Estrogen prevents articular cartilage destruction in a mouse model of AMPK deficiency via ERK-mTOR pathway

Ge, Yuxiang; Zhou, Sheng; Li, Yixuan; Wang, Zixu; Chen, Shuai; Xia, Tianwei; Shen, Jirong; Teng, Huajian; Jiang, Qing

doi:10.21037/atm.2019.06.77

Cited by 33 publications

(26 citation statements)

References 36 publications

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“…In this regard, it is possible that estrogen may exert a compensatory effect for AMPKα1 deletion. For example, previous studies reported that double global genetic deficiency of AMPKα1 and AMPKα2 in female mice did not affect the inflammatory process of osteoarthritis; whereas estrogen prevented articular cartilage destruction (35,36). Since in our study male and female H-AMPKα1 WT mice exhibited similar organ injury and outcomes after sepsis, we speculate that the differential hormonal milieu between male and female may, indeed, result in a diversification of mitochondria quality control during acute stress only in condition of dysregulation of AMPKα1 and the level of expression per se of this enzyme is most likely a key element for sex-dependent switch of metabolic regulation.…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte-Specific Deletion of AMPKα1 Results in Worse Outcomes in Mice Subjected to Sepsis in a Sex-Specific Manner

et al. 2020

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Alterations in the energy homeostasis contribute to sepsis-mediated multiple organ failure. The liver plays a central role in metabolism and participates to the innate immune and inflammatory responses of sepsis. Several clinical and experimental studies have suggested that females are less susceptible to the adverse outcome of sepsis. However, underlying mechanisms of organ damage in sepsis remain largely undefined. AMP-activated protein kinase (AMPK) is an important regulator of mitochondrial quality control. The AMPK catalytic α1 isoform is abundantly expressed in the liver. Here, we determined the role of hepatocyte AMPKα1 in sepsis by using hepatocyte-specific AMPKα1 knockout mice (H-AMPKα1 KO) generated with Cre-recombinase expression under the control of the albumin promoter. Using a clinically relevant model of polymicrobial sepsis by cecal ligation and puncture (CLP), we observed that male H-AMPKα1 KO mice had higher plasma levels of tumor necrosis factor-α and interleukin-6 and exhibited a more severe liver and lung injury than male H-AMPKα1 WT mice, as evaluated by histology and neutrophil infiltration at 18 h after CLP. Plasma levels of interleukin-10 and the keratinocyte-derived chemokine were similarly elevated in both KO and WT male mice. At transmission electron microscopy analysis, male H-AMPKα1 KO mice exhibited higher liver mitochondrial damage, which was associated with a significant decrease in liver ATP levels when compared to WT mice at 18 h after sepsis. Mortality rate was significantly higher in the male H-AMPKα1 KO group (91%) when compared to WT mice (60%) at 7 days after CLP. Female H-AMPKα1 WT mice exhibited a similar degree of histological liver and lung injury, but significantly milder liver mitochondrial damage and higher autophagy when compared to male WT mice after CLP. Interestingly, H-AMPKα1 KO female mice had lower organ neutrophil infiltration, lower liver mitochondrial damage and lower levels of cytokines than WT female mice. There was no significant difference in survival rate between WT and KO mice in the female group. In conclusion, our study demonstrates that AMPKα1 is a crucial hepatoprotective enzyme during sepsis. Furthermore, our results suggest that AMPK-dependent liver metabolic functions may influence the susceptibility to multiple organ injury in a sex-dependent manner.

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Section: Discussionmentioning

confidence: 99%

Hepatocyte-Specific Deletion of AMPKα1 Results in Worse Outcomes in Mice Subjected to Sepsis in a Sex-Specific Manner

et al. 2020

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“…AMPK consists of a catalytic subunit (α 1, α2) and two regulatory subunits β (β1 and β2) and γ (γ1, γ2, and γ3). AMPK regulated variety of biochemical pathways, which control the signal of cellular energy metabolism, whereas its dysfunction is associated with many human diseases (Ge et al, 2019). mTOR is present in both mTORC1 and mTORC2 complexes and has a negative regulatory effect on autophagy.…”

Section: Tan Iia Induces Tumor Cell Autophagymentioning

confidence: 99%

The Anticancer Properties of Tanshinones and the Pharmacological Effects of Their Active Ingredients

Han

Zhou

et al. 2020

Front. Pharmacol.

