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The selective BCR-ABL tyrosine kinase inhibitor imatinib is one of the first-line therapies in the management of chronic myeloid leukaemia (CML). However, acquired resistance to this inhibitor, which is especially conferred by the T315I point mutation in BCR-ABL, impedes the efficacy of imatinib therapy. Therefore, the discovery and development of novel agents to overcome imatinib resistance is urgently needed. Pseudolaric acid B (PAB), a small molecule isolated from the traditional Chinese medicine Cortex pseudolaricis, has been reported to be a potential candidate for immune disorders and cancer treatment. However, its effects on CML and the involved molecular mechanism have not been reported. In the current study, by performing both in vitro and in vivo experiments in CML cells, we showed that PAB blocked the cell cycle at G 2 /M phase and subsequently activated the caspase pathway, cleaved the BCR-ABL protein and inhibited the BCR-ABL downstream pathways, ultimately leading to cell proliferation inhibition, cytotoxicity and apoptosis. These events were observed in both imatinib-sensitive and imatinib-insensitive CML cell lines. Moreover, PAB decreased the viability of primary blood mononuclear cells from CML patients and induced apoptosis in these cells. Our findings suggest that PAB could be used as a novel agent to sensitize imatinib-resistant CML., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The first line therapy for patients with diffuse large B cell (DLBCL) is R-CHOP. About half of DLBCL patients are either refractory to, or will relapse, after the treatment. Therefore, identifying novel drug targets and effective therapeutic agents is urgently needed for improving DLBCL patient survival. b-AP15, a selective small molecule inhibitor of proteasomal USP14 and UCHL5 deubiquitinases (DUBs), has shown selectivity and efficacy in several other types of cancer cells. This is the first study to report the effect of b-AP15 in DLBCL., Methods: Cell lines of two DLBCL subtypes, Germinal Center B Cell/ GCB (SU-DHL-4, OCI-LY-1, OCI-LY-19) and Activated B Cell/ABC (SU-DHL-2), were used in the current study. Cell viability was measured by MTS assay, proliferation by trypan blue exclusion staining assay, cellular apoptosis by Annexin V-FITC/PI staining and mitochondrial outer membrane permeability assays, the activities of 20S proteasome peptidases by cleavage of specific fluorogenic substrates, and cell migration was detected by transwell assay in these GCB- and ABC-DLBCL cell lines. Mouse xenograft models of SU-DHL-4 and SU-DHL-2 cells were used to determine in vivo effects of b-AP15 in DLBCL tumors., Results: b-AP15 inhibited proteasome DUB activities and activated cell death pathway, as evident by caspase activation and mitochondria apoptosis in GCB- and ABC- DLBCL cell lines. b-AP15 treatment suppressed migration of GCB- and ABC-DLBCL cells via inhibiting Wnt/β-catenin and TGFβ/Smad pathways. Additionally, b-AP15 significantly inhibited the growth of GCB- and ABC DLBCL in xenograft models., Conclusions: These results indicate that b-AP15 inhibits cell migration and induces apoptosis in GCB- and ABC-DLBCL cells, and suggest that inhibition of 19S proteasomal DUB should be a novel strategy for DLBCL treatment.

Calcium ion (Ca2+) is one of the key intracellular signals, which is implicated in the regulation of cell functions such as impregnation, cell proliferation, differentiation and death. Cadmium (Cd) is a toxic environmental pollutant that can disturb cell functions and even lead to cell death. Recently, we have found that Cd induced apoptosis in gill cells of the freshwater crab Sinopotamon henanense via caspase activation. In the present study, we further investigated the role of calcium signaling in the Cd-induced apoptosis in the animals. Our data showed that Cd triggered gill cell apoptosis which is evidenced by apoptotic DNA fragmentation, activations of caspases-3, -8 and -9 and the presence of apoptotic morphological features. Moreover, Cd elevated the intracellular concentration of Ca2+, the protein concentration of calmodulin (CaM) and the activity of Ca2+-ATPase in the gill cells of the crabs. Pretreatment of the animals with ethylene glycol-bis-(b-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), Ca2+ chelator, inhibited Cd-induced activation of caspases-3, -8 and -9 as well as blocked the Cd-triggered apoptotic DNA fragmentation. The apoptotic morphological features were no longer observed in gill cells pretreated with the Ca2+ signaling inhibitors before Cd treatment. Our results indicate that Cd evokes gill cell apoptosis through activating Ca2+-CaM signaling transduction pathway.

