bcl2 expression
Recently Published Documents


TOTAL DOCUMENTS

160
(FIVE YEARS 58)

H-INDEX

18
(FIVE YEARS 3)

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e12571
Author(s):  
Ye Zhang ◽  
Peng Lu ◽  
Yan Zhou ◽  
Lifei Zhang

Ibrutinib, a bruton tyrosine kinase (BTK) inhibitor which suppresses B-cell receptor signaling, has remarkably improved the outcome of patients with mantle cell lymphoma (MCL). However, approximately 33% of MCL patients have primary Ibrutinib resistance, and acquired Ibrutinib resistance is nearly universal. Long intergenic non-coding RNA for kinase activation (LINK-A) exerts oncogenic role in different types of tumors, but the role of LINK-A in intrinsic ibrutinib resistance in MCL is still unclear. Here, LINK-A expression level was first assessed using quantitative Real-time PCR (qPCR) and immunofluorescence analysis in five MCL cell lines. The effect of LINK-A on regulating MCL cells viability and apoptosis was assayed using CCK-8 and TdT-mediated dUTP nick end labeling (TUNEL) assay, respectively. The association of LINK-A with AKT activation and B cell lymphoma 2 (Bcl2)expression was evaluated using qPCR and western blot analysis. We found that LINK-A level was elevated in Ibrutinib-resistant MCL cell lines (Mino, REC-1, MAVER-1, and Granta-519) compared to Ibrutinib-sensitive MCL cell lines (Jeko-1). Functionally, LINK-A overexpression in Jeko-1 cells enhanced cell viability and repressed Ibrutinib-induced cell apoptosis. LINK-A knockdown in MAVER-1 cells decreased cell viability and further accelerated Ibrutinib-induced cell apoptosis. LINK-A overexpression enhanced Bcl2 expression in Jeko-1 cells, and Bcl2 inhibition blocked the effect of LINK-A on increasing cell viability in the presence of Ibrutinib. On the contrary, LINK-A knockdown reduced Bcl2 expression in MAVER-1 cells, and Bcl2 overexpression damaged the role of LINK-A inhibition in regulating cell viability. Mechanistically, LINK-A positively regulated the activation of AKT signaling, and inhibition of AKT signaling destroyed LINK-A-induced increased of Bcl2 and resulted in a subsequent suppression of cell viability. Taken together, the current results demonstrate that LINK-A inhibition overcomes Ibrutinib resistance in MCL cells by regulating AKT/Bcl2 pathway.


2021 ◽  
Author(s):  
Azusa Tanimoto ◽  
Carminia M. Della Corte ◽  
Kavya Ramkumar ◽  
Robert J. Cardnell ◽  
Allison C. Stewart ◽  
...  

Author(s):  
M Ozkaraca ◽  
S Ozdemir ◽  
S Comakli ◽  
MO Timurkan

The aim of this study was to investigate the activity of apoptosis and autophagy in animals (cows, horses, donkeys, dogs and cats) naturally infected with rabies by using immunohistochemistry, immunofluorescence, and qPCR. The mRNA transcript levels of caspase-3, Bax, Bcl2 and LC3B were determined with qPCR. Caspase-3 and AIF immunopositivity were not observed in the immunohistochemical and immunofluorescence staining, whereas LC3B immunopositivity was determined intensively in the infected animals compared to the control groups. LC3B immunopositivity was detected in the cytoplasm of the Purkinje cells in the cerebellum of the cows, horses and donkeys, and also in the cytoplasm of the neurons in the cornu ammonis of the dogs and cats. While the expression levels of caspase-3 and Bax were downregulated, the Bcl2 expression was up-regulated in the infected animals compared to the uninfected animals. In addition, the LC3B levels were found to be significantly higher in the infected animals. To the best of our knowledge, this work represents the first report of neuronal death in the central nervous system by autophagy, rather than by caspase-dependent or AIF-containing caspase-independent apoptosis.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1135-1135
Author(s):  
Adeleh Taghi Khani ◽  
Anil Kumar ◽  
Kelly Radecki ◽  
Sung June Lee ◽  
Mary Lorenson ◽  
...  

