To test the hypothesis that adoptive transfer of regulatory T cells (Tregs) may dose-dependently inhibit the formation of angiotensin II–induced abdominal aortic aneurysm in apolipoprotein E knockout mice, we established an animal model of abdominal aortic aneurysm by angiotensin II infusion in apolipoprotein E knockout mice. Then mice received different treatment with PBS, low-dose Tregs, high-dose Tregs, or CD25-depleting PC61 antibody. Histopathologic analysis showed that the incidence of abdominal aortic aneurysm was 80%, 76%, 27%, and 71% in the PBS, low-dose Tregs, high-dose Tregs, and PC61 groups, respectively. Tregs treatment markedly decreased macrophage and CD4 + T-cell infiltration and preserved the medial smooth muscle cells. Furthermore, Tregs decreased the levels of proinflammatory cytokines, matrix metalloproteinase-2 (MMP-2) and MMP-9, increased the expression of anti-inflammatory interleukin-10 and transforming growth factor-β, and suppressed apoptosis and oxidative stress. In vitro, Tregs inhibited the response of human aortic smooth muscle cells to angiotensin II and reduced the expression of proinflammatory cytokines, MMP-2 and MMP-9, possibly by inhibiting the activation of nuclear factor-κB and extracellular signal-regulate kinase 1/2. In addition, Tregs downregulated macrophage type 1–related genes and upregulated macrophage type 2–related genes. However, Tregs-mediated effects were largely reversed by disrupting cell–cell contact or using neutralizing antibodies against interleukin-10 and transforming growth factor-β. Adoptive transfer of Tregs dose-dependently prevents angiotensin II–induced abdominal aortic aneurysm in apolipoprotein E knockout mice. The mechanisms may involve declined proinflammatory cytokine expression and MMP-2 and MMP-9 levels and enhanced anti-inflammatory cytokine expression, which is mediated by direct cell–cell contact and soluble mediators.
+ regulatory T cells (Tregs) mediate immune suppression and prevent autoimmune disorders. Recently, Tregs were found to present in atherosclerotic lesions and play an important role in the progression of atherosclerosis. Statins have immunomodulatory properties, and the effect of statins on atherosclerosis depends in part on their immunomodulatory mechanisms. We sought to determine whether statins exhibit an effect on Tregs in atherosclerotic plaques and in peripheral circulation of patients with acute coronary syndrome (ACS). In an in vivo experiment, we induced atherosclerotic plaques in apolipoprotein E-deficient (ApoE
Triptolide (TP), an oxygenated diterpene, has a variety of beneficial pharmacodynamic activities but its clinical applications are restricted due to severe testicular injury. This study aimed to delineate the molecular mechanisms of TP-induced testicular injury in vitro and in vivo. TP (5-50000 nmol/L) dose-dependently decreased the viability of TM4 Sertoli cells with an IC value of 669.5-269.45 nmol/L at 24 h. TP (125, 250, and 500 nmol/L) dose-dependently increased the accumulation of ROS, the phosphorylation of JNK, mitochondrial dysfunction and activation of the intrinsic apoptosis pathway in TM4 cells. These processes were attenuated by co-treatment with the antioxidant N-acetyl cysteine (NAC, 1 mmol/L). Furthermore, TP treatment inhibited the translocation of Nrf2 from cytoplasm into the nucleus as well as the expression of downstream genes NAD(P)H quinone oxidoreductase1 (NQO1), catalase (CAT) and hemeoxygenase 1 (HO-1), thus abrogating Nrf2-mediated defense mechanisms against oxidative stress. Moreover, siRNA knockdown of Nrf2 significantly potentiated TP-induced apoptosis of TM4 cells. The above results from in vitro experiments were further validated in male mice after oral administration of TP (30, 60, and 120 mg·kg·d, for 14 d), as evidenced by the detected indexes, including dose-dependently decreased SDH activity, increased MDA concentration, altered testicle histomorphology, elevated caspase-3 activation, apoptosis induction, increased phosphorylation of JNK, and decreased gene expression of NQO1, CAT and HO-1 as well as nuclear protein expression of Nrf2 in testicular tissue. Our results demonstrate that TP activates apoptosis of Sertoli cells and injury of the testis via the ROS/JNK-mediated mitochondrial-dependent apoptosis pathway and down-regulates Nrf2 activation.
The past decade has seen tremendous efforts in the research and development of new chemotherapeutic drugs using target-based approaches. These efforts have led to the discovery of small molecule tyrosine kinase inhibitors (TKIs). Following the initial approval of imatinib by the US FDA in 2001, more than 15 TKIs targeting different tyrosine kinases have been approved, and numerous others are in various phases of clinical evaluation. Unlike conventional chemotherapy that can cause non-discriminating damage to both normal and cancerous cells, TKIs attack cancer-specific targets and therefore have a more favorable safety profile. However, although TKIs have had outstanding success in cancer therapy, there has been increasing evidence of resistance to TKIs. The enhanced efflux of TKIs by ATP-binding cassette (ABC) transporters over-expressed in cancer cells has been found to be one such important resistance mechanism. Another major drawback of TKI therapies that has been increasingly recognized is the extensive inter-individual pharmacokinetic variability, in which ABC transporters seem to play a major role as well. This review covers recent findings on the interactions of small molecule TKIs with ABC transporters. The effects of ABC transporters on anticancer efficacy and the absorption, distribution, metabolism, excretion, and toxicity (ADME-Tox) of the small molecule TKIs are summarized in detail. Since TKIs have been found to not only serve as substrates of ABC transporters, but also as modulators of these proteins via inhibition or induction, their influence upon ABC transporters and potential role on TKI-drug interactions are discussed as well.
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