Ghrelin protects small intestinal epithelium against sepsis-induced injury by enhancing the autophagy of intestinal epithelial cells

Wan, Shengxia; Shi, Bin; Lou, Xiaoli; Liu, Jingquan; Ma, Guoguang; Dong, Liang; Ma, Shuang

doi:10.1016/j.biopha.2016.08.048

Cited by 38 publications

(31 citation statements)

References 32 publications

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“…Autophagy is a mechanism which recycles damaged organelles and cellular components in response to various stress conditions such as nutrient deprivation (Filomeni et al, 2015), metabolic balance (Maiuri et al, 2007), apoptosis (Maiuri et al, 2007) and inflammation (Kimura et al, 2017), and is beneficial for cell survival. Clinical and preclinical studies confirm that sepsis triggers autophagy in multiple organs, including the kidney (Wan et al, 2016;Chung et al, 2017;Kimura et al, 2017;Sun et al, 2019), and an increasing amount of evidence suggests that stimulating autophagy via pharmacological approaches protects the kidney during sepsis (Mei et al, 2016). Mitophagy, the selective removal of mitochondria by autophagy, also plays an important role in SAKI (Kaushal and Shah, 2016).…”

Section: Introductionmentioning

confidence: 99%

Dexmedetomidine Protects Against Lipopolysaccharide-Induced Acute Kidney Injury by Enhancing Autophagy Through Inhibition of the PI3K/AKT/mTOR Pathway

Zhao

Feng

et al. 2020

Front. Pharmacol.

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Background: Acute kidney injury (AKI) is often secondary to sepsis. Previous studies suggest that damaged mitochondria and the inhibition of autophagy results in AKI during sepsis, but dexmedetomidine (DEX) alleviates lipopolysaccharide (LPS)-induced AKI. However, it is uncertain whether the renoprotection of DEX is related to autophagy or the clearance of damaged mitochondria in sepsis-induced AKI. Methods: In this study, AKI was induced in rats by injecting 10 mg/kg of LPS intraperitoneally (i.p.). The rats were also pretreated with DEX (30 mg/kg, i.p.) 30 min before the injection of LPS. The structure and function of kidneys harvested from the rats were evaluated, and the protein levels of autophagy-related proteins, oxidative stress levels, and apoptosis levels were measured. Further, atipamezole (Atip) and 3-Methyladenine (3-MA), which are inhibitors of DEX and autophagy, respectively, were administered before the injection of DEX to examine the protective mechanism of DEX. Results: Pretreatment with DEX ameliorated kidney structure and function. DEX decreased the levels of blood urea nitrogen (BUN) and creatinine (Cre), urine kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), reactive oxygen species (ROS), and apoptosis proteins (such as cleaved caspase-9 and cleaved caspase-3). However, DEX upregulated the levels of autophagy and mitophagy proteins, such as Beclin-1, LC3 II and PINK1. These results suggest that DEX ameliorated LPS-induced AKI by reducing oxidative stress and apoptosis and enhancing autophagy. To promote autophagy, DEX inhibited the phosphorylation levels of PI3K, AKT, and mTOR. Furthermore, the administration of Atip and 3-MA inhibitors blocked the renoprotection effects of DEX. Conclusions: Here, we demonstrate a novel mechanism in which DEX protects against LPS-induced AKI. DEX enhances autophagy, which results in the removal of damaged

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Section: Introductionmentioning

confidence: 99%

Dexmedetomidine Protects Against Lipopolysaccharide-Induced Acute Kidney Injury by Enhancing Autophagy Through Inhibition of the PI3K/AKT/mTOR Pathway

Zhao

Feng

et al. 2020

Front. Pharmacol.

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“…Studies have shown that autophagy is mobilized early in sepsis and seen in various organs, manifested by increased accumulation of autophagic vacuoles and enhanced expression of autophagy-associated proteins ( 11 ). For example, microtubule-associated protein light chain 3 (LC3), one of key molecules for autophagy, showed enhanced expression at 6 h after cecal ligation and puncture (CLP) and released a cascade of benefits by eliminating invaded pathogens, avoiding overproduction of stress proteins and modulating the function of multiple organelles ( 12 ). SQSTM1/p62, another specific marker for dynamic autophagic process that is also termed autophagic flux, revealed rapid alteration after sepsis initiation and further contributed to functional stability of various cells ( 11 ).…”

Section: Introductionmentioning

confidence: 99%

Autophagy: A Potential Therapeutic Target for Reversing Sepsis-Induced Immunosuppression

Ren

Zhang

et al. 2017

Front. Immunol.

