A novel mTOR inhibitor is efficacious in a murine model of colitis

Bhonde, Mandar; Gupte, Ravindra D.; Dadarkar, Shruta D; Jadhav, Mahesh; Tannu, Aditi A; Bhatt, Pooja; Bhatia, Dimple; Desai, Nikesh; Deore, Vijaykumar; Yewalkar, Nilambari; Vishwakarma, Ram A.; Sharma, Somesh; Kumar, Sanjay; Dagia, Nilesh M.

doi:10.1152/ajpgi.90537.2008

Cited by 31 publications

(28 citation statements)

References 57 publications

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“…LY294002 and SB203580 were used as positive controls for inhibition of AKT and IKK/IB␣, respectively. Densitometry analysis was performed as reported previously (6).…”

Section: Western Blot Analysismentioning

confidence: 99%

“…Human peripheral blood mononuclear cells (hPBMC) were harvested using FicollHypaque density gradient centrifugation (1.077 g/ml; Sigma Aldrich, St. Louis, MO) (6,13,15) and suspended in assay medium (RPMI 1640 culture medium; Sigma Aldrich) containing 10% heat-inactivated fetal bovine serum (JRH), 100 U/ml penicillin (Sigma Chemical), and 100 g/ml streptomycin (Sigma Chemical). Monocytes in the hPBMCs were counted using a Coulter counter, following which the cells were resuspended at 2 ϫ 10 5 monocytes/ml of assay medium.…”

Section: Human Monocyte Assaymentioning

confidence: 99%

“…The procedure followed to ascertain the effects of PIK-75 on in vivo LPS-induced production of TNF-␣ and IL-6 was as reported elsewhere (6). PIK-75 was orally administered at doses of 1, 10, 25, and 50 mg/kg in the form of a suspension in carboxymethylcellulose (CMC; Sigma Aldrich).…”

Section: In Vivo Lps Assaymentioning

confidence: 99%

“…The above, combined with the observation that an oral dose of 10 mg/kg PIK-75 blunts in vivo-induced production of TNF-␣ and IL-6 by Ͼ50%, but Ͻ100% (see RESULTS section), led us to investigate the effect of PIK-75 in experimental colitis at an oral dose of 10 mg/kg. Colitis was induced in mice by giving 3% (wt/vol) dextran sulfate sodium (DSS; molecular mass 30 -40 kDa; ICN Biomedicals, Aurora, OH) in drinking water ad libitum, as described previously (6,15). DSS-induced colitis was assessed by macroscopic and histological analyses of the colon, as described previously (6,15).…”

Section: Monocyte Endothelial Cell Adhesion Assaymentioning

confidence: 99%

“…Colitis was induced in mice by giving 3% (wt/vol) dextran sulfate sodium (DSS; molecular mass 30 -40 kDa; ICN Biomedicals, Aurora, OH) in drinking water ad libitum, as described previously (6,15). DSS-induced colitis was assessed by macroscopic and histological analyses of the colon, as described previously (6,15). To probe the efficacy of PIK-75, a group of mice were given daily oral administration of 10 mg/kg PIK-75 suspension in CMC (Sigma Aldrich).…”

Section: Monocyte Endothelial Cell Adhesion Assaymentioning

confidence: 99%

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A preferential p110α/γ PI3K inhibitor attenuates experimental inflammation by suppressing the production of proinflammatory mediators in a NF-κB-dependent manner

Dagia¹,

Agarwal²,

Kamath³

et al. 2010

American Journal of Physiology-Cell Physiology

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“…LY294002 and SB203580 were used as positive controls for inhibition of AKT and IKK/IB␣, respectively. Densitometry analysis was performed as reported previously (6).…”

Section: Western Blot Analysismentioning

confidence: 99%

Section: Human Monocyte Assaymentioning

confidence: 99%

Section: In Vivo Lps Assaymentioning

confidence: 99%

Section: Monocyte Endothelial Cell Adhesion Assaymentioning

confidence: 99%

Section: Monocyte Endothelial Cell Adhesion Assaymentioning

confidence: 99%

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A preferential p110α/γ PI3K inhibitor attenuates experimental inflammation by suppressing the production of proinflammatory mediators in a NF-κB-dependent manner

