Sonic hedgehog protects endometrial hyperplasial cells against oxidative stress via suppressing mitochondrial fission protein dynamin-like GTPase (Drp1).

Hh/Gli1 cascade as well as Gsk3β-Gli1 crosstalk play crucial role in estrogen-dependent progression of endometrial hyperplasia (EH). However, the underlying mechanisms involved in progression of disease still remain unclear. In the present study, we explored the role of Hh signaling in protection of endometrial hyperplasial cells against oxidative stress and the underlying mechanism involved therein. EH cells were found to be more resistant towards H2O2-induced oxidative stress (IC50: ~ 3×) as compared with normal endometrial cells. Estrogen (E2) pre-treatment followed by cytotoxic dose of H2O2, almost rescued the EH cells from apoptosis and caused the increased expression of downstream Shh signaling molecules i.e., Smo, Ptch and Gli1. Whereas pretreatment with cyclopamine was not able to curtail H2O2-induced effects indicating that estrogen protects these cells via activation of Shh pathway. Further, H2O2-induced ROS and lipid peroxidation alongwith decreased activities of antioxidant enzymes glutathione peroxidase and superoxide dismutase were found to be reversed in EH cells pre-exposed to E2 or rShh. The rShh suppressed H2O2-induced cell death and caused attenuation of mitochondrial apoptotic mediators and prevented disruption in mitochondrial morphology and mitochondrial membrane potential in EH cells. The functional blockage of signaling by Shh siRNA or Gli1siRNA led to significantly increased expression of mitochondrial fission protein dynamin-like GTPase (Drp1). The H2O2-treated EH cells showed diminished Gli1 and increased Drp1 expression, concurrent with reduced p-Drp1-(serine637). Whereas rShh pre-treated EH cells presented normal mitochondrial dynamics with dense, long networks of mitochondria alongwith nuclear accumulation of Gli1 and the decreased expression of Drp1. Overall, our results implicated that Shh signaling modulates antioxidant defense system and stabilizes mitochondrial dynamics by suppressing Drp1 protein which maintains survival of EH cells against oxidative stress.

Kaushal JB ，Popli P ，Sankhwar P ，Shukla V ，Dwivedi A ... -  《-》

The regulation of Hh/Gli1 signaling cascade involves Gsk3β- mediated mechanism in estrogen-derived endometrial hyperplasia.

Kaushal JB ，Sankhwar P ，Kumari S ，Popli P ，Shukla V ，Hussain MK ，Hajela K ，Dwivedi A ... -  《-》

Baicalin Attenuates Alcoholic Liver Injury through Modulation of Hepatic Oxidative Stress, Inflammation and Sonic Hedgehog Pathway in Rats.

Lipid accumulation, inflammatory responses and oxidative stress have been implicated in the pathology of alcoholic liver disease (ALD). Targeting inhibition of these features may provide a promising therapeutic strategy for ALD. Baicalin, a flavonoid isolated from Scutellaria baicalensis Georgi, has been shown to exert a hepatoprotective effect. However, its effects on ALD remain obscure. This study was aimed to investigate the effects of baicalin on alcohol-induced liver injury and its related mechanisms. For in vivo experiments, rats were supplied intragastrical administration of alcohol continuously for 4 or 8 weeks, and then received baicalin treatment in the latter 4 weeks in the presence / absence of alcohol intake. Liver histology and function, inflammatory cytokines, oxidative mediators, and the components of the Sonic hedgehog pathway were evaluated. For in vitro experiments, alcohol-stimulated human normal liver cells LO2 were used. Baicalin treatment significantly alleviated alcoholic liver injury, improved liver function impaired by alcohol, and inhibited hepatocytes apoptosis. In addition, baicalin decreased the expression levels of proinflammatory cytokines TNF-α, IL-1β, IL-6) and malonyldialdehyde (MDA), and increased the activities of antioxidant enzymes SOD and GSH-Px. Furthermore, baicalin modulated the activation of Sonic hedgehog (Shh) pathway. Administration of baicalin upregulated the expression of sonic hedgehog (Shh), patched (Ptc), Smoothened (Smo), and Glioblastoma-1(Gli-1). Blockade of the Shh pathway in cyclopamine abolished the effects of baicalin in vitro. Both in vivo and in vitro experimental results indicate that baicalin exerts hepatoprotective roles in alcohol-induced liver injury through inhibiting oxidative stress, inflammatory response, and the regulation of the Shh pathway.

Wang H ，Zhang Y ，Bai R ，Wang M ，Du S ... -  《-》

Sonic hedgehog signaling pathway in Myelodysplastic Syndrome: Abnormal activation and jervine intervention.

This study aims to investigate the roles of Sonic hedgehog (Shh) signaling pathway in the occurrence and progression of Myelodysplastic Syndrome (MDS) and further evaluate using jervine as therapeutic strategy for MDS by inhibiting Shh pathway. CD34+ cells from the bone marrow of 53 MDS patients were counted by flow cytometry and isolated by magnetic bead sorting. Shh, Smo, Ptch-1 and Gli-1 (involved in Shh pathway) in CD34+ cells were examined by RT-qPCR. Besides, the relationship between Shh pathway-related genes and the clinical features or prognosis of MDS were analyzed. Further, the effects of jervine on MUTZ-1 cells regarding their proliferation, apoptosis and cell cycle as well as Shh pathway-related gene and protein expression were analyzed. Gene expression level of Shh, Gli-1 and Smo was significantly increased in MDS patients. Herein, Smo and Gli-1 were correlated with chromosome karyotype classification and IPSS. MDS patients with high expression of Smo or Gli-1 had a poor prognosis. Jervine inhibited gene and protein expression of Shh, Smo, Ptch-1 and Gli-1. Besides, jervine suppressed the proliferation and promoted the apoptosis of MUTZ-1 cells, as well as inhibited the transition of cells from G1 to S phase. Shh signaling pathway of MDS patients is abnormally activated and participated in the occurrence and progression of MDS. Jervine intervention is a potential therapeutic strategy for MDS.

Qin Y ，Jiang M ，Tuerxung N ，Wang H ，Zhao F ，Zhen Y ，Hao J ... -  《-》

Iron overload promotes mitochondrial fragmentation in mesenchymal stromal cells from myelodysplastic syndrome patients through activation of the AMPK/MFF/Drp1 pathway.

Zheng Q ，Zhao Y ，Guo J ，Zhao S ，Fei C ，Xiao C ，Wu D ，Wu L ，Li X ，Chang C ... -  《Cell Death & Disease》