Scutellarin suppresses cartilage destruction in osteoarthritis mouse model by inhibiting the NF-κB and PI3K/AKT signaling pathways

Abstract Background: Human umbilical cord mesenchymal stem cells (hUCMSCs) transplantation has been proposed as a promising therapeutic approach for treating acute liver failure (ALF), but its application is limited by immune rejection and tumor formation. Exosomes contain various bioactive cargos including mRNA, microRNA, and protein that can alter the cellular enviroment to enhance tissue repair. However, the exact effects of hUCMSCs derived exosomes (hUCMSC-Exo) on the healing of ALF and their potential mechanisms are not explored.Methods: In vivo, mouse model of ALF were set up through a single intraperitoneal injection of acetaminophen (APAP, 380 mg/kg). In vitro, human hepatocyte cells LO2 were treated with APAP (5 mM). Then APAP-induced ALF mice and APAP-injured LO2 cells were treated with hUCMSC-Exo. Finally, the effects and the mechanisms were estimated.Results: We found that a single tail vein administration of hucMSC-Exo effectively enhanced the survival rate, inhibited apoptosis in hepatocytes, and improved liver function in APAP-induced mouse model of ALF. Furthermore, the deletion of glutathione (GSH) and superoxide dismutase (SOD), generation of malondialdehyde (MDA), and the over expression of cytochrome P450 E1 (CYP2E1) and 4-hydroxynonenal (4-HNE) caused by APAP were also inhibited by hucMSC-Exo, indicating that hucMSC-Exo inhibited APAP-induced apoptosis of hepatocytes by reducing oxidative stress. Moreover, hucMSC-Exo significantly down-regulated the levels of inflammatory cytokines IL-6, IL-1β, and TNF-α in APAP-treated livers. Western blot showed that hucMSC-Exo significantly promoted the activation of ERK1/2 and IGF-1R/PI3K/AKT signaling pathways in APAP-injured LO2 cells, resulting in the inhibition of apoptosis of LO2 cells. Importantly, PI3K inhibitor LY294002 and ERK1/2 inhibitor PD98059 could reverse the function of hucMSC-Exo on APAP-injured LO2 cells in some extent. Conclusions: Our results suggest that hucMSC-Exo offer antioxidant hepatoprotection against APAP in vitro and in vivo by inhibitiing oxidative stress-induced apoptosis via upregulation of ERK1/2 and PI3K/AKT signaling pathways, suggesting that administration of hucMSC-Exo may be an alternative approach for the treatment of ALF.

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Faculty Opinions recommendation of Mouse model of human ovarian endometrioid adenocarcinoma based on somatic defects in the Wnt/beta-catenin and PI3K/Pten signaling pathways.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1088082.541064 ◽

2007 ◽

Author(s):

Patrice Morin

Keyword(s):

Mouse Model ◽

Signaling Pathways ◽

Endometrioid Adenocarcinoma ◽

Beta Catenin

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Biological role of AKT, and regulation of AKT signaling pathway by thymoquinone: perspectives in cancer therapeutics

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557520666201005143818 ◽

2020 ◽

Vol 20 ◽

Author(s):

Md. Junaid ◽

Yeasmin Akter ◽

Syeda Samira Afrose ◽

Mousumi Tania ◽

Md. Asaduzzaman Khan

Keyword(s):

Clinical Trials ◽

Signaling Pathways ◽

Signaling Pathway ◽

Inhibitory Effect ◽

Akt Signaling ◽

Review Article ◽

Therapeutic Drug ◽

Akt Signaling Pathway ◽

Anti Cancer

Background: AKT/PKB is an important enzyme with numerous biological functions, and its overexpression is related to the carcinogenesis. AKT stimulates different signaling pathways that are downstream of activated tyrosine kinases and phosphatidylinositol 3-kinase, hence functions as an important target for anti-cancer drugs. Objective: In this review article, we have interpreted the role of AKT signaling pathways in cancer and natural inhibitory effect of Thymoquinone (TQ) in AKT and its possible mechanism. Method: We have collected the updated information and data on AKT, their role in cancer and inhibitory effect of TQ in AKT signaling pathway from google scholar, PubMed, Web of Science, Elsevier, Scopus and many more. Results: There are many drugs already developed, which can target AKT, but very few among them have passed clinical trials. TQ is a natural compound, mainly found in black cumin, which has been found to have potential anti-cancer activities. TQ targets numerous signaling pathways, including AKT, in different cancers. In fact, many studies revealed that AKT is one of the major targets of TQ. The preclinical success of TQ suggests its clinical studies on cancer. Conclusion: This review article summarizes the role of AKT in carcinogenesis, its potent inhibitors in clinical trials, and how TQ acts as an inhibitor of AKT and TQ’s future as a cancer therapeutic drug.

