Repeat dose and reproductive toxicity of thrombopoietin mimic peptide in Sprague-Dawley rats.

Thrombopoietin mimic peptide (TMP) is a novel thrombopoietin receptor agonist. In this report, we evaluated the potential toxicity of TMP in repeat-dose toxicity and reproductive/developmental toxicity studies (segment Ⅰ, Ⅱ, Ⅲ). TMP was administered subcutaneously to Sprague-Dawley (SD) rats at 5, 15 or 50 mcg/kg. In repeat-dose toxicity study, the rats were administrated three times a week for 26 week with a 4-week recovery. TMP could produce anti-drug antibodies and induce platelet counts increase, megakaryocyte proliferation. While platelet counts decreased gradually and returned to normal after 4 weeks in male rats. Other significant findings included myelofibrosis of bone marrow, hepatic extramedullary hematopoiesis, splenic lymphocytic depletion and bone hyperostosis. All treatment-related effects were reversed following recovery. The NOAEL of repeat-dose toxicity in female rats is 5 mcg/kg. In the reproductive/developmental toxicity (segment Ⅰ, Ⅲ), no deaths occurred, and no general toxicological effects or abnormal reproductive functions were observed. In embryo-fetal developmental toxicity study (segment Ⅱ), the number of resorbed fetuses in the 50 mcg/kg group was significantly increased. The NOAEL as related to reproductive/developmental toxicity in these rats was 15 mcg/kg.

Lysosome passivation triggered by silver nanoparticles enhances subcellular-targeted drug therapy.

Frequently, subcellular-targeted drugs tend to accumulate in lysosomes after cellular absorption, a process termed the lysosomal trap. This accumulation often interferes with the drug's ability to bind to its target, resulting in decreased efficiency. Existing methods for addressing lysosome-induced drug resistance mainly involve improving the structures of small molecules or enveloping drugs in nanomaterials. Nonetheless, these approaches can lead to changes in the drug structure or potentially trigger unexpected reactions within organisms. To address these issues, we introduced a strategy that involves inactivating the lysosome with the use of Ag nanoparticles (Cy3.5@Ag NPs). In this method, the Cy3.5@Ag NPs gradually accumulate inside lysosomes, leading to permeation of the lysosomal membrane and subsequent lysosomal inactivation. In addition, Cy3.5@Ag NPs also significantly affected the motility of lysosomes and induced the occurrence of lysosome passivation. Importantly, coincubating Cy3.5@Ag NPs with various subcellular-targeted drugs was found to significantly increase the efficiency of these treatments. Our strategy illustrates the potential of using lysosomal inactivation to enhance drug efficacy, providing a promising therapeutic strategy for cancer.

mtDNA release promotes cGAS-STING activation and accelerated aging of postmitotic muscle cells.

The mechanism regulating cellular senescence of postmitotic muscle cells is still unknown. cGAS-STING innate immune signaling was found to mediate cellular senescence in various types of cells, including postmitotic neuron cells, which however has not been explored in postmitotic muscle cells. Here by studying the myofibers from Zmpste24-/- progeria aged mice [an established mice model for Hutchinson-Gilford progeria syndrome (HGPS)], we observed senescence-associated phenotypes in Zmpste24-/- myofibers, which is coupled with increased oxidative damage to mitochondrial DNA (mtDNA) and secretion of senescence-associated secretory phenotype (SASP) factors. Also, Zmpste24-/- myofibers feature increased release of mtDNA from damaged mitochondria, mitophagy dysfunction, and activation of cGAS-STING. Meanwhile, increased mtDNA release in Zmpste24-/- myofibers appeared to be related with increased VDAC1 oligomerization. Further, the inhibition of VDAC1 oligomerization in Zmpste24-/- myofibers with VBIT4 reduced mtDNA release, cGAS-STING activation, and the expression of SASP factors. Our results reveal a novel mechanism of innate immune activation-associated cellular senescence in postmitotic muscle cells in aged muscle, which may help identify novel sets of diagnostic markers and therapeutic targets for progeria aging and aging-associated muscle diseases.

Pharmacokinetics and pharmacodynamics of Astragali Radix-Corni Fructus Herb-pair Extract, in kidney-yin deficiency model

Abstract To investigate the pharmacokinetics and pharmacodynamics of Astragali Radix-Corni Fructus herb-pair in kidney-yin deficiency model, which was made by continuously oral gavage of thyroxine. A simple and rapid LC-MS/MS method was developed and validated for the determination of loganin and morroniside in rat plasma and used for the pharmacokinetics study. The kidney-yin deficiency significantly changed the AUC(0-∞), Cmax and CLz/F of loganin and morroniside. The T1/2z of morroniside increased significantly in the kidney-yin deficiency rats. For the pharmacodynamics study, the liver index, kidney index, and ALT, TBIL, UREA, CREA level in the kidney-yin deficiency mice were examined. The herb-pair had been proved to be effective for the treatment of kidney-yin deficiency by affecting the liver, kidney, ALT, UREA and CREA, which showed positively correlated with the dose. The pharmacokinetics and pharmacodynamics studies in the pathological status could offer more valuable information for the future application of Astragali Radix-Corni Fructus herb-pair.