scholarly journals Melatonin ameliorates myocardial injury by reducing apoptosis and autophagy of cardiomyocytes in a rat cardiopulmonary bypass model

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11264
Author(s):  
Xiaolin Huang ◽  
Jian Hou ◽  
Suiqing Huang ◽  
Kangni Feng ◽  
Yuan Yue ◽  
...  
Keyword(s):  
Cardiopulmonary Bypass ◽  
B Cell ◽  
Signaling Pathways ◽  
Myocardial Injury ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Mtor Signaling ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Tunel Staining ◽  
Sham Operation

Background Myocardial injury is a frequent complication after cardiac surgery with cardiopulmonary bypass (CPB). This study aimed to test the hypothesis that melatonin could attenuate myocardial injury in a rat CPB model. Methods Eighteen male Sprague-Dawley rats were randomly divided into three groups, n = 6 for each group: the sham operation (SO) group, CPB group and melatonin group. Rats in the SO group underwent cannulation without CPB, rats in CPB group intraperitoneal injected an equal volume of vehicle daily for 7 days before being subjected to CPB and rats in melatonin group intraperitoneal injected 20 mg/kg of melatonin solution daily for 7 days before being subjected to CPB. After 120 min for CPB, the expression levels of plasma interleukin (IL) -6, IL-1β, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), creatine kinase (CK) -MB and cardiac troponin T (cTnT) were measured. Reactive oxygen species (ROS) were detected by dihydroethidium (DHE). Apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining. Mitochondrial damage and autophagosomes were detected by electron microscopy. Apoptosis inducing factor (AIF) was detected by immunofluorescence. The expression of B cell lymphoma/leukemia2 associated X (Bax), B cell lymphoma/leukemia 2 (Bcl-2), cytochrome C (Cyto-C), cleaved caspase-9, AKT, p-AKT, signal transducer and activator of transcription 3 (STAT3), p-STAT3, LC3, P62, mechanistic target of rapamycin kinase (mTOR), p-mTOR and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were determined using western blotting. Results Melatonin significantly decreased the levels of IL-1β, IL-6, MDA, CK-MB and cTnT and increased the levels of SOD and GSH-Px, all of which were altered by CPB. Melatonin reduced cardiomyocyte superoxide production, the apoptosis index and autophagy in cardiomyocytes induced by CPB. The AKT, STAT3 and mTOR signaling pathways were activated by melatonin during CPB. Conclusion Melatonin may serve as a cardioprotective factor in CPB by inhibiting oxidative damage, apoptosis and autophagy. The AKT, STAT3 and mTOR signaling pathways were involved in this process.

scholarly journals Cilostazol Minimizes Venous Ischemic Injury in Diabetic and Normal Rats

2011 ◽  
Vol 31 (10) ◽  
pp. 2030-2040 ◽  
Author(s):  
Daisuke Wajima ◽  
Mitsutoshi Nakamura ◽  
Kaoru Horiuchi ◽  
Yasuhiro Takeshima ◽  
Fumihiko Nishimura ◽  
...  
Keyword(s):  
Infarct Size ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Diabetic Rats ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Doppler Flowmetry ◽  
Vessel Wall Thickness ◽  
Venous Infarcts ◽  
And Control

We evaluated the effects of cilostazol on venous infarction produced by a photothrombotic two-vein occlusion (2VO) model in diabetic and control rats. The cerebral blood flow (CBF) between the occluded veins was measured by laser Doppler flowmetry for 4 hours after 2VO. Infarct size and immunohistochemistry were evaluated 24, 48, 96, and 168 hours after 2VO. Cilostazol was administered 1 hour after 2VO, and thereafter at a continuous oral dose of 60 mg/kg per day. Cilostazol reduced the infarct size, and the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)-positive apoptotic and B-cell lymphoma 2-associated X protein (Bax)-positive cells, and improved the CBF in control rats. In diabetic rats, cilostazol reduced the infarct size, and the number of TUNEL-positive apoptotic and Bax-positive cells, 96 and 168 hours after 2VO, but did not improve the CBF 4 hours after 2VO. Cilostazol increased the number of B-cell lymphoma 2 (Bcl-2)-positive cells in both strains 48, 96, and 168 hours after 2VO, but did not improve vessel wall thickness or collagen deposits. Cilostazol appeared to limit venous infarcts by improving the penumbral CBF in nondiabetic rats, and inhibited pro-apoptotic changes through Bcl-2 overexpression, without improving the CBF in diabetic rats.

scholarly journals Obinutuzumab (GA101) Significantly Inhibits Cell Proliferation and Induces Programmed Cell Death in Primary Mediastinal B-Cell Lymphoma (PMBL): Obinutuzumab May be a Future Targeted Agent for the Treatment of PMBL

