scholarly journals Important Role of SDF-1/CXCR4 Axis in the Homing of Systemically Transplanted Human Amnion-Derived Mesenchymal Stem Cells (Had-Mscs) to Ovaries in Rats with Chemotherapy-Induced Premature Ovarian Insufficiency (POI)

2021 ◽  
Author(s):  
Li Ling ◽  
Jiying Hou ◽  
Dandan Liu ◽  
Dongyuan Tang ◽  
Yanqin Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Signaling Pathway ◽  
Ovarian Function ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Ovarian Insufficiency ◽  
Human Amnion ◽  
Cxcr4 Axis

Abstract Background: Chemotherapy can induce premature ovarian insufficiency (POI). POI causes multiple sequelae and is currently incurable. Our previous studies have demonstrated that systemically transplanted human amnion-derived mesenchymal stem cells (hAD-MSCs) can home to chemotherapy-induced POI ovaries, and thus reduce ovarian injury and improve ovarian function in rats with POI. However, the cellular mechanisms that direct the migration and homing of hAD-MSCs to chemotherapy-induced POI ovaries are barely understood. This study was to investigate the role of SDF-1/CXCR4 axis in the migration and homing of systemically transplanted hAD-MSCs to chemotherapy-induced POI ovaries and its relevant downstream signaling pathways.Methods: CXCR4 expression in hAD-MSCs was tested by western blot and immunofluorescence assay. hAD-MSC migration was tested by transwell migration assay. SDF-1 level in rats was detected by ELISA. 72 of female SD rats were randomly divided into the control, POI, hAD-MSCs and hAD-MSCs+AMD3100 groups. POI rat models were established by intraperitoneal injection of cyclophosphamide. For the inhibitor treatment, hAD-MSCs were pretreated with AMD3100 before transplantation. hAD-MSCs labeled with PKH26 were injected into the tail vein of POI rats at 24 h after chemotherapy. After hAD-MSC transplantation, the homing of hAD-MSCs in ovaries, and ovarian function and pathological changes were examined. To further investigate molecular mechanisms, PI3K/Akt and ERK1/2 signaling pathways were detected. Results: hAD-MSCs expressed CXCR4. SDF-1 induced hAD-MSC migration in vitro. SDF-1 levels in ovaries and serum significantly increased in POI rats induced by chemotherapy, and POI ovaries attracted the homing of hAD-MSCs expressing CXCR4. The block of SDF-1/CXCR4 axis with AMD3100 can significantly reduce the number of hAD-MSCs homing to the POI ovaries, and further reduce their efficacy in POI treatment. The binding of SDF-1 to CXCR4 activated PI3K/Akt signaling pathway, and LY294002 significantly inhibited hAD-MSC migration induced by SDF-1 in vitro. Moreover, inhibition of PI3K/Akt signaling pathway significantly reduced the number of systemically transplanted hAD-MSCs homing to chemotherapy-induced POI ovaries in rats.Conclusions: SDF-1/CXCR4 axis partially mediates the migration and homing of systemically transplanted hAD-MSCs to chemotherapy-induced POI ovaries in rats, and PI3K/Akt signaling pathway might be involved in the migration and homing of hAD-MSCs mediated by SDF-1/CXCR4 axis.

scholarly journals Small extracellular vesicles derived from embryonic stem cells restore ovarian function of premature ovarian failure through PI3K/AKT signaling pathway

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Mengyu Liu ◽  
Yu Qiu ◽  
Zhuowei Xue ◽  
Ruoyu Wu ◽  
Jie Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Signaling Pathway ◽  
Granulosa Cells ◽  
Premature Ovarian Failure ◽  
Ovarian Function ◽  
Embryonic Stem ◽  
Akt Signaling ◽  
Akt Signaling Pathway

