Neeraj K Satija | INDIAN INSTITUTE OF TOXICOLOGY RESEARCH (original) (raw)

Papers by Neeraj K Satija

Research paper thumbnail of A comparative analysis of daunorubicin and its metabolite daunorubicinol interaction with apoptotic and drug resistance proteins using in silico approach

Journal of Biomolecular Structure and Dynamics

Research paper thumbnail of Stem Cell c-<i>KIT</i>and<i>HOXB4</i>Genes: Critical Roles and Mechanisms in Self-Renewal, Proliferation, and Differentiation

Stem Cells and Development, Dec 1, 2006

Hematopoietic stem cells (HSCs) possess a distinct ability to perpetuate through self-renewal and... more Hematopoietic stem cells (HSCs) possess a distinct ability to perpetuate through self-renewal and to generate progeny that differentiate into mature cells of myeloid and lymphoid lineages. A better understanding of the molecular mechanisms by which HSCs replicate and differentiate from the perspective of developing new approaches for HSC transplantation is necessary for further advances. The interaction of the receptor tyrosine kinase--c-KIT--with its ligand stem cell factor plays a key role in HSC survival, mitogenesis, proliferation, differentiation, adhesion, homing, migration, and functional activation. Evidence that activating site-directed point mutations in the c-KIT gene contributes to its ligand-independent constitutive activation, which induces enhanced proliferation of HSCs, is accumulating. Similarly, and equally important, self-renewal is a process by which HSCs generate daughter cells via division. Self-renewal is necessary for retaining the HSC pool. Therefore, elucidating the molecular machinery that governs self-renewal is of key importance. The transcription factor, HOXB4 is a key molecule that has been reported to induce the in vitro expansion of HSCs via self-renewal. However, critical downstream effector molecules of HOXB4 remain to be determined. This concisely reviewed information on c-KIT and HOXB4 helps us to update our understanding of their function and mechanism of action in self-renewal, proliferation, and differentiation of HSCs, particularly modulation by c-KIT mutant interactions, and HOXB4 overexpression showing certain therapeutic implications.

Research paper thumbnail of Stromal-Derived Factor-1/<i>CXCR4</i>Signaling: Indispensable Role in Homing and Engraftment of Hematopoietic Stem Cells in Bone Marrow

Stem Cells and Development, Jun 1, 2011

Homing and engraftment of hematopoietic stem/progenitor cells (HSPCs) in bone marrow is the major... more Homing and engraftment of hematopoietic stem/progenitor cells (HSPCs) in bone marrow is the major determining factor in success of hematopoietic stem cell transplantation. This is a complex, multistep process orchestrated by the coordinated interplay between adhesion molecules, cytokines, growth factors, and regulatory cofactors, many of which remain to be defined. Recent studies have highlighted the pivotal role of unique stromal-derived factor-1 (SDF-1)/CXCR4 signaling in the regulation of HSPC homing and subsequent engraftment. In addition, studies suggest that SDF-1/CXCR4 signaling acts as an essential survival-promoting factor of transplanted HSPCs as well as maintenance of quiescent HSCs in bone marrow niche. These pleiotropic effects exerted by SDF-1/CXCR4 axis make this unique signaling initiator very promising, not only for optimal hematopoietic reconstitution but also for the development of innovative approaches to achieve restoration, regeneration, or repair of other damaged tissues potentially amendable to reversal by stem cell transplantation. This goal can only be achieved when the role of SDF-1/CXCR4 axis in hematopoietic transplantation is clearly defined. Hence, this review presents current knowledge of the mechanisms through which SDF-1/CXCR4 signaling promotes restoration of hematopoiesis by regulating the homing and engraftment of HSPCs.

Research paper thumbnail of Oxidative Stress-Targeted Therapies for the Treatment of Acute Myeloid Leukemia

Research paper thumbnail of Importance of targeted therapies in acute myeloid leukemia

Elsevier eBooks, 2021

Abstract Conventional chemotherapy nonspecifically targets leukemic cells, which increases the ri... more Abstract Conventional chemotherapy nonspecifically targets leukemic cells, which increases the risk of other health problems. However, increased understanding of molecular pathways in leukemic cells, as well as the role of bone marrow niche in leukemia, has come with the opportunity to develop targeted therapies that promise to be both more effective and less toxic than current chemotherapy. Specific target identification (target discovery) requires different strategies and technologies. These strategies can be broadly divided into two groups: “molecular” and “systems” approach. Molecular approach uses in vitro models, proteomics, genomics, and genetic association for target discovery while systems approach uses clinical and in vivo models to identify potential targets. Recently, targets such as histone deacetylase, FLT3, IDH1/2 are under investigation for developing drugs toward specific leukemia subtypes. However, biological research has not been that successful in discovering novel targets for leukemia as it was expected. In addition to many technical difficulties, probably the most significant problem in relation to target discovery in leukemia is the involvement of multiple pathways and the presence of leukemic stem cells that are presently the main focus of many biotechnology research. This chapter discusses the strategies and methodologies being used for the identification of novel targets and pathways in leukemia. These include recent technological advances in the fields of genomics and proteomics, as well as targeted delivery systems. Currently approved therapies and those in clinical trials are discussed along with prevailing challenges in acute myeloid leukemia treatment.

