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Journal articles on the topic 'Apoptosis - Theses'

Author: Grafiati

Published: 4 June 2021

Last updated: 1 February 2022

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Mannava, Sudha, DaZhong Zhuang, Jayakumar R. Nair, et al. "KLF9 is a novel transcriptional regulator of bortezomib- and LBH589-induced apoptosis in multiple myeloma cells." Blood 119, no. 6 (2012): 1450–58. http://dx.doi.org/10.1182/blood-2011-04-346676.

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Abstract Bortezomib, a therapeutic agent for multiple myeloma (MM) and mantle cell lymphoma, suppresses proteosomal degradation leading to substantial changes in cellular transcriptional programs and ultimately resulting in apoptosis. Transcriptional regulators required for bortezomib-induced apoptosis in MM cells are largely unknown. Using gene expression profiling, we identified 36 transcription factors that displayed altered expression in MM cells treated with bortezomib. Analysis of a publically available database identified Kruppel-like family factor 9 (KLF9) as the only transcription factor with significantly higher basal expression in MM cells from patients who responded to bortezomib compared with nonresponders. We demonstrated that KLF9 in cultured MM cells was up-regulated by bortezomib; however, it was not through the induction of endoplasmic reticulum stress. Instead, KLF9 levels correlated with bortezomib-dependent inhibition of histone deacetylases (HDAC) and were increased by the HDAC inhibitor LBH589 (panobinostat). Furthermore, bortezomib induced binding of endogenous KLF9 to the promoter of the proapoptotic gene NOXA. Importantly, KLF9 knockdown impaired NOXA up-regulation and apoptosis caused by bortezomib, LBH589, or a combination of theses drugs, whereas KLF9 overexpression induced apoptosis that was partially NOXA-dependent. Our data identify KLF9 as a novel and potentially clinically relevant transcriptional regulator of drug-induced apoptosis in MM cells.

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Antonawich, Francis J., Stanislaw Krajewski, John C. Reed, and James N. Davis. "Bcl-x1 Bax Interaction after Transient Global Ischemia." Journal of Cerebral Blood Flow & Metabolism 18, no. 8 (1998): 882–86. http://dx.doi.org/10.1097/00004647-199808000-00008.

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Five minutes of bilateral common carotid artery occlusion in the Mongolian gerbil results in a selective, delayed death of CA1 pyramidal neurons. Although Bcl-2 appears to protect a variety of cells from cell death, the precise role of this apoptosis-regulating protein is complicated. We used immunoblots to estimate levels of Bcl-2, Bcl-xl, and Bax at various times after carotid occlusion. Rather than Bcl-2, Bcl-xl appears to be the predominant neuroprotective form of this family of proto-oncogenes in the gerbil hippocampus. After transient ischemia, Bcl-2 and Bcl-xl protein levels remained the same. However, Bax levels were dramatically increased at 6 hours after ischemia, compared with sham-operated animals, and were still elevated at 72 hours after ischemia. To monitor dimerization interactions among theses apoptosis-regulating molecules, immunoprecipitation studies were conducted. These studies demonstrated that Bcl-xl association with Bax increases after ischemia. Therefore, Bax may disrupt the more favorable Bcl-xl (Bcl-2) interactions necessary for normal neuronal functioning and thus promote transient ischemic death.

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Li, Ruiwen, Shuting Cheng, and Zhengrong Wang. "Circadian Clock Gene Plays a Key Role on Ovarian Cycle and Spontaneous Abortion." Cellular Physiology and Biochemistry 37, no. 3 (2015): 911–20. http://dx.doi.org/10.1159/000430218.

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Background/Aims: Circadian locomotor output cycles protein kaput (CLOCK) plays a key role in maintaining circadian rhythms and activation of downstream elements. However, its function on human female reproductive system remains unknown. Methods: To investigate the potential role of CLOCK, CLOCK-shRNAs were transfected into mouse 129 ES cells or injected into the ovaries of adult female mice. Western blotting was utilized to analyze the protein interactions and flow cytometry was used to assess apoptosis. Results: The expression of CLOCK peaked at the 6th week in the healthy fetuses. However, an abnormal expression of CLOCK was detected in fetuses from spontaneous miscarriage. To determine the effect of CLOCK on female fertility, a small hairpin RNA (shRNA) strategy was used to specifically knockdown the CLOCK gene expression in vitro and in vivo. Knockdown of CLOCK induced apoptosis in mouse embryonic stem (mES) cells and inhibited the proliferation in mES cells in vitro. CLOCK knockdown also led to decreased release of oocytes and smaller litter size compared with control in vivo. Conclusions: Collectively, theses findings indicate that CLOCK plays an important role in fertility and that the CLOCK knockdown leads to reduction in reproduction and increased miscarriage risk.

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Xu, Dong, Ricardo E. Perez, Ikechukwu I. Ekekezie, Angels Navarro, and William E. Truog. "Epidermal growth factor-like domain 7 protects endothelial cells from hyperoxia-induced cell death." American Journal of Physiology-Lung Cellular and Molecular Physiology 294, no. 1 (2008): L17—L23. http://dx.doi.org/10.1152/ajplung.00178.2007.

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Hyperoxia is one of the major contributors to the development of bronchopulmonary dysplasia (BPD), a chronic lung disease in premature infants. Emerging evidence suggests that the arrested lung development of BPD is associated with pulmonary endothelial cell death and vascular dysfunction resulting from hyperoxia-induced lung injury. A better understanding of the mechanism of hyperoxia-induced endothelial cell death will provide critical information for the pathogenesis and therapeutic development of BPD. Epidermal growth factor-like domain 7 (EGFL7) is a protein secreted from endothelial cells. It plays an important role in vascular tubulogenesis. In the present study, we found that Egfl7 gene expression was significantly decreased in the neonatal rat lungs after hyperoxic exposure. The Egfl7 expression was returned to near normal level 2 wk after discounting oxygen exposure during recovery period. In cultured human endothelial cells, hyperoxia also significantly reduced Egfl7 expression. These observations suggest that diminished levels of Egfl7 expression might be associated with hyperoxia-induced endothelial cell death and lung injury. When we overexpressed human Egfl7 ( hEgfl7) in EA.hy926 human endothelial cell line, we found that hEgfl7 overexpression could partially block cytochrome c release from mitochondria and decrease caspase-3 activation. Further Western blotting analyses showed that hEgfl7 overexpression could reduce expression of a proapoptotic protein, Bax, and increase expression of an antiapoptotic protein, Bcl-xL. Theses findings indicate that hEGFL7 may protect endothelial cell from hyperoxia-induced apoptosis by inhibition of mitochondria-dependent apoptosis pathway.

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Langrová, Tereza, Zbyšek Sládek, and Dušan Ryšánek. "The effect of the bacterial pathogens Staphylococcus aureus and Streptococcus uberis on morphological features of apoptosis of heifers mammary gland neutrophils." Acta Universitatis Agriculturae et Silviculturae Mendelianae Brunensis 53, no. 4 (2005): 61–74. http://dx.doi.org/10.11118/actaun200553040061.

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The aim of the student thesis was to review the effect of the significant bacterial pathogens,Staphylococcus aureusand Steptococcus uberis on programmed cell death – apoptosisin vitro, and to determine the dynamic of morphological changes during aging neutrophil granulocytes of heifers mammary glandin vitro. Using light and electron microscopy we have noted characteristic alterations of apoptotic neutrophils. These are running in three consequential phases. We found out, that the interaction of bacterial pathogens with neutrophils during the incubation have lead in expressive quantitative and qualitative changes in apoptotic cells proportion. Concretely, the influence of both pathogens on mammary gland neutrophils caused the defer of apoptosis expression. Here,S. aureuscaused lower number of apoptotic neutrophils in comprasion withS. uberis. The outcomes testified, thatS. aureusandS. uberisinteraction with heifers mammary gland neutrophilsin vitrocauses alterations relating to apoptosis of these cells. Looking at the results of the study, we can conclude, that the pathogensS. aureusandS. uberisare not only significant heifers mammary gland – affection causers, but they significantly influence the cells of defensive system in their functions too. They significantly decrease the appereance of morphological apoptosis manifestations on neotrophils of tissue pool of the heifers mammary gland. The numbers of apoptotic cells in neutrophil population confirm, that during the interaction with mentioned pathogens the defer of morphological apoptosis manifestations happens. Then, higher number of apoptotic neutrophils in stages of apoptotic corpuscles implies increasing dynamic of this process. Beside that, the dynamic of apoptotic process is influenced by the specifity of certain bacterious actor too.