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Sepsis remains the leading cause of mortality in intensive care units and an intractable condition due to uncontrolled inflammation together with immune suppression. Dysfunction of immune cells is considered as a major cause for poor outcome of septic patients but with little specific treatments. Currently, autophagy that is recognized as an important self-protective mechanism for cellular survival exhibits great potential for maintaining immune homeostasis and alleviating multiple organ failure, which further improves survival of septic animals. The protective effect of autophagy on immune cells covers both innate and adaptive immune responses and refers to various cellular receptors and intracellular signaling. Multiple drugs and measures are reportedly beneficial for septic challenge by inducing autophagy process. Therefore, autophagy might be an effective target for reversing immunosuppression compromised by sepsis.

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“…Increasing evidence has recently indicated that sepsis patients and animal models of sepsis exhibit reduced ATG5/ATG16L1 expression and autophagic activity in the late stage of sepsis and this lagging suppression of autophagic activity may contribute to inflammatory dysregulation, mitochondrial dysfunction and apoptosis, which are strongly correlated with organ dysfunction and mortality following sepsis 37 – 40 . It has also been reported that the autophagic dysfunction induced by genomic deletion of ATG5 or ATG16L1 has a lethal effect in murine models of sepsis 23 – 25 , whereas therapeutic activation of autophagy protects against septic insults 41 , 42 . Our results showed that ATG5 and ATG16L1 expression levels in sepsis patients were significantly reduced relative to healthy controls, and that it decreased with the aggravation of sepsis which was consistent with these previous studies.…”

Section: Discussionmentioning

confidence: 99%

Association between genetic polymorphisms in the autophagy-related 5 gene promoter and the risk of sepsis

Shao

Chen

et al. 2017

Sci Rep

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Previous studies demonstrated significant roles of autophagy in the pathogenesis of sepsis, but few studies focused on the effect of autophagy-related SNPs on sepsis susceptibility. In this present study, five polymorphisms of ATG5/ATG16L1 were investigated for the possible risk on sepsis in a Chinese Han population. Our results showed that ATG5 expression levels decreased with the severity of sepsis, and rs506027 T > C and rs510432 G > A were associated with sepsis progression and mortality. Moreover, the rs506027 TT and rs510432 GG carriers also exhibited increased expression levels of ATG5. Functional assays showed that ATG5 knockdown elevated the secretion of pro-inflammatory cytokines in THP-1 cells, and the extracted mononuclear cell of the risk C-A carriers exhibited decreased ATG5 expression levels, leading to enhanced releases of TNF-α and IL-1β under LPS stimulation in vitro. Furthermore, ATG5 T-G haplotype mutation showed higher promoter activities compared to C-A haplotype mutation, suggesting the effect of these SNPs on ATG5 gene transcription. Taken together, these results above indicated that these two ATG5 promoter polymorphisms may be functional and clinically significant for sepsis progression, underscoring its potentially therapeutic implications for sepsis and other inflammatory diseases.

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Ghrelin protects small intestinal epithelium against sepsis-induced injury by enhancing the autophagy of intestinal epithelial cells

Cited by 38 publications

References 32 publications

Dexmedetomidine Protects Against Lipopolysaccharide-Induced Acute Kidney Injury by Enhancing Autophagy Through Inhibition of the PI3K/AKT/mTOR Pathway

Dexmedetomidine Protects Against Lipopolysaccharide-Induced Acute Kidney Injury by Enhancing Autophagy Through Inhibition of the PI3K/AKT/mTOR Pathway

Autophagy: A Potential Therapeutic Target for Reversing Sepsis-Induced Immunosuppression

Association between genetic polymorphisms in the autophagy-related 5 gene promoter and the risk of sepsis

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