Pachymic Acid Ameliorates Pulmonary Hypertension by Regulating Nrf2-Keap1-ARE Pathway

Objective:Pulmonary hypertension(PH)is a severe pulmonary vascular disease that eventually leads to right ventricular failure and death.The purpose of this study was to investigate the mechanism by which pachymic acid(PA)pretreatment affects PH and pulmonary vascular remodeling in rats.Methods:PH was induced via hypoxia exposure and administration of PA(5 mg/kg per day)in male Sprague-Dawley rats.Hemodynamic parameters were measured using a right ventricular floating catheter and pulmonary vascular morphometry was measured by hematoxylin-eosin(HE),a-SMA and Masson staining.MTT assays and EdU staining were used to detect cell proliferation,and apoptosis was analyzed by TUNEL staining.Western blotting and immunohistochemistry were used to detect the expression of proteins related to the Nrf2-Keapl-ARE pathway.

Diagnostic and Prognostic Significance of Keapl mRNA Expression for Lung Cancer Based on Microarray and Clinical Information from Oncomine Database

We performed a bioinformatics analysis with validation by multiple databases,aiming to evaluate the diagnostic and prognostic value of Kelch-like ECH-associated protein 1(Keapl)mRNA for lung cancer,and to explore possible mechanisms.Diagnostic performance of Keapl mRNA was determined by receiver operating characteristic(ROC)curve analysis.Prognostic implication of Keapl mRNA was estimated by Kaplan-Meier survival analysis.Co-expressed genes with both Keapl and Nfe2L2 were identified by LinkedOmics.Mechanisms of Keapl-Nfe2L2-co-expressed genes underlying the pathogenesis of lung cancer were explored by function enrichment and pathway analysis.The ROC curve analysis determined a good diagnostic performance of Keapl mRNA for lung squamous cell carcinoma(LUSC),with an area under the ROC curve(AUC)of 0.833,sensitivity of 72.7%,and specificity of 90.6%(P<0.001).Multivariate Cox regression recognized high Keapl mRNA to be an independent risk factor of mortality for overall lung cancer[hazard ratio(HR):11.034,P=0.044],but an independent antagonistic factor for lung adenocarcinoma(LUAD)(HR:0.404,P<0.001).Validation by UALCAN and GEPIA supported Oncomine findings regarding the diagnostic value of Keapl mRNA for LUSC,but denied its prognostic value.After screening,we identified 17 co-expressed genes with both Keapl and Nfe2L2 for LUAD,and 22 for LUSC,mainly enriched in signaling pathway of oxidative stress-induced gene expression via Nrf2.In conclusion,Keapl mRNA has a good diagnostic performance,but controversial prognostic efficacy for LUSC.The pathogenesis of lung cancer is associated with Keapl-Nfe2L2-co-expressed genes by signaling pathway of oxidative stress-induced gene expression via Nrf2.

CRISPR-Cas9-based genome-wide screening identified novel targets for treating sorafenib-resistant hepatocellular carcinoma:a cross-talk between FGF21 and the NRF2 pathway

The treatment of hepatocellular carcinoma(HCC)has been dominated by multikinase inhibitors for more than a decade.However,drug resistance can severely restrict the efficacy of these drugs.Using CRISPR/CAS9 genome library screening,we evaluated Kelch-like ECH-associated protein 1(KEAP1)as a key regulator of sorafenib’s susceptibility in HCC.We also investigated whether KEAP1’s knockdown can stabilize nuclear factor(erythroid-derived 2)-like 2(NRF2)protein levels that led to sorafenib’s resistance,including an NRF2 inhibitor that can synergize with sorafenib to abolish HCC’s growth in vitro and in vivo.Furthermore,we clarified that fibroblast growth factor 21(FGF21)is an important downstream regulator of NRF2 in HCC.Intriguingly,we observed that FGF21 bound to NRF2 through the C-terminus of FGF21,thereby stabilizing NRF2 by reducing its ubiquitination and generating a positive feedback loop in sorafenib-resistant HCC.These findings,therefore,propose that targeting FGF21 is a promising strategy to combat HCC sorafenib’s resistance.