fluorescein isothiocyanate (FITC)-conjugated Annexin V and propidium iodide., Results: The HPPCn was highly expressed in human HCC cells and secreted into culture medium (CM). FITC-labeled recombinant human protein (rhHPPCn) could specifically bind to its receptor on HepaG2 cells. Treatment with 400 ng/mL rhHPPCn dramatically increased the viability of HCC-derived cells from 48.1% and 36.9% to 85.6% and 88.4%, respectively (P < 0.05). HPPCn silenced by small-interfering RNA reduced the expression and secretion of HPPCn and increased the apoptosis induced by trichostatin A. Additionally, HPPCn could up-regulate the expression of myeloid cell leukemia-1 (Mcl-1) in HCC cells via mitogen-activated protein kinase (MAPK) and sphingosine kinase-1., Conclusion: HPPCn is a novel hepatic growth factor that can be secreted to CM and suppresses apoptosis of HCC cells by up-regulating Mcl-1 expression.

Background: Adenovirus-mediated angiogenic growth factor gene transfer provides a new therapeutic strategy for treatment of coronary heart disease. Preclinical studies showed that direct intramyocardial injection of recombinant adenovirus with hepatocyte growth factor gene (Ad-HGF) was able to promote neovascularization, improve heart function and abate the area of ischemic myocardia in animal models. However, the safety and therapeutic effect of Ad-HGF were not evaluated in clinical trials., Patients and Methods: A open-label, safety and tolerance trial of Ad-HGF in 18 patients suffering from coronary heart disease was performed. Three groups, each with 6 patients, received 5x10(8) (low dosage), 1.5 x 10(9) (medium dosage) and 5x10(9) (high dosage) pfu of Ad-HGF/person respectively, by direct multipoint injection into the myocardium while accepting coronary artery bypass surgery. The changes of vital symptoms, blood and urea routine analyses, as well as myocardial perfusion before and after treatment were analyzed., Results: There was no evidence of systemic or cardiac-related adverse events after intramyocardial administration of the Ad-HGF. Myocardial perfusion of the Ad-HGF-injected area was improved in 3 cases of the low-dose group, 5 cases of the medium-dose group, and all of the high-dose group., Conclusion: These preliminary clinical data indicate that direct intramyocardial administration of Ad-HGF was well tolerated and could improve myocardial perfusion with a dose-effect relationship, encouraging larger and randomized efficacy trials.