Fisetin alleviates sepsis-induced multiple organ dysfunction in mice via inhibiting p38 MAPK/MK2 signaling

Zhang, Haifeng; Zhang, Haibo; Wu, Xueping; Guo, Yaling; Cheng, Wan-Jung; Qian, Feng

doi:10.1038/s41401-020-0462-y

Cited by 31 publications

(25 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To identify small molecules facilitating the induction of NCCs to differentiate into CEC destined cells, we built a chemical library of 30 small molecules that targeted almost all the key pathways of stem cell differentiation and corneal development ( Table 1 ). The final concentration of each compound added to the medium was based on previously reported data and testing for the ED50s in the NCCs via Cell Counting Kit-8 (CCK-8) assay ( Miner et al, 2003 ; Bouzakri et al, 2004 ; Moreno et al, 2008 ; Johnson et al, 2012 ; Yap et al, 2012 ; Cho et al, 2013 ; Han et al, 2014 ; Schelleman et al, 2014 ; Kampa-Schittenhelm et al, 2017 ; Pinkosky et al, 2020 ; Zhang et al, 2020 ; Gampala et al, 2021 ; Ma et al, 2021 ). For initial screening, NCCs derived from dual-SMAD inhibition of hiPSCs for 6 days were cultured in a 24-well plate and treated with small molecules for another 3 days.…”

Section: Resultsmentioning

confidence: 99%

Small-Molecule Induction Promotes Corneal Endothelial Cell Differentiation From Human iPS Cells

Chen

Wang

et al. 2021

Front. Bioeng. Biotechnol.

View full text Add to dashboard Cite

Purpose: Corneal endothelial cells (CECs) serve as a barrier and foothold for the corneal stroma to maintain the function and transparency of the cornea. Loss of CECs during aging or disease states leads to blindness, and cell replacement therapy using either donated or artificially differentiated CECs remains the only curative approach.Methods: Human induced pluripotent stem cells (hiPSCs) that were cultured in chemically defined medium were induced with dual-SMAD inhibition to differentiate into neural crest cells (NCCs). A small-molecule library was screened to differentiate the NCCs into corneal endothelial-like cells. The characteristics of these cells were identified with real-time PCR and immunofluorescence. Western blotting was applied to detect the signaling pathways and key factors regulated by the small molecules.Results: We developed an effective protocol to differentiate hiPSCs into CECs with defined small molecules. The hiPSC-CECs were characterized by ZO-1, AQP1, Vimentin and Na+/K+-ATPase. Based on our small-molecule screen, we identified a small-molecule combination, A769662 and AT13148, that enabled the most efficient production of CECs. The combination of A769662 and AT13148 upregulated the PKA/AKT signaling pathway, FOXO1 and PITX2 to promote the conversion of NCCs to CECs.Conclusion: We established an efficient small molecule-based method to differentiate hiPSCs into corneal endothelial-like cells, which might facilitate drug discovery and the development of cell-based therapies for corneal diseases.

show abstract

Section: Resultsmentioning

confidence: 99%

Small-Molecule Induction Promotes Corneal Endothelial Cell Differentiation From Human iPS Cells

Chen

Wang

et al. 2021

Front. Bioeng. Biotechnol.

View full text Add to dashboard Cite

show abstract

“…By literature reviewing, we found fisetin can activate multiple signaling pathways including JNK, PPAR γ , and p38MAPK [ 40 , 44 , 45 ]. To further elucidate in which pathway fisetin may regulate the expression of PON2, we screened these classic signaling inhibitors and found that GW9662, an inhibitor of PPAR γ signaling pathway, effectively blocked the upregulation effect of fisetin on PON2 expression.…”

Section: Discussionmentioning

confidence: 99%

Fisetin Alleviates Neointimal Hyperplasia via PPARγ/PON2 Antioxidative Pathway in SHR Rat Artery Injury Model