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4492-4492
Author(s):  
Changhong Yin ◽  
Sanghoon Lee ◽  
Timmy O'Connell ◽  
Janet Ayello ◽  
Carmella van de Ven ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Cell Death ◽  
Programmed Cell Death ◽  
B Cell ◽  
Signaling Pathways ◽  
Expression Profiling ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Targeted Agent

Abstract BACKGROUND: Primary Mediastinal large B-cell lymphoma (PMBL) is a rare form of Non Hodgkin Lymphoma (NHL) representing 2% of mature B-cell non-Hodgkin lymphoma in patients less than 18 years of age (Lones/Cairo et al, JCO 2000; Burkhardt et al, BJH 2005). PMBL has histological features somewhere between Diffuse Large B-Cell Lymphoma (DLBCL) and classical HL (cHL) (Abramson et al, Blood 2005). Gene expression studies suggested that the molecular signature of PMBL had a striking resemblance to the expression profile of cHL (Rosenwald et al, JEM 2003). We have recently reported that a significant decrease in EFS among children and adolescent PMBL patients compared with other stage III non-PMBL pediatric DLBCL patients following FAB/LMB 96 therapy, suggesting that children and adolescent with PMBL required alternative treatment strategies (Gerrard/Cairo et al, Blood 2013). PMBL has been demonstrated to have an over-activated NF-kB pathway by gene expression profiling (Rosenwald et al, JEM 2003). Since over 95% of PMBL express CD20, targeting the CD20 receptor with a CD20 antibody is of high clinical interest. Obinutuzumab (GA101) is novel glycoengineered anti-CD20 targeted monoclonal antibody recognizing a unique CD20 type II epitope and it has been demonstrated to have greater efficacy in reducing tumor size, inducing remission and improving survival in other B-NHL xenograft models (Mössner et al, Blood 2010). Obinutuzumab has been recently approved by FDA for first line treatment of chronic lymphocytic leukemia (CLL) in combination with chlorambucil. OBJECTIVES: We hypothesize that obinutuzumab may be a future potential targeted agent for the treatment of PMBL, and therefore, we investigated whether obinutuzumab treatment results in significant changes in signaling pathways, genes expression, programmed cell death and cell proliferation in PMBL. METHODS: Karpas-1106P cells (DSMZ) were treated with obinutuzumab (generously provided by Dr. Klein, Roche) at every 24 hours (1-100ug/ml). qRT-PCR, western blot, MTS, Caspase 3/7 assay (Promega) and FACS analysis were performed. The BeadChip array (Illumina, HumanHT-12) was used for gene expression profiling. RESULTS: There was a significant decrease of cell proliferation in obinutuzumab-treated Karpas cells with 10ug/ml (0.69 ± 0.025, p<0.005) vs control (1.00 ± 0.000) at 48 hours. Concomitantly, there was a significant increase in programmed cell death in 10ug/ml obinutuzumab treated Karpas (37.80 ± 10.096, p<0.05) vs control (1.19 ± 0.762) at 48 hours. We also observed a significant decrease of CD20 expression (0.74± 0.010, p<0.05) with 10ug/ml obinutuzumab treatment at 48 hours. A total of 133 differentially expressed genes were identified by gene expression profiling (>1.5-fold, 0.57%) and 77.5% of genes including apoptosis related genes (CASP2 and PAK2) and MAPK signaling pathways (RASA1 and JUN) and EGR1 were upregulated and 22.5% of genes including ID3, GRAP and RAB6B were downregulated in obinutuzumab treated Karpas vs control (Fig 1). There were significant decreases of p-STAT6 (0.72± 0.011, p=0.01), p-Akt (0.69± 0.011, p<0.05), p-ikBα (0.70± 0.017, p<0.05) and p-Erk (0.56± 0.019, p<0.05) with 10ug/ml obinutuzumab treatment at 48 hours (Fig 2). Additionally, There were significant down-regulation of mRNA expression of Bcl-xL (0.91±0.011, p<0.04) and Bax (0.66±0.022, p<0.02) vs control. CONCLUSIONS: We observed that obinutuzumab significantly inhibited cell proliferation and induced programmed cell death and downregulated downstream of PI3k/Akt and NF-kB signaling pathways. Gene expression analysis indicated obinutuzumab induced changes in the expression of genes in Karpas that were involved in apoptosis and signaling pathways including CASP2, EGR1 and ID3. Future studies 1) will investigate the efficacy of combination therapies to enhance programmed cell death, and 2) will assess the proteomic signature induced by obinutuzumab in obinutuzumab sensitive and resistant PMBL, and furthermore, 3) will focus on the in vivo effects of obinutuzumab in a NOD/SCID PMBL xenograft mouse model. Obinutuzumab may be a future potential targeted agent for the adjuvant treatment of PMBL lymphoma. Disclosures No relevant conflicts of interest to declare.