Abstract Rationale B cell malignancies, including leukemia and lymphoma, are high-risk lymphoid neoplasms. B cell malignancies predispose to autoimmune diseases including systemic lupus erythematosus (SLE) which increase the risk of developing these malignancies by >5-fold. Increased prolactin (PRL) expression is known to exacerbate SLE and promote the survival of autoreactive B cells. Furthermore, PRL induces expression of the protooncogenes, MYC and BCL2, in lymphoid tissues. However, whether PRL drives the initiation and maintenance of B cell malignancies was not known. Results We first tested our hypothesis that PRL, specifically signaling through the pro-proliferative and anti-apoptotic long isoform (LF) of the PRL receptor (PRLR), drives the progression of SLE to B cell malignancies. To this end, we knocked down the LF PRLR in MRL-lpr mice predisposed to developing SLE using a splice-modulating oligomer (SMO) that blocks splicing to produce the LF PRLR without affecting the short isoforms. LF PRLR knockdown reduced splenic and circulating B cell numbers in MRL-lpr SLE mice (Fig.1a). Consistent with reduced B cell numbers, BCL2 expression in B cells of SLE mice was suppressed after LF PRLR knockdown, although MYC was unaltered (Fig.1b). By sequencing the immunoglobulin heavy chains (IGH), we compared the composition of the splenic B cell repertoire between control- and LF PRLR SMO-treated SLE mice. Control oligomer treated SLE mice accumulated splenic B cells with long complementary determining region 3 (CDR3) and B cells with non-functional IGH, characteristics of autoreactive B cells. Treatment with the LF PRLR SMO reduced both. We then measured the expression of enzymes known to induce malignant transformation of B cells, namely recombination activating genes 1/2 (RAG1/2) and activation-induced cytidine deaminase (AID), in B cells of SLE mice in controls versus LF PRLR knockdown. Importantly, LF PRLR knockdown significantly reduced RAG1 (Fig.1c) and AID expression in splenic B cells of SLE mice (Fig.1d,e). Our findings thus underscore a causal role for LF PRLR signaling in promoting of malignant transformation of B cells in SLE. Because PRL induces the expression of BCL2 and MYC in lymphocytes, we next determined whether LF PRLR promotes the survival of overt B cell malignancies that overexpress MYC and BCL2, including diffuse large B cell lymphoma (DLBCL) and B-cell acute lymphoblastic leukemia (B-ALL). We observed that B-lymphoblasts expressed significantly higher levels of PRL and the LF PRLR as compared to normal B cells (Fig.1f). We also found that higher expression of PRL at diagnosis predicts poor clinical outcome in DLBCL patients (P=0.0244), and that patients with MYC/BCL2-overexpressing ALLs with a poor prognosis had significantly higher expression of the LF PRLR compared to their MYC lowBCL2 low counterparts (P<0.0001). These observations suggested that LF PRLR may modulate MYC and BCL2 expression. Knockdown of the LF PRLR using the LF PRLR SMO in MYC/BCL2-driven human B cell malignancies killed lymphoblasts and reduced MYC and BCL2 protein levels (Fig.1g). Because we previously showed that MYC-driven lymphoid malignancies are sensitive to natural killer (NK) cell-mediated immune clearance, we also examined whether LF PRLR knockdown synergized with NK cells in killing DLBCL. We found that LF PRLR knockdown enhanced NK cell-mediated killing of B-lymphoblasts (Fig.1h). Of note, no reductions were observed in NK cell viability or MYC levels within NK cells upon LF PRLR knockdown, suggesting that LF PRLR selectively kills B-lymphoblasts without negatively impacting NK homeostasis. Conclusion Our studies identify the specific knockdown of LF PRLR as a potentially safe and targeted strategy to prevent the onset of B cell malignancies in SLE patients and to treat flagrant DLBCL and B-ALL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4706-4706
Author(s):  
Susan Bal ◽  
Ahmet Dogan ◽  
Hani Hassoun ◽  
Sham Mailankody ◽  
Sergio A Giralt ◽  
...  

