Lin28a expression protects against streptozotocin‐induced β‐cell destruction and prevents diabetes in mice

Sung, Yonghun; Jeong, Jin Woo; Kang, Ri Jin; Choi, Minjee; Park, Song; Kwon, Wookbong; Lee, Jin‐Hee; Jang, Soyoung; Park, Si Jun; Kim, Sung Hyun; Yi, Junkoo; Choi, Seong Kyoon; Lee, Mee-Hyun; Liu, Kangdong; Dong, Zigang; Ryoo, Zae Young; Kim, Myoung Ok

doi:10.1002/cbf.3376

Cited by 13 publications

(11 citation statements)

References 37 publications

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“…We suggest that it is possible that the upregulation of Let-7 in the hippocampus could aggravate the toxic effects of STZ via further dysregulation and inhibition of the insulin signaling pathway. This suggestion can be supported by a recent study that found that LIN-28a, which is a powerful inhibitor of Let-7 biogenesis, prevented the toxic effects of STZ on pancreatic β-cells, and that LIN-28a downregulation of Let-7 was associated with increased phosphorylation of PI3K and Akt in a mouse insulinoma cell line (Sung et al, 2019). Interestingly, estrogen binding to G-coupled estrogen receptor (GPER) could result in the activation of the PI3K/Akt pathway (Peixoto et al, 2017;Bian et al, 2019), which could lead to memory enhancement (Frick, 2019).…”

Section: Discussionmentioning

confidence: 70%

Effect of Letrozole on hippocampal let-7 microRNAs and their correlation with working memory and phosphorylated Tau protein level in an Alzheimer's disease rat model

Moustafa¹,

El-Sayed²,

Abd-Allah³

et al. 2021

Preprint

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Let-7 microRNAs may contribute to neurodegeneration, including Alzheimer's disease (AD), but, they were not investigated in Streptozotocin (STZ)-induced AD. Letrozole increases the expression of Let-7 in cell lines, with conflicting evidence regarding its effects on memory. This study examined Let-7 microRNAs in STZ-induced AD, their correlation with memory and hyperphosphorylated Tau (p-Tau) and the effects of Letrozole on them. Seven groups of adult Sprague Dawley rats were used: Intact, Letrozole, Letrozole Vehicle, STZ (with AD induced by intracerebroventricular injection of STZ in artificial CSF), CSF Control, STZ + Letrozole (STZ-L), and CSF + Letrozole Vehicle. Alternation percentage in T-maze was used as a measure of working memory. Let-7a, b and e and p-Tau levels in the hippocampus were estimated using qRT-PCR and ELISA, respectively. There were significant decreases in alternation percentage and increase in p-Tau in the STZ, Letrozole and STZ-L groups. Expression levels of all studied microRNAs were significantly elevated in the Letrozole and the STZ + L groups, with no difference between the two, suggesting that this elevation was due to Letrozole. Negative correlations were found between alternation percentage and the levels of all studied microRNAs, while positive ones were found between p-Tau concentration and the levels of studied microRNAs. These findings support the theory that Letrozole aggravates pre-existing lesions and add to the evidence of Let-7 neurotoxicity.

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Section: Discussionmentioning

confidence: 70%

Effect of Letrozole on hippocampal let-7 microRNAs and their correlation with working memory and phosphorylated Tau protein level in an Alzheimer's disease rat model

Moustafa¹,

El-Sayed²,

Abd-Allah³

et al. 2021

Preprint

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“…Several studies have shown that constitutively active Akt inhibits fatty acid-stimulated apoptosis in β-cells ( 27 , 28 ), and β-cell specific overexpression of Akt has also been shown to prolong cell survival and protect against streptozotocin-induced diabetes ( 29 ). In several cells, pancreatic β-cells, muscle cell and cardiomyocytes Lin28a has been reported to prevent apoptosis and regulate the PI3K/Akt/mTOR pathway through downregulation of micro RNA Let-7 ( 15 , 30 , 31 ). We found that INS-1 cells treated with high glucose had decreased phosphorylation of Akt and mTOR while Lin28a overexpression recovered the high glucose-induced downregulation of p-Akt and p-mTOR.…”

