Protective effect of 7-O-succinyl macrolactin A against intestinal inflammation is mediated through PI3-kinase/Akt/mTOR and NF-κB signaling pathways

Park, Sumin; Regmi, Sushil Chandra; Park, Su‐Young; Lee, Eun Kyoung; Chang, Jae‐Hoon; Ku, Sae Kwang; Kim, Dong‐Hee; Kim, Jung-Ae

doi:10.1016/j.ejphar.2014.04.024

Cited by 45 publications

(29 citation statements)

References 43 publications

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“…2). TNF-␣ is the only known factor to activate mTORC1 via TSC1 rather than TSC2 and activates IB kinase-␤ (IKK␤), which interacts and inactivates TSC1 physically, to activate mTORC1 (43,56).…”

Section: Role Of the Mtor/s6k1 Signaling Pathway In Linking Overnutrimentioning

confidence: 99%

Overnutrition, mTOR signaling, and cardiovascular diseases

Jia

Aroor

Martinez‐Lemus

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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The prevalence of obesity and associated medical disorders has increased dramatically in the United States and throughout much of the world in the past decade. Obesity, induced by excess intake of carbohydrates and fats, is a major cause of Type 2 diabetes, hypertension, and the cardiorenal metabolic syndrome. There is emerging evidence that excessive nutrient intake promotes signaling through the mammalian target of rapamycin (mTOR), which, in turn, may lead to alterations of cellular metabolic signaling leading to insulin resistance and obesity-related diseases, such as diabetes, cardiovascular and kidney disease, as well as cancer. While the pivotal role of mTOR signaling in regulating metabolic stress, autophagy, and adaptive immune responses has received increasing attention, there remain many gaps in our knowledge regarding this important nutrient sensor. For example, the precise cellular signaling mechanisms linking excessive nutrient intake and enhanced mTOR signaling with increased cardiovascular and kidney disease, as well as cancer, are not well understood. In this review, we focus on the effects that the interaction between excess intake of nutrients and enhanced mTOR signaling have on the promotion of obesity-associated diseases and potential therapeutic strategies involving targeting mTOR signaling.

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Section: Role Of the Mtor/s6k1 Signaling Pathway In Linking Overnutrimentioning

confidence: 99%

Overnutrition, mTOR signaling, and cardiovascular diseases

Jia

Aroor

Martinez‐Lemus

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Macrolactin A (MA), a macrolide antibiotic with a 24-member lactone ring (Gustafson et al 1989), shows inhibitory effect on the proliferation of B16-F10 murine melanoma cancer cells and mammalian Herpes simplex viruses (type I and II), and protective effect on T-lymphocyte from HIV infection (Gustafson et al 1989). Recently, we reported that anti-inflammatory activity of 7-O-succinyl derivative of MA (SMA) is mediated through PI3K/Akt/mTOR pathway in colon epithelial cells (Park et al 2014). Compared to 14-membered ring macrolides such as roxithromycin and clarithromycin, which possess anti-angiogenic and anti-tumor activities (Yatsunami et al 1998(Yatsunami et al , 1999, MA and SMA have not been studied for their anti-angiogenic actions.…”

Section: Introductionmentioning

confidence: 99%

Anti-angiogenic activity of macrolactin A and its succinyl derivative is mediated through inhibition of class I PI3K activity and its signaling