Dagia¹,

Agarwal²,

Kamath³

et al. 2010

American Journal of Physiology-Cell Physiology

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Mango polyphenolics reduce inflammation in intestinal colitis-involvement of the miR-126/PI3K/AKT/mTOR axis in vitro and in vivo

et al. 2016

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This study sought to elucidate the mechanisms underlying the anti-inflammatory effect of mango (Mangifera Indica L.) polyphenolics containing gallic acid and gallotanins, and the role of the miR-126/PI3K/AKT/mTOR signaling axis in vitro and in vivo. Polyphenolics extracted from mango (var. Keitt) were investigated in lipopolysaccharide (LPS)-treated CCD-18Co cells. Rats received either a beverage with mango polyphenolics or a control beverage, and were exposed to three cycles of 3% dextran sodium sulfate (DSS) followed by a 2-wk recovery period. The mango extract (10 mg GAE/L) suppressed the protein expression of NF-κB, p-NF-κB, PI3K (p85β), HIF-1α, p70S6K1, and RPS6 in LPS-treated CCD-18Co cells. LPS reduced miR-126 expression, whereas, the mango extract induced miR-126 expression in a dose-dependent manner. The relationship between miR-126 and its target, PI3K (p85β), was confirmed by treating cells with miR-126 antagomiR where mango polyphenols reversed the effects of the antagomiR. In vivo, mango beverage protected against DSS-induced colonic inflammation (47%, P = 0.05) and decreased the Ki-67 labeling index in the central and basal regions compared to the control. Mango beverage significantly attenuated the expression of pro-inflammatory cytokines such as TNF-α, IL-1β, and iNOS at the mRNA and protein level. Moreover, the expression of PI3K, AKT, and mTOR was reduced, whereas, miR-126 was upregulated by the mango treatment. These results suggest that mango polyphenols attenuated inflammatory response by modulating the PI3K/AKT/mTOR pathway at least in part through upregulation of miRNA-126 expression both in vitro and in vivo; thus, mango polyphenolics might be relevant as preventive agents in ulcerative colitis.

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Comparison of anti‐inflammatory mechanisms of mango (Mangifera Indica L.) and pomegranate (Punica Granatum L.) in a preclinical model of colitis

Kim

Banerjee

Ivanov

et al. 2016

Molecular Nutrition Food Res

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Scope Tannin-rich fruits have been evaluated as alternative prevention strategies for colorectal cancer based on their anti-inflammatory properties. This study compared tannin-rich preparations from mango (rich in gallotannins) and pomegranate (rich in ellagitannins) in the dextran sodium sulfate-induced colitis model. Methods and results In rats, mango and pomegranate beverages decreased intestinal inflammation and the levels of pro-inflammatory cytokines in mucosa and serum. The mango beverage suppressed the ratio of phosphorylated/total protein expression of the IGF-1R-AKT/mTOR axis and down-regulated mRNA expression of Igf1, Insr, and pik3cv. Pomegranate decreased p70S6K and RPS6, as well as Rps6ka2, Map2k2, and Mapk1 mRNA. In silico modeling indicated a high binding-docked of gallic acid to the catalytic domain of IGF-1R, which may suppress the activity of the enzyme. Ellagic acid docked effectively into the catalytic domains of both IGF-1R and EGFR. In vitro assays with lipopolysaccharide-treated CCD-18Co cells using polyphenolic extracts from each beverage, as well as pure compounds, corroborated the predictions made in silico. Conclusion Mango polyphenols inhibited the IGF-1R- AKT/mTOR axis, and pomegranate polyphenols downregulate the mTOR downstream pathway through reductions in ERK1/2. These results suggest that extracts rich in gallo- and ellagitannins act on different molecular targets in the protection against ulcerative colitis.

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A novel mTOR inhibitor is efficacious in a murine model of colitis

Abstract: Bhonde MR, Gupte RD, Dadarkar SD, Jadhav MG, Tannu AA, Bhatt P, Bhatia DR, Desai NK, Deore V, Yewalkar N, Vishwakarma RA, Sharma S, Kumar S, Dagia NM. A novel mTOR inhibitor is efficacious in a murine model of colitis.

Cited by 31 publications

References 57 publications

A preferential p110α/γ PI3K inhibitor attenuates experimental inflammation by suppressing the production of proinflammatory mediators in a NF-κB-dependent manner

A preferential p110α/γ PI3K inhibitor attenuates experimental inflammation by suppressing the production of proinflammatory mediators in a NF-κB-dependent manner

Mango polyphenolics reduce inflammation in intestinal colitis-involvement of the miR-126/PI3K/AKT/mTOR axis in vitro and in vivo

Comparison of anti‐inflammatory mechanisms of mango (Mangifera Indica L.) and pomegranate (Punica Granatum L.) in a preclinical model of colitis

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