Abstract
Objectives The “nAG” protein is the key protein mediating the regeneration of amputated limbs in salamanders. The senior author (MMA) developed the original hypothesis that since “nAG” is a “regenerative” protein, it must be also an “antifibrotic' protein. The antifibrotic properties were later confirmed in a rabbit skin hypertrophic scar model as well as in a rat spinal cord injury model. The aim of this study is to evaluate the potential therapeutic properties of the nAG protein in a rat liver fibrosis model. Methodology Liver fibrosis was induced using intraperitoneal injections of carbon tetrachloride (CCL4). A total of 45 rats were divided equally into 3 groups: Group I (the control group) received normal saline injections for 8 weeks, Group II received CCL4 for 8 weeks, and Group III received CCL4 and nAG for 8 weeks. At the end of the experiment, the serum levels of 6 proteins (hyaluronic acid, PDGF-AB, TIMP-1, laminin, procollagen III N-terminal peptide, and collagen IV-alpha 1 chain) were measured. Liver biopsies were also taken and the stages of live fibrosis were assessed histologically. Results The CCL4 treatment resulted in a significant increase in the serum levels of all 6 measured proteins. The nAG treatment significantly reduced these high levels. The degree of liver fibrosis was also significantly reduced in the CCL4/nAG group compared to the CCL4 group. Conclusions nAG treatment was able to significantly reduce the serum levels of several protein markers of liver fibrosis and also significantly reduced the histological degree of liver fibrosis.
Highlights
Salamanders are known to regenerate their amputated limbs
Hyaluronic acid doubled in the CCL4 group compared to the control group (P
The serum levels of Platelet Derived Growth Factor-AB (PDGF-AB) increased more than 10-fold in the CCL4 group compared to the control group (P
Summary
Salamanders (which are lower vertebrates) are known to regenerate their amputated limbs. The “nAG” protein (nAG stands for newt Anterior Gradient) is the key protein mediating this form of regeneration [1]. The amputation stump of the salamander forms a blastema (a mound of proliferating mesenchymal cells) in which nAg is expressed. The nAG protein is expressed by Schwann cells of regenerating axons and peaks at 5–7 days postamputation. A new nAG gene (suitable for higher vertebrates including humans) was designed, synthesized, and cloned. NAG expression was found to suppress the expression of collagen in human fibroblasts regardless of the presence of Transforming Growth Factor Beta (TGFβ) [2]. The antifibrotic properties of the nAG protein were later shown in several animal models such as a rabbit model of hypertrophic scar [3], a mouse model of digital tip amputation [4], and a rat spinal cord crush injury
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