et al. 2014

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In the current study, macrolactin compounds, macrolactin A (MA) and 7-O-succinyl macrolactin A (SMA), were investigated for their anti-angiogenic activities and action mechanism. MA and SMA inhibited in vitro and in vivo angiogenesis induced by three different classes of pro-angiogenic factors, VEGF, IL-8, and TNF-α. SMA exhibited stronger anti-angiogenic activity than MA, and such anti-angiogenic activity of SMA was consistently observed in MDA-MB-231 human breast cancer cell-inoculated CAM assay showing dose-dependent suppression of tumor growth and tumor-induced angiogenesis. In an in vitro PI3K competitive activity assay, SMA induced concentration-dependent inhibition of class I PI3K isoforms, p110α, p110β, p110δ, and p110γ. In addition, non-receptor tyrosine kinase c-Src, which is involved in the activation of PI3K heterodimer, was suppressed by MA and SMA. Correspondingly, MA and SMA significantly inhibited the stimulus-induced phosphorylation of Akt, mTOR, p70S6K, and ribosomal S6 in human umbilical vein endothelial cells (HUVECs). At the same time, the stimulus-induced production of reactive oxygen species (ROS) and activation of NF-κB were significantly suppressed by MA and SMA. Moreover, the macrolactins suppressed NF-κB-regulated HSP90 protein expression, which stabilizes phosphorylated Akt and NADPH oxidase. Suppression of NF-κB in macrolactin-treated HUVECs with concurrent inhibition of rS6 indicates that MAs effectively block angiogenesis through down-regulation of genes related to angiogenesis at both transcriptional and translational levels. Taken together, the results demonstrate that anti-angiogenic effect of MA and SMA is mediated through inhibition of PI3K/Akt and NADPH oxidase-derived ROS/NF-κB signaling pathways. These results further indicate that MA and SMA may be applicable for treatment of various diseases associated with angiogenesis.

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“…TNF-a induces phosphorylation of PI3K, Akt, and mTOR in colonic epithelial cell lines HT-29 and U937 cells [34]. In keratinocytes, we assessed whether TNF-a-induced production of inflammatory mediators and activation of NF-jB were mediated by the activation of Akt and mTOR.…”

Section: Discussionmentioning

confidence: 99%

Rotundarpene inhibits TNF-α-induced activation of the Akt, mTOR, and NF-κB pathways, and the JNK and p38 associated with production of reactive oxygen species

et al. 2017

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Ilex Rotunda Thunb has been shown to have anti-inflammatory and antioxidant effects. In human keratinocytes, we investigated the effect of rotundarpene (4-caffeoyl-3-methyl-but-2-ene-1,4-diol) on the TNF-α-stimulated production of inflammatory mediators in relation to the Akt, mTOR, and NF-κB pathways, and the JNK and p38-MAPK. Rotundarpene, Akt inhibitor, Bay 11-7085, rapamycin, and N-acetylcysteine inhibited the TNF-α-stimulated production of cytokines and chemokines, increase in the levels of p-Akt and mTOR, activation of NF-κB, and production of reactive oxygen species in keratinocytes. TNF-α treatment induced phosphorylation of the JNK and p38-MAPK. Inhibitors of the c-JNK (SP600125) and p38-MAPK (SB203580) reduced the TNF-α-induced production of inflammatory mediators, binding of NF-κB to DNA, and activation of the JNK and p38-MAPK in keratinocytes. The results show that rotundarpene may reduce the TNF-α-stimulated inflammatory mediator production by suppressing the reactive oxygen species-dependent activation of the Akt, mTOR, and NF-κB pathways, and activation of the JNK and p38-MAPK in human keratinocytes. Additionally, rotundarpene appears to attenuate the Akt, mTOR, and NF-κB pathways and the JNK and p38-MAPK-mediated inflammatory skin diseases.

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Protective effect of 7-O-succinyl macrolactin A against intestinal inflammation is mediated through PI3-kinase/Akt/mTOR and NF-κB signaling pathways

Cited by 45 publications

References 43 publications

Overnutrition, mTOR signaling, and cardiovascular diseases

Overnutrition, mTOR signaling, and cardiovascular diseases

Anti-angiogenic activity of macrolactin A and its succinyl derivative is mediated through inhibition of class I PI3K activity and its signaling

Rotundarpene inhibits TNF-α-induced activation of the Akt, mTOR, and NF-κB pathways, and the JNK and p38 associated with production of reactive oxygen species

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