Mesenchymal stem cells (MSCs)-derived exosomes were considered a novel therapeutic approach in many aging-related diseases. This study aimed to clarify the protective effects of human placenta MSCs-derived exosomes (hPMSC-Exo) in aging-related CD4+ T cell senescence and identified the underlying mechanisms using a D-gal induced mouse aging model. Senescent T cells were detected SA-β-gal stain. The degree of DNA damage was evaluated by detecting the level of 8-OH-dG. The superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) activities were measured. The expression of aging-related proteins and senescence-associated secretory phenotype (SASP) were detected by Western blot and RT-PCR. We found that hPMSC-Exo treatment markedly decreased oxidative stress damage (ROS and 8-OH-dG), SA-β-gal positive cell number, aging-related protein expression (p53 and γ-H2AX), and SASP expression (IL-6 and OPN) in senescent CD4+ T cells. Additionally, hPMSC-Exo containing miR-21 effectively downregulated the expression of PTEN, increased p-PI3K and p-AKT expression, and Nrf2 nuclear translocation and the expression of downstream target genes (NQO1 and HO-1) in senescent CD4+ T cells. Furthermore, in vitro studies uncovered that hPMSC-Exo attenuated CD4+ T cell senescence by improving the PTEN/PI3K-Nrf2 axis by using the PTEN inhibitor bpV (HOpic). We also validated that PTEN was a target of miR-21 by using a luciferase reporter assay. Collectively, the obtained results suggested that hPMSC-Exo attenuates CD4+ T cells senescence via carrying miRNA-21 and activating PTEN/PI3K-Nrf2 axis mediated exogenous antioxidant defenses.
Ischemic/reperfusion (I/R) injury is the primary cause of acute kidney injury (AKI). Hydroxysafflor yellow A (HSYA), a natural compound isolated from Carthamus tinctorius L., has been found to possess anti-inflammatory and antioxidant properties. However, the protective effects and potential mechanism of HSYA on I/R-induced AKI remains unclear. In the present study, the in vitro hypoxia/reoxygenation (H/R) and in vivo renal I/R models were employed to investigate the renal protective effects and molecular mechanisms of HSYA on I/R-induced AKI. The present results indicated that HSYA pretreatment significantly ameliorated renal damage and dysfunction in the I/R injury mice via enhancing the antioxidant capacity and suppressing the oxidative stress injury, inflammatory response, and apoptosis. Mechanistic studies showed that HSYA could upregulate Akt/GSK-3β/Fyn-Nrf2 axis-mediated antioxidant gene expression both in vitro and in vivo. Moreover, HSYA-mediated improvement in antioxidant, anti-inflammatory, and anti-apoptotic effects in H/R-treated HK-2 cells was abrogated by Akt inhibitor LY294002 supplementation. In summary, the present results demonstrated that HSYA attenuated kidney oxidative stress, inflammation response, and apoptosis induced by I/R, at least in part, via activating the Akt/GSK-3β/Fyn-Nrf2 axis pathway. These findings provided evidence that HSYA may be applied as a potential therapeutic agent in the treatment of I/R induced AKI.
It has been reported that c-Met and TRK synergistically promote multiple tumour progression, and therefore blocking the cross-signalling pathway between them may inhibit the growth of multiple tumours. In this study, we developed a tyrosine kinase inhibitor 1D228, which exhibited great anti-tumor activity by targeting TRK and c-Met. In the in vitro models, 1D228 showed a significant better inhibition on cancer cell proliferation and migration than the similar drug tepotinib. In the in vivo tumor models, 1D228 showed robust anti-tumor effect on gastric (TGI, 1D228-8 mg/kg/d: 94.8%; tepotinib 8mg/kg/d: 67.61%) and liver (TGI, 1D228-4 mg/kg/d: 93.4%; tepotinib 4mg/kg/d: 63.9%) tumor growth. Importantly, compared with the combination of larotrectinib and tepotinib, 1D228 monotherapy showed stronger antitumor activity and lower toxicity. Mechanistic studies showed that 1D228 can largely inhibit the phosphorylation of TRK and c-Met, thereby blocking downstream signaling pathways of TRK and c-Met. Interestingly, both kinases can be co-expressed at high levels in patients with gastric cancer. Cell cycle analysis found that 1D228 induced G0/G1 arrest by inhibiting cyclin D1. In addition, vascular endothelial cells also showed a pronounced response to 1D228 due to its expression of TRKB and c-Met. 1D228 suppressed the migration and tube formation of endothelial cells, which are the key functions of tumor angiogenesis. By histology analysis from the in vivo tumor tissues, we confirmed that 1D228 induced cancer cell apoptosis and inhibited tumor angiogenesis, leading to tumor growth retardation. Taken together, compound 1D228 may be a promising candidate for the next generation of c-Met and TRK inhibitors for cancer treatment, and offers a novel potential treatment strategy for gastric and hepatocellular carcinoma.
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