Abstract Background Premature ovarian failure (POF) has a great impact on reproductive endocrine function in females, and it is an important cause of infertility. Previous studies have demonstrated that small extracellular vesicles (sEVs) derived from stem cells play an important role in tissue regeneration. This study aimed to investigate the therapeutic effect of sEVs derived from embryonic stem cells (ESCs-sEVs) on damaged ovaries and explore the underlying molecular mechanisms. Methods Mice POF models were established by injecting mice with cyclophosphamide and busulfan. Then, ESCs-sEVs were intravenously transplanted into POF mice. The plasma of mice was harvested at 1 and 2 weeks after treatment to analyze the levels of anti-Mullerian hormone (AMH), estradiol (E2), and follicle stimulating hormone (FSH) by ELISA. The morphology of ovaries and follicles was observed by H&E staining, and apoptosis of granulosa cells was detected by TUNEL. In vitro, EdU and CCK-8 tests were used to evaluate the proliferation of cultured granulosa cells stimulated by ESCs-sEVs. Western blotting was used to determine the expression of PI3K/AKT and apoptotic-related proteins. Results After transplantation of ESCs-sEVs, the levels of serum sex hormones recovered to normal levels. In addition, the number of follicles was significantly increased, and the number of apoptotic cells was decreased. The results in vitro revealed that ESCs-sEVs could significantly improve the proliferation rate of granulosa cells and increase the expression of phosphorylated PI3K and AKT. Meanwhile, the positive effect on proliferation and the negative effect on apoptosis observed in granulosa cells were obviously decreased when the PI3K/AKT signaling pathway was inhibited. Conclusion Our findings suggested that ESCs-sEVs could improve ovarian function by regulating the PI3K/AKT signaling pathway, which could provide a promising clinical therapy for POF.

scholarly journals Leptin-R and its association with PI3K/AKT signaling pathway in papillary thyroid carcinoma

2010 ◽  
Vol 17 (1) ◽  
pp. 191-202 ◽  
Author(s):  
Shahab Uddin ◽  
Prashant Bavi ◽  
Abdul K Siraj ◽  
Maqbool Ahmed ◽  
Maha Al-Rasheed ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Prognostic Marker ◽  
Disease Free Survival ◽  
Akt Signaling ◽  
Papillary Thyroid ◽  
Akt Signaling Pathway ◽  
Free Survival ◽  
Disease Free

The putative role of leptin and its receptor (Ob-R) in the pathogenesis of various primary human malignancies has been reported; however, their role in papillary thyroid cancer (PTC) has not yet been evaluated. We investigated the role of Ob-R in a large tissue microarray cohort of PTC followed by in vitro studies using a panel of PTC cell lines. Ob-R overexpression was seen in 80% PTCs and was significantly associated with poor disease-free survival (P=0.0235). PTCs that overexpressed Ob-R showed a aggressive phenotype characterized by older age, extrathyroid extension, larger tumor size, nodal metastasis, advanced stage, tall cell variant histological subtype, and a poor disease-free survival (P=0.0005, P=0.0006, P=0.0398, P=0.0004, P=0.0111, P=0.0003, and P=0.0235 respectively). However, Ob-R expression was not an independent prognostic marker to predict disease-free survival in multivariate analysis. PTCs with overexpression of Ob-R showed a significant direct association with overexpression of XIAP (P<0.0001) and Bcl-XL (P<0.0001). In vitro analysis showed that leptin stimulated cell proliferation and inhibited apoptosis via activation of phosphatidylinisitol 3′ kinase (PI3K)/protein kinase B (AKT) signaling pathway. Inhibition of PI3K activity by its inhibitor LY294002 abrogated leptin-mediated PI3K/AKT signaling. Gene silencing of Ob-R in PTC cells resulted in downregulation of phospho-AKT, Bcl-XL, and XIAP expression suggesting that leptin-mediated pathogenesis of PTC occurs via involvement of these downstream targets. Altogether, these data show that leptin plays an important role in PTC pathogenesis through PI3K/AKT pathway via Ob-R and is a potential prognostic marker associated with an aggressive phenotype and poor disease-free survival.

microRNA-382 suppresses the progression of pancreatic cancer through the PI3K/Akt signaling pathway by inhibition of Anxa3

2020 ◽  
Vol 319 (3) ◽  
pp. G309-G322
Author(s):  
Xiaohui Wan ◽  
Dongrui Guo ◽  
Qi Zhu ◽  
Rongfeng Qu
Keyword(s):  
Pancreatic Cancer ◽  
Signaling Pathway ◽  
Epithelial Mesenchymal Transition ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Mesenchymal Transition ◽  
Node Metastasis