Research paper thumbnail of Comprehensive Review Stem Cell c-KIT and HOXB4 Genes: Critical Roles and Mechanisms in Self-Renewal, Proliferation, and Differentiation

Hematopoietic stem cells (HSCs) possess a distinct ability to perpetuate through self-renewal and... more Hematopoietic stem cells (HSCs) possess a distinct ability to perpetuate through self-renewal and to generate progeny that differentiate into mature cells of myeloid and lymphoid lineages. A better understanding of the molecular mechanisms by which HSCs replicate and differentiate from the perspective of developing new approaches for HSC transplantation is necessary for further advances. The interaction of the receptor tyrosine kinase—c-KIT—with its ligand stem cell factor plays a key role in HSC survival, mitogenesis, proliferation, differentiation, adhesion, homing, migration, and functional activation. Evidence that activating site-directed point mutations in the c-KIT gene contributes to its ligand-independent constitutive activation, which induces enhanced proliferation of HSCs, is accumulating. Similarly, and equally important, self-renewal is a process by which HSCs generate daughter cells via division. Self-renewal is necessary for retaining the HSC pool. Therefore, elucidat...

Research paper thumbnail of Bare plasmonic metal nanoparticles: synthesis, characterisation and in vitro toxicity assessment on a liver carcinoma cell line

IET Nanobiotechnology, 2020

Metal nanoparticles have generated great interest due to their excellent optical and chemical pro... more Metal nanoparticles have generated great interest due to their excellent optical and chemical properties. The widely used chemical method for synthesising nanoparticles involves capping agents for colloidal stability. However, there are scarce reports on the application of metal nanoparticles synthesised without using capping agents. Hence, there is a need to develop pristine nanoparticles devoid of capping that can be used for translational research. Here, the authors developed a facile and rapid method for synthesising bare metal nanoparticles (platinum/silver/gold) that are chemically reactive and stable for a month upon storage. They synthesised bare metal nanoparticles of sub-15 nm and characterised using standard techniques (UV-VIS-NIR/DLS/zeta//TEM/XRD). They assessed the safety of the synthesised nanoparticles on the liver carcinoma cell line (HepG2). Bare gold and platinum nanoparticles were non-toxic in comparison to bare silver nanoparticles. Bare metal nanoparticles were also checked for metal detection wherein antimony, mercury and chromium were detected using bare gold and silver nanoparticles. The spectroscopic shifts of the nanoparticles when bound to metals resulted in blue and red shifting of the plasmon band, indicating the sensing of metals. These results show that bare metal nanoparticles have the potential to emerge as a promising candidate for biomedical and sensing applications.

Research paper thumbnail of A Novel Approach towards Synthesis and Characterization of Non-Cytotoxic Gold Nanoparticles Using Taurine as Capping Agent

Nanomaterials, 2019

Metal gold nanoparticles are of great interest due to their unique physico-chemical properties an... more Metal gold nanoparticles are of great interest due to their unique physico-chemical properties and their potential to be used as nano-probes in biosensors, drug delivery, and therapeutic applications. Currently, many capping agents are used for metal gold nanoparticles, such as cetyltrimethylammonium bromide (CTAB) and tri-sodium citrate that have been reported to be toxic and hinders biological applications. To address this issue, we report, for the first time, the use of taurine as a stable non-cytotoxic capping agent for synthesizing gold nanoparticles by using an in situ wet-chemical method. This facile method resulted in monodisperse gold nanospheres with a high yield and stability. Monodisperse gold nanospheres with average diameters of 6.9 nm and 46 nm were synthesized at a high yield with controlled morphology. Temperature played a critical role in determining the size of the taurine-capped gold nanoparticles. The subtle changes in the reaction parameters had a tremendous ef...

Research paper thumbnail of Intricatinol synergistically enhances the anticancerous activity of cisplatin in human A549 cells via p38 MAPK/p53 signalling

Apoptosis : an international journal on programmed cell death, Oct 29, 2017

Platinum containing drugs are widely used to treat advanced lung carcinomas. However, their clini... more Platinum containing drugs are widely used to treat advanced lung carcinomas. However, their clinical success is still limited due to severe side effects, and drug resistance. Alternative approaches are warranted to augment efficacy of platinum based chemotherapeutic drugs with minimal side effects. Intricatinol (INT), a homoisoflavonoid, has been shown to possess anti-tubercular, antioxidant, hypoglycaemic, and hypolipidemic activity. However, its anticancer activity largely remains unknown. In the present study, we have evaluated anticancer potential of INT alone or in combination with cisplatin (CIS) in non-small cell lung carcinoma (A549) cells. Treatment with INT alone reduced the viability of A549 cells in a dose-dependent manner. Interestingly, the combination of low doses of INT and CIS exerted a synergistic effect and induced apoptosis as evident by DNA fragmentation and Annexin V positive cells. Enhanced Bax:Bcl-2 ratio, loss of Δψm, cytochrome c release, cleavage of caspas...

