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Exendin-4 Exhibits Enhanced Anti-tumor Effects in Diabetic Mice.

ABSTRACT: Type 2 diabetes (T2D) is associated with increased risk of cancers. In this connection, we previously demonstrated the promoting effect of diabetes on HPV-associated carcinogenesis using a xenograft model in db/db diabetic mice. The underlying mechanism of this observation might be partly contributed by dysregulated immune response in diabetes. In this study, we hypothesized that the impaired anti-tumor immune response in diabetic status could be modulated by exendin-4, a glucagon-like protein receptor agonist which exhibits anti-diabetic effects. We inoculated 10-week old db/db mice with 2?×?10⁷ CUP-1 cells (Human Papilloma Virus (HPV)-16 E7 transfected continuous cell line) subcutaneously underneath the scruff, and treated mice with high (30 nmol/kg) or low (10 nmol/kg) dose of exendin-4 for 13 days. Compared with control groups, exendin-4 suppressed subcutaneous tumor growth in a dose-dependent manner, accompanied by increased interferon (IFN)-? secreting CD8⁺ cytotoxic T lymphocyte (CTL)/Foxp3⁺ regulatory T cell (Treg) ratio as well as Th1 proinflammatory cytokines IFN-? and IL-2. Collectively, these findings suggested an anti-tumor effect of exendin-4 in diabetic conditions, which might be resulted from direct immunomodulation.

SUBMITTER: He L

PROVIDER: S-EPMC5431757 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Exendin-4 Exhibits Enhanced Anti-tumor Effects in Diabetic Mice.

He Lan L Law Priscilla T Y PTY Wong Chun Kwok CK Chan Juliana C N JCN Chan Paul K S PKS

Scientific reports 20170511 1

Type 2 diabetes (T2D) is associated with increased risk of cancers. In this connection, we previously demonstrated the promoting effect of diabetes on HPV-associated carcinogenesis using a xenograft model in db/db diabetic mice. The underlying mechanism of this observation might be partly contributed by dysregulated immune response in diabetes. In this study, we hypothesized that the impaired anti-tumor immune response in diabetic status could be modulated by exendin-4, a glucagon-like protein r ...[more]

PMID: 28496193

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Project description:BackgroundCurculigo recurvata (C. recurvata) is an enthnomedicinally important herb reported to have significant medicinal values. The present study aimed to explore the in vivo and in silico anti-nociceptive and anti-diarrheal effects of a C. recurvate rhizome methanol extract (Me-RCR).MethodsThe analgesic effects of Me-RCR were assessed using acetic acid-induced writhing and the formalin-induced flicking test. The drugs were administered intraperitoneally (IP) at doses of 200 and 400 mg/kg body weight (bw). Anti-diarrheal activity was evaluated by assessing intestinal motility, hypersecretion, and fecal score in mice at oral doses of 200 and 400 mg/kg·bw. Computer facilitated analyses for anti-nociceptive and anti-diarrheal activities of three isolated compounds from C. recurvata were undertaken to identify the best-fit phytoconstituents.ResultsThe Me-RCR showed significant (P < .05) peripheral anti-nociception at the highest dose. The extract inhibited both early and late phases of nociception in the formalin-induced writhing test. In the castor oil-induced diarrhoea model, the extract significantly (P < .05) prolonged the onset time of diarrhoea, inhibited percentage of diarrhoea, and decreased both the volume and weight of intestinal contents. Rates of intestinal fluid accumulation inhibition were (33.61 ± 1.00)% and (46.44 ± 0.89)% at Me-RCR doses of 200 and 400 mg/kg·bw, respectively. Moreover, a significant (P < .05) reduction in gastrointestinal motility was observed. An absorption, distribution, metabolism, excretion and/or toxicity (ADME/T) test showed that the selected compounds yielded promising results, satisfying Lipinski's rule of five for predicting drug-like potential. Notably, of the three phytoconstituents curculigine and isocurculigine possessed the highest affinity for the COX-1 and COX-2. Isocurculigine was also identified as the most effective anti-diarrheal compound in the computer-facilitated model.ConclusionAn extract of the plant C. recurvata showed potential analgesic and anti-diarrheal activity due to the presence of one or more active secondary metabolite(s).

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Exendin-4 Exhibits Enhanced Anti-tumor Effects in Diabetic Mice.

Publications

Exendin-4 Exhibits Enhanced Anti-tumor Effects in Diabetic Mice.

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