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Schirmer, Melanie, Manon Queudeville, Luca Trentin, Sarah M. Eckhoff, Lueder H. Meyer, and Klaus-Michael Debatin. "Overcoming Apoptosis Resistance In High Risk Acute Lymphoblastic Leukemia By Smac Mimetics In a Preclinical ALL Xenograft Model In Vivo." Blood 122, no. 21 (2013): 1433. http://dx.doi.org/10.1182/blood.v122.21.1433.1433.

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Abstract Intensified treatment of pediatric acute lymphoblastic leukemia (ALL) has lead to increased survival rates of about 80%, however therapy fails in the remaining patients leading to relapse of the disease associated with inferior prognosis. Because treatment failure is, at least in part, due to defects in apoptosis programs, novel therapeutic strategies that counter apoptosis resistance are needed. “Inhibitor of Apoptosis” (IAP) proteins block the apoptosis machinery at a central point and are highly expressed in acute leukemias, thereby providing a target structure for therapeutic intervention. Molecules antagonizing these apoptosis inhibitors, so called SMAC-mimetics, therefore provide a promising strategy to overcome apoptosis deficiency and effectively treat high risk ALL. In this study, we investigated the effects of the small molecule SMAC-mimetic BV6 (kindly provided by Genentech) in B cell precursor- (BCP-) ALL. BV6 showed a clear induction of cell death at nanomolar concentrations in ALL cell lines. ALL cells sensitive for SMAC-mimetic induced cell death showed rapid cIAP degradation, NFkB activation and secretion of TNF-alpha (TNF-a). Interestingly, mitochondrial perturbation and caspase activation could be inhibited by the soluble TNF-a receptor Etanercept indicating the induction of a TNF-a dependent feed forward loop by the SMAC-mimetic BV6. In addition to cell lines, we investigated the effects of BV6 on a series of 42 primary ALL samples isolated from ALL bearing mice of established patient derived NOD/SCID/huALL xenograft leukemias. Intriguingly, upon treatment with the small molecule SMAC mimetic BV6, induction of cell death was observed in a majority of 70% of all individual patient-derived leukemias and BV6 induced cell death was inhibited by Etanercept demonstrating TNF-a dependency also in primary ALL. We previously described that rapid engraftment of ALL cells transplanted onto NOD/SCID mice (short Time To Leukemia, TTLshort) is associated with deficient apoptosis signaling in the ALL cells and indicative for early patient relapse. Importantly, primary xenograft ALL samples with a TTLshort/early relapse phenotype showed increased cell death upon treatment with SMAC-mimetic BV6 and activation of the constitutive deficient apoptosis signaling pathway, demonstrating that SMAC-mimetics induce intact apoptosis signaling in former apoptosis resistant primary ALL cells. Based on theses findings, we further evaluated the in vivo effectivity of the SMAC-mimetic BV6 on high risk ALL using our NOD/SCID/huALL xenograft model in a preclinical setting. ALL bearing recipients were treated with either BV6 or solvent for a given time of two weeks and further investigated for the presence of leukemia. Most interestingly, a significant delay of post-treatment leukemia reoccurrence was observed upon BV6 in vivo treatment along with a profound reduction of tumor load in the recipients compared to solvent treated animals. In a clinical setting, high-risk disease is unlikely to be treated by one compound alone. Therefore, we combined BV6 with multidrug chemotherapy resembling ALL induction treatment and observed a significant delay of ALL reoccurrence and prolonged survival of animals treated with the combination of the SMAC-mimetic and chemotherapy in contrast to chemotherapy alone. Most importantly, concomitant in vivo therapy with Etanercept revoked the cell death sensitizing effect of BV6, both in single treatment and in combination with chemotherapy. This indicates that BV6 induced apoptosis sensitization involves signaling via TNF-a and thereby provides a potential biomarker for the identification of patients who would benefit from SMAC-mimetic treatment. Taken together, we show that the small molecule SMAC-mimetic BV6 induces cell death via a TNF-a loop ex vivo and in vivo in primary patient-derived ALL. Moreover, BV6 is able to overcome apoptosis deficiency of high risk ALL leading to prolonged in vivo survival in a preclinical therapy model of patient-derived ALL xenograft ALL. Thus, induction of cell death by new generation small molecule SMAC-mimetics provides a promising novel strategy for targeted therapy of high-risk acute lymphoblastic leukemia and involvement of TNF-a signaling in BV6-sensitive patients points to its potential use as biomarker indicating effective cell death sensitization. Disclosures: No relevant conflicts of interest to declare.

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Roccaro, Aldo M., Xavier Leleu, Antonio Sacco, et al. "Dual targeting of the proteasome regulates survival and homing in Waldenström macroglobulinemia." Blood 111, no. 9 (2008): 4752–63. http://dx.doi.org/10.1182/blood-2007-11-120972.

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AbstractWaldenström macroglobulinemia (WM) is an incurable low-grade B-cell lymphoma characterized by high protein turnover. We dissected the biologic role of the proteasome in WM using 2 proteasome inhibitors, NPI-0052 and bortezomib. We found that NPI-0052 inhibited proliferation and induced apoptosis in WM cells, and that the combination of NPI-0052 and bortezomib induced synergistic cytotoxicity in WM cells, leading to inhibition of nuclear translocation of p65NF-κB and synergistic induction of caspases-3, -8, and -9 and PARP cleavage. These 2 agents inhibited the canonical and noncanonical NF-κB pathways and acted synergistically through their differential effect on Akt activity and on chymotrypsin-like, caspaselike, and trypsinlike activities of the proteasome. We demonstrated that NPI-0052–induced cytotoxicity was completely abrogated in an Akt knockdown cell line, indicating that its major activity is mediated through the Akt pathway. Moreover, we demonstrated that NPI-0052 and bortezomib inhibited migration and adhesion in vitro and homing of WM cells in vivo, and overcame resistance induced by mesenchymal cells or by the addition of interleukin-6 in a coculture in vitro system. Theses studies enhance our understanding of the biologic role of the proteasome pathway in WM, and provide the preclinical basis for clinical trials of combinations of proteasome inhibitors in WM.

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Alenzi, Faris Q. B., and Anthony N. Warrens. "Cellular and molecular themes in apoptosis." Wiener Klinische Wochenschrift 115, no. 15-16 (2003): 563–74. http://dx.doi.org/10.1007/bf03040450.

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SCHAUMBURG, F., D. HIPPE, P. VUTOVA, and C. G. K. LÜDER. "Pro- and anti-apoptotic activities of protozoan parasites." Parasitology 132, S1 (2006): S69—S85. http://dx.doi.org/10.1017/s0031182006000874.

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During infection, programmed cell death, i.e. apoptosis, is an important effector mechanism of innate and adaptive host responses to parasites. In addition, it fulfils essential functions in regulating host immunity and tissue homeostasis. Not surprisingly, however, adaptation of parasitic protozoa to their hosts also involves modulation or even exploitation of cell death in order to facilitate parasite survival in a hostile environment. During recent years, considerable progress has been made in our understanding of apoptosis during parasitic infections and there is now convincing evidence that apoptosis and its modulation by protozoan parasites has a major impact on the parasite-host interaction and on the pathogenesis of disease. This review updates our current knowledge on the diverse functions apoptosis may fulfil during infections with diverse protozoan parasites including apicomplexans, kinetoplastids and amoebae. Furthermore, we also summarize common mechanistic themes of the pro- and anti-apoptotic activities of protozoan parasites. The diverse and complex effects which parasitic protozoa exert on apoptotic cell death within the host highlight fascinating interactions of parasites and their hosts. Importantly, they also stress the importance of further investigations before the modulation of host cell apoptosis can be exploited to combat parasitic infections.

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Fujiki, Atsushi, Toshihiko Imamura, Yoshifumi Hirashima, et al. "Monocytic Differentiation of Myeloid Leukemia Cell Lines Induced by ATRA and 5-Aza-2'-Deoxycitidine." Blood 114, no. 22 (2009): 3111. http://dx.doi.org/10.1182/blood.v114.22.3111.3111.