Research paper thumbnail of Autophagy perturbation upon acute pyrethroid treatment impacts adipogenic commitment of mesenchymal stem cells

Pesticide Biochemistry and Physiology

Research paper thumbnail of Control Release of Adenosine Potentiate Osteogenic Differentiation within a Bone Integrative EGCG-g-NOCC/Collagen Composite Scaffold toward Guided Bone Regeneration in a Critical-Sized Calvarial Defect

Biomacromolecules, 2021

The regeneration of critical-sized bone defects with biomimetic scaffolds remains clinically chal... more The regeneration of critical-sized bone defects with biomimetic scaffolds remains clinically challenging due to avascular necrosis, chronic inflammation, and altered osteogenic activity. Two confounding mechanisms, efficacy manipulation, and temporal regulation dictate the scaffold's bone regenerative ability. Equally critical is the priming of the mesenchymal stromal cells (MSCs) toward lineage-specific differentiation into bone-forming osteoblast, which particularly depends on varied mechanochemical and biological cues during bone tissue regeneration. This study sought to design and develop an optimized osteogenic scaffold, adenosine/epigallocatechin gallate-N,O-carboxymethyl chitosan/collagen type I (AD/EGCG-g-NOCC@clgn I), having osteoinductive components toward swift bone regeneration in a calvarial defect BALB/c mice model. The ex vivo findings distinctly establish the pro-osteogenic potential of adenosine and EGCG, stimulating MSCs toward osteoblast differentiation with s...

Research paper thumbnail of Oxidative Stress Targeted Therapies for the Treatment of Acute Myeloid Leukemia

Handbook of Oxidative Stress in Cancer: Mechanistic Aspects

Research paper thumbnail of Mesenchymal Stem Cells: Molecular Targets for Tissue Engineering

Http Dx Doi Org 10 1089 Scd 2006 9998, Feb 1, 2007

the bone marrow, but in a number of tissues, including blood, adipose tissue, muscle, and dermis.... more the bone marrow, but in a number of tissues, including blood, adipose tissue, muscle, and dermis. Their extensive proliferation and transdifferentiation potential makes them best suited for tissue engineering applications. Identification of growth factors and signaling pathways involved in self-renewal and differentiation is important for designing strategies to overcome replicative senescence and attain directed differentiation. Wnt, bone morphogenetic protein (BMP), and Notch pathways have been implicated to play key roles in self-renewal and differentiation of hematopoietic, intestinal, and epidermal stem cells. They are also involved in regulating MSC differentiation. However, MSC self-renewal has not received much attention, with Nucleostemin being the only recently identified proliferation molecule. Although immortalization using viral oncogenes and telomerase has been achieved, transformation in long-term cultures is a potential risk. Understanding of the mechanisms governing osteogenic differentiation of MSCs is expanding with the recent identification of two major transcription factors, Osterix and Runx2. Enhanced expansion as well as osteogenic differentiation of MSCs can be attained using a combinatorial approach involving co-expression of proliferation and differentiation genes. However, a thorough understanding of the molecular mechanism is necessary for enhancing the self-renewal ability and osteogenic potential in vitro.

Research paper thumbnail of Stem Cell c- KIT and HOXB4 Genes: Critical Roles and Mechanisms in Self-Renewal, Proliferation, and Differentiation

Stem Cells Dev, 2006

Hematopoietic stem cells (HSCs) possess a distinct ability to perpetuate through self-renewal and... more Hematopoietic stem cells (HSCs) possess a distinct ability to perpetuate through self-renewal and to generate progeny that differentiate into mature cells of myeloid and lymphoid lineages. A better understanding of the molecular mechanisms by which HSCs replicate and differentiate from the perspective of developing new approaches for HSC transplantation is necessary for further advances. The interaction of the receptor tyrosine kinase-c-KIT-with its ligand stem cell factor plays a key role in HSC survival, mitogenesis, proliferation, differentiation, adhesion, homing, migration, and functional activation. Evidence that activating site-directed point mutations in the c-KIT gene contributes to its ligand-independent constitutive activation, which induces enhanced proliferation of HSCs, is accumulating. Similarly, and equally important, self-renewal is a process by which HSCs generate daughter cells via division. Self-renewal is necessary for retaining the HSC pool. Therefore, elucidating the molecular machinery that governs self-renewal is of key importance. The transcription factor, HOXB4 is a key molecule that has been reported to induce the in vitro expansion of HSCs via self-renewal. However, critical downstream effector molecules of HOXB4 remain to be determined. This concisely reviewed information on c-KIT and HOXB4 helps us to update our understanding of their function and mechanism of action in self-renewal, proliferation, and differentiation of HSCs, particularly modulation by c-KIT mutant interactions, and HOXB4 overexpression showing certain therapeutic implications. 755

