scholarly journals Recent Advances in the Pathogenesis and Treatment of Chronic Lymphocytic Leukemia

PRILOZI ◽  
2014 ◽  
Vol 35 (3) ◽  
pp. 105-120
Author(s):  
Dimitar G. Efremov ◽  
Luca Laurenti
Keyword(s):  
Molecular Mechanisms ◽  
Critical Role ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Great Promise ◽  
Next Generation Sequencing Technology ◽  
Recent Advances ◽  
Leukaemic Cells ◽  
Near Future

AbstractChronic lymphocytic leukaemia (CLL) is a common lymphoid malignancy characterized by the expansion and progressive accumulation of mature autoreactive B lymphocytes. The disease is clinically heterogeneous and incurable by standard chemotherapy. A major feature of the disease is the marked dependence of the leukaemic cells on various microenvironmental stimuli, which promote leukaemia cell growth, survival, and drug-resistance. Recently, considerable progress has been made in the understanding of the molecular mechanisms that drive CLL. The identification of recurrent genetic lesions using next generation sequencing technology has provided new data on the pathophysiology of the disease and has improved its prognostication. The recognition of the critical role of the B cell receptor (BCR) in driving the disease has resulted in the development of BCR pathway inhibitors that have the potential to completely transform CLL treatment in the near future. Other novel therapeutic agents, such as BCL2 antagonists and chimeric antigen receptor (CAR)-modified T-cells, are also showing great promise in clinical trials. In this review, we summarize some of these recent advances, with a particular focus on the BCR and corresponding pathway inhibitors.

The Role of the Endothelium in Premature Atherosclerosis: Molecular Mechanisms

2020 ◽  
Vol 27 (7) ◽  
pp. 1041-1051 ◽  
Author(s):  
Michael Spartalis ◽  
Eleftherios Spartalis ◽  
Antonios Athanasiou ◽  
Stavroula A. Paschou ◽  
Christos Kontogiannis ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Low Density Lipoprotein ◽  
Critical Role ◽  
Density Lipoprotein ◽  
Number Of Genes ◽  
Causes Of Mortality ◽  
Artery Disease ◽  
Genetic And Environmental Factors ◽  
Made In

Atherosclerotic disease is still one of the leading causes of mortality. Atherosclerosis is a complex progressive and systematic artery disease that involves the intima of the large and middle artery vessels. The inflammation has a key role in the pathophysiological process of the disease and the infiltration of the intima from monocytes, macrophages and T-lymphocytes combined with endothelial dysfunction and accumulated oxidized low-density lipoprotein (LDL) are the main findings of atherogenesis. The development of atherosclerosis involves multiple genetic and environmental factors. Although a large number of genes, genetic polymorphisms, and susceptible loci have been identified in chromosomal regions associated with atherosclerosis, it is the epigenetic process that regulates the chromosomal organization and genetic expression that plays a critical role in the pathogenesis of atherosclerosis. Despite the positive progress made in understanding the pathogenesis of atherosclerosis, the knowledge about the disease remains scarce.

LncRNA SNHG12 Improves Cerebral Ischemic-reperfusion Injury by Activating SIRT1/FOXO3a Pathway through I nhibition of Autophagy and Oxidative Stress

2020 ◽  
Vol 17 (4) ◽  
pp. 394-401
Author(s):  
Yuanhua Wu ◽  
Yuan Huang ◽  
Jing Cai ◽  
Donglan Zhang ◽  
Shixi Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Cell Activity ◽  
Ht22 Cells ◽  
Cerebral Ischemic ◽  
Cerebral Ischemic Reperfusion ◽  
And Oxidative Stress

Background: Ischemia/reperfusion (I/R) injury involves complex biological processes and molecular mechanisms such as autophagy. Oxidative stress plays a critical role in the pathogenesis of I/R injury. LncRNAs are the regulatory factor of cerebral I/R injury. Methods: This study constructs cerebral I/R model to investigate role of autophagy and oxidative stress in cerebral I/R injury and the underline regulatory mechanism of SIRT1/ FOXO3a pathway. In this study, lncRNA SNHG12 and FOXO3a expression was up-regulated and SIRT1 expression was down-regulated in HT22 cells of I/R model. Results: Overexpression of lncRNA SNHG12 significantly increased the cell viability and inhibited cerebral ischemicreperfusion injury induced by I/Rthrough inhibition of autophagy. In addition, the transfected p-SIRT1 significantly suppressed the release of LDH and SOD compared with cells co-transfected with SIRT1 and FOXO3a group and cells induced by I/R and transfected with p-SNHG12 group and overexpression of cells co-transfected with SIRT1 and FOXO3 further decreased the I/R induced release of ROS and MDA. Conclusion: In conclusion, lncRNA SNHG12 increased cell activity and inhibited oxidative stress through inhibition of SIRT1/FOXO3a signaling-mediated autophagy in HT22 cells of I/R model. This study might provide new potential therapeutic targets for further investigating the mechanisms in cerebral I/R injury and provide.