Pei

Peng

et al. 2021

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

The phenotypic transformation of proliferation and migration in vascular smooth muscle cells (VSMCs) from media to intima is the basic pathology of neointimal hyperplasia after angioplasty in hypertensive patients. Angiotensin II (AngII) stimulates oxidative stress in VSMC, inducing VSMC proliferation and migration, which is a critical factor in both developments of hypertension and angioplasty-induced arterial restenosis. Fisetin, a plant flavonoid polyphenol, has been reported to be antioxidative and potent senolytic. It is unknown whether fisetin would inhibit neointimal hyperplasia. Therefore, we investigated the role of fisetin in neointimal formation in vitro and in vivo. The rat thoracic aortic smooth muscle cells (A10 cells) stimulated by AngII were used as the in vitro neointimal hyperplasia model, where AngII significantly induced the proliferation and migration in A10 cells. We found that fisetin could dose-dependently inhibit the effect of AngII via inducing the expression of an antioxidant, paraoxonase-2 (PON2), whose overexpression could inhibit the proliferation and migration of A10 cells and downexpression by siRNA had the opposite effect. Furthermore, we found the mechanism of fisetin’s inducing PON2 expression involved PPARγ. Rosiglitazone, a PPARγ agonist, could increase PON2 expression in A10 cells, while the PPARγ inhibitor prevented the effect of fisetin on PON2. The in vivo neointimal hyperplasia model was established 2 weeks after the carotid artery balloon injury in SHR rats. Administration of fisetin (ip 3 mg/kg daily for 2 weeks) right after the injury significantly increased PON2 expression in the artery, inhibiting ROS production, and efficiently reduced carotid neointimal hyperplasia. These results indicate that fisetin increases the expression of antioxidant PON2 via activation of PPARγ, reducing oxidative stress, inhibiting VSMC proliferation and migration, and alleviates neointimal hyperplasia after intimal injury. PON2 may be a potential therapeutic target to reduce arterial remodeling after angioplasty in hypertensive patients.

show abstract

“…In the neonatal hypoxic ischemic encephalopathy models established in 10-day-neonatal Sprague Dawley rats, TAK1/NF-κB signaling was significant increased by oxidative stress and inflammatory responses [ 39 ]. TAK1 was found to be critically involved in sepsis-induced multiple organ dysfunction [ 40 ]. DSS-induced colitis was also revealed to be mediated by TAK1 activity in its pathology, containing clinical manifestations, histopathological damage, loss of tight junction function, and imbalanced intestinal microenvironment [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

Olea europaea Suppresses Inflammation by Targeting TAK1-Mediated MAP Kinase Activation

2021

View full text Add to dashboard Cite

Possessing a variety of medicinal functions, Olea europaea L. is widely cultivated across the world. However, the anti-inflammatory mechanism of Olea europaea is not yet fully elucidated. In this study, how the methanol extract of the leaves of Olea europaea (Oe-ME) can suppress in vitro inflammatory responses was examined in terms of the identification of the target protein. RAW264.7 and HEK293T cells were used to study macrophage-mediated inflammatory responses and to validate the target protein using PCR, immunoblotting, nuclear fraction, overexpression, and cellular thermal shift assay (CETSA) under fixed conditions. Oe-ME treatment inhibited the mRNA expression levels of cyclooxygenase (COX)-2, matrix metallopeptidase (MMP)-9, and intercellular adhesion molecule-1 (ICAM-1) in activated RAW264.7 cells. Oe-ME diminished the activation of activator protein (AP)-1 and the phosphorylation of its upstream signaling cascades, including extracellular signal regulated kinase (ERK), mitogen-activated protein kinase kinase 1/2 (MEK1/2), c-Jun N-terminal kinase (JNK), mitogen-activated protein kinase kinase 3/6 (MKK3/6), p38, MKK7, and transforming growth factor-β-activated kinase 1 (TAK1), in stimulated-RAW264.7 cells. Overexpression and CETSA were carried out to verify that TAK1 is the target of Oe-ME. Our results suggest that the anti-inflammatory effect of Oe-ME could be attributed to its control of posttranslational modification and transcription of TAK1.

show abstract

Fisetin alleviates sepsis-induced multiple organ dysfunction in mice via inhibiting p38 MAPK/MK2 signaling

Cited by 31 publications

References 49 publications

Small-Molecule Induction Promotes Corneal Endothelial Cell Differentiation From Human iPS Cells

Small-Molecule Induction Promotes Corneal Endothelial Cell Differentiation From Human iPS Cells

Fisetin Alleviates Neointimal Hyperplasia via PPARγ/PON2 Antioxidative Pathway in SHR Rat Artery Injury Model

Olea europaea Suppresses Inflammation by Targeting TAK1-Mediated MAP Kinase Activation

Contact Info

Product

Resources

About