scholarly journals RUNX1 cooperates with FLT3-ITD to induce leukemia

2017 ◽  
Vol 214 (3) ◽  
pp. 737-752 ◽  
Author(s):  
Kira Behrens ◽  
Katrin Maul ◽  
Nilgün Tekin ◽  
Neele Kriebitzsch ◽  
Daniela Indenbirken ◽  
...  
Keyword(s):  
Ribosome Biogenesis ◽  
Therapeutic Approaches ◽  
Cooperative Action ◽  
Proliferation And Differentiation ◽  
Flt3 Inhibitors ◽  
Direct Target ◽  
Differentiation Block ◽  
The Impact ◽  
Oncogenic Function ◽  
Tandem Duplications

Acute myeloid leukemia (AML) is induced by the cooperative action of deregulated genes that perturb self-renewal, proliferation, and differentiation. Internal tandem duplications (ITDs) in the FLT3 receptor tyrosine kinase are common mutations in AML, confer poor prognosis, and stimulate myeloproliferation. AML patient samples with FLT3-ITD express high levels of RUNX1, a transcription factor with known tumor-suppressor function. In this study, to understand this paradox, we investigated the impact of RUNX1 and FLT3-ITD coexpression. FLT3-ITD directly impacts on RUNX1 activity, whereby up-regulated and phosphorylated RUNX1 cooperates with FLT3-ITD to induce AML. Inactivating RUNX1 in tumors releases the differentiation block and down-regulates genes controlling ribosome biogenesis. We identified Hhex as a direct target of RUNX1 and FLT3-ITD stimulation and confirmed high HHEX expression in FLT3-ITD AMLs. HHEX could replace RUNX1 in cooperating with FLT3-ITD to induce AML. These results establish and elucidate the unanticipated oncogenic function of RUNX1 in AML. We predict that blocking RUNX1 activity will greatly enhance current therapeutic approaches using FLT3 inhibitors.

scholarly journals Gata2b haploinsufficiency causes aberrant transcriptional signatures in HSPCs resulting in myeloid and erythroid dysplasia in zebrafish

2021 ◽  
Author(s):  
Emanuele Gioacchino ◽  
Cansu Koyunlar ◽  
Joke Zink ◽  
Hans de Looper ◽  
Kirsten J Gussinklo ◽  
...  
Keyword(s):  
Ribosome Biogenesis ◽  
Morphological Analysis ◽  
Clinical Symptoms ◽  
Bone Marrow Failure ◽  
Heterozygous Mutation ◽  
Erythroid Progenitors ◽  
Zebrafish Model ◽  
Hematopoietic Stem ◽  
Differentiation Block ◽  
The Impact

The transcription factor GATA2 has pivotal roles in hematopoiesis. Germline GATA2 mutations result in GATA2 haploinsufficiency characterized by immunodeficiency, bone marrow failure and predispositions to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Clinical symptoms in GATA2 patients are diverse and mechanisms driving GATA2 related phenotypes are largely unknown. To explore the impact of GATA2 haploinsufficiency on hematopoiesis, we generated a zebrafish model carrying a heterozygous mutation in gata2b, an orthologue of GATA2. Morphological analysis revealed progression of myeloid and erythroid dysplasia in gata2b+/- kidney marrow (KM). Single cell RNA sequencing on KM cells showed that the erythroid dysplasia in gata2b+/- zebrafish was preceded by a differentiation block in erythroid progenitors, hallmarked by downregulation of cytoskeletal transcripts, aberrant proliferative signatures and ribosome biogenesis. Additionally, transcriptional and functional analysis of Gata2b haploinsufficient hematopoietic stem cells (HSCs) indicated that proliferative stress within the HSC compartment possibly contributes to the development of myeloid and erythroid dysplasia in gata2b+/- zebrafish.

Role of melatonin in regulating neurogenesis: Implications for the neurodegenerative pathology and analogous therapeutics for Alzheimer’s disease

2020 ◽  
Vol 3 (2) ◽  
pp. 216-242 ◽  
Author(s):  
Mayuri Shukla ◽  
Areechun Sotthibundhu ◽  
Piyarat Govitrapong
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Adult Neurogenesis ◽  
Adult Brain ◽  
Therapeutic Approaches ◽  
Therapeutic Implications ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
Progenitor Cell Proliferation