Classic and Novel Signaling Pathways Involved in Cancer: Targeting the NF-κB and Syk Signaling Pathways

2019 ◽  
Vol 14 (3) ◽  
pp. 219-225 ◽  
Author(s):  
Cong Tang ◽  
Guodong Zhu
Keyword(s):  
Cancer Therapy ◽  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Cell Receptor ◽  
Transmembrane Receptors ◽  
Biological Responses ◽  
Different Types

The nuclear factor kappa B (NF-κB) consists of a family of transcription factors involved in the regulation of a wide variety of biological responses. Growing evidence support that NF-κB plays a major role in oncogenesis as well as its well-known function in the regulation of immune responses and inflammation. Therefore, we made a review of the diverse molecular mechanisms by which the NF-κB pathway is constitutively activated in different types of human cancers and the potential role of various oncogenic genes regulated by this transcription factor in cancer development and progression. We also discussed various pharmacological approaches employed to target the deregulated NF-κB signaling pathway and their possible therapeutic potential in cancer therapy. Moreover, Syk (Spleen tyrosine kinase), non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immune-receptors like the B-cell receptor (BCR), which can also activate the inflammasome and NF-κB-mediated transcription of chemokines and cytokines in the presence of pathogens would be discussed as well. The highlight of this review article is to summarize the classic and novel signaling pathways involved in NF-κB and Syk signaling and then raise some possibilities for cancer therapy.

scholarly journals The laterodorsal tegmentum-ventral tegmental area circuit controls depression-like behaviors by activating ErbB4 in DA neurons

2021 ◽  
Author(s):  
Hongsheng Wang ◽  
Wanpeng Cui ◽  
Wenbing Chen ◽  
Fang Liu ◽  
Zhaoqi Dong ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Coping With Stress ◽  
Chemical Genetic ◽  
Chronic Social Defeat Stress ◽  
Ventral Tegmental ◽  
Laterodorsal Tegmentum ◽  
Specific Deletion

AbstractDopamine (DA) neurons in the ventral tegmental area (VTA) are critical to coping with stress. However, molecular mechanisms regulating their activity and stress-induced depression were not well understood. We found that the receptor tyrosine kinase ErbB4 in VTA was activated in stress-susceptible mice. Deleting ErbB4 in VTA or in DA neurons, or chemical genetic inhibition of ErbB4 kinase activity in VTA suppressed the development of chronic social defeat stress (CSDS)-induced depression-like behaviors. ErbB4 activation required the expression of NRG1 in the laterodorsal tegmentum (LDTg); LDTg-specific deletion of NRG1 inhibited depression-like behaviors. NRG1 and ErbB4 suppressed potassium currents of VTA DA neurons and increased their firing activity. Finally, we showed that acute inhibition of ErbB4 after stress attenuated DA neuron hyperactivity and expression of depression-like behaviors. Together, these observations demonstrate a critical role of NRG1-ErbB4 signaling in regulating depression-like behaviors and identify an unexpected mechanism by which the LDTg-VTA circuit regulates the activity of DA neurons.

scholarly journals Deciphering the Mounting Complexity of the p53 Regulatory Network in Correlation to Long Non-Coding RNAs (lncRNAs) in Ovarian Cancer

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 527 ◽  
Author(s):  
Sonali Pal ◽  
Manoj Garg ◽  
Amit Kumar Pandey
Keyword(s):  
Ovarian Cancer ◽  
Molecular Mechanisms ◽  
Human Cancer ◽  
Critical Role ◽  
Functional Characterization ◽  
Great Promise ◽  
Altered Expression ◽  
Disease Biology ◽  
Non Coding Rnas ◽  
Post Transcriptional Regulation

Amongst the various gynecological malignancies affecting female health globally, ovarian cancer is one of the predominant and lethal among all. The identification and functional characterization of long non-coding RNAs (lncRNAs) are made possible with the advent of RNA-seq and the advancement of computational logarithm in understanding human disease biology. LncRNAs can interact with deoxyribonucleic acid (DNA), ribonucleic acid (RNA), proteins and their combinations. Moreover, lncRNAs regulate orchestra of diverse functions including chromatin organization and transcriptional and post-transcriptional regulation. LncRNAs have conferred their critical role in key biological processes in human cancer including tumor initiation, proliferation, cell cycle, apoptosis, necroptosis, autophagy, and metastasis. The interwoven function of tumor-suppressor protein p53-linked lncRNAs in the ovarian cancer paradigm is of paramount importance. Several lncRNAs operate as p53 regulators or effectors and modulates a diverse array of functions either by participating in various signaling cascades or via interaction with different proteins. This review highlights the recent progress made in the identification of p53 associated lncRNAs while elucidating their molecular mechanisms behind the altered expression in ovarian cancer tumorigenesis. Moreover, the development of novel clinical and therapeutic strategies for targeting lncRNAs in human cancers harbors great promise.

