rhFGF-21 accelerates corneal epithelial wound healing through the attenuation of oxidative stress and inflammatory mediators in diabetic mice.

Diabetic keratopathy, commonly associated with a hyperactive inflammatory response, is one of the most common eye complications of diabetes. The peptide hormone fibroblast growth factor-21 (FGF-21) has been demonstrated to have anti-inflammatory and antioxidant properties. However, whether administration of recombinant human (rh) FGF-21 can potentially regulate diabetic keratopathy is still unknown. Therefore, in this work, we investigated the role of rhFGF-21 in the modulation of corneal epithelial wound healing, the inflammation response, and oxidative stress using type 1 diabetic mice and high glucose-treated human corneal epithelial cells. Our experimental results indicated that the application of rhFGF-21 contributed to the enhancement of epithelial wound healing. This treatment also led to advancements in tear production and reduction in corneal edema. Moreover, there was a notable reduction in the levels of proinflammatory cytokines such as TNF-α, IL-6, IL-1ß, MCP-1, IFN-γ, MMP-2, and MMP-9 in both diabetic mouse corneal epithelium and human corneal epithelial cells treated with high glucose. Furthermore, we found rhFGF-21 treatment inhibited reactive oxygen species production and increased levels of anti-inflammatory molecules IL-10 and SOD-1, which suggests that FGF-21 has a protective role in diabetic corneal epithelial healing by increasing the antioxidant capacity and reducing the release of inflammatory mediators and matrix metalloproteinases. Therefore, we propose that administration of FGF-21 may represent a potential treatment for diabetic keratopathy.

KGF-2 and FGF-21 poloxamer 407 hydrogel coordinates inflammation and proliferation homeostasis to enhance wound repair of scalded skin in diabetic rats.

OBJECTIVE: The present study focused on the development of a poloxamer 407 thermosensitive hydrogel loaded with keratinocyte growth factor-2 (KGF-2) and fibroblast growth factor-21 (FGF-21) as a therapeutic biomaterial in a scald-wound model of type-2 diabetes in Goto-Kakizaki (GK) rats. RESEARCH DESIGN AND METHODS: In this study, a poloxamer 407 thermosensitive hydrogel loaded with KGF-2 and/or FGF-21 was prepared and its physical and biological properties were characterized. The repairing effects of this hydrogel were investigated in a scald-wound model of type-2 diabetes in GK rats. The wound healing rate, epithelialization, and formation of granulation tissue were examined, and biomarkers reflecting regulation of proliferation and inflammation were quantified by immunostaining and Western blotting. T tests and analyses of variance were used for statistical analysis via Graphpad Prism V.6.0. RESULTS: A 17.0% (w/w) poloxamer 407 combined with 1.0% (w/w) glycerol exhibited controlled release characteristics and a three-dimensional structure. A KGF-2/FGF-21 poloxamer hydrogel promoted cellular migration without apoptosis. This KGF-2/FGF-21 poloxamer hydrogel also accelerated wound healing of scalded skin in GK rats better than that of a KGF-2 or FGF-21 hydrogel alone due to accelerated epithelialization, formation of granulation tissue, collagen synthesis, and angiogenesis via inhibition of inflammatory responses and increased expression of alpha-smooth muscle actin (α-SMA), collagen III, pan-keratin, transforming growth factor-ß (TGF-ß), vascular endothelial growth factor (VEGF), and CD31. CONCLUSIONS: A KGF-2/FGF-21 poloxamer hydrogel accelerated wound healing of scalded skin in GK rats, which was attributed to a synergistic effect of KGF-2-mediated cellular proliferation and FGF-21-mediated inhibition of inflammatory responses. Taken together, our findings provide a novel and potentially important insight into improving wound healing in patients with diabetic ulcers.

Long-Term Toxicity Study of Topical Administration of a Highly-Stable rh-aFGF Carbomer 940 Hydrogel in a Rabbit Skin Wound Model.

We developed a highly stable recombinant human acidic fibroblast growth factor (rh-aFGF) carbomer 940 hydrogel for wound healing. This study aimed to reveal toxicity target organs and the toxicity dose-response in the long-term administration of rh-aFGF carbomer 940 hydrogel in a rabbit skin wound model. New Zealand rabbits were topically administrated rh-aFGF carbomer 940 hydrogel at a daily dose of 900 IU/cm2, 1,800 IU/cm2, and 3,600 IU/cm2 for 28 days. Lyophilized rh-aFGF agent was used as the positive control group. General behavior, serum chemistry, skin irritation, immunogenicity, immunotoxicity, and histopathology were analyzed at designated time points. Results revealed that food intake, body weight, body temperature, heart rate, and eye examinations were all normal, suggesting no obvious toxicity induced by the rh-aFGF hydrogel. Medium and high dose rh-aFGF hydrogel groups and the positive control group displayed increased cell numbers in the local lymph nodes near the site of administration, likely caused mesenteric lymph node follicular hyperplasia, and this observation was alleviated after 14 days of recovery. Immunogenicity studies demonstrated that the serum antibody titer against rh-aFGF increased with the duration and number of drug applications but were not neutralization antibodies. After administration stopped, antibody titer decreased and disappeared in some mice. In summary, the safe dose for long-term administration of rh-aFGF carbomer 940 hydrogel for persistently damaged skin was 900 IU/cm2, which is 10 times that of the proposed clinical dosing.

TGF-ß1 Promotes Hepatocellular Carcinoma Invasion and Metastasis via ERK Pathway-Mediated FGFR4 Expression.

BACKGROUND/AIMS: TGF-ß1 is beneficial during early liver disease but is tumor-progressive during late stages especially for hepatocellular carcinoma (HCC). Thus, exploring the underlying mechanisms may provide information about a potentially therapeutic role of TGF-ß1 in HCC. METHODS: Western blot and real-time quantitative PCR were used to quantify FGFR4 expression in HCC cell lines and a normal liver cell line. After constructing the best silencing FGFR4 expression vector, migration and invasiveness of TGF-ß1 in HCC was studied in vitro and in vivo. Western blot was used to study the mechanism of TGF-ß1 induction on FGFR4 expression with various inhibitors. RESULTS: HepG2 cell lines had the most FGFR4 expression, and data show that silencing FGFR4 suppressed cell proliferation, invasion and migration in HCC induced by TGF-ß1 in vitro and in vivo. Moreover, TGF-ß1 induced FGFR4 expression through the ERK pathway. CONCLUSION: Promoting FGFR4 expression via the ERK pathway, TGF-ß1 contributes to HCC invasion and metastasis.