Research paper thumbnail of Induced pluripotent stem cells: fundamentals and applications of the reprogramming process and its ramifications on regenerative medicine

Stem cell reviews, 2012

To provide a comprehensive source of information about the reprogramming process and induced plur... more To provide a comprehensive source of information about the reprogramming process and induced pluripotency. The ability of stem cells to renew their own population and to differentiate into specialized cell types has always attracted researchers looking to exploit this potential for cellular replacement therapies, pharmaceutical testing and studying developmental pathways. While adult stem cell therapy has already been brought to the clinic, embryonic stem cell research has been beset with legal and ethical impediments. The conversion of human somatic cells to human induced pluripotent stem cells (hiPSCs), which are equivalent to human embryonic stem cells (hESCs), provides a system to sidestep these barriers and expedite pluripotent stem cell research for the aforementioned purposes. However, being a very recent discovery, iPSCs have yet to overcome many other obstacles and criticism to be proven safe and feasible for clinical use. This review introduces iPSC, the various methods th...

Research paper thumbnail of High-Throughput Transcriptome Profiling Of Human Mesenchymal Stem Cells Reveals A Role For Wnt/GSK-3 Signaling In Their Hypoimmunomodulation

Nature Precedings, 2011

Mesenchymal stem cells (MSCs) are gaining importance among clinicians following recent demonstrat... more Mesenchymal stem cells (MSCs) are gaining importance among clinicians following recent demonstration of safe allogeneic transplantation due to their ability to modulate the immune response. However, the molecular machinery regulating the expression of immunomodulatory factors in MSCs is unknown. We, therefore, inhibited glycogen synthase kinase-3 (GSK-3), a Wnt signaling inhibitor, to elucidate the role of Wnt signaling in mediating immunoregulatory effects of human MSCs using gene expression profiling. Our results highlight enhanced ability of GSK-3 inhibitor (lithium) treated MSCs to evade immune response as a result of decreased expression of immune stimulatory cytokines and chemokines.

Research paper thumbnail of Stromal-Derived Factor-1/ CXCR4 Signaling: Indispensable Role in Homing and Engraftment of Hematopoietic Stem Cells in Bone Marrow

Stem Cells and Development, 2011

Homing and engraftment of hematopoietic stem/progenitor cells (HSPCs) in bone marrow is the major... more Homing and engraftment of hematopoietic stem/progenitor cells (HSPCs) in bone marrow is the major determining factor in success of hematopoietic stem cell transplantation. This is a complex, multistep process orchestrated by the coordinated interplay between adhesion molecules, cytokines, growth factors, and regulatory cofactors, many of which remain to be defined. Recent studies have highlighted the pivotal role of unique stromal-derived factor-1 (SDF-1)/CXCR4 signaling in the regulation of HSPC homing and subsequent engraftment. In addition, studies suggest that SDF-1/CXCR4 signaling acts as an essential survival-promoting factor of transplanted HSPCs as well as maintenance of quiescent HSCs in bone marrow niche. These pleiotropic effects exerted by SDF-1/CXCR4 axis make this unique signaling initiator very promising, not only for optimal hematopoietic reconstitution but also for the development of innovative approaches to achieve restoration, regeneration, or repair of other damaged tissues potentially amendable to reversal by stem cell transplantation. This goal can only be achieved when the role of SDF-1/CXCR4 axis in hematopoietic transplantation is clearly defined. Hence, this review presents current knowledge of the mechanisms through which SDF-1/CXCR4 signaling promotes restoration of hematopoiesis by regulating the homing and engraftment of HSPCs.

Research paper thumbnail of Mesenchymal Stem Cells: Molecular Targets for Tissue Engineering

Stem Cells and Development, 2007

the bone marrow, but in a number of tissues, including blood, adipose tissue, muscle, and dermis.... more the bone marrow, but in a number of tissues, including blood, adipose tissue, muscle, and dermis. Their extensive proliferation and transdifferentiation potential makes them best suited for tissue engineering applications. Identification of growth factors and signaling pathways involved in self-renewal and differentiation is important for designing strategies to overcome replicative senescence and attain directed differentiation. Wnt, bone morphogenetic protein (BMP), and Notch pathways have been implicated to play key roles in self-renewal and differentiation of hematopoietic, intestinal, and epidermal stem cells. They are also involved in regulating MSC differentiation. However, MSC self-renewal has not received much attention, with Nucleostemin being the only recently identified proliferation molecule. Although immortalization using viral oncogenes and telomerase has been achieved, transformation in long-term cultures is a potential risk. Understanding of the mechanisms governing osteogenic differentiation of MSCs is expanding with the recent identification of two major transcription factors, Osterix and Runx2. Enhanced expansion as well as osteogenic differentiation of MSCs can be attained using a combinatorial approach involving co-expression of proliferation and differentiation genes. However, a thorough understanding of the molecular mechanism is necessary for enhancing the self-renewal ability and osteogenic potential in vitro.

