Insulinotropic and anti-apoptotic effects of nobiletin in INS-1D β-cells

Takii, Miki; Kaneko, Yukiko; Akiyama, Kiriko; Aoyagi, Yuki; Tara, Yuki; Asakawa, Tomohiro; Inai, Makoto; Kobayashi, Toshiyuki; Nemoto, Kiyomitsu; Ishikawa, Tomohisa

doi:10.1016/j.jff.2016.12.037

Cited by 15 publications

(12 citation statements)

References 44 publications

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“…The anti-apoptotic and insulinotopic features of nobiletin on the human isolated islets are similar to glucagon-like peptide-1and prolactin 31,32 where both these drugs reduced the number of apoptotic islets via inhibition of active Caspase-8, -9, and -3 and up-regulation of Bcl-2 in the cultured rat islets and improved the function of islets through increase in the insulin secretion 31,32 . In a recent report, nobiletin (10 µM) also inhibited β-cell apoptosis through activation of cyclic adenosine monophosphate (cAMP) pathway and downstream target protein kinase A (PKA) in INS-1D β-cell line and enhanced insulin secretion through another downstream target of cAMP called exchange proteins directly activated by cAMP (EPACs) 24 . Of note to this study, nobiletin may act via cAMP pathway in the isolated islets.…”

Section: Discussionmentioning

confidence: 99%

“…Findings have suggested that nobiletin protects the cells from apoptosis through activation of cyclic AMP-responsive element binding protein (CREB) and PI3/Akt pathways. These pathways promoted their target molecules including brain-derived neurotrophic factor (BDNF) and B-cell lymphoma 2 (Bcl-2), and inhibited Bcl-2-associated X protein (Bax) and caspase-3 16,21–24 . It has also been reported that nobiletin reduces the oxidative stress-induced apoptosis via decreasing ROS and increasing the anti-oxidant enzyme activities 21,25,26 .…”

Section: Introductionmentioning

confidence: 99%

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Protective effect of nobiletin on isolated human islets survival and function against hypoxia and oxidative stress-induced apoptosis

Keshtkar

Kaviani

Jabbarpour

et al. 2019

Sci Rep

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Islets transplantation, as a treatment of type 1 diabetes, faces challenges, including the loss of islets in the process of isolation and pre-transplantation due to cellular stresses-induced apoptosis. Accordingly, the optimization of culture plays a decisive role in the transplantation success. In this study, we evaluated the effect of nobiletin on the cultured human islets. Isolated human islets were treated by different concentrations of nobiletin and cultured for 24 and 72 hours. Then, the islets viability, apoptosis, insulin and C-peptide secretion, and apoptosis markers were evaluated. Also, the production of reactive oxygen species (ROS), hypoxia inducible factor 1 alpha (HIF-1α), and its target genes in the islets were examined. Our findings showed that the islets were encountered with hypoxia and oxidative stress after isolation and during culture. These insults induced apoptosis and reduced viability during culture period. Moreover, the secretion of insulin and C-peptide decreased. Nobiletin treatments significantly improved the islets survival through reduction of HIF-1α and ROS production and suppression of apoptosis, along with increased islets function. Islet protective effect of nobiletin might be related to its anti-oxidant, anti-apoptotic and insulinotropic properties. Hence, in order to achieve viable and functional islets for clinical transplantation, the application of nobiletin during pre-transplantation period is useful.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Protective effect of nobiletin on isolated human islets survival and function against hypoxia and oxidative stress-induced apoptosis

Keshtkar

Kaviani

Jabbarpour

et al. 2019

Sci Rep

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“…The modified synthesis of pentamethoxybenzene (10) started from inexpensive 1,2,3-trimethoxybenzene (11) (Scheme 3). The introduction of the hydroxyl group was achieved by formylation followed by Baeyer−Villiger oxidation.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…This total synthesis of 1 was accomplished in 35% total yield in 11 steps starting from 11. 10 Our synthetic route illustrated in Scheme 4 was applied to the hundred gram scale preparation of nobiletin by USHIOchemix Ltd., and we and our collaborators are currently using this material for detailed investigation of its biological activities 11 and toxicological testing.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Practical Synthesis of Polymethylated Flavones: Nobiletin and Its Desmethyl Derivatives

Asakawa

Sagara

Kanakogi

et al. 2019

Org. Process Res. Dev.