scholarly journals Wedding of Molecular Alterations and Immune Checkpoint Blockade: Genomics as a Matchmaker

2021 ◽  
Author(s):  
Elena Fountzilas ◽  
Razelle Kurzrock ◽  
Henry Hiep Vo ◽  
Apostolia-Maria Tsimberidou
Keyword(s):  
Molecular Mechanisms ◽  
Cell Receptor ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Beta Catenin ◽  
Molecular Alterations ◽  
Receptor Repertoire ◽  
Repair Deficiency ◽  
Tumor Mutational Burden

Abstract The development of checkpoint blockade immunotherapy has transformed the medical oncology armamentarium. But, despite its favorable impact on clinical outcomes, immunotherapy benefits only a subset of patients, and a substantial proportion of these individuals eventually manifest resistance. Serious immune-related adverse events and hyper-progression have also been reported. It is therefore essential to understand the molecular mechanisms and identify the drivers of therapeutic response and resistance. In this review, we provide an overview of the current and emerging clinically relevant genomic biomarkers implicated in checkpoint blockade outcome. U.S. Food and Drug Administration–approved molecular biomarkers of immunotherapy response include mismatch repair deficiency/microsatellite instability and tumor mutational burden ≥10 mutations/megabase. Investigational genomic-associated biomarkers for immunotherapy response include alterations of the following genes/associated pathways: chromatin remodeling (ARID1A, PBRM1, SMARCA4, SMARCB1, BAP1), major histocompatibility complex, specific (e.g., ultraviolet, APOBEC) mutational signatures, T-cell receptor repertoire, PDL1, POLE/POLD1, and neo-antigens produced by the mutanome; those potentially associated with resistance include β2-microglobulin, EGFR, Keap1, JAK1/JAK2/interferon-gamma signaling, MDM2, PTEN, STK11, and Wnt/Beta-catenin pathway alterations. Prospective clinical trials are needed to assess the role of a composite of these biomarkers in order to optimize the implementation of precision immunotherapy in patient care.

Distinct gene expression patterns in chronic lymphocytic leukemia defined by usage of specific VH genes

Blood ◽  
2006 ◽  
Vol 107 (5) ◽  
pp. 2090-2093 ◽  
Author(s):  
Dirk Kienle ◽  
Axel Benner ◽  
Alexander Kröber ◽  
Dirk Winkler ◽  
Daniel Mertens ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Lymphocytic Leukemia ◽  
Expression Patterns ◽  
Gene Expression Pattern ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Expression Of Genes ◽  
Vh Genes ◽  
Signaling Activation

The mutation status and usage of specific VH genes such as V3-21 and V1-69 are potentially independent pathogenic and prognostic factors in chronic lymphocytic leukemia (CLL). To investigate the role of antigenic stimulation, we analyzed the expression of genes involved in B-cell receptor (BCR) signaling/activation, cell cycle, and apoptosis control in CLL using these specific VH genes compared to VH mutated (VH-MUT) and VH unmutated (VH-UM) CLL not using these VH genes. V3-21 cases showed characteristic expression differences compared to VH-MUT (up: ZAP70 [or ZAP-70]; down: CCND2, P27) and VH-UM (down: PI3K, CCND2, P27, CDK4, BAX) involving several BCR-related genes. Similarly, there was a marked difference between VH unmutated cases using the V1-69 gene and VH-UM (up: FOS; down: BLNK, SYK, CDK4, TP53). Therefore, usage of specific VH genes appears to have a strong influence on the gene expression pattern pointing to antigen recognition and ongoing BCR stimulation as a pathogenic factor in these CLL subgroups.

Geldanamycin-induced Lyn dissociation from aberrant Hsp90-stabilized cytosolic complex is an early event in apoptotic mechanisms in B-chronic lymphocytic leukemia

Blood ◽  
2008 ◽  
Vol 112 (12) ◽  
pp. 4665-4674 ◽  
Author(s):  
Livio Trentin ◽  
Martina Frasson ◽  
Arianna Donella-Deana ◽  
Federica Frezzato ◽  
Mario A. Pagano ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Molecular Mechanisms ◽  
Catalytic Domain ◽  
Cell Receptor ◽  
Hsp90 Inhibitor ◽  
Lymphocytic Leukemia ◽  
Early Event ◽  
Downstream Signaling ◽  
Transient Interactions

