FGF4, A New Potential Regulator in Gestational Diabetes Mellitus.

Background: Gestational diabetes mellitus (GDM) is associated with adverse maternal and neonatal outcomes, however the underlying mechanisms remain elusive. The aim of this study was to find efficient regulator of FGFs in response to the pathogenesis of GDM and explore the role of the FGFs in GDM. Methods: We performed a systematic screening of placental FGFs in GDM patients and further in two different GDM mouse models to investigate their expression changes. Significant changed FGF4 was selected, engineered, purified, and used to treat GDM mice in order to examine whether it can regulate the adverse metabolic phenotypes of the diabetic mice and protect their fetus. Results: We found FGF4 expression was elevated in GDM patients and its level was positively correlated to blood glucose, indicating a physiological relevance of FGF4 with respect to the development of GDM. Recombinant FGF4 (rFGF4) treatment could effectively normalize the adverse metabolic phenotypes in high fat diet induced GDM mice but not in STZ induced GDM mice. However, rFGF4 was highly effective in reduce of neural tube defects (NTDs) of embryos in both the two GDM models. Mechanistically, rFGF4 treatment inhibits pro-inflammatory signaling cascades and neuroepithelial cell apoptosis of both GDM models, which was independent of glucose regulation. Conclusions/interpretation: Our study provides novel insight into the important roles of placental FGF4 and suggests that it may serve as a promising diagnostic factor and therapeutic target for GDM.

Fibroblast growth factor 1 ameliorates adipose tissue inflammation and systemic insulin resistance via enhancing adipocyte mTORC2/Rictor signal.

Obesity-induced activation and proliferation of resident macrophages and infiltration of circulating monocytes in adipose tissues contribute to adipose tissue inflammation and insulin resistance. These effects further promote the development of metabolic syndromes, such as type 2 diabetes, which is one of the most prevalent health conditions severely threatening human health worldwide. Our study examined the potential molecular mechanism employed by fibroblast growth factor 1 (FGF1) to improve insulin sensitivity. The leptin receptor-deficient obese mice (db/db) served as an insulin-resistant model. Our results demonstrated that FGF1-induced amelioration of insulin resistance in obese mice was related to the decreased levels of pro-inflammatory adipose tissue macrophages (ATMs) and plasma inflammatory factors. We found that FGF1 enhanced the adipocyte mTORC2/Rictor signalling pathway to inhibit C-C chemokine ligand 2 (CCL2) production, the major cause of circulating monocytes infiltration, activation and proliferation of resident macrophages in adipose tissues. Conversely, these alleviating effects of FGF1 were substantially abrogated in adipocytes with reduced expression of mTORC2/rictor. Furthermore, a model of adipocyte-specific mTORC2/Rictor-knockout (AdRiKO) obese mice was developed to further understand the in vitro result. Altogether, these results demonstrated adipocyte mTORC2/Rictor was a crucial target for FGF1 function on adipose tissue inflammation and insulin sensitivity.

Structure-guided design, generation, and biofunction of PEGylated fibroblast growth factor 2 variants for wound healing.

Fibroblast growth factor 2 (FGF2) plays an important role in multiple physiological functions such as tissue repair. However, FGF2 has a short half-life in vivo due to protease degradation, thus limiting its clinical application. Traditional PEGylation has typically focused on the N-terminal α-amino group of FGF2. These modifications do not consider potential effects on protein function or structure, and sometimes lead to decreased bioactivity. In this study, we generated three PEGylated FGF2 variants based on the structure of the FGF2-FGFR-heparin ternary complex via gene mutation and PEGylation, and investigated the effects of these PEGylated sites on protein stability and bioactivity. Compared with native FGF2, all PEG-FGF2 conjugates exhibited significantly improved stability. Conjugates PEGylated at a site separated from both binding regions more effectively promoted proliferation, migration and angiogenesis than FGF2 in vitro, and exhibited excellent wound healing activity in vivo, making these conjugates potential therapeutic candidates for wound healing. Computer-assisted modification based on structure reveals the detailed structural characteristics of proteins, allowing efficient protein modification for improved stability and activity. This structure-guided PEGylation offers a more reliable modification strategy and should be applied for the rational design of protein-based therapeutics.

Production of bioactive recombinant human myeloid-derived growth factor in Escherichia coli and its mechanism on vascular endothelial cell proliferation.

Myeloid-derived growth factor (MYDGF) is a novel protein secreted by bone marrow cells that features important physiological functions. In recent years, MYDGF has gained considerable interest due to their extensive beneficial effect on cardiac repair and protects cardiomyocytes from cell death. However, its precise molecular mechanisms have not been well elucidated. The purpose of this study was to produce sufficient amount of biologically active recombinant human (rh) MYDGF more economically and effectively by using in vitro molecular cloning techniques to study its clinical application. The prokaryotic expression system of Escherichia coli was established for the preparation of rhMYDGF. Finally, a large amount of high biologically active and purified form of recombinant protein was obtained. Moreover, we investigated the potential mechanism of rhMYDGF-mediated proliferation and survival in human coronary artery endothelial cells (HCAECs). Mechanistically, the results suggested that MAPK/STAT3 and the cyclin D1 signalling pathways are indispensable for rhMYDGF-mediated HCAEC proliferation and survival. Therefore, this study successfully established a preparation protocol for biologically active rhMYDGF and it may be a most economical way to produce high-quality active rhMYDGF for future clinical application.

FGF1ΔHBS ameliorates chronic kidney disease via PI3K/AKT mediated suppression of oxidative stress and inflammation.

Currently, there is a lack of effective therapeutic approaches to the treatment of chronic kidney disease (CKD) with irreversible deterioration of renal function. This study aimed to investigate the ability of mutant FGF1 (FGF1ΔHBS, which has reduced mitogenic activity) to alleviate CKD and to study its associated mechanisms. We found that FGF1ΔHBS exhibited much weaker mitogenic activity than wild-type FGF1 (FGF1WT) in renal tissues. RNA-seq analysis revealed that FGF1ΔHBS inhibited oxidative stress and inflammatory signals in mouse podocytes challenged with high glucose. These antioxidative stress and anti-inflammatory activities of FGF1ΔHBS prevented CKD in two mouse models: a diabetic nephropathy model and an adriamycin-induced nephropathy model. Further mechanistic analyses suggested that the inhibitory effects of FGF1ΔHBS on oxidative stress and inflammation were mediated by activation of the GSK-3ß/Nrf2 pathway and inhibition of the ASK1/JNK signaling pathway, respectively. An in-depth study demonstrated that both pathways are under control of PI3K/AKT signaling activated by FGF1ΔHBS. This finding expands the potential uses of FGF1ΔHBS for the treatment of various kinds of CKD associated with oxidative stress and inflammation.