Research paper thumbnail of Stem Cell c- KIT and HOXB4 Genes: Critical Roles and Mechanisms in Self-Renewal, Proliferation, and Differentiation

Stem Cells and Development, 2006

Hematopoietic stem cells (HSCs) possess a distinct ability to perpetuate through self-renewal and... more Hematopoietic stem cells (HSCs) possess a distinct ability to perpetuate through self-renewal and to generate progeny that differentiate into mature cells of myeloid and lymphoid lineages. A better understanding of the molecular mechanisms by which HSCs replicate and differentiate from the perspective of developing new approaches for HSC transplantation is necessary for further advances. The interaction of the receptor tyrosine kinase-c-KIT-with its ligand stem cell factor plays a key role in HSC survival, mitogenesis, proliferation, differentiation, adhesion, homing, migration, and functional activation. Evidence that activating site-directed point mutations in the c-KIT gene contributes to its ligand-independent constitutive activation, which induces enhanced proliferation of HSCs, is accumulating. Similarly, and equally important, self-renewal is a process by which HSCs generate daughter cells via division. Self-renewal is necessary for retaining the HSC pool. Therefore, elucidating the molecular machinery that governs self-renewal is of key importance. The transcription factor, HOXB4 is a key molecule that has been reported to induce the in vitro expansion of HSCs via self-renewal. However, critical downstream effector molecules of HOXB4 remain to be determined. This concisely reviewed information on c-KIT and HOXB4 helps us to update our understanding of their function and mechanism of action in self-renewal, proliferation, and differentiation of HSCs, particularly modulation by c-KIT mutant interactions, and HOXB4 overexpression showing certain therapeutic implications. 755

Research paper thumbnail of High Throughput Transcriptome Profiling of Lithium Stimulated Human Mesenchymal Stem Cells Reveals Priming towards Osteoblastic Lineage

PLoS ONE, 2013

Human mesenchymal stem cells (hMSCs) present in the bone marrow are the precursors of osteoblasts... more Human mesenchymal stem cells (hMSCs) present in the bone marrow are the precursors of osteoblasts, chondrocytes and adipocytes, and hold tremendous potential for osteoregenerative therapy. However, achieving directed differentiation into osteoblasts has been a major concern. The use of lithium for enhancing osteogenic differentiation has been documented in animal models but its effect in humans is not clear. We, therefore, performed high throughput transcriptome analysis of lithium-treated hMSCs to identify altered gene expression and its relevance to osteogenic differentiation. Our results show suppression of proliferation and enhancement of alkaline phosphatase (ALP) activity upon lithium treatment of hMSCs under non-osteogenic conditions. Microarray profiling of lithium-stimulated hMSC revealed decreased expression of adipogenic genes (CEBPA, CMKLR1, HSD11B1) and genes involved in lipid biosynthesis. Interestingly, osteoclastogenic factors and immune responsive genes (IL7, IL8, CXCL1, CXCL12, CCL20) were also downregulated. Negative transcriptional regulators of the osteogenic program (TWIST1 and PBX1) were suppressed while genes involved in mineralization like CLEC3B and ATF4 were induced. Gene ontology analysis revealed enrichment of upregulated genes related to mesenchymal cell differentiation and signal transduction. Lithium priming led to enhanced collagen 1 synthesis and osteogenic induction of lithium pretreated MSCs resulted in enhanced expression of Runx2, ALP and bone sialoprotein. However, siRNA-mediated knockdown of RRAD, CLEC3B and ATF4 attenuated lithium-induced osteogenic priming, identifying a role for RRAD, a member of small GTP binding protein family, in osteoblast differentiation. In conclusion, our data highlight the transcriptome reprogramming potential of lithium resulting in higher propensity of lithium ''primed'' MSCs for osteoblastic differentiation.

Research paper thumbnail of A comparative analysis of daunorubicin and its metabolite daunorubicinol interaction with apoptotic and drug resistance proteins using in silico approach

Journal of Biomolecular Structure and Dynamics

Research paper thumbnail of Stem Cell c-<i>KIT</i>and<i>HOXB4</i>Genes: Critical Roles and Mechanisms in Self-Renewal, Proliferation, and Differentiation