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Abstract Abstract 3111 Poster Board III-48 Backgrounds and Introduction The CCAAT/enhancer binding protein (C/EBP)αa is a transcriptional factor of hematopoietic system and plays a key role in monocytic differentiation. Recently, several studies have reported that C/EBPαa expression is down-regulated in acute myeloid leukemia (AML), leading to block of granulocytic and monocytic differentiation. Differentiation therapy of ATRA is highly effective for acute promyelocytic leukemia (APL). The mechanism of induction of differentiation in the treatment of APL is induction of a set of transcriptional factors which are responsible for myeloid differentiation. However, ATRA alone is not sufficient to treat another type of AML. Thus, it is worth to explore the agents which intensify the efficacy of ATRA. To assess the possibility of differentiation therapy in AML, except for APL, we evaluated the efficacy of demethylation agent combined with ATRA for various AML cell lines. Materials and Methods The five AML cell lines (K562, U-937, HL-60, THP-1, and KOCL48 expressing MLL-AF4) were treated with 50nM 5-Aza-2'-deoxycytidine (5-Aza) for two days and 1 mM ATRA for additional five days. Then, we analyzed cell growth with counting nuclei using Coulter counter. The cell cycle analysis was also performed by flow cytometry (FCM). In addition, Annexin V assay was performed to determine whether apoptosis occurred or not. To assess whether monocytic differentiation was induced or not, the expression of CD11b was evaluated by FCM. In addition, the expression of transcriptional factors, such as C/EBPαa, PU.1 and c-myc ) were analyzed by real time PCR analysis. Methylation specific PCR was also performed to evaluate the methylation status of promoter region of C/EBPαa. Results HL-60 was highly sensitive to ATRA (growth inhibition rate: 80%). THP-1 and KOCL-48 were moderately sensitive to ATRA (growth inhibition rate: 50-60%). Addition of 5-Aza induced suppression of the growth in these two cell lines efficiently (growth inhibition rate: 80%). K562 and U937 were resistant to ATRA (growth inhibition rate: 10-20%). Addition of 5-Aza induced suppression of cell-growth in U937 (growth inhibition rate: 70%). However, 5-Aza did not show the effect in K562. Morphological studies revealed the characteristic features, such as extended cytoplasm with vacuoles, fine granules and irregular shaped nucleus, were evident in four cell lines which was sensitive to 5-Aza. FCM analysis revealed intensification of CD11b expression. In addition, real time PCR determined the increased expression of C/EBPαa and PU.1 (Fold change: 2-3.0) in the four cell lines except for K562. On the other hand, the expression level of c-myc was decreased under treatment with ATRA and 5-Aza (Fold change: 0.2). Cell cycle analysis revealed G1 arrest was occurred. Annexin V assay also revealed that combination therapy of ATRA and 5-Aza induced apoptosis in theses cell lines except for K562. Methylation specific PCR did not identified hypermetylation of pormorter region of C/EBPαa in these cell lines except for K562. Conclusion Addition of 5-Aza to ATRA induced further expression of C/EBPαa and PU.1 efficiently, leading to monocytic differentiation in AML cell lines. Monocytic differentiation was accompanied with G1 arrest through down-regulation of c-myc, and apoptosis was induced finally. Combination of ATRA and 5-Aza might be effective therapeutic option even for AML which is resistant to differentiation therapy with ATRA. Disclosures No relevant conflicts of interest to declare.

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Domen, Jos, and Irving L. Weissman. "Hematopoietic Stem Cells Need Two Signals to Prevent Apoptosis; Bcl-2 Can Provide One of These, Kitl/C-KIT Signaling the Other." Journal of Experimental Medicine 192, no. 12 (2000): 1707–18. http://dx.doi.org/10.1084/jem.192.12.1707.

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Growth factors can cause cells to proliferate, differentiate, survive, or die. Distinguishing between these responses is difficult in multicellular, multiparameter systems. Yet this is essential to understand the impact on cells like hematopoietic stem cells (HSCs), which have strict and still poorly understood growth factor requirements. Single cell plating in serum-free medium allows direct assessment of growth factor responses. The range of tested factors can be expanded if the cells are protected from growth factor deprivation–induced apoptosis. BCL-2 is overexpressed in HSCs of H2K-BCL-2 transgenic mice, protecting them from many apoptotic stimuli. The response of single wild-type and transgenic HSCs to stimulations with individual factors was tested. Surprisingly, we find that high level BCL-2 expression does not prevent rapid death under serum-free conditions, even though it does in the presence of serum. We also find that transgenic, but not wild-type cells, survive and proliferate rapidly in response to steel factor (Kit ligand). These studies show that two separate signals are necessary to prevent apoptosis in HSCs, and that Kit ligand by itself provides a strong proliferative stimulus to HSCs. However, the proliferative response does not result in self-renewal, but in differentiation to all known hematopoietic oligolineage progenitors.

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Levayer, Romain, and Eduardo Moreno. "Mechanisms of cell competition: Themes and variations." Journal of Cell Biology 200, no. 6 (2013): 689–98. http://dx.doi.org/10.1083/jcb.201301051.

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Cell competition is the short-range elimination of slow-dividing cells through apoptosis when confronted with a faster growing population. It is based on the comparison of relative cell fitness between neighboring cells and is a striking example of tissue adaptability that could play a central role in developmental error correction and cancer progression in both Drosophila melanogaster and mammals. Cell competition has led to the discovery of multiple pathways that affect cell fitness and drive cell elimination. The diversity of these pathways could reflect unrelated phenomena, yet recent evidence suggests some common wiring and the existence of a bona fide fitness comparison pathway.

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Dalanezi, F. M., F. C. Destro, R. A. Ferrazza, et al. "183 GENE EXPRESSION OF IN VITRO-MATURATED OOCYTES CAN BE MODULATED BY FOLLICLE EXOSOMES FROM COWS KEPT UNDER THERMONEUTRAL OR HEAT STRESS CONDITIONS." Reproduction, Fertility and Development 29, no. 1 (2017): 200. http://dx.doi.org/10.1071/rdv29n1ab183.

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There are several intrafollicular agents that have the ability to interfere with the metabolism and development of the oocyte, among these we highlight the exosomes (EXO). Thus, the aim of this study was to evaluate the capacity of EXO extracted from the follicular fluid of cows kept under thermoneutral or heat stress conditions to modulate oocyte maturation in vitro. Twenty-four Holstein cows were subjected to the following treatments for 14 days: heat stress (HS; n = 12), 38°C, 60% RH, temperature-humidity index = 88; and thermo-neutral (TN; n = 12), 24°C, 60% RH, temperature-humidity index = 71. Cows had their follicles aspirated when their diameter reached 9 to 12 mm; all follicles with this diameter were aspirated. All follicular fluid aspirated from cows subjected to HS or TN was pooled forming the groups (HS and TN). The EXO were obtained by ultracentrifugation of follicular fluid (120,000 × g for 70 min at 4°C, twice) and had their presence confirmed by transmission electron microscopy. Bos indicus cumulus-oocyte complexes (COC) collected from ovaries obtained in commercial slaughterhouse, were pooled in groups of 20 COC and randomly subjected to 1 of the following treatments: Control, matured in standard medium (TCM 199, supplemented with Earle’s salts, glutamine, NaHCO3, pyruvate, FSH, and amikacin); HS-EXO, matured in standard medium added with 10 µL of a solution of follicular EXO from HS cows; and TN-EXO, matured in standard medium added with 10 µL of a solution of follicular EXO from TN cows. The procedures were repeated 4 times, always with 20 COC per treatment in each replica. After 22 h of maturation, COC were recovered and the expression of genes related to apoptosis protection (BCL2), cell viability (STAT3), cell maintenance (RPL15), oocyte competence (BMP15), oxidative stress (CPT1B), cumulus cell expansion (HAS2), cell cycle (CDCA8), and heat stress protection (HSF1) were assessed. Oocyte genes were differentially expressed according to the source of EXO. Groups were statistically analysed using ANOVA and Tukey tests. All genes, except CPT1B, showed lower expression in TN-EXO oocytes when compared with control and HS-EXO (P < 0.05). CPT1B showed a higher expression in HS-EXO oocytes (P < 0.05). The results showed that the addition of EXO from exogenous follicles can modulate the expression of oocytes genes related to cell viability and survival. The lower expression of these genes in TN-EXO suggested that the EXO obtained in TN conditions attenuate several genes related to the oocytes maturation and viability. Surprisingly, the control oocytes showed a similar gene expression pattern of the HS-EXO. In conclusion, EXO derived from follicular fluid of cows submitted to TN or HS conditions can modulate the gene expression of oocytes matured in vitro. These results open new perspectives for the use of theses EXO as a tool to increase the efficiency of in vitro oocyte maturation. Financial support from FAPESP #12/18297–7.

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Dalle, Jean-Hugues, José Menezes, Eric Wagner, Martin A. Champagne, and Michel Duval. "Anti-Thymocyte Globulin Increases Dramatically Natural Killer Cell Interferon Gamma Production While Respecting Other Functionnal Aspects of These Cells." Blood 104, no. 11 (2004): 4957. http://dx.doi.org/10.1182/blood.v104.11.4957.4957.

