Yalan Wu,Shengjun Wu,Xin-an Huang,Qingping Zeng,Tao Deng,Fang Liu
Primaquine (PMQ), an important anti-malarial drug, has been recommended by the World Health Organization (WHO) for the treatment of life-threatening infections caused by P. vivax and ovale. However, PMQ has unwanted adverse effects that lead to acute hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. There is a need to develop simple and reliable methods for PMQ determination with the purpose of dosage monitoring. In early 2019, we have reported an UV-Vis and naked-eye based approach for PMQ colorimetric quantification. The detection was based on a Griess-like reaction between PMQ and anilines, which can generate colored azo products. The detection limit for direct measurement of PMQ in synthetic urine is in the nanomolar range. Moreover, this method has shown great potential for PMQ quantification from human serum samples at clinically relevant concentrations. In this protocol, we will describe the technical details regarding the syntheses and characterization of colored azo products, the reagent preparation, and the procedures for PMQ determination.
Background The global prevalence of type 2 diabetes mellitus (T2DM) raises the rates of its complications, such as diabetic nephropathy and cardiovascular diseases. To conquer the complications, new strategies to reverse the deterioration of T2DM are urgently needed. In this project, we aimed to examine the hypoglycemic effect of primaquine and explore its specific target. Methods In vitro T2DM insulin resistance model was built in HepG2 cells to screen the potential anti-diabetic chemicals. On the other hand, the potential protein targets were explored by molecular docking. Accordingly, we chose C57BL/6 N mice to establish T2DM model to verify the effect of the chemicals on anti-hyperglycemia and diabetic complications. Results By targeting the Keratin 7 (K7) to activate EGFR/Akt glucose metabolism signaling pathway, primaquine poses a potent hypoglycemic effect. The level of acetyl-CoA is enhanced markedly, supporting that primaquine upregulates the aerobic glycolysis. Moreover, primaquine ameliorates kidney function by reducing the secretion of urinary proteins and creatinine, especially for the urea nitrogen which is significantly decreased compared to no-treatment T2DM mice. Notably, primaquine restores the level of plasma low-density lipoprotein cholesterol (LDL-C) nearly to normal, minimizing the incidence of cardiovascular diseases. Conclusions We find that primaquine may reverse the dysregulated metabolism to prevent diabetic complications by stimulating EGFR/Akt signaling axis, shedding new light on the therapy of T2DM. Graphical abstract
Insulin resistance is characterized by reduced p-Akt and glucose metabolism, dominated by anaerobic glycolysis. Primaquine activates the complex made of K7 and EGFR, further stimulating Akt phosphorylation. Then, p-Akt promotes the aerobic glucose metabolism and upregulates Ac-CoA to mobilize TCA cycle, improving insulin sensitivity.
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