Anandamide-induced apoptosis in Chang liver cells involves ceramide and JNK/AP-1 pathway

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Clearance of defective muscle stem cells by senolytics reduces the expression of senescence-associated secretory phenotype and restores myogenesis in myotonic dystrophy type 1

Muscle weakness and atrophy are clinical hallmarks of myotonic dystrophy type 1 (DM1). Muscle stem cells, which contribute to skeletal muscle growth and repair, are also affected in this disease. However, the molecular mechanisms leading to this defective activity and the impact on the disease severity are still elusive. Here, we explored through an unbiased approach the molecular signature leading to myogenic cell defects in DM1. Single cell RNAseq data revealed the presence of a specific subset of DM1 myogenic cells expressing a senescence signature, characterized by the high expression of genes related to senescence-associated secretory phenotype (SASP). This profile was confirmed using different senescence markers in vitro and in situ. Accumulation of intranuclear RNA foci in senescent cells, suggest that RNA-mediated toxicity contribute to senescence induction. High expression of IL-6, a prominent SASP cytokine, in the serum of DM1 patients was identified as a biomarker correlating with muscle weakness and functional capacity limitations. Drug screening revealed that the BCL-XL inhibitor (A1155463), a senolytic drug, can specifically target senescent DM1 myoblasts to induce their apoptosis and reduce their SASP. Removal of senescent cells re-established the myogenic function of the non-senescent DM1 myoblasts, which displayed improved proliferation and differentiation capacity in vitro; and enhanced engraftment following transplantation in vivo. Altogether this study presents a well-defined senescent molecular signature in DM1 untangling part of the pathological mechanisms observed in the disease; additionally, we demonstrate the therapeutic potential of targeting these defective cells with senolytics to restore myogenesis

Diorganotin(IV) N-acetyl-L-cysteinate complexes: Synthesis, solid state, solution phase, DFT and biological investigations.

Diorganotin(IV) complexes of N-acetyl-L-cysteine (H2NAC; (R)-2-acetamido-3-sulfanylpropanoic acid) have been synthesized and their solid and solution-phase structural configurations investigated by FTIR, Mössbauer, 1H, 13C and 119Sn NMR spectroscopy. FTIR results suggested that in R2Sn(IV)NAC (R=Me, Bu, Ph) complexes NAC2− behaves as dianionic tridentate ligand coordinating the tin(IV) atom, through estertype carboxylate, acetate carbonyl oxygen atom and the deprotonated thiolate group. From 119Sn Mössbauer spectroscopy it could be inferred that the tin atom is pentacoordinated, with equatorial R2Sn(IV) trigonal bipyramidal configuration. In DMSO-d6 solution, NMR spectroscopic data showed the coordination of one solvent molecule to tin atom, while the coordination mode of the ligand through the ester-type carboxylate and the deprotonated thiolate group was retained in solution. DFT (Density Functional Theory) study confirmed the proposed structures in solution phase as well as the determination of the most probable stable ring conformation. Biological investigations showed that Bu2SnCl2 and NAC2 induce loss of viability in HCC cells and only moderate effects in non-tumor Chang liver cells. NAC2 showed lower cytotoxic activity than Bu2SnCl2, suggesting that the binding with NAC2− modulates the marked cytotoxic activity exerted by Bu2SnCl2. Therefore, these novel butyl derivatives could represent a new class of anticancer drugs