Abstract:Regulated in development and DNA damage responses 1 (REDD-1), an inhibitor of mammalian target of rapamycin (mTOR), is induced by various cell stressors, including LPS, a major player in the pathogenesis of endotoxemic shock. However, the pathologic role of REDD-1 in endotoxemia is largely unknown. We found that LPS increased REDD-1 expression, nuclear transcription factor-κB (NF-κB) activation, and inflammation and that these responses were suppressed by REDD-1 knockdown and in REDD-1 macrophages. REDD-1 over… Show more
“…Redd1 expression is stimulated by cellular stress and influences a wide spectrum of cellular processes mainly through inhibition of mTOR signaling [ 22 – 25 ]. It was reported that Redd1 expression in the hippocampus increases markedly during normal aging, suggesting that Redd1 is an aging-associated factor [ 32 ].…”
Section: Discussionmentioning
confidence: 99%
“…Regulated in development and DNA damage response-1 (Redd1), also known as DNA Damage-Inducible Transcript 4 (DDIT4), is a stress-response gene that is transcriptionally induced in various types of cells by stressful stimuli such as DNA damage, hypoxia, and energy deficits [ 20 , 21 ]. Redd1 is a potent inhibitor of mammalian Target of Rapamycin (mTOR) Complex-1 (mTORC1), and its expression influences a wide spectrum of cellular processes and biological functions, such as cell cycle, autophagy, energy homeostasis, and inflammation [ 22 – 25 ]. A regulatory role for Redd1 was reported in phenylephrine-induced cardiac hypertrophy [ 26 ] and myocardial ischemia/reperfusion injury [ 27 , 28 ].…”
Regulated in development and DNA damage response-1 (Redd1) is a stress-response gene that is transcriptionally induced by diverse stressful stimuli to influence cellular growth and survival. Although evidence suggests that aging may drive Redd1 expression in skeletal muscles, the expression patterns and functions of Redd1 in senescent cardiomyocytes remain unspecified. To address this issue,
in vitro
and
in vivo
models of cardiomyocyte senescence were established by administration of doxorubicin (Dox). Redd1 overexpression and knockdown was achieved in cultured H9c2 cardiomyocytes and mouse tissues using, respectively, lentivirals and adeno-associated virus 9 (AAV9) vectors. In the hearts of both aged (24 months old) and Dox-treated mice, as well as in Dox-exposed H9c2 cardiomyocytes, high Redd1 expression accompanied the increase in both cellular senescence markers (p16
INK4a
and p21) and pro-inflammatory cytokine expression indicative of a stress-associated secretory phenotype (SASP). Notably, Redd1 overexpression accentuated, whereas Redd1 silencing markedly attenuated, Dox-induced cardiomyocyte senescence features both
in vitro
and
in vivo
. Notably, AAV9-shRNA-mediated Redd1 silencing significantly alleviated Dox-induced cardiac dysfunction. Moreover, through pharmacological inhibition, immunofluorescence, and western blotting, signaling pathway analyses indicated that Redd1 promotes cardiomyocyte senescence as a downstream effector of p38 MAPK to promote NF-kB signaling via p65 phosphorylation and nuclear translocation.