Abstract Introduction Dysproteinemia refers to a spectrum of gammopathies in which an aberrant clone(s) of late stage B lymphoid cells or plasma cells produces monoclonal immunoglobulins and/or fragments. The spectrum includes incidentally noted benign conditions like monoclonal gammopathy of undetermined significance (MGUS) to life threatening diseases such as multiple myeloma (MM) and systemic light chain (AL) amyloidosis. Exploitation of normal plasma cell biology forms the basis of treatments used in both MM and AL amyloidosis. In recent years, immunotherapeutic strategies targeting plasma cells have redefined the treatment landscape of MM and could be particularly useful in AL amyloidosis which is distinguished by a low burden of less proliferative disease and a paucity of high risk genetics. We sought to characterize the expression of potentially clinically relevant and/or immunotherapeutic targets in amyloidogenic plasma cells. Methods All patients diagnosed with systemic AL amyloidosis at Memorial Sloan Kettering Cancer Center, NY between January 1, 2012, and December 31, 2018, who had unstained bone marrow samples were identified. Decalcified formalin fixed paraffin embedded bone marrow biopsy sections were stained for G protein-coupled receptor, class C group 5 member D (GPRC5D), Cyclin D1 (CCND1), B-cell lymphoma 2 (BCL2), and B-cell maturation antigen (BCMA) expression using standard laboratory developed Immunohistochemistry (IHC) assays in a CLIA compliant setting. We scored the biopsies for percentage expression, and intensity of staining. We also obtained the demographic details, staging, and cytogenetic information for the patients from whom these samples were obtained. Results During the queried period, 32 unstained samples were available for testing from 27 unique patients. There were 27 diagnostic and 5 patients had additional samples from the time of relapse. The median age was 63 years (range 41-73). 64% of patients were male and 75% had lambda restricted plasma cells. Cytogenetic abnormalities using fluorescence in situ hybridization (FISH) were reviewed, t(11;14) was seen in 38% samples. The median clonal PC burden in BM at diagnosis was 10% (range 2-80%) and 36% had >10% plasma cells. In clonal PCs, the median BCL2 expression was 100% (range 80-100%) with a staining intensity of 2 (range 1-3). 84% (27) samples had BCL2 expression meeting threshold used in the Bellini study. CCND1 expression could be tested in 16 samples median expression 100% (range 20-100%) and median staining intensity 2 (range 1-3). Patients with CCND1 expression also had 100% BCL2 staining. GPRC5D expression was available in 18 samples and all samples tested expressed GPRC5D with median 80% (range 30-100%) with median intensity 1 (range 1-3). BCMA expression was available for 25 samples, with median expression 80% (range 50-100%) with a median staining intensity 2 (range 1-3). Among the five patients with samples from diagnosis and relapse, samples retained their expression of BCL2, BCMA, and GPRC5D. Among samples with t(11;14) by FISH, 92% expressed BCL2 (per Bellini study) and 58% expressed CCND1. Conclusion Cell surface expression of novel targets has enabled the development of several efficacious therapeutic strategies in MM. Amyloidogenic plasma cells express GPRC5D, BCMA and BCL2. Our data provides the rationale for careful investigation and development of targeted agents (BCL2 inhibitors, e.g.venetoclax) and immunotherapeutic strategies directed at GPRC5D and BCMA in AL amyloidosis. Figure 1 Figure 1. Disclosures Dogan: Roche: Consultancy, Research Funding; Peer View: Honoraria; Seattle Genetics: Consultancy; Takeda: Consultancy, Research Funding; Physicians' Education Resource: Honoraria; EUSA Pharma: Consultancy. Hassoun: Celgene, Takeda, Janssen: Research Funding. Mailankody: Fate Therapeutics: Research Funding; Allogene Therapeutics: Research Funding; Bristol Myers Squibb/Juno: Research Funding; Plexus Communications: Honoraria; Legend Biotech: Consultancy; Evicore: Consultancy; Jansen Oncology: Research Funding; Physician Education Resource: Honoraria; Takeda Oncology: Research Funding. Giralt: SANOFI: Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees; JENSENN: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; JAZZ: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; PFIZER: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees; Actinnum: Membership on an entity's Board of Directors or advisory committees. Landau: Takeda: Research Funding; Genzyme: Honoraria; Takeda, Janssen, Caelum Biosciences, Celgene, Pfizer, Genzyme: Membership on an entity's Board of Directors or advisory committees.


2021 ◽  
Author(s):  
Dianshan Ke ◽  
Xinwen Wang ◽  
Yinquan Lin ◽  
Shengwang Wei

Abstract Lactoferrin, as the main component of milk, can maintain osteoblast formation, which is conducive to the prevention and treatment of osteoporosis. Lactoferrin also serves as an autophagy regulator, especially in osteoblasts. This study aimed to explore the significance of autophagy in osteoblast formation regulated by Lactoferrin and the internal mechanism. Our results showed that Lactoferrin enhanced the autophagy activity of primary osteoblasts. Importantly, Lactoferrin inhibited BCL2 expression and the co-immunoprecipitation of BCL2 and Beclin1 in osteoblasts. Moreover, Lactoferrin-promoted autophagy was reversed by BCL2 overexpression or Beclin1 inhibition with spautin-1 in osteoblasts. In conclusion, Lactoferrin can inhibit BCL2 expression in osteoblasts, further enhancing Beclin1-dependent autophagy activation.