Stem Cells and Development, Dec 1, 2006

Hematopoietic stem cells (HSCs) possess a distinct ability to perpetuate through self-renewal and... more Hematopoietic stem cells (HSCs) possess a distinct ability to perpetuate through self-renewal and to generate progeny that differentiate into mature cells of myeloid and lymphoid lineages. A better understanding of the molecular mechanisms by which HSCs replicate and differentiate from the perspective of developing new approaches for HSC transplantation is necessary for further advances. The interaction of the receptor tyrosine kinase--c-KIT--with its ligand stem cell factor plays a key role in HSC survival, mitogenesis, proliferation, differentiation, adhesion, homing, migration, and functional activation. Evidence that activating site-directed point mutations in the c-KIT gene contributes to its ligand-independent constitutive activation, which induces enhanced proliferation of HSCs, is accumulating. Similarly, and equally important, self-renewal is a process by which HSCs generate daughter cells via division. Self-renewal is necessary for retaining the HSC pool. Therefore, elucidating the molecular machinery that governs self-renewal is of key importance. The transcription factor, HOXB4 is a key molecule that has been reported to induce the in vitro expansion of HSCs via self-renewal. However, critical downstream effector molecules of HOXB4 remain to be determined. This concisely reviewed information on c-KIT and HOXB4 helps us to update our understanding of their function and mechanism of action in self-renewal, proliferation, and differentiation of HSCs, particularly modulation by c-KIT mutant interactions, and HOXB4 overexpression showing certain therapeutic implications.

Research paper thumbnail of Stromal-Derived Factor-1/<i>CXCR4</i>Signaling: Indispensable Role in Homing and Engraftment of Hematopoietic Stem Cells in Bone Marrow

Stem Cells and Development, Jun 1, 2011

Homing and engraftment of hematopoietic stem/progenitor cells (HSPCs) in bone marrow is the major... more Homing and engraftment of hematopoietic stem/progenitor cells (HSPCs) in bone marrow is the major determining factor in success of hematopoietic stem cell transplantation. This is a complex, multistep process orchestrated by the coordinated interplay between adhesion molecules, cytokines, growth factors, and regulatory cofactors, many of which remain to be defined. Recent studies have highlighted the pivotal role of unique stromal-derived factor-1 (SDF-1)/CXCR4 signaling in the regulation of HSPC homing and subsequent engraftment. In addition, studies suggest that SDF-1/CXCR4 signaling acts as an essential survival-promoting factor of transplanted HSPCs as well as maintenance of quiescent HSCs in bone marrow niche. These pleiotropic effects exerted by SDF-1/CXCR4 axis make this unique signaling initiator very promising, not only for optimal hematopoietic reconstitution but also for the development of innovative approaches to achieve restoration, regeneration, or repair of other damaged tissues potentially amendable to reversal by stem cell transplantation. This goal can only be achieved when the role of SDF-1/CXCR4 axis in hematopoietic transplantation is clearly defined. Hence, this review presents current knowledge of the mechanisms through which SDF-1/CXCR4 signaling promotes restoration of hematopoiesis by regulating the homing and engraftment of HSPCs.

Research paper thumbnail of Oxidative Stress-Targeted Therapies for the Treatment of Acute Myeloid Leukemia

Research paper thumbnail of Importance of targeted therapies in acute myeloid leukemia

Elsevier eBooks, 2021

Abstract Conventional chemotherapy nonspecifically targets leukemic cells, which increases the ri... more Abstract Conventional chemotherapy nonspecifically targets leukemic cells, which increases the risk of other health problems. However, increased understanding of molecular pathways in leukemic cells, as well as the role of bone marrow niche in leukemia, has come with the opportunity to develop targeted therapies that promise to be both more effective and less toxic than current chemotherapy. Specific target identification (target discovery) requires different strategies and technologies. These strategies can be broadly divided into two groups: “molecular” and “systems” approach. Molecular approach uses in vitro models, proteomics, genomics, and genetic association for target discovery while systems approach uses clinical and in vivo models to identify potential targets. Recently, targets such as histone deacetylase, FLT3, IDH1/2 are under investigation for developing drugs toward specific leukemia subtypes. However, biological research has not been that successful in discovering novel targets for leukemia as it was expected. In addition to many technical difficulties, probably the most significant problem in relation to target discovery in leukemia is the involvement of multiple pathways and the presence of leukemic stem cells that are presently the main focus of many biotechnology research. This chapter discusses the strategies and methodologies being used for the identification of novel targets and pathways in leukemia. These include recent technological advances in the fields of genomics and proteomics, as well as targeted delivery systems. Currently approved therapies and those in clinical trials are discussed along with prevailing challenges in acute myeloid leukemia treatment.

Research paper thumbnail of Comprehensive Review Stem Cell c-KIT and HOXB4 Genes: Critical Roles and Mechanisms in Self-Renewal, Proliferation, and Differentiation

Hematopoietic stem cells (HSCs) possess a distinct ability to perpetuate through self-renewal and... more Hematopoietic stem cells (HSCs) possess a distinct ability to perpetuate through self-renewal and to generate progeny that differentiate into mature cells of myeloid and lymphoid lineages. A better understanding of the molecular mechanisms by which HSCs replicate and differentiate from the perspective of developing new approaches for HSC transplantation is necessary for further advances. The interaction of the receptor tyrosine kinase—c-KIT—with its ligand stem cell factor plays a key role in HSC survival, mitogenesis, proliferation, differentiation, adhesion, homing, migration, and functional activation. Evidence that activating site-directed point mutations in the c-KIT gene contributes to its ligand-independent constitutive activation, which induces enhanced proliferation of HSCs, is accumulating. Similarly, and equally important, self-renewal is a process by which HSCs generate daughter cells via division. Self-renewal is necessary for retaining the HSC pool. Therefore, elucidat...