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Abstract Rational: The beneficial effect of NK cells after clinical hematopoietic transplantation has been seen when anti-thymocyte globulin (ATG) was used within the conditioning regimen. We therefore investigated the effect of ATG on human NK cells. Materials and methods: Percentages of CD3+ and CD3−/CD56+ among PBMC from either normal adult volunteers or cord blood were assessed by flow cytometry. Negatively purified NK cells were cultured for 2–4 days either alone or in the presence of rabbit ATG (Thymoglobuline, Sangstat) and/or IL-15, and then assessed for cell viability and functional properties: apoptosis were investigated by Annexin V staining. Cell proliferation was assessed by CFSE dye dilution. IFN-gamma secretion was quantified by ELISA. Cytotoxicity against K562 cells was studied by a 51Cr release assay. Binding of monoclonal antibodies to NK cells was assessed alone or after competition with whole ATG or ATG-Fab’2 fragments. Results: The percentage of CD3+ cells in PBMC was over 65% before or after culture without ATG. In contrast, no T cell was detected after culture with ATG, whereas the percentage of NK cells increased from less than 15% to more than 50%. Both whole ATG and Fab’2 fragments bound NK cells while rabbit Fc fragments did not. ATG did not modify apoptotic and necrotic NK cells percentages. Proliferation was not affected by ATG. IFN-gamma production was dramatically increased by ATG treatment (figure). ATG respected IL15 induced NK cell cytolytic activity. Competition assays showed that ATG did not alter CD2, CD11a, CD16, CD56, CD57, CD62L, CD94, CD158a, CD158b, NKG2a, NKG2d, HLA-DR expression. CD18 and NKp46 expression was slightly decreased. Conclusion: Our data show that ATG may play a role in the results of KIR mismatch hematopoietic stem cell transplantation. It may be possible that ATG confers functional advantages to NK cells versus T cells. Figure Figure

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González-Juanatey, JoséRamón, María J. Iglesias, Roberto Piñeiro, et al. "1106-188 Ghrelin is synthesized and secreted by human cardiomyocytes protecting these cells from apoptosis." Journal of the American College of Cardiology 43, no. 5 (2004): A494. http://dx.doi.org/10.1016/s0735-1097(04)92091-8.

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Wermeling, Fredrik, Yunying Chen, Timo Pikkarainen, et al. "Class A scavenger receptors regulate tolerance against apoptotic cells, and autoantibodies against these receptors are predictive of systemic lupus." Journal of Experimental Medicine 204, no. 10 (2007): 2259–65. http://dx.doi.org/10.1084/jem.20070600.

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Apoptotic cells are considered to be a major source for autoantigens in autoimmune diseases such as systemic lupus erythematosus (SLE). In agreement with this, defective clearance of apoptotic cells has been shown to increase disease susceptibility. Still, little is known about how apoptotic cell–derived self-antigens activate autoreactive B cells and where this takes place. In this study, we find that apoptotic cells are taken up by specific scavenger receptors expressed on macrophages in the splenic marginal zone and that mice deficient in these receptors have a lower threshold for autoantibody responses. Furthermore, antibodies against scavenger receptors are found before the onset of clinical symptoms in SLE-prone mice, and they are also found in diagnosed SLE patients. Our findings describe a novel mechanism where autoantibodies toward scavenger receptors can alter the response to apoptotic cells, affect tolerance, and thus promote disease progression. Because the autoantibodies can be detected before onset of disease in mice, they could have predictive value as early indicators of SLE.

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Andrea Gühna, Jasmin Traichel, Lepu Zhou, et al. "Rapid astroglial stress response and elevation of endogenous BiP levels promote neuronal survival in hippocampal slice cultures." World Journal of Biology Pharmacy and Health Sciences 7, no. 2 (2021): 019–31. http://dx.doi.org/10.30574/wjbphs.2021.7.2.0078.

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A hallmark of neurodegenerative diseases is the accumulation of protein aggregates, the formation of which is prevented by chaperone proteins. BiP is the central chaperone in the endoplasmic reticulum. In this study we investigated the pattern of BiP in tunicamycin-stressed murine organotypic hippocampal slice cultures (OHCs). In stressed OHCs highest apoptotic rates occur in neurons of the CA1 regions and the dentate gyrus, in which we found BiP levels to be lowest. Highest BiP protein levels were found in astrocytes. Cell culture experiments indicated that the stress response of glial cells is faster and stronger than in neuronal cells. We hypothesize that the rapid and pronounced BiP expression in astrocytes helps to maintain the fine-balanced micromilieu necessary for survival of neurons. SubAB is a toxin, which cleaves and inactivates BiP. Low dosages of SubAB did not elicit a specific glial response and apoptosis was not induced in a specific hippocampal subfield. Mild prestressing with SubAB promoted neuronal viability in tunicamycin-treated OHCs. We conclude that preconditioning of hippocampal tissue with stressors that elevate endogenous chaperone levels exert a protective effect thereby promoting neuronal survival. These experiments strengthen the thesis that preconditoning with mild stressors positively affects the survival of neuronal cells.

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JOSEFSSON, E., J. BERGQUIST, R. EKMAN, and A. TARKOWSKI. "Catecholamines are synthesized by mouse lymphocytes and regulate function of these cells by induction of apoptosis." Immunology 88, no. 1 (1996): 140–46. http://dx.doi.org/10.1046/j.1365-2567.1996.d01-653.x.

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Ozaki, Ken, Hiroyuki Takeda, Hiroyoshi Iwahashi, Shigeo Kitano та Shigemasa Hanazawa. "NF-κ B inhibitors stimulate apoptosis of rabbit mature osteoclasts and inhibit bone resorption by these cells". FEBS Letters 410, № 2-3 (1997): 297–300. http://dx.doi.org/10.1016/s0014-5793(97)00653-4.

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Soltani, Behrooz, Nasser Ghaemi, Majid Sadeghizadeh, and Farhood Najafi. "Curcumin confers protection to irradiated THP-1 cells while its nanoformulation sensitizes these cells via apoptosis induction." Cell Biology and Toxicology 32, no. 6 (2016): 543–61. http://dx.doi.org/10.1007/s10565-016-9354-9.

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Miyashita, Kazuya, Noritaka Kagaya, Miho Izumikawa, et al. "Growth Suppressing Activity of Lhx2 in Human T Cell Acute Lymphoblastic Leukemia (T-ALL)-Derived Cells and Large-Scale Screening of a Lead Compounds Targeting T-ALL." Blood 128, no. 22 (2016): 2813. http://dx.doi.org/10.1182/blood.v128.22.2813.2813.

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Abstract Acute lymphoblastic leukemia (ALL) is one of the most frequently occurring cancers in infants and young children. For patients suffering from CD20-positive B-cell ALL (B-ALL) and Ph-positive ALL, overall survival rates have been greatly improved after clinical introduction of rituximab and imatinib, respectively. However, T-cell ALL (T-ALL) patients still exhibit poor prognosis, since there is no such an efficient molecular-targeted drug. It is known that LIM-only transcriptional co-factor LMO2 and its target gene HHEX are essential for self-renewal of T cell precursors and onset of T-ALL. LMO2 directly associates with LDB1 in a large DNA-containing nuclear complex and controls the transcription of T-ALL-related downstream genes. Recently, we reported that overexpression of LIM-homeodomain transcription factor Lhx2 results in liberation of Lmo2 protein from the Lmo2-Ldb1 complex followed by degradation by ubiquitin-proteasome system. We found that proliferation of 5 different human T-ALL-derived cell lines including CCRF-CEM was significantly suppressed by retroviral overexpression of Lhx2. In contrast, enforced overexpression of Lhx2 did not reduce the growth rate of B lymphoma-derived cell line Raji, oral cancer-derived cell line HSC-3, and osteosarcoma-derived cell line Saos-2. Majority of the Lhx2-transduced CCRF-CEM cells was arrested in G0 phase and subsequently underwent apoptosis. Expression of LMO2 protein and HHEX mRNA was repressed by the Lhx2 transduction. Importantly, the Lhx2-mediated growth inhibition was partially rescued by the simultaneous overexpression of Lmo2. However, both C-terminal LIM-domain and homeodomain of Lhx2 were required for the growth-suppressive activity. These data indicated that Lhx2 is capable to blocking proliferation of T-ALL-derived cells in LMO2-dependent and independent fashions. Lhx2 would be a useful molecular tool for designing a new type of anti-T-ALL drug. In order to develop a new drug that mimics the aforementioned activity of Lhx2, we performed large-scale screening of natural compound libraries to find out a compound that suppresses the proliferation of T-ALL cell line CCRF-CEM, but does not inhibit the growth of B lymphoma cell line Raji. Among 150,000 different compounds, we successfully identified 3 low-molecular-weight compounds (44D-L008, 31D-F005, 21D-D016) that fulfilled the above criteria. 44D-L008 and 31D-F005 possessed a common chemical structure. In the presence of 5μM of 44D-L008 and 31D-F005, proliferation of 5 human T-ALL cell lines including CCRF-CEM was severely blocked. On the other hand, Raji, HSC-3 and Saos-2 were completely resistant to both compounds in the same experimental settings. Intriguingly, 44D-L008 decreased viability of human skin fibroblasts in culture, whereas 31D-F005 displayed no such negative effects on skin fibroblasts, peripheral blood mononuclear cells, and peripheral blood T cells of human origin. These results indicated that small differences in the chemical structure between 44D-L008 and 31D-F005 are responsible for the side effect on normal cells. Finally, we collaborated with a hospital and found that 0.5 μM of 31D-F005 efficiently suppressed the in vitro growth of primary cancer cells of a T-ALL patient. Taken together, theses data demonstrated that 31D-F005 is a promising lead compound for a new anti-T-ALL drug. Disclosures No relevant conflicts of interest to declare.

