JOURNAL OF DRUG TARGETING
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2024
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IF 4.3
Xiaoli Li,Duanfang Zhou,Mingpu Liu,Hongfang Zeng,Xiaoping Yu,Yi Song,Qichen He,Xu Liu,Huan Zhang,Zhengze Shen,Zeng Zhu,Mingyan Gu,Xiangnan Hu,Weiying Zhou
Emerging data suggest that cocrystal of two compounds may have a different pharmacological effect from two compounds alone or their physical combination. Glimepiride (Gli) and metformin (Met) are two types of anti-diabetic drugs. Previously we generated the glimepiride/metformin cocrystal (GM). In this study, we evaluated the anti-diabetic effects of GM and explored the underlying mechanisms. Our result showed that GM reduced the blood glucose and HbA1c levels in db/db mice, and low doses of GM can achieve the hypoglycemic effect as Gli or Met alone, and high dose of GM was better than Gli and Met alone in improving the pathological changes of liver. In vivo studies showed that GM activated AMPK and STAT3 signaling, downregulated TXNIP expression and upregulated MaFA expression. Moreover, GM promoted the secretion of insulin in pancreas of db/db mice and in high glucose-treated INS-1 and MIN-6 cells. Together, GM possesses slightly better anti-diabetic effects than Met or Gli alone in db/db mice, and the mechanism of GM protecting β-cell dysfunction induced by glucotoxicity may be associated with activation of the AMPK/TXNIP/MaFA pathway.
研究领域:
药理学
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糖尿病研究
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
World Journal of Stem Cells
·
2025
·Vol. 17
·期 7
·104607
·
IF 3.6
Kun Wang,Wei Lin,Jun-Yong Han,Jin-Yan Chen,Rong-Hua Liu,Zhen Yu,Jing-Jun Jin
BACKGROUND Type 1 diabetes (T1D) results from the autoimmune-mediated loss of pancreatic β-cells. Current insulin therapies offer symptomatic relief but fall short of providing a definitive cure. Islet cell transplantation, while promising, faces limitations related to donor scarcity, procedural complexities, and the necessity for long-term immunosuppression. Consequently, there is an urgent need for innovative strategies aimed at β-cell regeneration. Patient-derived induced pluripotent stem cells (iPSCs), obtained from peripheral blood mononuclear cells (PBMCs) of T1D patients, hold great potential as a source of cells for therapeutic purposes. Therefore, the differentiation of T1D-iPSCs into functional pancreatic β-cells is a critical step toward effective β-cell replacement therapy. AIM To assess the potential of patient-derived T1D-β-like cells (differentiated from T1D-iPSCs reprogrammed from T1D-PBMCs) for restoring β-cell function in T1D. METHODS T1D-iPSCs were reprogrammed from T1D-PBMCs using an episomal vector-based approach. Pluripotency was confirmed by flow cytometry (FCM), quantitative real-time polymerase chain reaction, genomic stability analysis, and teratoma formation assays. Differentiation into pancreatic β-cells was optimized using triiodothyronine (T3), vitamin C (Vc), and an adenovirus (M3C) encoding pancreatic duodenal homeobox-1, neurogenin 3 ( Ngn3 ), and MAF bZIP transcription factor A ( MafA ). Following characterization of β-cell features by immunofluorescence, quantitative real-time polymerase chain reaction, and flow cytometry, therapeutic efficacy was assessed through blood glucose monitoring after transplantation under the renal capsule of streptozotocin-induced diabetic mice. RESULTS T1D-iPSCs were successfully generated from T1D-PBMCs. These cells exhibited the hallmark characteristics of pluripotent stem cells, including appropriate morphology, differentiation potential, genomic integrity, and expression of pluripotency-associated genes. Differentiation yielded insulin-positive (insulin + ) pancreatic β-like cells that, at the mRNA level, expressed key β-cell markers such as pancreatic duodenal homeobox-1, Ngn3 , MafA , NeuroD , glucagon-like peptide-1 receptor, Nkx6.1 , glucose transporter 2, and Kir6.2 . Notably, the T3 + Vc group displayed the lowest Ngn3 expression (1.31 ± 0.38 vs 1.96 ± 0.25 vs 2.51 ± 0.24, P < 0.01), while the M3C + T3 + Vc group exhibited the highest MafA expression (0.49 ± 0.11 vs 0.32 ± 0.06 vs 0.29 ± 0.08, P < 0.05). Both in vitro and in vivo assessments confirmed the insulin secretion ability of the generated β-like cells; however, they did not demonstrate appropriate modulation of insulin release in response to variations in extracellular glucose concentrations. CONCLUSION T1D-iPSCs derived from T1D-PBMCs can be differentiated into insulin + β-like cells, albeit with functional immaturity. These cells represent a potential source of seed cells for β-cell replacement therapy in T1D.
研究领域:
干细胞生物学
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糖尿病研究
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再生医学
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细胞分化
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基因表达
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转化医学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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