Dihydroartemisinin Attenuates Hypoxia-Induced Pulmonary Hypertension Through the ELAVL2/miR-503/PI3K/AKT Axis.

ABSTRACT: Dihydroartemisinin (DHA) is an active form of artemisinin extracted from the traditional Chinese medicine Artemisia annua , which is used to treat malaria. Previous studies have shown that DHA has a therapeutic effect on pulmonary hypertension (PH), but its specific mechanism has not been fully elucidated. In this study, a hypoxia-induced PH mouse model was established and DHA was administered as a therapeutic intervention. We measured hemodynamics and right ventricular hypertrophy and observed hematoxylin and eosin staining of lung tissue sections, proving the therapeutic effect of DHA on PH. Furthermore, cell counting kit-8 and 5-ethynyl-2'-deoxyuridine (EdU) cell proliferation assay kit were performed to examine cell proliferation of pulmonary artery smooth muscle cells cultured in hypoxia or in normoxia. Transwell migration chamber assay was performed to examine cell migration of the same cell model. Consistent with the therapeutic effect in vivo, DHA inhibited hypoxia-induced cell proliferation and migration. Through high-throughput sequencing of mouse lung tissue, we screened embryonic lethal abnormal vision-like 2 (ELAVL2) as a key RNA binding protein in PH. Mechanistically, DHA inhibited the proliferation and migration of pulmonary artery smooth muscle cells by promoting the expression of ELAVL2 and regulating the miR-503/PI3K/AKT pathway. The binding relationship between ELAVL2 and pre-miR-503 was verified by RNA binding protein immunoprecipitation assay. In conclusion, we first propose that DHA alleviates PH through the ELAVL2/miR-503/PI3K/AKT pathway, which may provide a basis for new therapeutic strategies of PH.

Fibroblast growth factor 10 protects against particulate matter-induced airway inflammatory response through regulating inflammatory signaling and apoptosis.

Chronic respiratory disorders are some of the most frequent and severe chronic diseases in China. Epidemiological research has shown that particulate matter (PM) is a risk factor and is closely correlated to the progression of numerous respiratory diseases. Fibroblast growth factor 10 (FGF10) is a mesenchymal-epithelial signaling messenger essential for the development and environmental stability of several tissues. Nevertheless, its role in PM-induced airway inflammation remains unclear. The present study aimed to explore the mechanisms underlying the FGF10-related slowing of lung injury and inflammation in vivo and in vitro, as well as the therapeutic potential of these phenomena. Mice were intraperitoneally injected with a vehicle (PBS) or FGF10 (0.5 mg/kg) at one hour before intratracheal treatment with vehicle (PBS) or PM (4 mg/kg) for two consecutive days. Human airway epithelial BEAS-2B cells were exposed to a vehicle (PBS) or FGF10 (10 ng/ml) in vitro at one hour prior to incubation with a vehicle or PM (200 ug/ml) for 24 hours. Then, the impact on inflammatory molecules was investigated. In vivo, it was found that FGF10 diminished the inflammatory cell aggregation and reduced the apoptosis. Interestingly, in the PM group, the level of FGF10 increased in the bronchoalveolar lavage fluid (BALF). However, the pre-treatment with FGF10 markedly impaired the PM-induced increase in IL-6, IL-8, TNF-α and PGE2 levels in BALF and the cell supernatant. In conclusion, the present findings indicate that FGF10 attenuates PM-induced airway inflammation by inhibiting apoptosis and inflammation. This may be exploited for the prevention and management of PM-induced airway inflammation.

Aminocyanopyridines as anti-lung cancer agents by inhibiting the STAT3 pathway.

Lung cancer is a leading cause of cancer-related death worldwide. Cyanopyridines and aminocyanopyridines with carbon-nitrogen bonds have been proved to exert significant anticancer, antibacterial, and anti-inflammatory effects. In this study, we showed that aminocyanopyridine 3o and 3k displaying potent antitumor activity via inhibiting the signal transducer and activator of transcription 3 (STAT3) pathway. They blocked the constitutive STAT3 phosphorylation in a dose- and time-dependent manner and regulated the transcription of STAT3 target genes encoding apoptosis factors. Most importantly, 3o also inhibited interleukin-6-induced STAT3 activation and nuclear localization. Furthermore, 3o significantly inhibited the tumor growth of H460-derived xenografts. Taken together, these findings suggest that 3o and 3k are promising therapeutic drug candidates for lung cancer by inhibiting persistent STAT3 signaling.

Fibroblast growth factor 21 attenuates hypoxia-induced pulmonary hypertension by upregulating PPARγ expression and suppressing inflammatory cytokine levels.

Hypoxia-induced pulmonary hypertension (HPH) is a progressive disease characterized by a sustained, elevated pulmonary arterial pressure and vascular remodeling. The latter pathogenesis mainly involves overproliferation of pulmonary artery smooth muscle cells (PASMCs). Fibroblast growth factor 21 (FGF21) has recently emerged as a novel regulator that prevents cardiac hypertrophic remodeling. However, its possible role in pulmonary remodeling remains unclear. The activation of peroxisome proliferator activated receptor γ (PPARγ) is reported to attenuate HPH by suppressing proliferative signals. Loss of PPARγ in the lung contributes to abnormal proliferation of PASMCs. FGF21 is a key regulator of PPARγ activity in adipocytes, but its role has not been elucidated in PASMCs. Therefore, we hypothesized that FGF21 may confer therapeutic effects in HPH by upregulating the expression of PPARγ. Sprague-Dawley rats were exposed to hypoxia and treated with FGF21 for 4 weeks. In parallel, hypoxic conditions and FGF21 were administered to rat PASMCs for 48 h. FGF21 attenuated the hypoxia-induced elevation in mean pulmonary arterial pressure (mPAP), right ventricular hypertrophy (RVH), medial thickening and overproliferation of PASMCs. Furthermore, FGF21 abrogated the reductions in PPARγ expression and increases in TNF-α, IL-1 and IL-6 levels in PASMC culture media. Collectively, these results demonstrate that FGF21 could potentially attenuate the pathogenic derangements of HPH by targeting PPARγ and inflammatory cytokines.