PDX-1: A Promising Therapeutic Target to Reverse Diabetes
Abstract
:1. Introduction
2. Gene Structure and Location, Protein Molecular Structure, Distribution, and Expression of PDX-1
2.1. Localization and Molecular Structure of PDX-1
2.2. Tissue Distribution and Expression of PDX-1
3. Factors Regulating PDX-1 Expression
3.1. Nutrient Substances
3.2. Hormones
3.3. Oxidative Stress
3.4. Cytokines
4. PDX-1 and the Pancreas
4.1. PDX-1 Promotes Pancreatic Development and Islet Cell Differentiation
4.2. PDX-1 Adjusts the Dedifferentiation, Redifferentiation, and Transdifferentiation of β-Cell
4.3. PDX-1 Regulates the Expression of the Insulin Gene and Insulin Secretion-Related Genes
4.3.1. Insulin
4.3.2. GCK
4.3.3. GLUT-2
4.3.4. IAPP
4.4. Mitochondrial Dysfunction
5. PDX-1 Is Involved in the Regulation of the Insulin Signaling Pathway
6. PDX-1 and the Reversal of T2DM
7. Conclusions and Future Prospects
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Upstream | Downstream | |
---|---|---|
1 | glucose | insulin |
2 | lipid | GCK |
3 | GLP-1 | GLUT-2 |
4 | ROS | IAPP |
5 | HNF-3β | somatostatin |
6 | HNF-6 | Ngn3 |
7 | TGF-β | Insm2 |
8 | PPAR-γ | synaptophysin |
9 | HNF-1α | Pax4 |
10 | Sp1 | MafA |
11 | HMGA1 | Nkx6.1 |
12 | FoxO1 | |
13 | Foxa1 | |
14 | Foxa2 | |
15 | PKA | |
16 | c-JUN | |
17 | JNK |
Number | Name | Experimental Model | Administration Dose | Drug Effect | Reference |
---|---|---|---|---|---|
1 | Swietenine (Stn) and swietenolide (Std) | INS-1 cells (Procell CL-0368) | 2 μM, 5 μM, 8 μM, 10 μM, 15 μM, 20 μM, 30 μM, 40 μM, 50 μM | It up-regulates the expression of PDX-1 protein, improves the insulin secretion function, protects oxidative stress injury, and reduces apoptosis. | [150] |
2 | Loureirin B | 3-week-old male C57BL/6J mice (14–15 g) | 45 mg/kg i.g. | It activates the AKT/PDX-1 signaling pathway. | [151] |
3 | Medicago sativa L. | Bone marrow mesenchymal stem cells (MSCs) | 50 μg/mL | It has the potential of differentiation induction of MSCs into IPCs with the characteristics of pancreatic β-like cells. | [152] |
4 | Nigella sativa seed | Male diabetic Wistar rats | 200 mg/kg, 400 mg/kg p.o. | It reduces oxidative stress and tissue damage, modifies the expression levels of PDX-1 and MafA genes, and regulates insulin secretion and blood glucose levels. | [153] |
5 | HDPs-2A (a polysaccharide purified from Hovenia dulcis) | 7-week-old male Sprague Dawley (SD) rats (170 ± 10 g) | 300 mg/kg, 200 mg/kg, 100 mg/kg, p.o. | It up-regulates PDX-1, activates and up-regulates IRS2 expression, and regulates apoptosis and regeneration of islet β cells to recover islet β-cell function injury in TIDM rats. | [154] |
6 | Thiamine disulfide (TD) | 4-week-old male Wistar rats (180–250 g) | 40 mg/kg i.p. | It increases serum insulin levels, IIR, and expression of PDX-1 and GLUT-2 genes. | [155] |
7 | Gymnemic acid (GA) | 2-month-old male albino Wistar rats (130–150 g) | 150 mg/kg p.o. | It ameliorates pancreatic β-cell dysfunction by modulating PDX-1 expression. | [156] |
8 | Cordycepin | INS-1 cells | 0.5~20 μM | It upregulates the mRNA level and protein expression of insulin, PDX-1, and GLUT-1. | [157] |
9 | Carnosic acid (CA) | INS-1 cells | 2.5 μM, 5 μM, 10 μM | It can protect β-cells through the PI3K/AKT/PDX-1/insulin pathway and mitochondria-mediated apoptosis. | [158] |
10 | Icariin | 6-week-old male albino rats (170–200 g) | 100 mg/kg p.o. | Icariin, and/or MSCs promoted the regeneration of pancreatic tissues by releasing PDX-1 and MafA involved in the recruitment of stem/progenitor cells in the tissue. | [159] |