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Wang, Yue, Qian Cheng, Jing Liu, and Min Dong. "Leukemia Stem Cell-Released Microvesicles Promote the Survival and Migration of Myeloid Leukemia Cells and These Effects Can Be Inhibited by MicroRNA34a Overexpression." Stem Cells International 2016 (2016): 1–8. http://dx.doi.org/10.1155/2016/9313425.

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Leukemia stem cells (LSCs) play the major role in relapse of acute myeloid leukemia (AML). Recent evidence indicates that microvesicles (MVs) released from cancer stem cells can promote tumor growth and invasion. In this study, we investigated whether LSCs-released MVs (LMVs) can regulate the malignance of AML cells and whether overexpression of tumor suppressive microRNA (miR), miR34a, is able to interrupt this process. LSCs were transfected with miRNA control (miRCtrl) or miR34a mimic for producing LMVs, respectively, defined asLMVsmiRCtrlandLMVsmiR34a. The effect of miR34a transfection on LSC proliferation and the effects ofLMVsmiRCtrlorLMVsmiR34aon the proliferation, migration, and apoptosis of AML cells (after LSC depletion) were determined. The levels of miR34a targets, caspase-3 and T cell immunoglobulin mucin-3 (Tim-3), were analyzed. Results showed that (1)LMVsmiRCtrlpromoted proliferation and migration and inhibited apoptosis of AML cells, which were associated with miR34a deficit; (2) transfection of miR34a mimic inhibited LSC proliferation and increased miR34a level inLMVsmiR34a; (3)LMVsmiR34aproduced opposite effects as compared withLMVsmiRCtrl, which were associated with the changes of caspase-3 and Tim-3 levels. In summary, LMVs support AML cell malignance and modulating miR34a could offer a new approach for the management of AML.

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Xu, Yishi, Carla Bianca Luena Victorio, Qimei Ng, Yee Joo Tan, and Kaw Bing Chua. "Saffold virus is able to productively infect primate and rodent cell lines and induces apoptosis in these cells." Emerging Microbes & Infections 3, no. 1 (2014): 1–8. http://dx.doi.org/10.1038/emi.2014.15.

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Edwards, Sara J., Lynne Hananeia, Michael R. Eccles, You Fang Zhang, and Antony W. Braithwaite. "The proline-rich region of mouse p53 influences transactivation and apoptosis but is largely dispensable for these functions." Oncogene 22, no. 29 (2003): 4517–23. http://dx.doi.org/10.1038/sj.onc.1206726.

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Ghosh, Sanjoy, Simon Ting, Howard Lau, et al. "Increased efflux of glutathione conjugate in acutely diabetic cardiomyocytes." Canadian Journal of Physiology and Pharmacology 82, no. 10 (2004): 879–87. http://dx.doi.org/10.1139/y04-060.

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In diabetes, cell death and resultant cardiomyopathy have been linked to oxidative stress and depletion of antioxidants like glutathione (GSH). Although the de novo synthesis and recycling of GSH have been extensively studied in the chronically diabetic heart, their contribution in modulating cardiac oxidative stress in acute diabetes has been largely ignored. Additionally, the possible contribution of cellular efflux in regulating GSH levels during diabetes is unknown. We used streptozotocin to make Wistar rats acutely diabetic and after 4 days examined the different processes that regulate cardiac GSH. Reduction in myocyte GSH in diabetic rats was accompanied by increased oxidative stress, excessive reactive oxygen species, and an elevated apoptotic cell death. The effect on GSH was not associated with any change in either synthesis or recycling, as both γ-glutamylcysteine synthetase gene expression (responsible for bio syn thesis) and glutathione reductase activity (involved with GSH recycling) remained unchanged. However, gene expression of multidrug resistance protein 1, a transporter implicated in effluxing GSH during oxidative stress, was elevated. GSH conjugate efflux mediated by multidrug resistance protein 1 also increased in diabetic cardiomyocytes, an effect that was blocked using MK-571, a specific inhibitor of this transporter. As MK-571 also decreased oxidative stress in diabetic cardiomyocytes, an important role can be proposed for this transporter in GSH and reactive oxygen species homeostasis in the acutely diabetic heart. Key words: cardiomyocytes, apoptosis, multidrug resistance protein, reactive oxygen species.

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Nishida, Hiroko, Hiroko Madokoro, Hiroshi Suzuki, et al. "CD26 Is a Novel Target for the Treatment of Tumor Progression and Its Related Osteolytic Bone Disease in Multiple Myeloma." Blood 126, no. 23 (2015): 1809. http://dx.doi.org/10.1182/blood.v126.23.1809.1809.

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Abstract Background: CD26, a 110-kDa transmembrane glycoprotein with DPPIV activity, has been implicated in tumorigenesis and shown to be expressed in several tumor cells including malignant lymphoma, whereas its role has not been characterized in plasma cell malignancies, yet. We have recently shown that CD26 is intensely expressed in activated osteoclasts (OCs) in osteolytic bone tumors including multiple myeloma (MM). CD26 is not expressed in hematopoietic stem cells, but M-CSF and sRANKL induced human OC differentiation with the upregulation of CD26 expression in monocyte-macrophage lineage cells, OC precursor cells and OCs. Blockade of CD26 signaling with humanized anti-CD26 monoclonal antibody (YS110) impaired OC differentiation via inhibiting RANKL-induced MKK3/6-p38MAPK-mi/Mitf phosphorylation in OC precursor cells (Nishida et al., 2014). In the present study, we characterize the biological function of CD26 in MM cells in the bone marrow (BM) and investigate the therapeutic potential of YS110 to treat MM cell growth and reduce MM-induced osteolytic lesions. Methods and Results: Although CD26 expression was not detected any of 11 MM cell lines in mono-culture, CD26 expression levels were upregulated in all MM cell lines when co-cultured with OCs for 72 hours by flow cytometry and immunohistochemistry analysis. CD26 protein levels in MM cell lines were also enhanced in co-culture with OCs by immunoblotting. To determine the factors responsible for CD26 upregulation in MM cells, we examined CD26 expression in MM cell lines under transwell co-culture conditions with OCs or under stimulation with anti-apoptotic cytokines produced by OCs. CD26 expression in MM cell lines was reduced under transwell co-culture conditions with OCs. TNFα, BAFF, APRIL and SDF-1 slightly upregulated CD26 expression in MM cell lines. To further explore CD26 expression in BM of MM patients, we performed immunohistochemical stainig on decalcified bone sections of biopsy specimens of MM cases. CD26/CD138 positive plasma cells were detected around CD26 positive OCs and certain endothelial vascular cells in several cases. Next, to clarify the role of CD26 in MM cell survival, we examined the effects of YS110 on MM cell growth and related osteolytic bone lesions in vitro and in vivo. YS110 had no significant effects on viability of MM cell lines in mono-culture, but dose-dependently inhibited growth of MM cell lines in co-culture with OCs. YS110 immediately inhibited p38 activation and its downstream Hsp27 phosphorylation in MM cells. Contitnued treatment of MM cells with YS110 also led to the reduction of total Hsp27 protein at 12 hours and 16 hours after the treatment of YS110, with commensurate decrease of phospho-Hsp27 and to increased MM apoptosis correlated with the induction of p53, increased activation of caspases and PARP, as well as the reduction of Mcl-1 and c-Myc. In parallel, we constructed a xenograft of murine model of human MM. A total of 5x106 CD26 positive MM cell lines by co-culture with OCs were inoculated to mice (NOD/SCID-s.c. mice) or directly injected into the implanted human bone chips in mice (NOD/SCID-hu mice). Mice treated with YS110 (500μg/dose) showed a significant effect in inhibiting MM tumor weight compared with control mice 4 weeks after tumor cell inoculation. To further investigate whether YS110 could reduce MM-induced osteolysis as well as suppress MM cell growth, we used NOD/SCID-hu mice model. Mice were treated with YS110 after the first detection of tumor growth. Continuous YS110 treatment significantly suppressed MM cell growth after 4 weeks. Immunohistochemistry for CD138 and TRAP staining showed decreased numbers of MM cells and TRAP positive OCs, with decreased bone resorption activity in human bones from YS110-treated versus control mice. Lastly, we examined the effects of targeting CD26 with YS110 in CD26 positive myeloma stem-like cells (SP cells). CD26 expression was demonstrated in SP cells of several MM cell lines in co-culture with OCs. YS110 dose-dependently inhibited cell viability of CD26 positive SP cells co-cultured with OCs, indicating targeting CD26 might reduce chemoresistance in MM. Conclusions: Theses results suggest that CD26 may be a promising novel target in MM, strongly supporting YS110 to inhibit MM cell growth in the BM as well as its related osteolytic bone lesions. Our results provide the framework for clinical development of YS110 as a novel therapeutic option in MM. Disclosures Morimoto: Y's Therapeutics: Consultancy, Research Funding. Yamada:Y's Therapeutics: Consultancy, Research Funding.