Research paper thumbnail of Bare plasmonic metal nanoparticles: synthesis, characterisation and in vitro toxicity assessment on a liver carcinoma cell line

IET Nanobiotechnology, 2020

Metal nanoparticles have generated great interest due to their excellent optical and chemical pro... more Metal nanoparticles have generated great interest due to their excellent optical and chemical properties. The widely used chemical method for synthesising nanoparticles involves capping agents for colloidal stability. However, there are scarce reports on the application of metal nanoparticles synthesised without using capping agents. Hence, there is a need to develop pristine nanoparticles devoid of capping that can be used for translational research. Here, the authors developed a facile and rapid method for synthesising bare metal nanoparticles (platinum/silver/gold) that are chemically reactive and stable for a month upon storage. They synthesised bare metal nanoparticles of sub-15 nm and characterised using standard techniques (UV-VIS-NIR/DLS/zeta//TEM/XRD). They assessed the safety of the synthesised nanoparticles on the liver carcinoma cell line (HepG2). Bare gold and platinum nanoparticles were non-toxic in comparison to bare silver nanoparticles. Bare metal nanoparticles were also checked for metal detection wherein antimony, mercury and chromium were detected using bare gold and silver nanoparticles. The spectroscopic shifts of the nanoparticles when bound to metals resulted in blue and red shifting of the plasmon band, indicating the sensing of metals. These results show that bare metal nanoparticles have the potential to emerge as a promising candidate for biomedical and sensing applications.

Research paper thumbnail of A Novel Approach towards Synthesis and Characterization of Non-Cytotoxic Gold Nanoparticles Using Taurine as Capping Agent

Nanomaterials, 2019

Metal gold nanoparticles are of great interest due to their unique physico-chemical properties an... more Metal gold nanoparticles are of great interest due to their unique physico-chemical properties and their potential to be used as nano-probes in biosensors, drug delivery, and therapeutic applications. Currently, many capping agents are used for metal gold nanoparticles, such as cetyltrimethylammonium bromide (CTAB) and tri-sodium citrate that have been reported to be toxic and hinders biological applications. To address this issue, we report, for the first time, the use of taurine as a stable non-cytotoxic capping agent for synthesizing gold nanoparticles by using an in situ wet-chemical method. This facile method resulted in monodisperse gold nanospheres with a high yield and stability. Monodisperse gold nanospheres with average diameters of 6.9 nm and 46 nm were synthesized at a high yield with controlled morphology. Temperature played a critical role in determining the size of the taurine-capped gold nanoparticles. The subtle changes in the reaction parameters had a tremendous ef...

Research paper thumbnail of Intricatinol synergistically enhances the anticancerous activity of cisplatin in human A549 cells via p38 MAPK/p53 signalling

Apoptosis : an international journal on programmed cell death, Oct 29, 2017

Platinum containing drugs are widely used to treat advanced lung carcinomas. However, their clini... more Platinum containing drugs are widely used to treat advanced lung carcinomas. However, their clinical success is still limited due to severe side effects, and drug resistance. Alternative approaches are warranted to augment efficacy of platinum based chemotherapeutic drugs with minimal side effects. Intricatinol (INT), a homoisoflavonoid, has been shown to possess anti-tubercular, antioxidant, hypoglycaemic, and hypolipidemic activity. However, its anticancer activity largely remains unknown. In the present study, we have evaluated anticancer potential of INT alone or in combination with cisplatin (CIS) in non-small cell lung carcinoma (A549) cells. Treatment with INT alone reduced the viability of A549 cells in a dose-dependent manner. Interestingly, the combination of low doses of INT and CIS exerted a synergistic effect and induced apoptosis as evident by DNA fragmentation and Annexin V positive cells. Enhanced Bax:Bcl-2 ratio, loss of Δψm, cytochrome c release, cleavage of caspas...

Research paper thumbnail of Autophagy perturbation upon acute pyrethroid treatment impacts adipogenic commitment of mesenchymal stem cells

Pesticide Biochemistry and Physiology

Research paper thumbnail of Control Release of Adenosine Potentiate Osteogenic Differentiation within a Bone Integrative EGCG-g-NOCC/Collagen Composite Scaffold toward Guided Bone Regeneration in a Critical-Sized Calvarial Defect

Biomacromolecules, 2021

The regeneration of critical-sized bone defects with biomimetic scaffolds remains clinically chal... more The regeneration of critical-sized bone defects with biomimetic scaffolds remains clinically challenging due to avascular necrosis, chronic inflammation, and altered osteogenic activity. Two confounding mechanisms, efficacy manipulation, and temporal regulation dictate the scaffold's bone regenerative ability. Equally critical is the priming of the mesenchymal stromal cells (MSCs) toward lineage-specific differentiation into bone-forming osteoblast, which particularly depends on varied mechanochemical and biological cues during bone tissue regeneration. This study sought to design and develop an optimized osteogenic scaffold, adenosine/epigallocatechin gallate-N,O-carboxymethyl chitosan/collagen type I (AD/EGCG-g-NOCC@clgn I), having osteoinductive components toward swift bone regeneration in a calvarial defect BALB/c mice model. The ex vivo findings distinctly establish the pro-osteogenic potential of adenosine and EGCG, stimulating MSCs toward osteoblast differentiation with s...