scholarly journals B-Cell Lymphoma 2 (Bcl-2) and Regulation of Apoptosis after Traumatic Brain Injury: A Clinical Perspective

Medicina ◽  
2020 ◽  
Vol 56 (6) ◽  
pp. 300
Author(s):  
Hansen Deng ◽  
John K. Yue ◽  
Benjamin E. Zusman ◽  
Enyinna L. Nwachuku ◽  
Hussam Abou-Al-Shaar ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Cell Death ◽  
Brain Injury ◽  
B Cell ◽  
Head Trauma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Post Injury ◽  
Pubmed Database

Background and Objectives: The injury burden after head trauma is exacerbated by secondary sequelae, which leads to further neuronal loss. B-cell lymphoma 2 (Bcl-2) is an anti-apoptotic protein and a key modulator of the programmed cell death (PCD) pathways. The current study evaluates the clinical evidence on Bcl-2 and neurological recovery in patients after traumatic brain injury (TBI). Materials and Methods: All studies in English were queried from the National Library of Medicine PubMed database using the following search terms: (B-cell lymphoma 2/Bcl-2/Bcl2) AND (brain injury/head injury/head trauma/traumatic brain injury) AND (human/patient/subject). There were 10 investigations conducted on Bcl-2 and apoptosis in TBI patients, of which 5 analyzed the pericontutional brain tissue obtained from surgical decompression, 4 studied Bcl-2 expression as a biomarker in the cerebrospinal fluid (CSF), and 1 was a prospective randomized trial. Results: Immunohistochemistry (IHC) in 94 adults with severe TBI showed upregulation of Bcl-2 in the pericontusional tissue. Bcl-2 was detected in 36–75% of TBI patients, while it was generally absent in the non-TBI controls, with Bcl-2 expression increased 2.9- to 17-fold in TBI patients. Terminal deoxynucleotidyl transferase-mediated biotinylated dUTP nick-end labeling (TUNEL) positivity for cell death was detected in 33–73% of TBI patients. CSF analysis in 113 TBI subjects (90 adults, 23 pediatric patients) showed upregulation of Bcl-2 that peaked on post-injury day 3 and subsequently declined after day 5. Increased Bcl-2 in the peritraumatic tissue, rising CSF Bcl-2 levels, and the variant allele of rs17759659 are associated with improved mortality and better outcomes on the Glasgow Outcome Score (GOS). Conclusions: Bcl-2 is upregulated in the pericontusional brain and CSF in the acute period after TBI. Bcl-2 has a neuroprotective role as a pro-survival protein in experimental models, and increased expression in patients can contribute to improvement in clinical outcomes. Its utility as a biomarker and therapeutic target to block neuronal apoptosis after TBI warrants further evaluation.

scholarly journals Distinct inhibitory effects on mTOR signaling by ethanol and INK128 in diffuse large B-cell lymphoma

2015 ◽  
Vol 13 (1) ◽  
pp. 15 ◽  
Author(s):  
Krystyna Mazan-Mamczarz ◽  
Raymond J Peroutka ◽  
James J Steinhardt ◽  
Moriah Gidoni ◽  
Yongqing Zhang ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Mtor Signaling ◽  
Inhibitory Effects ◽  
Large B Cell Lymphoma ◽  
Large B Cell