11 | Hesperidin | Male Sprague Dawley rats | 100 mg·kg−1 p.o. | It enhances β-cell proliferation and repair and raises serum insulin levels. | [160] |
12 | A new form of silymarin solution (NFSM) | Male Wistar rats (220–250 g) | 100 mg/kg p.o. | It increases the expression of PDX-1 and insulin genes. | [161] |
13 | Oligosaccharide fraction isolated from Rosa canina | 8-week-old male Wistar rats (200–250 g) | 10, 20 and 30 mg/kg i.g. | It increases the expression of PDX-1 and may contribute to the modulation of DNA methylation. | [162] |
14 | Andrographolide named C1037 | 8-week-old male Kunming mice (18–22 g) | 50 mg/kg i.g. | It promotes pancreatic duct cell differentiation into insulin-producing cells by targeting PDX-1. | [149] |
15 | Tectorigenin | INS-1 cells;Diet-induced obese C57BL/6J mice | 40 μg/mL; 10, 20, 40 mg/kg i.p. | It enhances PDX-1 expression and protects pancreatic β-cells by activating ERK and reducing ER stress. | [145] |
16 | Stigmasterol-3-O-β-d-glucoside | INS-1 cells | 5 μM,10 μM | It enhances the PI3K-dependent phosphorylation of Akt at Ser473. The PI3K-dependent phosphorylation of Akt induces the movement of PDX-1 from the nucleus to the cytoplasm and regulates the proliferation of pancreatic β-cells. | [147] |
17 | Naringin (4′,5,7-Trihydroxyflavanone 7-Rhamnoglucoside) | Male adult Wistar rats (250–300 g) | 100 mg/kg p.o. | It increases insulin gene expression and insulin secretion by upregulating the PDX-1 gene and protein expression. | [148] |
18 | Small molecule kaempferol | INS-1E cells | 0.1 μM, 1 μM, 10 μM | It protects islet cells through PDX-1/cAMP/PKA/CREB signaling pathway. | [163] |
19 | Resveratrol | αTC9 cells | 25 μM | It inhibits histone deacetylase and promotes insulin expression synthesis by increasing PDX-1 expression levels. | [164] |
20 | Jin-tang-ning (JTN) | 8-week-old female KKAy mice and gender-matched C57BL/6J mice | 8 g JTN powder/kg | It upregulates expression levels of GCK and PDX-1. | [165] |
21 | DA-1241 | 7-week-old male ICR mice and Sprague-Dawley (SD) rats | 100 mg/kg i.p. | It can preserve pancreatic functions by suppressing ER stress and increasing PDX-1 expression. | [142] |
22 | Acarbose | 8-week-old db/db mice and male -+/db mice | 9 g/kg | It prevents the nuclear export of PDX-1 and blocks the increase in methylated PDX-1 in T2DM mouse β-cells. | [144] |
23 | Liraglutide | Rat RINm5F β-cell | 0.1 μmol/L | It can restore the expression of PDX-1 and upregulate mitophagy to restore mitochondrial function and ameliorate β-cell impairment. | [143] |
24 | Exendin-4 | 3-week-old C57BL/6J mice | 10 μg/kg | It can improve T2DM progression by reversing global pancreatic histone H3K9 and H3K23 acetylation, H3K4 mono-methylation, and H3K9 di-methylation and also reverse the inhibitory state of PDX-1. | [141] |
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Zhang, Y.; Fang, X.; Wei, J.; Miao, R.; Wu, H.; Ma, K.; Tian, J. PDX-1: A Promising Therapeutic Target to Reverse Diabetes. Biomolecules 2022, 12, 1785. https://doi.org/10.3390/biom12121785
Zhang Y, Fang X, Wei J, Miao R, Wu H, Ma K, Tian J. PDX-1: A Promising Therapeutic Target to Reverse Diabetes. Biomolecules. 2022; 12(12):1785. https://doi.org/10.3390/biom12121785
Chicago/Turabian StyleZhang, Yanjiao, Xinyi Fang, Jiahua Wei, Runyu Miao, Haoran Wu, Kaile Ma, and Jiaxing Tian. 2022. "PDX-1: A Promising Therapeutic Target to Reverse Diabetes" Biomolecules 12, no. 12: 1785. https://doi.org/10.3390/biom12121785