Fibroblast growth factor 21 (FGF21), a primarily liver-derived endocrine factor, has the beneficial effect of protecting blood vessels. Peroxisome proliferator-activated receptor γ (PPARγ), a ligand-activated nuclear transcription factor, has been reported to effectively inhibit pulmonary hypertension (PH). The purpose of this study is to investigate the role of FGF21 in hypoxia-induced PH (HPH) and explore the relationship between FGF21 and PPARγ in this disorder. Adult C57BL/6 mice were subjected to four weeks of hypoxia to establish a PH model. The effects of FGF21 and PPARγ agonists and antagonists were investigated in HPH mice, as well as the relationship between FGF21 and PPARγ in this model. Moreover, we investigated the underlying mechanisms of this relationship between FGF21 and PPARγ in vivo and in vitro. In vivo, we found that hypoxia resulted in pulmonary hypertension, right ventricular hypertrophy, pulmonary arterial remodeling, and pulmonary arterial collagen deposition. Furthermore, hypoxia decreased FGF21 and PPARγ levels. These changes were reversed by exogenous FGF21 and a PPARγ agonist and were further enhanced by a PPARγ antagonist. The hypoxia-induced decrease in β-klotho (KLB) expression was improved by the PPARγ agonist and further reduced by the PPARγ antagonist. Exogenous FGF21 increased adenosine monophosphate-activated protein kinase (AMPK) phosphorylation (Thr172) and PPARγ coactivator-1α (PGC-1α) expression in PH mouse lung homogenates. In vitro, we found that knockdown of AMPK or using an AMPK antagonist inhibited the FGF21-mediated up-regulation of PPARγ expression, and the PPARγ-mediated up-regulation of FGF21 expression was inhibited by knockdown of KLB. These results indicated that FGF21 exerts protective effects in inhibiting HPH. FGF21 and PPARγ mutually promote each other’s expression in HPH via the AMPK/PGC-1α pathway and KLB protein. Impact statement In this study, we reported for the first time that FGF21 alleviated hypoxia-induced pulmonary hypertension through attenuation of increased pulmonary arterial pressure, pulmonary arterial remodeling and collagen deposition in vivo, and we confirmed the mutual promotion of FGF21 and PPARγ in hypoxia-induced pulmonary hypertension. Additionally, we found that FGF21 and PPARγ mutually promote each other’s expression via the AMPK/PGC-1α pathway and KLB protein in vitro and in vivo. Pulmonary hypertension is a progressive and serious pathological phenomenon with a poor prognosis, and current therapies are highly limited. Our results provide novel insight into potential clinical therapies for pulmonary hypertension and establish the possibility of using this drug combination and potential dosage reductions in clinical settings.

Carboxypeptidase A4 (CPA4) is a member of the metallocarboxypeptidase family. A previous study indicated that CPA4 may participate in the modulation of peptide hormone activity and hormone‐regulated tissue growth and differentiation. However, the role of CPA4 in lung tumorigenesis remains unclear. Our study revealed that CPA4 expression was higher in both lung cancer cells and tumor tissues. We performed 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide assays, colony‐formation assays, and Cellomics ArrayScan Infinity analysis to demonstrate that CPA4 knockdown inhibited non small–cell lung cancer (NSCLC) cell proliferation. Conversely, ectopic expression of CPA4 enhanced lung cancer cell proliferation. Consistent with these observations, we generated xenograft tumor models to confirm that CPA4 downregulation suppressed NSCLC cell growth. Mechanistically, we revealed that CPA4 downregulation may induce apoptosis and G1‐S arrest by suppressing the protein kinase B/c‐MYC pathway. These results suggest that CPA4 has an oncogenic effect on lung cancer growth. Taken together, we identified a novel gene in lung cancer that might provide a basis for new therapeutic targets.

Background and Purpose Pulmonary arterial hypertension (PAH) is a pulmonary vasculature obstructive disease that leads to right heart failure and death. Maresin 1 is an endogenous lipid mediator known to promote inflammation resolution. However, the effect of Maresin 1 on PAH remains unclear. Experimental Approach The serum Maresin 1 concentration was assessed using UPLC. A mouse model of PAH was established by combining the Sugen 5416 injection and hypoxia exposure. After treatment with Maresin 1, the right ventricular systolic pressure (RVSP) and right ventricular function were measured by haemodynamic measurement and echocardiography, respectively. Vascular remodelling was evaluated by histological staining. Confocal microscopy and western blot were used to test related protein expression. In vitro cell migration, proliferation and apoptosis assays were performed in primary rat pulmonary artery smooth muscle cells (PASMCs). Western blotting and siRNA transfection were used to clarify the mechanism of Maresin 1. Key Results Endogenous serum Maresin 1 was decreased in PAH patients and mice. Maresin 1 treatment decreased RVSP and attenuated right ventricular dysfunction (RVD) in the murine PAH model. Maresin 1 reversed abnormal changes in pulmonary vascular remodelling, attenuating endothelial to mesenchymal transformation and enhancing apoptosis of α‐SMA positive cells. Furthermore, Maresin 1 inhibited PASMC proliferation and promoted apoptosis by inhibiting STAT, AKT, ERK, and FoxO1 phosphorylation via LGR6. Conclusion and Implications Maresin 1 improved abnormal pulmonary vascular remodelling and right ventricular dysfunction in PAH mice, targeting aberrant PASMC proliferation. This suggests Maresin 1 may have a potent therapeutic effect in vascular disease.

Translational medicine aims to improve human health by exploring potential treatment methods developed during basic scientific research and applying them to the treatment of patients in clinical settings. The advanced perceptions of gene functions have remarkably revolutionized clinical treatment strategies for target agents. However, the progress in gene editing therapy has been hindered due to the severe off‐target effects and limited editing sites. Fortunately, the development in the clustered regularly interspaced short palindromic repeats associated protein 9 (CRISPR‐Cas9) system has renewed hope for gene therapy field. The CRISPR‐Cas9 system can fulfill various simple or complex purposes, including gene knockout, knock‐in, activation, interference, base editing, and sequence detection. Accordingly, the CRISPR‐Cas9 system is adaptable to translational medicine, which calls for the alteration of genomic sequences. This review aims to present the latest CRISPR‐Cas9 technology achievements and prospect to translational medicine advances. The principle and characterization of the CRISPR‐Cas9 system are firstly introduced. The authors then focus on recent pre‐clinical and clinical research directions, including the construction of disease models, disease‐related gene screening and regulation, and disease treatment and diagnosis for multiple refractory diseases. Finally, some clinical challenges including off‐target effects, in vivo vectors, and ethical problems, and future perspective are also discussed.

Pulmonary hypertension (PH) is characterized by progressive vasoconstriction and pulmonary artery remodelling. 1 Uncontrolled expansion of pulmonary artery smooth muscle cells (PASMCs), pulmonary vascular endothelium damage and excessive extracellular matrix deposition are the common pathological hallmarks of PH. 2 Despite the availability of treatments that provide symptomatic relief, till date, there has been no effective treatment for PH. Thus, there is still an urgent need to find possible regulatory targets to develop effective anti-PH agents.Fibroblast growth factor 21 (FGF21) is a member of the family of endocrine fibroblast growth factors, whose beneficial effects on