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.

Progress on the application of growth factor-related drugs in ophthalmology.

Vascular endothelial growth factor（VEGF）, fibroblast growth factor（FGF）, nerve growth factor（NGF）, epidermal growth factor and interferon are important endogenous proteins that regulate cell proliferation, differentiation and regeneration. Biological products targeting growth factors are used in the treatment of ocular diseases such as wet age-related macular degeneration, corneal injury and neurotrophic keratitis. Anti-VEGF drugs can regulate the proliferation of vascular endothelia, reduce the edema and exudation of retinal tissue，which are the main therapeutic agents for wet age-related macular degeneration and diabetic retinopathy. The basic FGF (b-FGF) can promote the proliferation, differentiation, and migration of corneal epithelial cells, accelerating the healing of the corneal injury and reduces corneal inflammation；and bovine b-FGF has been approved for the treatment of corneal injuries. The NGF promotes the growth, development, and differentiation of central and peripheral neurons, thus accelerating the repair of nerve damage；and the European Medicines Agency approved the use of nerve growth factor for the treatment of neurotrophic keratitis in 2017. Recent clinical studies show that patients with moderate or severe neurotrophic keratitis achieved complete corneal healing following 8 weeks of NGF therapy. Epidermal growth factor derivative eye drops have been approved for the treatment of corneal epithelial injuries. Recombinant human interferon has been clinically used in the treatment of ocular viral infections. This article reviews the research progress in the development of new cell growth factor drugs for the treatment of ophthalmic diseases, to provide insights for expanding the application of cell growth factors in ophthalmology.

Roles of growth factors in eye development and ophthalmic diseases.

Growth factors are active substances secreted by a variety of cells, which act as messengers to regulate cell migration, proliferation and differentiation. Many growth factors are involved in the eye development or the pathophysiological processes of eye diseases. Growth factors such as vascular endothelial growth factor and basic fibroblast growth factor mediate the occurrence and development of diabetic retinopathy, choroidal neovascularization, cataract, diabetic macular edema, and other retinal diseases. On the other hand, growth factors like nerve growth factor, ciliary neurotrophic factor, glial cell line-derived neurotrophic factor, pigment epithelial-derived factor and granulocyte colony-stimulating factor are known to promote optic nerve injury repair. Growth factors are also related to the pathogenesis of myopia. Fibroblast growth factor, transforming growth factor-ß, and insulin-like growth factor regulate scleral thickness and influence the occurrence and development of myopia. This article reviews growth factors involved in ocular development and ocular pathophysiology, discusses the relationship between growth factors and ocular diseases, to provide reference for the application of growth factors in ophthalmology.

Real-world outcomes of chemotherapy plus immune checkpoint inhibitors versus chemotherapy alone in advanced, unresectable, and recurrent intrahepatic cholangiocarcinoma.

Background: There are limited treatment options available to improve the prognosis of patients with advanced or metastatic cholangiocarcinoma particularly intrahepatic cholangiocarcinoma (iCCA). This study aimed to evaluate the efficacy and safety of combining chemotherapy plus anti-PD-1/L1 drugs compared to chemotherapy alone in advanced, unresectable, and recurrent intrahepatic cholangiocarcinoma patients. Methods: Patients with advanced, unresectable, or recurrent iCCA who received chemotherapy combined with PD-1/PD-L1 inhibitors or chemotherapy alone were retrospectively screened and analyzed. The primary outcomes were overall survival (OS) and progression-free survival (PFS). The secondary outcomes were overall response rate (ORR), disease control rate (DCR), and safety. Results: 81 eligible patients were included in the study (chemotherapy plus anti-PD-1/L1 group n=51, and chemotherapy-alone group n=30). The median OS was 11 months for the chemotherapy plus anti-PD-1/L1 group, significantly longer than the 8 months in the chemotherapy-alone group, with a hazard ratio (HR) of 0.53 (95% CI 0.30-0.94, P = 0.008). The median PFS of 7 months in the chemotherapy plus anti-PD-1/L1 group was significantly longer than the 4 months in the chemotherapy-alone group, with HR of 0.48 (95% CI 0.27-0.87); P = 0.002). Similarly, the combined therapy group showed a higher ORR (29.4%) and DCR (78.4%) compared to 13.3% and 73.3% in the chemotherapy-alone group, respectively. More grade 3-4 treatment-related adverse effects were recorded in the chemotherapy plus anti-PD-1/L1 group (66.7%) compared to the chemotherapy-alone group (23.3%), however, they were manageable and tolerable. Conclusion: Chemotherapy plus anti-PD-1/L1 represents a more effective and tolerable treatment option for advanced, unresectable, and recurrent iCCA patients compared to chemotherapy alone.

Scarless wound healing: Current insights from the perspectives of TGF-ß, KGF-1, and KGF-2.

The process of wound healing involves a complex and vast interplay of growth factors and cytokines that coordinate the recruitment and interaction of various cell types. A series of events involving inflammation, proliferation, and remodeling eventually leads to the restoration of the damaged tissue. Abrogation in the regulation of these events has been shown to result in excessive scarring or non-healing wounds. While the process of wound healing is not fully elucidated, it has been documented that the early events of wound healing play a key role in the outcome of the wound. Furthermore, high levels of inflammation have been shown to lead to scarring. The regulation of these events may result in scarless wound healing, especially in adults. The inhibition of transforming growth factor-ß (TGF-ß) and the administration of keratinocyte growth factors (KGF), KGF-1 and KGF-2, has in recent years yielded positive results in the acceleration of wound closure and reduced scarring. Here, we encapsulate recent knowledge on the roles of TGF-ß, KGF1, and KGF2 in wound healing and scar formation and highlight the areas that need further investigation. We also discuss potential future directions for the use of growth factors in wound management.