Abstract Lyn, a tyrosine kinase belonging to the Src family, plays a key role as a switch molecule that couples the B-cell receptor to downstream signaling. In B-CLL cells, Lyn is overexpressed, anomalously present in the cytosol, and displays a high constitutive activity, compared with normal B lymphocytes. The aim of this work was to gain insights into the molecular mechanisms underlying these aberrant properties of Lyn, which have already been demonstrated to be related to defective apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells. Herein, Lyn is described to be in an active conformation as integral component of an aberrant cytosolic 600-kDa multiprotein complex in B-CLL cells, associated with several proteins, such as Hsp90 through its catalytic domain, and HS1 and SHP-1L through its SH3 domain. In particular, Hsp90 appears tightly bound to cytosolic Lyn (CL), thus stabilizing the aberrant complex and converting individual transient interactions into stable ones. We also demonstrate that treatment of B-CLL cells with geldanamycin, an Hsp90 inhibitor already reported to induce cell death, is capable of dissociating the CL complex in the early phases of apoptosis and thus inactivating CL itself. These data identify the CL complex as a potential target for therapy in B-CLL.

scholarly journals Suppression of eNOS-derived superoxide by caveolin-1: a biopterin-dependent mechanism

2011 ◽  
Vol 301 (3) ◽  
pp. H903-H911 ◽  
Author(s):  
Kanchana Karuppiah ◽  
Lawrence J. Druhan ◽  
Chun-an Chen ◽  
Travis Smith ◽  
Jay L. Zweier ◽  
...  
Keyword(s):  
Gene Silencing ◽  
Oxidase Activity ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Caveolin 1 ◽  
Calcium Calmodulin Dependent ◽  
Enos Uncoupling ◽  
Nadph Oxidation ◽  
Interfering Rna

In the vasculature, nitric oxide (NO) is generated by endothelial NO synthase (eNOS) in a calcium/calmodulin-dependent reaction. In the absence of the requisite eNOS cofactor tetrahydrobiopterin (BH4), NADPH oxidation is uncoupled from NO generation, leading to the production of superoxide. Although this phenomenon is apparent with purified enzyme, cellular studies suggest that formation of the BH4 oxidation product, dihydrobiopterin, is the molecular trigger for eNOS uncoupling rather than BH4 depletion alone. In the current study, we investigated the effects of both BH4 depletion and oxidation on eNOS-derived superoxide production in endothelial cells in an attempt to elucidate the molecular mechanisms regulating eNOS oxidase activity. Results demonstrated that pharmacological depletion of endothelial BH4 does not result in eNOS oxidase activity, whereas BH4 oxidation gave rise to significant eNOS-oxidase activity. These findings suggest that the endothelium possesses regulatory mechanisms, which prevent eNOS oxidase activity from pterin-free eNOS. Using a combination of gene silencing and pharmacological approaches, we demonstrate that eNOS-caveolin-1 association is increased under conditions of reduced pterin bioavailability and that this sequestration serves to suppress eNOS uncoupling. Using small interfering RNA approaches, we demonstrate that caveolin-1 gene silencing increases eNOS oxidase activity to 85% of that observed under conditions of BH4 oxidation. Moreover, when caveolin-1 silencing was combined with a pharmacological inhibitor of AKT, BH4 depletion increased eNOS-derived superoxide to 165% of that observed with BH4 oxidation. This study identifies a critical role of caveolin-1 in the regulation of eNOS uncoupling and provides new insight into the mechanisms through which disease-associated changes in caveolin-1 expression may contribute to endothelial dysfunction.

scholarly journals Prospects for p53-based cancer therapy.

2005 ◽  
Vol 52 (2) ◽  
pp. 321-328 ◽  
Author(s):  
Tomasz Stokłosa ◽  
Jakub Gołab
Keyword(s):  
Human Tumor ◽  
P53 Gene ◽  
Great Promise ◽  
Mutant Form ◽  
Wild Type ◽  
P53 Pathway ◽  
Cycle Arrest ◽  
Stress Signals ◽  
Near Future

The p53 tumor suppressor plays the role of a cellular hub which gathers stress signals such as damage to DNA or hypoxia and translates them into a complex response. p53 exerts its action mainly as a potent transcription factor. The two major outcomes of p53 activity are highlighted: cell cycle arrest and apoptosis. During malignant transformation p53 or p53-pathway related molecules are disabled extremely often. Mutations in p53 gene are present in every second human tumor. A mutant form of p53 may not only negate the wild type p53 function but may play additional role in tumor progression. Therefore p53 represents a relatively unique and specific target for anticancer drug design. Current approaches include several different molecules able to restore p53 wild-type conformation and activity. Such small molecule drugs hold great promise in treating human tumors with dysfunction of p53 pathway in the near future.

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