The revelation of adult brain exhibiting neurogenesis has established that the brain possesses great plasticity and that neurons could be spawned in the neurogenic zones where hippocampal adult neurogenesis attributes to learning and memory processes. With strong implications in brain functional homeostasis, aging and cognition, various aspects of adult neurogenesis reveal exuberant mechanistic associations thereby further aiding in facilitating the therapeutic approaches regarding the development of neurodegenerative processes in Alzheimer’s Disease (AD). Impaired neurogenesis has been significantly evident in AD with compromised hippocampal function and cognitive deficits. Melatonin the pineal indolamine augments neurogenesis and has been linked to AD development as its levels are compromised with disease progression. Here, in this review, we discuss and appraise the mechanisms via which melatonin regulates neurogenesis in pathophysiological conditions which would unravel the molecular basis in such conditions and its role in endogenous brain repair. Also, its components as key regulators of neural stem and progenitor cell proliferation and differentiation in the embryonic and adult brain would aid in accentuating the therapeutic implications of this indoleamine in line of prevention and treatment of AD.   

Alteraciones sistémicas y metabólicas producidas por lesión medular

2019 ◽  
Vol 1 (1) ◽  
pp. 59-75
Author(s):  
Gabriel Guízar Sahagún
Keyword(s):  
Spinal Cord ◽  
Daily Living ◽  
Autonomic Function ◽  
Clinical Presentation ◽  
Scientific Literature ◽  
International Standards ◽  
Therapeutic Approaches ◽  
Cord Injury ◽  
Life Threatening ◽  
The Impact

Besides the well-known loss of motor and sensory capabilities, people with spinal cord injury (SCI) experience a broad range of systemic and metabolic abnormalities including, among others, dysfunction of cardiovascular, respiratory, gastrointestinal, urinary, and endocrine systems. These alterations are a significant challenge for patients with SCI because such disorders severely interfere with their daily living and can be potentially life-threatening. Most of these disorders are associated with impairment of regulation of the autonomic nervous system, arising from disruption of connections between higher brain centers and the spinal cord caudal to the injured zone. Thus, the higher and more complete the lesion, the greater the autonomic dysfunction and the severity of complications.This article summarizes the medical scientific literature on key systemic and metabolic alterations derived of SCI. It provides information primarily focused on the pathophysiology and clinical presentation of these disorders, as well as some guides to prevent and alleviate such complications. Due to the impact of these alterations, this topic must be a priority and diffuse to those involved with the care of people with SCI, including the patient himself/herself. We consider that any collaborative effort should be supported, like the development of international standards, to evaluate autonomic function after SCI, as well as the development of novel therapeutic approaches.

scholarly journals The Effect of a Polyester Nanofibrous Membrane with a Fibrin-Platelet Lysate Coating on Keratinocytes and Endothelial Cells in a Co-Culture System

Nanomaterials ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 457
Author(s):  
Andreu Blanquer ◽  
Jana Musilkova ◽  
Elena Filova ◽  
Johanka Taborska ◽  
Eduard Brynda ◽  
...  
Keyword(s):  
Wound Healing ◽  
Endothelial Cells ◽  
Chronic Wounds ◽  
Human Keratinocytes ◽  
Skin Wound ◽  
Platelet Lysate ◽  
Therapeutic Approaches ◽  
Skin Wound Healing ◽  
New Therapeutic Approaches ◽  
Proliferation And Differentiation

Chronic wounds affect millions of patients worldwide, and it is estimated that this number will increase steadily in the future due to population ageing. The research of new therapeutic approaches to wound healing includes the development of nanofibrous meshes and the use of platelet lysate (PL) to stimulate skin regeneration. This study considers a combination of a degradable electrospun nanofibrous blend of poly(L-lactide-co-ε-caprolactone) and poly(ε-caprolactone) (PLCL/PCL) membranes (NF) and fibrin loaded with various concentrations of PL aimed at the development of bioactive skin wound healing dressings. The cytocompatibility of the NF membranes, as well as the effect of PL, was evaluated in both monocultures and co-cultures of human keratinocytes and human endothelial cells. We determined that the keratinocytes were able to adhere on all the membranes, and their increased proliferation and differentiation was observed on the membranes that contained fibrin with at least 50% of PL (Fbg + PL) after 14 days. With respect to the co-culture experiments, the membranes with fibrin with 20% of PL were observed to enhance the metabolic activity of endothelial cells and their migration, and the proliferation and differentiation of keratinocytes. The results suggest that the newly developed NF combined with fibrin and PL, described in the study, provides a promising dressing for chronic wound healing purposes.