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Chatterjee-Chakraborty, Munmun, and Diptendu Chatterjee. "Artificial rearing inhibits apoptotic cell death through action on pro-apoptotic signaling molecules during brain development: Replacement licking partially reverses these effects." Brain Research 1348 (August 2010): 10–20. http://dx.doi.org/10.1016/j.brainres.2010.05.092.

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Farrell, N. L., R. W. G. Watson, and J. M. Fitzpatrick. "Theres is an alteration in the expression of the inhibitors of apoptosis proteins between basal and secretory prostate epithelial cells." European Urology Supplements 2, no. 6 (2003): 136. http://dx.doi.org/10.1016/s1569-9056(03)90495-7.

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Baranova, Svetlana V., Pavel S. Dmitrienok, Valentina N. Buneva, and Georgy A. Nevinsky. "HIV-Infected Patients: Cross Site-Specific Hydrolysis of H2a and H2b Histones and Myelin Basic Protein with Antibodies against These Three Proteins." Biomolecules 10, no. 11 (2020): 1501. http://dx.doi.org/10.3390/biom10111501.

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Anti-DNA antibodies are usually produced against histone-DNA complexes appearing during cell apoptosis, while histones are known as damage-associated molecules. A myelin sheath of axons contains myelin basic protein (MBP) playing an important role in the pathogenesis of autoimmune diseases. Antibodies with enzymatic activities (abzymes) are distinctive features of some autoimmune and viral diseases. Abzymes against different proteins can usually only hydrolyze these specific proteins. Using sequential chromatographies of homogeneous IgG preparations from sera of HIV-infected patients on columns with immobilized MBP, H2a, and H2b histones, the anti-MBP, anti-H2a, and anti-H2b antibodies were obtained. It was first shown that IgGs against H2a and H2b effectively hydrolyze these histones and MBP, while anti-MBP split MBP, H2a, and H2b, but no other control proteins. Using the MALDI mass spectrometry, the cleavage sites of H2a, H2b, and MBP by abzymes against these three proteins were found. Among 14 sites of hydrolysis of H2a by IgGs against H2a and 10 sites by anti-MBP IgGs, only one site of hydrolysis was the same for these abzymes. Eleven cleavage sites of H2b with IgGs against H2b and 10 sites of its hydrolysis with antibodies against MBP were different. Anti-H2a, anti-H2b, and anti-MBP abzymes are unpredictable examples of IgGs possessing not only cross-complexation but also catalytic cross-reactivity, which may be a common phenomenon for such abzymes in patients with different autoimmune diseases. The existence of cross-reactivity of abzymes against H2a and H2b histones and MBP represent a great danger to humans since, in contrast with MBP, histones due to cell apoptosis constantly occur in human blood. Anti-H2a, anti-H2b, and anti-MBP can attack and hydrolyze myelin basic protein of the myelin sheath of axons and plays a negative role in the pathogenesis of several pathologies.

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Luedde, Tom, Ulrike Assmus, Torsten Wüstefeld, et al. "Deletion of IKK2 in hepatocytes does not sensitize these cells to TNF-induced apoptosis but protects from ischemia/reperfusion injury." Journal of Clinical Investigation 115, no. 4 (2005): 849–59. http://dx.doi.org/10.1172/jci23493.

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Chacon-Cruz, Enrique, E. Stephen Buescher, and David G. Oelberg. "Cycloheximide-induced apoptosis alters human neutrophil intracellular calcium metabolism and these effects are not reversed by cyclic-AMP exposure. 42." Pediatric Research 41 (April 1997): 9. http://dx.doi.org/10.1203/00006450-199704001-00063.

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Bharti, Alok C., Shishir Shishodia, James M. Reuben та ін. "Nuclear factor–κB and STAT3 are constitutively active in CD138+ cells derived from multiple myeloma patients, and suppression of these transcription factors leads to apoptosis". Blood 103, № 8 (2004): 3175–84. http://dx.doi.org/10.1182/blood-2003-06-2151.

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Abstract Chemoresistance is a major problem in the treatment of patients with multiple myeloma (MM). Because of the central role of the nuclear transcription factors nuclear factor–κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) in chemoresistance, cell survival, and proliferation, we investigated whether MM cells derived from patients express activated NF-κB and STAT3 and if their suppression induces apoptosis. We assayed CD138+ cells from the bone marrow of 22 MM patients and checked for the activated forms of NF-κB and STAT3 by immunocytochemistry. We found that MM cells from all the patients expressed the activated forms of NF-κB and STAT3 but to a variable degree (NF-κB: low, 3 of 22; moderate, 5 of 22; or high, 14 of 22; STAT3: none, 1 of 22; low, 3 of 22; moderate, 5 of 22; or high, 14 of 22). Constitutive activation of NF-κB was in some cases also independently confirmed by electrophoretic mobility gel shift assay. In contrast to MM patients, activated forms of NF-κB and STAT3 were absent in cells from healthy individuals. Suppression of NF-κB and STAT3 activation in MM cells by ex vivo treatment with curcumin (diferuloylmethane) resulted in a decrease in adhesion to bone marrow stromal cells, cytokine secretion, and in the viability of cells. When compared with curcumin, dexamethasone was less effective in suppression of NF-κB activation and induction of apoptosis in myeloma cells. Overall, our results indicate that fresh cells from MM patients express constitutively active NF-κB and STAT3, and suppression of these transcription factors inhibits the survival of the cells. (Blood. 2004;103:3175-3184)

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Forthun, Rakel Brendsdal, Emmet McCormack, Tanima Sengupta, et al. "Identification of Molecular Targets of AML by Phosphoproteomic Screening of Valproic Acid Treated BNML and C. Elegans RNAi Validation." Blood 114, no. 22 (2009): 4151. http://dx.doi.org/10.1182/blood.v114.22.4151.4151.