“…Redd1 expression is stimulated by cellular stress and influences a wide spectrum of cellular processes mainly through inhibition of mTOR signaling [ 22 – 25 ]. It was reported that Redd1 expression in the hippocampus increases markedly during normal aging, suggesting that Redd1 is an aging-associated factor [ 32 ].…”
Section: Discussionmentioning
confidence: 99%
“…Regulated in development and DNA damage response-1 (Redd1), also known as DNA Damage-Inducible Transcript 4 (DDIT4), is a stress-response gene that is transcriptionally induced in various types of cells by stressful stimuli such as DNA damage, hypoxia, and energy deficits [ 20 , 21 ]. Redd1 is a potent inhibitor of mammalian Target of Rapamycin (mTOR) Complex-1 (mTORC1), and its expression influences a wide spectrum of cellular processes and biological functions, such as cell cycle, autophagy, energy homeostasis, and inflammation [ 22 – 25 ]. A regulatory role for Redd1 was reported in phenylephrine-induced cardiac hypertrophy [ 26 ] and myocardial ischemia/reperfusion injury [ 27 , 28 ].…”
Regulated in development and DNA damage response-1 (Redd1) is a stress-response gene that is transcriptionally induced by diverse stressful stimuli to influence cellular growth and survival. Although evidence suggests that aging may drive Redd1 expression in skeletal muscles, the expression patterns and functions of Redd1 in senescent cardiomyocytes remain unspecified. To address this issue,
in vitro
and
in vivo
models of cardiomyocyte senescence were established by administration of doxorubicin (Dox). Redd1 overexpression and knockdown was achieved in cultured H9c2 cardiomyocytes and mouse tissues using, respectively, lentivirals and adeno-associated virus 9 (AAV9) vectors. In the hearts of both aged (24 months old) and Dox-treated mice, as well as in Dox-exposed H9c2 cardiomyocytes, high Redd1 expression accompanied the increase in both cellular senescence markers (p16
INK4a
and p21) and pro-inflammatory cytokine expression indicative of a stress-associated secretory phenotype (SASP). Notably, Redd1 overexpression accentuated, whereas Redd1 silencing markedly attenuated, Dox-induced cardiomyocyte senescence features both
in vitro
and
in vivo
. Notably, AAV9-shRNA-mediated Redd1 silencing significantly alleviated Dox-induced cardiac dysfunction. Moreover, through pharmacological inhibition, immunofluorescence, and western blotting, signaling pathway analyses indicated that Redd1 promotes cardiomyocyte senescence as a downstream effector of p38 MAPK to promote NF-kB signaling via p65 phosphorylation and nuclear translocation.
“…Meanwhile, the abnormal function of immune cells was involved in tumor resistance of pancreatic cancer. DDIT4 enhanced vascular inflammation and permeability in endotoxemia mice, leading to immune cell infiltration, systemic inflammation, caspase-3 activation, and apoptosis [ 27 ]. DDIT4 was related to the low level of reactive oxygen species of mitochondria in macrophages induced by IL-10 or hypoxia [ 28 ], and it inhibited the immune function of macrophages.…”
Pancreatic cancer is one of the most common malignancies worldwide. This study is aimed at searching the possible genetic mutations and the value of novel gene mutation in the DNA damage-inducible transcript 4 (DDIT4) and signaling pathway in pancreatic cancer. Polymerase chain reaction (PCR) was performed to amplify the DNA sequences of DDIT4 from patients with pancreatic ductal adenocarcinoma. In addition, we used IHC to detect the expression level of DDIT4 in patients with pancreatic cancer in different types of gene mutation. Double-labeled immunofluorescence was employed to explore the expression levels of DDIT4/LC3 and their potential correlation. Our work indicated the two novel stable gene mutations in DDIT4 mRNA 3
′
-untranslated region (m.990 U>A and m.1246 C>U). Thirteen samples were found to have mutation in the DDIT4 3
′
-untranslated regions (UTR). To further verify the influence of gene mutation on protein expression, we performed immunohistochemistry on different gene mutation types, and we found a correlation between DDIT4 expression and gene mutation, which is accompanied by nuclear staining deepening. In order to further discuss the clinical value of DDIT4 gene mutation, immunofluorescence suggested that the expression of DDIT4 colocated with LC3; thus, we speculated that DDIT4 mutation may be involved in autophagy in pancreatic cancer cell. In this study, we found mutation in the 3
′
-UTR region of DDIT4, which may be associated with DDIT4 expression and tumor autophagy in pancreatic cancer tissues.
“…Mitochondrial‐mediated regulation of autophagy has both a direct and indirect relationship with the onset of tumours and represents a key regulator of quality control in tumour cells. The outcome of activation of the autophagy pathway may differ depending on the stage of tumour development 45 . In this experiment, the relationship between NF‐κB and the activation of autophagy was examined by investigating the activation of LC3‐II protein.…”
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