Section: Discussionmentioning

confidence: 99%

Lin28a ameliorates glucotoxicity-induced β-cell dysfunction and apoptosis

et al. 2021

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An excessive and prolonged increase in glucose levels causes β-cell dysregulation, which is accompanied by impaired insulin synthesis and secretion, a condition known as glucotoxicity. Although it is known that both Lin28a and Lin28b regulate glucose metabolism, other molecular mechanisms that may protect against glucotoxicity are poorly understood. We investigated whether Lin28a overexpression can improve glucotoxicity-induced β-cell dysregulation in INS-1 and primary rat islet cells. INS-1, a rat insulinoma cell line was cultured and primary rat islet cells were isolated from SD-rats. To define the effect of Lin28a in chronic high glucose-induced β-cell dysregulation, we performed several in vitro and ex-vivo experiments. Chronic exposure to high glucose led to a downregulation of Lin28a mRNA and protein expression, followed by a decrease in insulin mRNA expression and secretion in β-cells. The mRNA and protein expression levels of PDX-1 and BETA2, were reduced; The levels of apoptotic factors, including c-caspase3 and the Bax/Bcl-2 ratio, were increased due to glucotoxicity. Adenovirus-mediated Lin28a overexpression in β-cells reversed the glucotoxicity-induced reduction of insulin secretion and insulin mRNA expression via regulation of β-cell-enriched transcription factors such as PDX-1 and BETA2. Adenovirus-mediated overexpression of Lin28a downregulated the glucotoxicity-induced upregulation of c-caspase3 levels and the Bax/Bcl-2 ratio, while inhibition of endogenous Lin28a by small interfering RNA resulted in their up-regulation. Lin28a counteracted glucotoxicity-induced downregulation of p-Akt and p-mTOR. Our results suggest that Lin28a protects pancreatic β-cells from glucotoxicity through inhibition of apoptotic factors via the PI3 kinase/Akt/mTOR pathway.

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“…The increase in the blood glucose level is attributed to the cytotoxic effect of STZ on pancreatic cells (Waly et al, 2015). In addition, STZ leads to destruction of β-cells of Islets of Langerhans and malfunctioning of the pancreas resulting in the blood glucose elevation (Sung et al, 2019;Agila and Kavitha, 2012).…”

Section: Discussionmentioning

confidence: 99%

Anti-diabetic Potential Properties of Two Edible Omani Wild Plants (Pteropyrum scoparium and Oxalis corniculata)

Al-Qalhati

Waly

Al-Subhi

et al. 2021

Jour. Agri. & Mar. Scie.

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Background:The use of plant for medicinal purposes has a long history worldwide. There is a lack of research that identifies the antidiabetic effect of edible Omani wild plants. Oxidative stress mediates the pathogenesis of diabetes and it has been suggested that natural antioxidants might be considered as an effective intervention for combating diabetes. Objective: This study aimed to assess the anti-diabetic and antioxidant potential properties of two edible Omani wild plants (Pteropyrum scoparium and Oxalis corniculata) or their mixture in streptozotocin (STZ)-induced diabetic rats. Methods: Thirty-seven male Sprague Dawley rats, weighting 250–300 grams, were allocated into 5 groups: non-diabetic (9 rats/group), diabetic group (7 rats/group), and three diabetic groups that received oral feeding of either Pteropyrum scoparium, Oxalis corniculata, or their mixture (7 rats/group). Diabetes was induced by a single intraperitoneal injection dose of STZ drug, 50 mg/kg body weight. At the end of the experimental trial, after 8 weeks, all rats were fasted overnight and sacrificed; blood glucose was measured, meanwhile pancreatic tissues were dissected and homogenized for the biochemical assessment of oxidative stress markers (glutathione, GSH, and total antioxidant capacity, TAC). Results: STZ resulted in hyperglycemia and oxidative stress (GSH depletion and TAC impairment) in diabetic group as compared to non-diabetic group. Meanwhile the concomitant treatment of diabetic groups with the two wild the edible Omani plants or their mixture have shown a protective effect against the STZ-induced hyperglycemia, but with no effect on oxidative stress. It was noted that for the final boy weight, the improvement was not significant as well. Histopathological examination of the pancreatic tissues showed that the STZ injection lead to pathological changes associated with diabetes in the pancreatic tissues of all diabetic groups. Conclusion: Pteropyrum scoparium and Oxalis corniculata combated the STZ-induced hyperglycemia with no effect on oxidative stress. Also, there was no synergistic effect of Pteropyrum scoparium and Oxalis corniculata on hyperglycemia or oxidative stress.

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Lin28a expression protects against streptozotocin‐induced β‐cell destruction and prevents diabetes in mice

Cited by 13 publications

References 37 publications

Effect of Letrozole on hippocampal let-7 microRNAs and their correlation with working memory and phosphorylated Tau protein level in an Alzheimer's disease rat model

Effect of Letrozole on hippocampal let-7 microRNAs and their correlation with working memory and phosphorylated Tau protein level in an Alzheimer's disease rat model

Lin28a ameliorates glucotoxicity-induced β-cell dysfunction and apoptosis

Anti-diabetic Potential Properties of Two Edible Omani Wild Plants (Pteropyrum scoparium and Oxalis corniculata)

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