scholarly journals Specialized Pro-Resolving Lipid Mediators in Neonatal Cardiovascular Physiology and Diseases

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 933
Author(s):  
Andrea Gila-Diaz ◽  
Gloria Herranz Carrillo ◽  
Pratibha Singh ◽  
David Ramiro-Cortijo
Keyword(s):  
Tissue Repair ◽  
Cardiovascular Health ◽  
Critical Role ◽  
Potential Effect ◽  
Lipid Mediators ◽  
Physiological Effects ◽  
Therapeutic Approaches ◽  
The Impact ◽  
Long Chain

Cardiovascular disease remains a leading cause of mortality worldwide. Unresolved inflammation plays a critical role in cardiovascular diseases development. Specialized Pro-Resolving Mediators (SPMs), derived from long chain polyunsaturated fatty acids (LCPUFAs), enhances the host defense, by resolving the inflammation and tissue repair. In addition, SPMs also have anti-inflammatory properties. These physiological effects depend on the availability of LCPUFAs precursors and cellular metabolic balance. Most of the studies have focused on the impact of SPMs in adult cardiovascular health and diseases. In this review, we discuss LCPUFAs metabolism, SPMs, and their potential effect on cardiovascular health and diseases primarily focusing in neonates. A better understanding of the role of these SPMs in cardiovascular health and diseases in neonates could lead to the development of novel therapeutic approaches in cardiovascular dysfunction.

Obstructive nephropathy and renal fibrosis

2002 ◽  
Vol 283 (5) ◽  
pp. F861-F875 ◽  
Author(s):  
Saulo Klahr ◽  
Jeremiah Morrissey
Keyword(s):  
Renal Disease ◽  
Renal Fibrosis ◽  
Interstitial Fibrosis ◽  
Rodent Model ◽  
Renal Diseases ◽  
Obstructive Nephropathy ◽  
Therapeutic Approaches ◽  
Cellular Events ◽  
The Impact ◽  
Made In

Interstitial fibrosis has a major role in the progression of renal diseases. Several animal models are available for the study of renal fibrosis. The models of aminonucleoside-induced nephrotic syndrome, cyclosporin nephrotoxicity, and passive Heyman nephritis are characterized by molecular and cellular events similar to those that occur in obstructive nephropathy. Additionally, inhibition of angiotensin-converting enzyme exerts salutary effects on the progression of renal fibrosis in obstructive nephropathy. Unilateral ureteral obstruction (UUO) has emerged as an important model for the study of the mechanisms of renal fibrosis and also for the evaluation of the impact of potential therapeutic approaches to ameliorate renal disease. Many quantifiable pathophysiological events occur over the span of 1 wk of UUO, making this an attractive model for study. This paper reviews some of the ongoing studies that utilized a rodent model of UUO. Some of the findings of the animal model have been compared with observations made in patients with obstructive nephropathy. Most of the evidence suggests that the rodent model of UUO is reflective of human renal disease processes.

The Impact of Status Differentials and Facilitated Feedback on Observer Responses to Abusive Supervision

2018 ◽  
Author(s):  
Zoe Chan
Keyword(s):  
Interpersonal Relationships ◽  
Undergraduate Students ◽  
Abusive Supervision ◽  
Third Party ◽  
Protective Mechanism ◽  
Work Experiences ◽  
Moral Exclusion ◽  
Direct Target ◽  
The Impact ◽  
Status Differences

When do third parties, individuals who are not the direct target of an act of mistreatment, choose to intervene or abstain from addressing abusive supervision on behalf of a target? Despite progress on understanding the causes and outcomes of abusive supervision, little research examines third-party reactions, and even less devotes attention to contextual factors that shape observer reactions. Given that supervisor-subordinate interactions are situated within and influenced by the broader environment that shapes individuals’ interpersonal relationships and work experiences, this oversight is critical to understanding when observers of abusive supervision choose to intervene on behalf of victims. Drawing from Opotow’s (1995) moral exclusion theory, this study investigates the implications of perceived utility in relation to a victim’s performance and status relative to the supervisor. To narrow the gap between an observer’s intended actions and actual behaviour towards addressing perceived mistreatment, this study introduces the use of facilitated feedback as a protective mechanism against the perceived status differences and risks of retaliation that may deter from expressing supervisory concerns. Through conducting a scenario laboratory experiment among 240 undergraduate students, this study offers practical insights and research implications into the contextual mechanisms that either facilitate or hinder confrontational responses towards abusive supervisors.