scholarly journals Combination of Enzastaurin and Ibrutinib Synergistically Induces Anti-Tumor Effects in Diffuse Large B Cell Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1666-1666
Author(s):  
Jun Zhu ◽  
Yizi He ◽  
Jiao Li ◽  
Ning Ding ◽  
Xiaogan Wang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cell ◽  
Signaling Pathways ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Mrna Levels ◽  
Low Doses ◽  
Rna Seq ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Background:Diffuse large B cell lymphoma(DLBCL), the most common form of lymphoma, is characterized by a heterogeneous tumor entity. Although durable remissions can be achieved in more than half of these patients, DLBCL remains a significant clinical challenge, with approximately 30% of patients not being cured. BCR-associated kinases (SYK, BTK, PI3K)inhibitors have exhibited encouraging pre-clinical and clinical effects, as reported by many researchers.Early studies demonstrated that PKCβ inhibitors alter phosphorylation level of BTK, which enhances activation of BTK signaling pathway.Here we aim to investigate whether the combination of PKCβ inhibitor enzastaurin and BTK inhibitor ibrutinib has synergistic anti-tumor effects in DLBCL. Methods:In vitro cell proliferation was analyzed using Cell Titer-Glo Luminescent Cell Viability Assay. Induction of apoptosis and cell cycle arrest were measured by flow cytometry. Western Blotting analysis was used to detect the essential regulatory enzymes in related signaling pathways. RNA-seq was conducted to evaluate the whole-transcriptome changes brought by co-treatment with low doses of enzastaurin and ibrutinib. The synergistic anti-tumor effect of enzastaurin and ibrutinib was also evaluated in vivo. Results: Combination of enzastaurin and ibrutinib produced a lasting synergistic effect on the survival and proliferation of ABC (HBL-1,TMD8,SU-DHL-2)and GCB (SU-DHL-6, OCI-LY7)DLBCL cells lines. Exposure of these DLBCL cells to minimally toxic concentration of enzastaurin and ibrutinib resulted in more significant inhibitory activity than each agent alone. In addition, the combination of these two agents led to an enhanced apoptosis and induced G1 phase arrest compared with monotherapy, which were accompanied by marked regulation of apoptosis-related and cell cycle-related proteins. Combination treatment with enzastaurin and ibrutinib, to some extent, also functioned synergistically to inhibit cell migration and invasion compared with single agent. Moreover, combination of enzastaurin and ibrutinib seemed to be more effective in inhibition p-ERK, p-AKT and p-P38 in DLBCL cell lines. In addition, RNA-seq results showed that co-treatment with low doses of enzastaurin and ibrutinib could effectively downregulate BCR, NF-κB, JAK and MAPK related signaling pathways, and the pathway analysis results were consistent with the immunoblotting analysis. Furthermore, the mRNA expression analysis using real-time PCR further indicated that treatment with enzastaurin and ibrutinib significantly decreased the mRNA levels of NOTCH1 which has been recognized as an important oncogenic regulator of hematological malignancy. The combination effect of enzastaurin and ibrutinib in inhibiting proliferation of DLBCL cells probably was realized through suppression of NOTCH1 expression. Finally, the anti-tumor activity of co-treatment with enzastaurin and ibrutinib was also demonstrated using xenograft mice models. Conclusion:We investigated the combination of enzastaurin and ibrutinib in ABC and GCB DLBCL, demonstrating the co-treatment had synergistic anti-tumor effects in DLBCL. These results provided a sound foundation for an attractive therapeutic treatment, and the simultaneous suppression of BTK and PKCβ might be an new treatment strategy for DLBCL. Disclosures No relevant conflicts of interest to declare.

Use of exon-based transcriptome profiling to identify novel signaling pathways and survival-associated genes in diffuse large B-cell lymphoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8074-8074
Author(s):  
Sirpa Leppa ◽  
Minna Taskinen ◽  
Satu Koivula ◽  
Ping Chen ◽  
Riku Louhimo ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Signaling Pathways ◽  
Differentially Expressed Genes ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Transcriptome Profiling ◽  
High Dose ◽  
Large B Cell Lymphoma ◽  
Large B Cell

8074 Background: Identification of biological prognostic factors that could be used to define poor risk diffuse large B-cell lymphoma (DLBCL) patients is a main concern. Methods: Study population consisted of 38 de novo high risk DLBCL patients less than 65 years old. The patients were treated in the Nordic phase II protocol with six courses of R-CHOEP14 followed by systemic central nervous system prophylaxis with one course of high dose methotrexate and one course of high dose cytarabine. Exon array-based profiling was used to screen signaling pathways and differentially expressed genes between the clinically high risk patients, who had relapsed or remained in remission in response to dose dense chemoimmunotherapy. At the time of the analysis, median follow up was 34 months, progression free survival (PFS) 78% and overall survival (OS) 78%. Results: The screen between relapsed patients and the patients in remission using criteria of p ≤ 0.05 and fold change ≥ 1.6 revealed 566 differentially expressed genes (131 protein coding), of which 24 were likely to be involved in conventional signaling pathways, including those regulating antigen processing and presentation (CIITA, HLA-DQA2, HLA-DQB1, RFXAP), Jak-STAT signaling (SOCS3), Notch signaling (NOTCH1) and Toll-like receptor signalling (IRF5). In cox univariate analysis, 12 of 24 genes were found to associate with PFS (p<0.05). Of these, high expression of CIITA, DLL4, HLA-DQA2, HLA-DQB1, IRF5, NOTCH1, PER1, RFXAP, SEMA4D and ZFP36 had a favorable impact on PFS, whereas high levels of ENPP3 and PRKAR2B were associated with adverse outcome. Differential expression of four genes was confirmed by quantitative PCR, and prognostic value of six genes validated using Lymphoma/Leukemia Molecular Profiling Project microarray data set. Immunohistochemical validation of the findings in a larger patient cohort is ongoing. Germinal centre B-cell signature did not predict survival in this cohort. Conclusions: The results provide evidence that exon-based transcriptome profiling can identify biologically relevant signaling pathways and genes that discriminate the outcome of homogenously treated young high risk DLBCL patients.

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