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Expression of PRIP, a phosphatidylinositol 4,5-bisphosphate binding protein, attenuates PI3K/AKT signaling and suppresses tumor growth in a xenograft mouse model

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2021.03.045 ◽

2021 ◽

Vol 552 ◽

pp. 106-113

Author(s):

Yuka Maetani ◽

Satoshi Asano ◽

Akiko Mizokami ◽

Yosuke Yamawaki ◽

Tomomi Sano ◽

...

Keyword(s):

Mouse Model ◽

Tumor Growth ◽

Binding Protein ◽

Akt Signaling ◽

Xenograft Mouse Model

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Soluble epoxide hydrolase inhibitor trifluoromethoxyphenyl‐3‐(1‐propionylpiperidin‐4‐yl)urea prevents hyperalgesia through regulating NLRC4 inflammasome‐related pro‐inflammatory and anti‐inflammatory signaling pathways in the lipopolysaccharide‐induced pain mouse model

Drug Development Research ◽

10.1002/ddr.21786 ◽

2021 ◽

Author(s):

Ali Cagli ◽

Sefika Pinar Senol ◽

Meryem Temiz‐Resitoglu ◽

Demet Sinem Guden ◽

Ayse Nihal Sari ◽

...

Keyword(s):

Mouse Model ◽

Signaling Pathways ◽

Epoxide Hydrolase ◽

Soluble Epoxide Hydrolase ◽

Inflammatory Signaling ◽

Soluble Epoxide Hydrolase Inhibitor ◽

Anti Inflammatory

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Akt signaling is activated by TGFβ2 and impacts tenogenic induction of mesenchymal stem cells

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02167-2 ◽

2021 ◽

Vol 12 (1) ◽

Cited By ~ 1

Author(s):

Sophia K. Theodossiou ◽

Jett B. Murray ◽

LeeAnn A. Hold ◽

Jeff M. Courtright ◽

Anne M. Carper ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Signaling Pathways ◽

Transforming Growth Factor ◽

Akt Signaling ◽

Cell Alignment ◽

Limited Information ◽

Akt Inhibitor ◽

Tenogenic Differentiation

Abstract Background Tissue engineered and regenerative approaches for treating tendon injuries are challenged by the limited information on the cellular signaling pathways driving tenogenic differentiation of stem cells. Members of the transforming growth factor (TGF) β family, particularly TGFβ2, play a role in tenogenesis, which may proceed via Smad-mediated signaling. However, recent evidence suggests some aspects of tenogenesis may be independent of Smad signaling, and other pathways potentially involved in tenogenesis are understudied. Here, we examined the role of Akt/mTORC1/P70S6K signaling in early TGFβ2-induced tenogenesis of mesenchymal stem cells (MSCs) and evaluated TGFβ2-induced tenogenic differentiation when Smad3 is inhibited. Methods Mouse MSCs were treated with TGFβ2 to induce tenogenesis, and Akt or Smad3 signaling was chemically inhibited using the Akt inhibitor, MK-2206, or the Smad3 inhibitor, SIS3. Effects of TGFβ2 alone and in combination with these inhibitors on the activation of Akt signaling and its downstream targets mTOR and P70S6K were quantified using western blot analysis, and cell morphology was assessed using confocal microscopy. Levels of the tendon marker protein, tenomodulin, were also assessed. Results TGFβ2 alone activated Akt signaling during early tenogenic induction. Chemically inhibiting Akt prevented increases in tenomodulin and attenuated tenogenic morphology of the MSCs in response to TGFβ2. Chemically inhibiting Smad3 did not prevent tenogenesis, but appeared to accelerate it. MSCs treated with both TGFβ2 and SIS3 produced significantly higher levels of tenomodulin at 7 days and morphology appeared tenogenic, with localized cell alignment and elongation. Finally, inhibiting Smad3 did not appear to impact Akt signaling, suggesting that Akt may allow TGFβ2-induced tenogenesis to proceed during disruption of Smad3 signaling. Conclusions These findings show that Akt signaling plays a role in TGFβ2-induced tenogenesis and that tenogenesis of MSCs can be initiated by TGFβ2 during disruption of Smad3 signaling. These findings provide new insights into the signaling pathways that regulate tenogenic induction in stem cells.

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