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As a classically known mitogen, fibroblast growth factor 1 (FGF1) has been found to exert other pleiotropic functions such as metabolic regulation and myocardial protection. Here, we show that serum levels of FGF1 were decreased and positively correlated with fraction shortening in diabetic cardiomyopathy (DCM) patients, indicating that FGF1 is a potential therapeutic target for DCM. We found that treatment with a FGF1 variant (FGF1∆HBS) with reduced proliferative potency prevented diabetes-induced cardiac injury and remodeling and restored cardiac function. RNA-Seq results obtained from the cardiac tissues of db/db mice showed significant increase in the expression levels of anti-oxidative genes and decrease of Nur77 by FGF1∆HBS treatment. Both in vivo and in vitro studies indicate that FGF1∆HBS exerted these beneficial effects by markedly reducing mitochondrial fragmentation, reactive oxygen species (ROS) generation and cytochrome c leakage and enhancing mitochondrial respiration rate and β-oxidation in a 5’ AMP-activated protein kinase (AMPK)/Nur77-dependent manner, all of which were not observed in the AMPK null mice. The favorable metabolic activity and reduced proliferative properties of FGF1∆HBS testify to its promising potential for use in the treatment of DCM and other metabolic disorders.

Recent evidence suggests that chloride channels are critical for cell proliferation, migration, and differentiation. We examined the effects of transforming growth factor (TGF)-β1 on chloride channel expression and associations with human conjunctival fibroblast (HConF) biology. To investigate the potential role of chloride channel (CLC)-2 in migration, transition to myofibroblasts and extracellular matrix (ECM) synthesis of HconF, a small interfering RNA (siRNA) approach was applied. TGF-β1-induced migration and transition of fibroblasts to myofibroblasts characterized by α-smooth muscle actin (α-SMA) expression, supported by increased endogenous expression of CLC-2 protein and mRNA transcripts. ECM (collagen I and fibronectin) synthesis in HConF was enhanced by TGF-β1. CLC-2 siRNA treatment reduced TGF-β1-induced cell migration, transition of fibroblasts to myofibroblasts, and ECM synthesis of HConF. CLC-2 siRNA treatment in the presence of TGF-β1 inhibited phosphorylation of PI3K and Akt in HConF. These findings demonstrate that CLC-2 chloride channels are important for TGF-β1-induced migration, differentiation, and ECM synthesis via PI3K/Akt signaling in HConF.

When treating glaucoma, excessive scar tissue reactions reduce the postoperative survival rate of the filtering bleb. Accumulating evidence has demonstrated that the proliferation, migration and extracellular matrix (ECM) synthesis of fibroblasts are important molecular mechanisms underlying scar formation. Recent evidence has demonstrated that chloride channels play an important role in controlling cell proliferation, apoptosis, migration and the cell cycle process in several cell types, but the effects of chloride channels on conjunctival fibroblasts have not be studied. The aim of the present study was to investigate the effects of the chloride channel blocker 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) on cell proliferation, apoptosis, migration, cell cycle progression and ECM synthesis in human conjunctival fibroblasts (HConFs), and to further investigate the mechanism of resistance to scar formation following glaucoma filtration surgery. HConFs were exposed to NPPB or lubiprostone. Cell proliferation and viability was evaluated using the Cell Counting Kit-8. Cell migration was measured using Transwell migration and scratch-wound assays. Flow cytometry was used to study apoptosis and cell cycle progression. Quantitative polymerase chain reaction and western blot analyses were performed to determine mRNA and protein expression levels, respectively. Following NPPB treatment, HConFs exhibited reduced proliferation and migration, along with increased apoptosis. NPPB also inhibited cell cycle progression by arresting cells in the G0/G1 phase and reducing collagen I and fibronectin expression, as well as the phosphorylation of phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT). However, lubiprostone treatment exerted the opposite effects on HConFs. Therefore, NPPB treatment inhibited proliferation, migration, cell cycle progression and synthesis of the ECM, while promoting apoptosis in HConFs, by inhibiting the PI3K/AKT signaling pathway.

Chronic kidney disease (CKD) is an ongoing deterioration of renal function that often progresses to end-stage renal disease. In this study, we aimed to screen and identify potential key genes for CKD using the weighted gene coexpression network (WGCNA) analysis tool. Gene expression data related to CKD were screened from GEO database, and expression datasets of GSE66494 and GSE62792 were obtained. After discrete analysis of samples, WGCNA analysis was performed to construct gene coexpression module, and the correlation between the module and disease was calculated. The modules with a significant correlation with the disease were selected for Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Then, the interaction network of related molecules was constructed, and the high score subnetwork was selected, and the candidate key molecules were identified. A total of 882 DEGs were identified in the screening datasets. A subnetwork containing 6 nodes was found with a high score of 12.08, including CEBPZ, IFI16, LYAR, BRIX1, BMS1, and DDX18. DEGs could significantly differentiate CKD and healthy individuals in principal component analysis. In addition, the MEturquiose, MEred, and MEblue in group were significantly correlated with disease in WGCNA. These 6 hub genes were found to significantly discriminate between CKD and healthy controls in the validation dataset, suggesting that they could use these molecules as candidate markers to distinguish CKD from healthy people. Overall, our study indicated that 6 hub genes may play key roles in the occurrence and development of CKD.

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Chronic exposure to nickel compounds is associated with increased incidence of certain types of human cancer, including lung and nasal cancers. Despite intensive investigation, the oncogenic processes remain poorly understood. Apoptosis resistance is a key feature for tumor cells to escape physiological surveillance and acquire growth advantage over normal cells. Although NiCl2 exposure induces transformation of human lung epithelial cells, little information is available with regard to its molecular mechanisms, it is also not clear if the transformed cells are apoptosis resistant and tumorigenic. We explored the apoptosis resistance properties of nickel chloride-transformed human lung epithelial cells and the underlying mechanisms. The results showed that transformed BEAS-2B human lung epithelial cells are resistant to NiCl2-induced apoptosis. They have increased Bcl-2, Bcl-xL and catalase protein levels over the passage matched non-transformed counterparts. The mechanisms of apoptosis resistance are mitochondria-mediated and caspase-dependent. Forced overexpression of Bcl-2, Bcl-xL and catalase proteins reduced NiCl2-induced cell death; siRNA-mediated knockdown of their expression sensitized the cells to nickel-induced apoptosis, suggesting that Bcl-2, Bcl-xl and catalase protein expression plays a critical role in apoptosis resistance. Akt also participates in this process, as its overexpression increases Bcl-xL protein expression levels and attenuates NiCl2-induced apoptosis. Furthermore, transformed cells are tumorigenic in a xenograft model. Together, these results demonstrate that nickel-transformed cells are apoptosis-resistant and tumorigenic. Increased expression of Bcl-2, Bcl-xL and catalase proteins are important mechanisms contributing to transformed cell oncogenic properties.