scholarly journals Epigenetic Regulations of Inflammatory Cyclooxygenase-Derived Prostanoids: Molecular Basis and Pathophysiological Consequences

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Hedi Harizi
Keyword(s):  
Target Genes ◽  
Inflammatory Diseases ◽  
Epigenetic Alterations ◽  
Therapeutic Approaches ◽  
Immunological Disorders ◽  
Tissue Microenvironment ◽  
Individual Variations ◽  
Fine Regulation ◽  
Additional Level ◽  
The Impact

The potential relevance of prostanoid signaling in immunity and immunological disorders, or disease susceptibility and individual variations in drug responses, is an important area for investigation. The deregulation of Cyclooxygenase- (COX-) derived prostanoids has been reported in several immunoinflammatory disorders such as asthma, rheumatoid arthritis, cancer, and autoimmune diseases. In addition to the environmental factors and the genetic background to diseases, epigenetic mechanisms involved in the fine regulation of prostanoid biosynthesis and/or receptor signaling appeared to be an additional level of complexity in the understanding of prostanoid biology and crucial in controlling the different components of the COX pathways. Epigenetic alterations targeting inflammatory components of prostanoid biosynthesis and signaling pathways may be important in the process of neoplasia, depending on the tissue microenvironment and target genes. Here, we focused on the epigenetic modifications of inflammatory prostanoids in physiological immune response and immunological disorders. We described how major prostanoids and their receptors can be functionally regulated epigenetically and consequently the impact of these processes in the pathogenesis inflammatory diseases and the development of therapeutic approaches that may have important clinical applications.

scholarly journals Targeting Dietary and Microbial Tryptophan-Indole Metabolism as Therapeutic Approaches to Colon Cancer

2021 ◽  
Author(s):  
K. Leigh Greathouse ◽  
Madhur Wyatt
Keyword(s):  
Immune Surveillance ◽  
Microbial Transformation ◽  
Colon Carcinogenesis ◽  
Tryptophan Metabolism ◽  
Host Cells ◽  
Therapeutic Approaches ◽  
Therapeutic Modalities ◽  
Indolic Compounds ◽  
Cancer Initiation ◽  
The Impact

Tryptophan metabolism, via the kynurenine (Kyn) pathway, and microbial transformation of tryptophan to indolic compounds, are fundamental for host health; both of which are altered in colon carcinogenesis. Alterations in tryptophan metabolism begin early in colon carcinogenesis as an adaptive mechanism for the tumor to escape immune surveillance and metastasize. The microbial community is a key part of the tumor microenvironment and influences cancer initiation, promotion and treatment response. A growing awareness of the impact of the microbiome on tryptophan (Trp) metabolism in the context of carcinogenesis has prompted this review. We first compare the different metabolic pathways of Trp under normal cellular physiology to colon carcinogenesis, in both the host cells and the microbiome. Second, we review how the microbiome, specifically indoles, influence host tryptophan pathways under normal and oncogenic metabolism. We conclude by proposing several dietary, microbial and drug therapeutic modalities that can be utilized in combination to abrogate tumorigenesis.

scholarly journals THE IDEALISM OF DIALOGUE AND THE ECONOMY OF THE COMMONS

2016 ◽  
Vol 2 (2) ◽  
pp. 14-27
Author(s):  
Fernando Suárez Müller ◽  
Christian Felber
Keyword(s):  
Economic Model ◽  
Common Good ◽  
Ethical Values ◽  
Governmental Organization ◽  
Cooperative Action ◽  
The Common Good ◽  
Private Interests ◽  
The Commons ◽  
The Common ◽  
The Impact

This paper explores the possibility of an economic system different from both capitalism and communism, that is based on the major ethical values that constitute the principles of human dialogue, the so-called Idealism of Dialogue. This implies an economic model based on cooperativism. An economy modelled in this way envisions the Common Good of society. This is more than the sum of the interests of individuals and it can be measured by looking at the intended impact on society of actions taken by organizations. If the impact of these organizations is oriented towards cooperative action they can be characterized as developing the Common Good. If they block cooperative action they can be seen to be serving private interests. This paper shows how a group of Austrian entrepreneurs has started a network of enterprises that functions both as a kind of cooperative and as a non-governmental organization (Gemeinwohl-Ökonomie). They promote the ideals of Greek oỉkonomía and at the same time consider their own efforts to be the accomplishment of the main principles of Enlightenment which are liberty, equality and fraternity. 

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