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Abstract Abstract 4151 Disease stabilisation, instead of cure, is proposed as the therapeutic strategy of choice in elderly or chemoresistant acute myeloid leukemia (AML). This approach may also be of particular benefit to patients for whom allogeneic bone marrow (re)transplantation is not an option. Previously, we have clinically investigated the addition of valproic acid (VPA) to various combination chemotherapies with initial results in AML indicating prolonged survival, with follow-up on a predominantly out-patient basis. Consequently, we aimed to identify further molecular targets of VPA, which may enhance its therapeutic efficacy through screening for VPA-modulated phosphoproteins in relevant preclinical models of AML, and validation of these targets in RNAi screen of Caenorhabditis elegans (C. elegans). Brown Norwegian Myeloid Leukemia (BNML) has previously been described as a particularly relevant preclinical rat model of AML. Indeed, leukemic rats treated with 170 mg/kg VPA twice-daily achieved therapeutic serum levels of VPA and demonstrated significant increases in survival in comparison to controls (p = 0.004). To screen for molecular targets of VPA effect in this responsive model, we investigated the differences in control and VPA treated BNML phosphoproteomes by difference gel electrophoresis (DIGE) separation and subsequent differential gel software analysis. This was achieved through harvest of phosphoproteins from leukemic blasts, isolated from the spleens of treated and control BNML rats by immobilized metal ion affinity chromatography (IMAC) and subsequent protein identification via Orbitrap mass-spectrometry. Significant differential expression of 9 phosphoproteins was found in VPA treated BNML rats compared to controls, including Tubulin α-1B chain (TBA1B) and Actin β (ACTB), indicating these genes as possible targets of VPA therapy. To validate the functionality of 7 of these genes, RNAi was performed in wild type Bristol N2 strain of C. elegans at larval stage L1, 24 hours prior to exposure to 15 mM VPA for 72 hours. Knockdown of 4 of 7 genes resulted in larval developmental arrest, defined as synthetic lethality. In order to ascertain if synthetic lethality induced by these 4 genes was resultant of apoptosis, we employed the CED-1::GFP transgenic reporter assay to quantify germline cell death following RNAi depletion and subsequent exposure to VPA (15 mM, 24 hours). Increased numbers of apoptotic corpses in the germline was determined for all genes examined. To further examine the role of p53 in the observed apoptotic induction we used the transgenic strain cep-1::CED-1::GFP, which expresses the C. elegans ortholog of p53, CEP-1. Successive RNAi knockdown of our 4 candidate genes, again effected increased basal number of apoptotic corpses independently of CEP-1. These results suggest that similar combinational treatment of AML may be beneficial, irrespective of p53 status. To further investigate this thesis in a human AML cell line, MOLM-13 cells were co-treated with VPA and small molecule inhibitors of prospective targets TBA1B and ACTB, namely paclitaxel, and cytochalasin B. Inhibition of actin polymerization or stabilisation of tubulin polymerization resulted in increased apoptosis when supplemented with VPA, as determined by DNA specific staining with Hoechst 33342. These results suggest that use of these combinations may be beneficial in the treatment of AML. In conclusion, this study indicates that phosphoproteomic screening of BNML and subsequent target verification in C. elegans worms has the potential to identify future drugable targets for effective combinatorial therapy with valproic acid in acute myeloid leukemia. Disclosures: No relevant conflicts of interest to declare.

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Li, Jianrong, and Timothy R. Billiar. "IV. Determinants of nitric oxide protection and toxicity in liver." American Journal of Physiology-Gastrointestinal and Liver Physiology 276, no. 5 (1999): G1069—G1073. http://dx.doi.org/10.1152/ajpgi.1999.276.5.g1069.

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Whereas nitric oxide (NO) produced by constitutive endothelial NO synthase is protective to the liver, NO produced by the inducible NO synthase (iNOS) can be either toxic or protective depending on the conditions. The availability of selective iNOS inhibitors and mice lacking various NOS isoforms made it possible to begin to elucidate the precise roles of NO in the liver. Under conditions of redox stress, induced NO contributes to hepatic damage. However, in acute inflammatory conditions associated with cytokine exposure, NO acts as a potent inhibitor of apoptosis in the liver. Our current understanding of the mechanisms by which NO exerts both hepatoprotective and hepatotoxic actions is discussed in this themes article.

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Ajuebor, Maureen N. "Role of NKT Cells in the Digestive System. I. Invariant NKT cells and liver diseases: is there strength in numbers?" American Journal of Physiology-Gastrointestinal and Liver Physiology 293, no. 4 (2007): G651—G656. http://dx.doi.org/10.1152/ajpgi.00298.2007.

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Information regarding the functional role of the innate immune T cell, invariant natural killer T (iNKT) cells, in the pathophysiology of liver diseases continues to emerge. Results from animal studies suggest that iNKT cells can have divergent roles by specifically promoting the development of proinflammatory or anti-inflammatory responses in liver diseases. In this themes article, I discuss the critical evidence from animal models that demonstrate a vital role for iNKT cells in the pathophysiology of liver diseases with emphasis on viral, autoimmune, and toxin-induced liver diseases. Furthermore, I discuss the controversial issues (including iNKT cell apoptosis) that typify some of these studies. Finally, I highlight areas that require additional investigation.

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Barzideh, J., R. J. Scott, and R. J. Aitken. "Analysis of the global methylation status of human spermatozoa and its association with the tendency of these cells to enter apoptosis." Andrologia 45, no. 6 (2012): 424–29. http://dx.doi.org/10.1111/and.12033.

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Tavassoli, M. "Tamoxifen inhibits the growth of head and neck cancer cells and sensitizes these cells to cisplatin induced-apoptosis: role of TGF-beta1." Carcinogenesis 23, no. 10 (2002): 1569–76. http://dx.doi.org/10.1093/carcin/23.10.1569.

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Wang, Min, and Eleftherios Papoutsakis. "Global Transcriptional Analysis Details Prior Knowledge and Identifies New Genes and Processes Associated with T-Cell Activation in the Context of Ex Vivo Expansion." Blood 108, no. 11 (2006): 1725. http://dx.doi.org/10.1182/blood.v108.11.1725.1725.

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Abstract Introduction. Ex vivo expanded T cells are increasingly employed in a variety of immunotherapy protocols. The success of such protocols requires large numbers of biologically active T cells. Several activation and culture protocols have been examined, but none in significant or molecular detail to allow more targeted protocol interventions. In this study, our aim was to better understand early T-cell activation using a comprehensive, microarray-based transcriptional analysis, in conjunction with targeted protein-level and functional analyses. Methods. Three biological experiments were transcriptionally analyzed. T cells were activated with anti-CD3/anti-CD28 Mab, cultured for 96 hours, and samples collected at 0, 4, 10, 48 and 96 hours. mRNA levels at each time point were compared to that of 0 hour. Genes were selected as follows: a minimum 1.8-fold difference in at least 6 time points of the 12 (3x4) time points. Data were subject to Gene Ontology (GO) analysis, EASE, to discover enriched biological themes. Interferon-γ (IFNG) and CCL20 ELISA assays and NF-κB p65 (active complex) assay by flow cytometry were carried out to confirm select findings of the transcriptional analysis. Results. 2340 genes passed the gene-selection criteria. GO analysis showed that the GO groups Immune Response, Regulation of Apoptosis, and Mitochondrion are among the most over-represented groups among differentially expressed genes during T-cell activation. The upregulated Immune Response group contained many genes coding cytokines typically produced by helper T cells. Highly upregulated genes in this category include IL2, CCL20, CXCL11, CXCL9, CXCL10, CD83, IFNG, CCL3, CSF2, IL23A, XCL2, TNF, CCL4, TNFSF6 and ICOS. Although several of these findings would have been expected, our data include a more extensive gene list and suggest potential use of these cytokines as T-cell ex vivo culture supplements. We singled out CCL20, sharing a very similar transcription pattern with IL2, and IFNG, for further analysis. ELISA assays of IFNG and CCL20 showed that the kinetics of secreted protein levels were in agreement with transcriptional data. In the GO group Regulation of Apoptosis, the downregulated gene cluster was enriched by pro-apoptotic genes, while the upregulated cluster was enriched by anti-apoptotic genes. Our data indicated that NF-κB complex activity changed upon T-cell activation. This was verified by NF-κB p65 Phosflow assay, showing that phosphorylated NF-κB p65 was suppressed up to 10 hours, and then increased until hour 96. Although it is known that mitochondrial hyperpolarization is important in T-cell activation, our transcriptional data suggest more profound changes in mitochondrial biology. Genes in this category include several having oxidoreductase activity, such as SOD2, SCO1, NDUFAB1, GLUD2, consistent with reported increases in intracellular ROS levels upon T-cell activation, and suggest the potential use of anti-oxidants in ex vivo T-cell expansion. Conclusion. Our data and analysis provide a better understanding of T-cell activation and identify several potential targets that can be explored to benefit T-cell expansion protocols for immunotherapy applications. Although there is much known about T-cell activation, modern genomic tools provide an extraordinary opportunity to verify, extend and enrich prior knowledge, and, discover new players and processes not previously associated with T-cell activation.

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Ezzat, Afaf, Abdo Abdelhamid, Ahmed Amin, Amal Abdelazeem, Mohamed Ragai, and Dina Mohammed. "Biochemical studies on the effect of nano particles of some nutrients on apoptosis modulation of breast cancer cells in experimental animals: Thesis Abstract." International Journal of Cancer and Biomedical Research 5 (May 1, 2021): 10. http://dx.doi.org/10.21608/jcbr.2021.60576.1149.

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Němcová‐Fürstová, Vlasta, Kamila Balušíková, Petr Halada, Nela Pavlíková, Jan Šrámek та Jan Kovář. "Stearate‐Induced Apoptosis in Human Pancreatic β‐Cells is Associated with Changes in Membrane Protein Expression and These Changes are Inhibited by Oleate". PROTEOMICS – Clinical Applications 13, № 4 (2019): 1800104. http://dx.doi.org/10.1002/prca.201800104.