2021 ◽  
pp. 1-4
Author(s):  
Maria Koutroumani ◽  
Stamatia Laidou ◽  
Konstantia Kotta ◽  
Kostas Stamatopoulos

Author(s):  
Qiaoyun Zhou ◽  
Yingfeng Deng ◽  
Xuelian Hu ◽  
Yinye Xu

Studies have shown that long-term exposure to sevoflurane (SEV) may cause postoperative cognitive dysfunction. This study aimed to investigate the effects of resveratrol (RES) treatment on the changes in the cognitive function of rats after prolonged anesthesia with SEV. Seventy-six adult male rats were used in this study. The SEV model was established under continuous anesthesia for 6 h. Rats were randomly classified into four groups as follows: control, SEV+vehicle, SEV+pre-RES (RES was administered 24 h before establishing the SEV model), and SEV+post-RES (RES was administered 1 h after establishing the SEV model) groups. Neurobehavioral outcomes and the potential mechanism underlying RES-mediated neuroprotection through the SIRT1/RhoA signaling pathway were evaluated. The water maze test showed that long-term exposure to SEV may lead to loss of learning and memory ability in rats (p<0.05). Compared with the SEV+vehicle group, the RES treatment groups showed significantly improved neurobehavioral scores (p<0.05). Additionally, the SEV+pre-RES group had a better outcome than the SEV+vehicle group on days 1 or 2 (p<0.05), unlike the SEV+post-RES group (p>0.05). Western blotting showed that SIRT1, RhoA, and cleaved Caspase-3 (CC3) expression significantly increased in the SEV+vehicle group (p<0.05), while Bcl2 expression decreased (p < 0.05). RES treatment further upregulated SIRT1 and Bcl2 expression and downregulated the expression of RhoA and CC3 (p<0.05). In conclusion, RES treatment improved cognitive dysfunction by reducing neuronal apoptosis in adult rats exposed to SEV. RES partly exerted a neuroprotective effect through the activation of the SIRT1/RhoA signaling pathway.


2021 ◽  
Vol 22 (13) ◽  
pp. 6839
Author(s):  
Ali H. El-Far ◽  
Yaser H. A. Elewa ◽  
Elsayeda-Zeinab A. Abdelfattah ◽  
Abdel-Wahab A. Alsenosy ◽  
Mustafa S. Atta ◽  
...  

D-galactose (D-gal) administration causes oxidative disorder and is widely utilized in aging animal models. Therefore, we subcutaneously injected D-gal at 200 mg/kg BW dose to assess the potential preventive effect of thymoquinone (TQ) and curcumin (Cur) against the oxidative alterations induced by D-gal. Other than the control, vehicle, and D-gal groups, the TQ and Cur treated groups were orally supplemented at 20 mg/kg BW of each alone or combined. TQ and Cur effectively suppressed the oxidative alterations induced by D-gal in brain and heart tissues. The TQ and Cur combination significantly decreased the elevated necrosis in the brain and heart by D-gal. It significantly reduced brain caspase 3, calbindin, and calcium-binding adapter molecule 1 (IBA1), heart caspase 3, and BCL2. Expression of mRNA of the brain and heart TP53, p21, Bax, and CASP-3 were significantly downregulated in the TQ and Cur combination group along with upregulation of BCL2 in comparison with the D-gal group. Data suggested that the TQ and Cur combination is a promising approach in aging prevention.


Author(s):  
Thiago Henrique M. Vargas ◽  
Camila N. Barra ◽  
Lidia H. Pulz ◽  
Greice C. Huete ◽  
Karine G. Cadrobbi ◽  
...  

AbstractMast cell tumour (MCT) is the most frequent skin neoplasm in dogs. These tumours are characterised by variable behaviour and clinical presentation that make prognosis an important and challenging task in the veterinary practice. Galectin-3 (Gal-3) is known to influence several biological processes that are important in the cancer context and has been described as a prognostic marker for several human cancers. The aim of the present work was to characterise Gal-3 immunolabelling in canine cutaneous MCTs and to investigate its value as a prognostic marker for the disease. Thirty-four random cases of canine cutaneous MCT that were surgically treated with wide margins were included in this study. Gal-3 expression was evaluated using immunohistochemistry and the results were compared with the expression of apoptosis-related proteins, Ki67 index, histopathological grades, mortality due to the disease and post-surgical survival. The majority of the MCTs (65.8%) were positive for Gal-3. Gal-3 immunolabelling was variable among the samples (2.7%–86.8% of the neoplastic cells). The protein was located in the cytoplasm or in the cytoplasm and the nucleus. Gal-3 positivity was correlated with BCL2 expression (P < 0.001; r = 0.604), but not with Ki67 and BAX. No significant differences were detected between histological grades or in the survival analysis. Gal-3 expression correlates with BCL2 expression in MCTs. Although an efficient marker for several human neoplasms, the results presented herein suggest that Gal-3 immunolabelling is not an independent prognostic indicator for this disease.


Sign in / Sign up

Export Citation Format

Share Document