Bufadienolides are the major pharmacologic constituents of traditional Chinese medicine Chan'su, which is frequently used clinically for cancer treatment in China. Motivated by reducing or avoiding the cardiac toxicity of bufadienolides, we have designed, synthesized, and evaluated the fibroblast activation protein α (FAPα) activated tripeptide arenobufagin prodrugs with the purpose of improving the safety of arenobufagin (a representative bufadienolide). Among these FAPα-activated prodrugs, 3f exhibited the best hydrolytic efficiency by recombinant human FAPα (rhFAPα) and was activated in tumors. The LD of 3f was 6.5-fold higher than that of arenobufagin. We also observed that there are nonapparent changes in echocardiography, pathological section of cardiac muscle, and the lactate dehydrogenase activities (LDH) in 3f-treatment tumor-bearing mice, even when the dose reached 3 times the amount of parent drug arenobufagin that was used. Compound 3f also exhibits significant antitumor activity in vitro and in vivo. The improved safety profile and favorable anticancer properties of 3f warrant further studies of the potential clinical implications. Our study suggests that FAPα prodrug strategy is an effective approach for successful increasing the therapeutic window of bufadienolides.

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Diabetic kidney disease (DKD) is the leading cause of end-stage renal failure, but therapeutic options for nephroprotection are limited. Oxidative stress plays a key role in the pathogenesis of DKD. Our previous studies demonstrated that tetramethylpyrazine nitrone (TBN), a novel nitrone derivative of tetramethylpyrazine with potent free radical-scavenging activity, exerted multifunctional neuroprotection in neurological diseases. However, the effect of TBN on DKD and its underlying mechanisms of action are not yet clear. Herein, we performed streptozotocin-induced rat models of DKD and found that TBN administrated orally twice daily for 6 weeks significantly lowered urinary albumin, N-acetyl-β-D-glycosaminidase, cystatin C, malonaldehyde, and 8-hydroxy-2′-deoxyguanosine levels. TBN also ameliorated renal histopathological changes. More importantly, in a nonhuman primate model of spontaneous stage III DKD, TBN increased the estimated glomerular filtration rate, decreased serum 3-nitrotyrosine, malonaldehyde and 8-hydroxy-2′-deoxyguanosine levels, and improved metabolic abnormalities. In HK-2 cells, TBN increased glycolytic and mitochondrial functions. The protective mechanism of TBN might involve the activation of AMPK/PGC-1α-mediated downstream signaling pathways, thereby improving mitochondrial function and reducing oxidative stress in the kidneys of DKD rodent models. These results support the clinical development of TBN for the treatment of DKD.

Porous hydroxyapatite-biochar composites with layered microstructures (SC–HA/C) were prepared by carbonizing sugarcane stem nodes and then soaking them in lime water and (NH4)2HPO4 solutions in rotation. The surface area of SC–HA/C ranges from 8.52 to 28.44 m2/g, and its microstructure inherits various macro-, meso-, and micro-pores in the cell walls of sugarcane and in the pits of the vessel walls. The maximum removal capacities were 11.50, 14.65, and 19.81 mg/g for the Cu (II) immobilization at 25 °C, 35 °C, and 45 °C with the solution Cu (II) concentration of 10~320 mg/L, respectively, which were in accordance with the copper sorption capacities of synthesized nano-hydroxylapatites. The Cu (II)-removal kinetics and isotherm followed the pseudo-second-order equation and the Langmuir equation very well. The formation of the Cu-containing hydroxylapatite solid solutions ((CuxCa1−x)5(PO4)3(OH)) through adsorption, ion exchange (x = 0.01~0.04), and dissolution-coprecipitation (x = 0.13~0.35) was the dominant process for the Cu (II) removal by the SC–HA/C composite.