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Lu, Jin-Jian, Yu-Jun Cai, and Jian Ding. "The short-time treatment with curcumin sufficiently decreases cell viability, induces apoptosis and copper enhances these effects in multidrug-resistant K562/A02 cells." Molecular and Cellular Biochemistry 360, no. 1-2 (2011): 253–60. http://dx.doi.org/10.1007/s11010-011-1064-2.

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Caruso, Rosario A., Francesco Fedele, Luciana Rigoli, et al. "Apoptotic-Like Tumor Cells and Apoptotic Neutrophils in Mitochondrion-Rich Gastric Adenocarcinomas: A Comparative Study with Light and Electron Microscopy between these Two Forms of Cell Death." Rare Tumors 5, no. 2 (2013): 68–71. http://dx.doi.org/10.4081/rt.2013.e18.

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Moustafa, Ahmed A., Hogyoung Kim, Rasha S. Albeltagy, Ola H. El-Habit, and Asim B. Abdel-Mageed. "MicroRNAs in prostate cancer: From function to biomarker discovery." Experimental Biology and Medicine 243, no. 10 (2018): 817–25. http://dx.doi.org/10.1177/1535370218775657.

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MicroRNAs (miRNAs) are a small functional non-coding RNAs that post-transcriptionally regulate gene expression through mRNA degradation or translational repression. miRNAs are key regulatory components of various cellular networks. Current evidence support that multiple mammalian genome-encoded miRNAs impact the cellular biology, including proliferation, apoptosis, differentiation, and tumorigenesis, by targeting specific subsets of mRNAs. This minireview is focused on the current themes underlying the interactions between miRNAs and their mRNA targets and pathways in prostate tumorigenesis and progression, and their potential clinical utility as biomarkers for prostate cancer. Impact statement The primary goal of this article was to review recent literature on miRNA biogenesis and further elaborate on the identity of newly discovered miRNAs and their potential functional significance in the complex biological network associated with prostate tumorigenesis and disease progression and as biomarkers for prostate cancer.

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Baranova, Svetlana V., Pavel S. Dmitrenok, Valentina N. Buneva, Sergey E. Sedykh, and Georgy A. Nevinsky. "HIV-Infected Patients: Cross Site-Specific Hydrolysis of H3 and H4 Histones and Myelin Basic Protein with Antibodies against These Three Proteins." Molecules 26, no. 2 (2021): 316. http://dx.doi.org/10.3390/molecules26020316.

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Histones play important roles in chromatin functioning and gene transcription, but in the intercellular space, they are harmful since they stimulate systemic inflammatory and toxic responses. Electrophoretically homogeneous IgGs against myelin basic protein (MBP), as well as H3 and H4 histones, were isolated from sera of HIV-infected patients. In contrast to known classical proteases, these IgGs split exclusively only histones and MBP but no other control proteins. Among 13 sites of hydrolysis of H3 by IgGs against H3 and 14 sites for anti-MBP IgGs, only two sites of the hydrolysis were the same. Between seven cleavage sites of H4 with IgGs against H4 and 9 sites of this histone hydrolysis by antibodies against MBP, only three sites were the same. The sites of hydrolysis of H3 (and H4) with abzymes against these histones and against MBP were different, but several expended protein clusters containing hydrolysis sites are partially overlapped. The existence of enzymatic cross-reactivity of abzymes against H3 and H4 and MBP represents a great menace to humans since due to cell apoptosis, histones constantly occur in human blood. They can hydrolyze MBP of the myelin sheath of axons and play a negative role in the pathogenesis of HIV-infected patients.

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Zhang, Jian-zhi, Mala Sinha, Bruce A. Luxon, and Xue-jie Yu. "Survival Strategy of Obligately IntracellularEhrlichia chaffeensis: Novel Modulation of Immune Response andHost CellCycles." Infection and Immunity 72, no. 1 (2004): 498–507. http://dx.doi.org/10.1128/iai.72.1.498-507.2004.

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ABSTRACT Ehrlichia chaffeensis is an obligatory intracellular bacterium which resides in an early endosome in monocytes. E. chaffeensis infection in a human monocyte cell line (THP1) significantly altered the transcriptional levels of 4.5% of host genes, including those coding for apoptosis inhibitors, proteins regulating cell differentiation, signal transduction, proinflammatory cytokines, biosynthetic and metabolic proteins, and membrane trafficking proteins. The transcriptional profile of the host cell revealed key themes in the pathogenesis of Ehrlichia. First, E. chaffeensis avoided stimulation of or repressed the transcription of cytokines involved in the early innate immune response and cell-mediated immune response to intracellular microbes, such as the interleukin-12 (IL-12), IL-15, and IL-18 genes, which might make Ehrlichia a stealth organism for the macrophage. Second, E. chaffeensis up-regulated NF-κB and apoptosis inhibitors and differentially regulated cell cyclins and CDK expression, which may enhance host cell survival. Third, E. chaffeensis also inhibited the gene transcription of RAB5A, SNAP23, and STX16, which are involved in membrane trafficking. By comparing the transcriptional response of macrophages infected with other bacteria and that of macrophages infected with E. chaffeensis, we have identified few genes that are commonly induced and no commonly repressed genes. These results illustrate the stereotyped macrophage response to other pathogens, in contrast with the novel host response to obligate intracellular Ehrlichia, whose survival depends entirely on a long evolutionary process of outmaneuvering macrophages.

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De la Iglesia Iñigo, Silvia, Carmen Elsa López-Jorge, Maria Teresa Gómez-Casares, et al. "Induction of apoptosis in leukemic cell lines treated with captopril, trandolapril and losartan: A new role in the treatment of leukaemia for these agents." Leukemia Research 33, no. 6 (2009): 810–16. http://dx.doi.org/10.1016/j.leukres.2008.09.029.

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Buchmaier, Bettina S., Asima Bibi, Gerhard A. Müller, et al. "Renal Cells Express Different Forms of Vimentin: The Independent Expression Alteration of these Forms is Important in Cell Resistance to Osmotic Stress and Apoptosis." PLoS ONE 8, no. 7 (2013): e68301. http://dx.doi.org/10.1371/journal.pone.0068301.

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Metcalf, Melissa G., Ryo Higuchi-Sanabria, Gilberto Garcia, C. Kimberly Tsui, and Andrew Dillin. "Beyond the cell factory: Homeostatic regulation of and by the UPRER." Science Advances 6, no. 29 (2020): eabb9614. http://dx.doi.org/10.1126/sciadv.abb9614.

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The endoplasmic reticulum (ER) is commonly referred to as the factory of the cell, as it is responsible for a large amount of protein and lipid synthesis. As a membrane-bound organelle, the ER has a distinct environment that is ideal for its functions in synthesizing these primary cellular components. Many different quality control machineries exist to maintain ER stability under the stresses associated with synthesizing, folding, and modifying complex proteins and lipids. The best understood of these mechanisms is the unfolded protein response of the ER (UPRER), in which transmembrane proteins serve as sensors, which trigger a coordinated transcriptional response of genes dedicated for mitigating the stress. As the name suggests, the UPRER is most well described as a functional response to protein misfolding stress. Here, we focus on recent findings and emerging themes in additional roles of the UPRER outside of protein homeostasis, including lipid homeostasis, autophagy, apoptosis, and immunity.

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Liu, Meng, Xia Li, Rui Fan, Xinhua Liu, and Ju Wang. "A Systematic Analysis of Candidate Genes Associated with Nicotine Addiction." BioMed Research International 2015 (2015): 1–9. http://dx.doi.org/10.1155/2015/313709.

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Nicotine, as the major psychoactive component of tobacco, has broad physiological effects within the central nervous system, but our understanding of the molecular mechanism underlying its neuronal effects remains incomplete. In this study, we performed a systematic analysis on a set of nicotine addiction-related genes to explore their characteristics at network levels. We found that NAGenes tended to have a more moderate degree and weaker clustering coefficient and to be less central in the network compared to alcohol addiction-related genes or cancer genes. Further, clustering of these genes resulted in six clusters with themes in synaptic transmission, signal transduction, metabolic process, and apoptosis, which provided an intuitional view on the major molecular functions of the genes. Moreover, functional enrichment analysis revealed that neurodevelopment, neurotransmission activity, and metabolism related biological processes were involved in nicotine addiction. In summary, by analyzing the overall characteristics of the nicotine addiction related genes, this study provided valuable information for understanding the molecular mechanisms underlying nicotine addiction.

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