We studied here the short-term toxicity effects of Cd on the oxidative state and cell death in the gill of freshwater crab Sinopotamon henanense. Crabs were exposed to Cd that resulted in Cd accumulation and a significant increase in the metallothionein (MT) level in the gill, but MT level increased disproportionally compared to the Cd accumulation with an extension of exposure time. Significant changes in the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were observed. An increase in the levels of reactive oxygen species (ROS) and lipid peroxidation (LPO) was detected that will cause oxidative stress. Histological abnormalities of the gills were discovered, including the expansion of gill cavity, a decrease in the numbers of connection of the upper and the lower of the gill lamellae and epithelial cells, and an increase in the number of hemocytes. The results of a TUNEL test and transmission electron microscope (TEM) showed that more gill cells had apoptotic characteristics after 48 h of Cd treatment compared to the control, but epithelial cell necrosis and inflammatory response appeared only after 72 h. It was concluded that (1) Cd induced the ROS production and accumulation through inhibiting antioxidant enzyme activities and exceeding the saturation values of MT binging; (2) Cd led to lipid peroxidation and histopathological alternations; and (3) Cd induced apoptotic response at short time exposure, followed by necrotic features and inflammatory reaction after longer time exposure.

Cadmium (Cd) is a well-known toxic heavy metal that accumulates in the aquatic environment. Cd has been reported to induce oxidative damage and apoptosis. We investigated the regulation mechanism of hydrogen peroxide (H(2)O(2)) on Cd-induced apoptosis. We show that in the gills of the freshwater crab Sinopotamon henanense Cd induced apoptosis, in a time- and concentration-dependent manner, as confirmed by DNA fragmentation analysis and transmission electron microscopy. Additionally, Cd caused production of H(2)O(2) after 2 h of treatment at 58 mg L(-1) Cd, and significantly increased the caspase-3/8/9 activity in crabs relative to the control group. Pre-treatment with the scavenger for H(2)O(2), dimethylthiourea (DMTU) and antioxidant, N-acetyl cysteine (NAC), effectively inhibited the activities of caspase-3 and caspase-9, eventually blocked Cd-induced DNA fragmentation and the appearance of markers for apoptotic cell death. These results suggest that Cd might induce intracellular H(2)O(2) generation to trigger the crab apoptotic processes by regulating the activities of caspase enzymes., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Sirtuin (SIRT)3 is closely related to inflammation and apoptosis and studies have described this relationship, including in the lungs. However, the expression of SIRT3 and its effect on apoptosis and inflammation in bronchial tissue in asthma remains to be elucidated. The present study found that SIRT3 expression decreased in the bronchial tissues of asthmatic mice and its upregulation could not only reduce increased bronchial epithelial cells apoptosis in the asthmatic mice but also significantly decreased the elevated expression of cytokines (TNF-α, IL-4, IL-5 and IL-13) in bronchoalveolar lavage fluid. Further study found that SIRT3 overexpression significantly decreased apoptosis-related protein expression (Bax/Bcl2 ratio and caspase 3 activity) and oxidative injury. In vitro, SIRT3 regulated oxidative stress-induced bronchial epithelial cell (16HBE) apoptosis and cytokine expression. In conclusion, SIRT3 expression decreased in bronchial tissues of asthmatic mice and the upregulation of SIRT3 expression could reduce the apoptosis of bronchial epithelium and airway inflammation. It was concluded that SIRT3 might be a potential target in asthma treatment. [ABSTRACT FROM AUTHOR]