This study focused on the mechanism of miR-382 in epithelial mesenchymal transition and lymph node metastasis in PC in relation to Anxa3 and the PI3K/Akt signaling pathway. We found the inhibitory role of miR-382 in PC in vitro and in vivo.

scholarly journals SDF-1/CXCR4 Augments the Therapeutic Effect of Bone Marrow Mesenchymal Stem Cells in the Treatment of Lipopolysaccharide-Induced Liver Injury by Promoting Their Migration Through PI3K/Akt Signaling Pathway

2020 ◽  
Vol 29 ◽  
pp. 096368972092999 ◽  
Author(s):  
Guanghui Xiu ◽  
Xiuling Li ◽  
Yunyu Yin ◽  
Jintao Li ◽  
Bingqin Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Liver Injury ◽  
Signaling Pathway ◽  
Therapeutic Effect ◽  
Acute Liver Injury ◽  
Akt Signaling ◽  
Akt Signaling Pathway

Mesenchymal stem cells (MSCs) are thought to have great potential in the therapy of acute liver injury. It is possible that these cells may be regulated by the stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor-4 (CXCR4) signaling axis, which has been shown to promote stem cells migration in the inflammation-associated diseases. However, the effects of SDF-1/CXCR4 axis on the MSCs-transplantation-based treatment for acute liver injury and the underlying mechanisms are largely unknown. In this study, we sought to determine whether SDF-1/CXCR4 would augment the therapeutic effect of bone marrow mesenchymal stem cells (BMSCs) by promoting their migration, which may result from activating the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, in a rat acute liver injury model induced by lipopolysaccharide (LPS). We found that BMSCs transplantation markedly attenuated liver injury and improved the survival of LPS-treated rats. Of interest, overexpression of CXCR4 in BMSCs could substantially promote their migration both in vitro and in vivo, and result in even better therapeutic effects. This might be attributed to the activation of PI3K/Akt signaling pathway in BMSCs that is downstream of CXCR4, as demonstrated by the use of the CXCR4 antagonist AMD3100 and PI3K pathway inhibitor LY294002 assays in vitro and in vivo. Together, our results unraveled a novel molecular mechanism for the therapeutic effect of BMSCs for the treatment of acute liver injury, which may shed a new light on the clinical application of BMSCs for acute liver failure.

scholarly journals In vivo and in vitro evidence of the neurotoxic effects of ropivacaine: The role of the Akt signaling pathway

2012 ◽  
Vol 6 (6) ◽  
pp. 1455-1459 ◽  
Author(s):  
ZHIHUA SUN ◽  
HUINING LIU ◽  
QULIAN GUO ◽  
XIAOPING XU ◽  
ZHONG ZHANG ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Neurotoxic Effects

scholarly journals The Potential Role of CERS1 in Autophagy Through PI3K/AKT Signaling Pathway in Hypophysoma

2020 ◽  
Vol 19 ◽  
pp. 153303382097753
Author(s):  
Jingtao Wang ◽  
Jimin Zhang ◽  
Dongzhou Ma ◽  
Xiushan Li
Keyword(s):  
Signaling Pathway ◽  
Potential Role ◽  
Mrna Level ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Rt Pcr ◽  
Proliferation And Invasion

To explore the role and mechanism of CERS1 in hypophysoma and investigate whether CERS1 overexpression can change the autophagy process of hypophysoma, and then to explore whether CERS1’s effect was regulated by the PI3K/AKT signaling pathway. Western blot and RT-PCR were used to analyze the expression or mRNA level of CERS1 at different tissues or cell lines. Afterwards, the occurrence and development of hypophysoma in vivo and in vitro, respectively, was observed by using CERS1 overexpression by lentivirus. Finally, MK-2206 and LY294002 were applied to discuss whether the role of CERS1 was regulated by the PI3K/AKT signaling pathway. Results show that the CERS1 expression and mRNA level in tumor or AtT-20 cells were decreased. CERS1 over-expressed by lentivirus could inhibit hypophysoma development in vivo and in vitro by reducing tumor volume and weight, weakening tumor proliferation and invasion, and enhancing apoptosis. In addition, shCERS1 could reverse the process. The above results indicate that CERS1 is possibly able to enhance autophagy in hypophysoma through the PI3K/AKT signaling pathway.