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Cancer is a common malignant disease worldwide with an increasing mortality in recent years. Salvia miltiorrhiza, a well-known traditional Chinese medicine, has been used for the treatment of cardiovascular and cerebrovascular diseases for thousands of years. The liposoluble tanshinones in S. miltiorrhiza are important bioactive components and mainly include tanshinone IIA, dihydrodanshinone, tanshinone I, and cryptotanshinone. Previous studies showed that these four tanshinones exhibited distinct inhibitory effects on tumor cells through different molecular mechanisms in vitro and in vivo. The mechanisms mainly include the inhibition of tumor cell growth, metastasis, invasion, and angiogenesis, apoptosis induction, cell autophagy, and antitumor immunity, and so on. In this review, we describe the latest progress on the antitumor functions and mechanisms of these four tanshinones to provide a deeper understanding of the efficacy. In addition, the important role of tumor immunology is also reviewed.

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“…However, the relationship between autophagy and the chondrogenic differentiation of SMSCs needs to be explored in further experiments. Decreased autophagy-related gene expression has been observed in damaged chondrocytes, and enhanced autophagy can slow the pathological progression of osteoarthritis [ 25 , 26 ]. In addition, autophagy deficiency may affect the growth plate chondrocytes, leading to cartilage development delays [ 27 , 28 ].…”

Section: Discussionmentioning

confidence: 99%

Rapamycin-Induced Autophagy Promotes the Chondrogenic Differentiation of Synovium-Derived Mesenchymal Stem Cells in the Temporomandibular Joint in Response to IL-1β

Liu

Wang

et al. 2020

BioMed Research International

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Cartilage defects in temporomandibular disorders (TMD) lead to chronic pain and seldom heal. Synovium-derived mesenchymal stem cells (SMSCs) exhibit superior chondrogenesis and have become promising seed cells for cartilage tissue engineering. However, local inflammatory conditions that affect the repair of articular cartilage by SMSCs present a challenge, and the specific mechanism through which the function remains unclear. Thus, it is important to explore the chondrogenesis of SMSCs under inflammatory conditions of TMD such that they can be used more effectively in clinical treatment. In this study, we obtained SMSCs from TMD patients with severe cartilage injuries. In response to stimulation with IL-1β, which is well known as one of the most prevalent cytokines in TMD, MMP13 expression increased, while that of SOX9, aggrecan, and collagen II decreased during chondrogenic differentiation. At the same time, IL-1β upregulated the expression of mTOR and decreased the ratio of LC3-II/LC3-I and the formation of autophagosomes. Further study revealed that rapamycin pretreatment promoted the migration of SMSCs and the expression of chondrogenesis-related markers in the presence of IL-1β by inducing autophagy. 3-Benzyl-5-((2-nitrophenoxy)methyl)-dihydrofuran-2(3H)-one (3BDO), a new activator of mTOR, inhibited autophagy and increased the expression of p-GSK3βser9 and β-catenin, simulating the effect of IL-1β stimulation. Furthermore, rapamycin reduced the expression of mTOR, whereas the promotion of LC3-II/LC3-I was blocked by the GSK3β inhibitor TWS119. Taken together, these results indicate that rapamycin enhances the chondrogenesis of SMSCs by inducing autophagy, and GSK3β may be an important regulator in the process of rapamycin-induced autophagy. Thus, inducing autophagy may be a useful approach in the chondrogenic differentiation of SMSCs in the inflammatory microenvironment and may represent a novel TMD treatment.

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Estrogen prevents articular cartilage destruction in a mouse model of AMPK deficiency via ERK-mTOR pathway

Cited by 33 publications

References 36 publications

Hepatocyte-Specific Deletion of AMPKα1 Results in Worse Outcomes in Mice Subjected to Sepsis in a Sex-Specific Manner

Hepatocyte-Specific Deletion of AMPKα1 Results in Worse Outcomes in Mice Subjected to Sepsis in a Sex-Specific Manner

The Anticancer Properties of Tanshinones and the Pharmacological Effects of Their Active Ingredients

Rapamycin-Induced Autophagy Promotes the Chondrogenic Differentiation of Synovium-Derived Mesenchymal Stem Cells in the Temporomandibular Joint in Response to IL-1β

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