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We present a practical synthesis of the polymethoxylated citrus flavone nobiletin that is suitable for use on a hundred gram scale. Ready availability of this compound and its derivatives will aid detailed chemical-biological investigations of their biological activities, including activation of signaling via the cAMP-dependent protein kinase A/extracellular signal-related protein kinase/cAMP response element-binding protein pathway.

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“…In non-tumor cells, NOB had an important protective effect on apoptosis induced by external factors. It has been reported that NOB inhibited apoptosis induced by thapsigargin in INS-1D β-cells [15] and hypoxia/reoxygenation in H9c2 cardiomyocytes [16]. After islets transplantation in humans, apoptosis of isolated islets cells could also be ameliorated by NOB [17].…”

Section: Introductionmentioning

confidence: 97%

The Effects of 5,6,7,8,3′,4′-Hexamethoxyflavone on Apoptosis of Cultured Human Choriocarcinoma Trophoblast Cells

Zhang

Liu

et al. 2020

Molecules

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5,6,7,8,3,4′-Hexamethoxyflavone, also called nobiletin (NOB), widely found in the citrus peel, is one of the main byproducts in citrus processing. NOB is considered safe, but its safety for women during pregnancy is unknown. Therefore, the effect of NOB on apoptosis in human choriocarcinoma trophoblast cells (BeWo cells) was evaluated. Cells were divided into four groups and cultured with different concentrations of NOB (0, 10, 33, and 100 μM) for 12, 24, 36, and 48 h respectively. Cell viability was detected by CCK-8 assay, cell morphology was detected by a Cell Imaging Multi-Mode Reader, and cell cycle and apoptosis were detected by flow cytometry. Cleaved PARP level, the expressions of B cell lymphoma 2 (BCL2) family proteins, and p53 pathway proteins were detected by Western blot. The results showed that after 48 h of cell culture, the cell viability was decreased significantly, but apoptosis was significantly increased. Compared to the cells without NOB treatment, the cells treated with NOB at 10 or 33 μΜ showed no significant differences in the number of suspended cells or late apoptosis rate, except the increase of cell viability. Treatment of NOB at the concentration of 100 μM improved cell viability, attenuated apoptosis, decreased suspended cells, and did not alter the G1 phase arrest, compared with the non-NOB-treated group after 48 h of culturing. The 100 μΜ NOB treatment increased the levels of BCL2 and BCLXL, and decreased p53 accumulation in BeWo cells at 48 h, but had no effect on the expression of BAX, BAK, BAD, p21, and G1 phase arrest. These findings provide evidence that NOB (10, 33, and 100 μΜ) was safe for BeWo cells. NOB at the concentration of 100 μΜ could attenuate apoptosis in BeWo cells, which might be helpful to prevent pregnancy-related diseases caused by apoptosis.

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Insulinotropic and anti-apoptotic effects of nobiletin in INS-1D β-cells

Cited by 15 publications

References 44 publications

Protective effect of nobiletin on isolated human islets survival and function against hypoxia and oxidative stress-induced apoptosis

Protective effect of nobiletin on isolated human islets survival and function against hypoxia and oxidative stress-induced apoptosis

Practical Synthesis of Polymethylated Flavones: Nobiletin and Its Desmethyl Derivatives

The Effects of 5,6,7,8,3′,4′-Hexamethoxyflavone on Apoptosis of Cultured Human Choriocarcinoma Trophoblast Cells

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