scholarly journals Flufenamic Acid Inhibits Adipogenic Differentiation of Mesenchymal Stem Cells by Antagonizing the PI3K/AKT Signaling Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Xuenan Liu ◽  
Zheng Li ◽  
Hao Liu ◽  
Yuan Zhu ◽  
Dandan Xia ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Signaling Pathway ◽  
Adipogenic Differentiation ◽  
Akt Signaling ◽  
Flufenamic Acid ◽  
Human Mscs ◽  
Akt Signaling Pathway

Objectives. Flufenamic acid (FFA) is a representative of the fenamic acids, an important group of NSAIDs. In the present study, we study the effects of FFA on adipogenesis of human mesenchymal stem cells (MSCs) and we explore the potential mechanism. Methods. To investigate the effects of FFA on adipogenic differentiation of hMSCs, human adipose-derived stem cells (hASCs) and human bone marrow mesenchymal stem cells (hBMMSCs), representative of hMSCs, were treated with FFA during adipogenic differentiation in vitro. The effects of FFA in vivo were evaluated using a heterotopic adipose formation assay in nude mice as well as ovariectomized (OVX) and aged mice. To explore the mechanism of FFA, Western blot was used to determine activation of the PI3K/AKT signaling pathway. Results. Our results demonstrate that, at certain concentrations, FFA inhibited adipogenesis of human MSCs both in vitro and in vivo. Mechanistically, FFA inhibited adipogenesis of human MSCs by inhibiting the PI3K/AKT pathway. Conclusions. The present study indicated that FFA could be used to inhibit adipogenesis of human MSCs in tissue engineering and diseases related to excessive adipogenic differentiation of MSCs.

scholarly journals IL-8 Enhances Therapeutic Effects of BMSCs on Bone Regeneration via CXCR2-Mediated PI3k/Akt Signaling Pathway

2018 ◽  
Vol 48 (1) ◽  
pp. 361-370 ◽  
Author(s):  
Aijun Yang ◽  
Yanzhu Lu ◽  
Junchao Xing ◽  
Zhilin Li ◽  
Xiaolong Yin ◽  
...  
Keyword(s):  
Bone Regeneration ◽  
Signaling Pathway ◽  
Bone Defect ◽  
Chondrogenic Differentiation ◽  
Akt Signaling ◽  
Host Cells ◽  
Therapeutic Effects ◽  
Akt Signaling Pathway

Background/Aims: Tissue engineering bone transplantation with bone marrow mesenchymal stem cells (BMSCs) is an effective technology to treat massive bone loss, while molecular regulation of the bone regeneration processes remains poorly understood. Here, we aimed to assess the role of interleukin-8 (IL-8) in the recruitment of host cells by seeded BMSCs and in the bone regeneration. Methods: A transwell assay was performed to examine the role of IL-8/CXCR1/CXCR2/PI3k/Akt on the migration potential of hBMSCs. The in vitro chondrogenic differentiation of hBMSCs was assessed by examination of 2 chondrogenic markers, Sox9 and type 2 collagen (COL2). mBMSCs were used in tissue engineered bone (TEB) with/without IL-8 implanted into bone defect area with CXCR2 or Akt inhibitors. Density and Masson staining of the regenerated bone were assessed. The chondrogenesis was assessed by expression levels of associated proteins, Sox9 and COL2, by RT-qPCR and by immunohistochemistry. Results: IL-8 may trigger in vitro migration of hBMSCs via CXCR2-mediated PI3k/Akt signaling pathway. IL-8 enhances osteogenesis in the TEB-implanted bone defect in mice. IL-8 induces chondrogenic differentiation of hBMSCs via CXCR2-mediated PI3k/Akt signaling pathway in vitro and in vivo. Conclusions: IL-8 enhances therapeutic effects of MSCs on bone regeneration via CXCR2-mediated PI3k/Akt signaling pathway.

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