Research paper thumbnail of Oxidative Stress Targeted Therapies for the Treatment of Acute Myeloid Leukemia

Handbook of Oxidative Stress in Cancer: Mechanistic Aspects

Research paper thumbnail of Mesenchymal Stem Cells: Molecular Targets for Tissue Engineering

Http Dx Doi Org 10 1089 Scd 2006 9998, Feb 1, 2007

the bone marrow, but in a number of tissues, including blood, adipose tissue, muscle, and dermis.... more the bone marrow, but in a number of tissues, including blood, adipose tissue, muscle, and dermis. Their extensive proliferation and transdifferentiation potential makes them best suited for tissue engineering applications. Identification of growth factors and signaling pathways involved in self-renewal and differentiation is important for designing strategies to overcome replicative senescence and attain directed differentiation. Wnt, bone morphogenetic protein (BMP), and Notch pathways have been implicated to play key roles in self-renewal and differentiation of hematopoietic, intestinal, and epidermal stem cells. They are also involved in regulating MSC differentiation. However, MSC self-renewal has not received much attention, with Nucleostemin being the only recently identified proliferation molecule. Although immortalization using viral oncogenes and telomerase has been achieved, transformation in long-term cultures is a potential risk. Understanding of the mechanisms governing osteogenic differentiation of MSCs is expanding with the recent identification of two major transcription factors, Osterix and Runx2. Enhanced expansion as well as osteogenic differentiation of MSCs can be attained using a combinatorial approach involving co-expression of proliferation and differentiation genes. However, a thorough understanding of the molecular mechanism is necessary for enhancing the self-renewal ability and osteogenic potential in vitro.

Research paper thumbnail of Stem Cell c- KIT and HOXB4 Genes: Critical Roles and Mechanisms in Self-Renewal, Proliferation, and Differentiation

Stem Cells Dev, 2006

Hematopoietic stem cells (HSCs) possess a distinct ability to perpetuate through self-renewal and... more Hematopoietic stem cells (HSCs) possess a distinct ability to perpetuate through self-renewal and to generate progeny that differentiate into mature cells of myeloid and lymphoid lineages. A better understanding of the molecular mechanisms by which HSCs replicate and differentiate from the perspective of developing new approaches for HSC transplantation is necessary for further advances. The interaction of the receptor tyrosine kinase-c-KIT-with its ligand stem cell factor plays a key role in HSC survival, mitogenesis, proliferation, differentiation, adhesion, homing, migration, and functional activation. Evidence that activating site-directed point mutations in the c-KIT gene contributes to its ligand-independent constitutive activation, which induces enhanced proliferation of HSCs, is accumulating. Similarly, and equally important, self-renewal is a process by which HSCs generate daughter cells via division. Self-renewal is necessary for retaining the HSC pool. Therefore, elucidating the molecular machinery that governs self-renewal is of key importance. The transcription factor, HOXB4 is a key molecule that has been reported to induce the in vitro expansion of HSCs via self-renewal. However, critical downstream effector molecules of HOXB4 remain to be determined. This concisely reviewed information on c-KIT and HOXB4 helps us to update our understanding of their function and mechanism of action in self-renewal, proliferation, and differentiation of HSCs, particularly modulation by c-KIT mutant interactions, and HOXB4 overexpression showing certain therapeutic implications. 755

Research paper thumbnail of Induced pluripotent stem cells: fundamentals and applications of the reprogramming process and its ramifications on regenerative medicine

Stem cell reviews, 2012

To provide a comprehensive source of information about the reprogramming process and induced plur... more To provide a comprehensive source of information about the reprogramming process and induced pluripotency. The ability of stem cells to renew their own population and to differentiate into specialized cell types has always attracted researchers looking to exploit this potential for cellular replacement therapies, pharmaceutical testing and studying developmental pathways. While adult stem cell therapy has already been brought to the clinic, embryonic stem cell research has been beset with legal and ethical impediments. The conversion of human somatic cells to human induced pluripotent stem cells (hiPSCs), which are equivalent to human embryonic stem cells (hESCs), provides a system to sidestep these barriers and expedite pluripotent stem cell research for the aforementioned purposes. However, being a very recent discovery, iPSCs have yet to overcome many other obstacles and criticism to be proven safe and feasible for clinical use. This review introduces iPSC, the various methods th...

Research paper thumbnail of High-Throughput Transcriptome Profiling Of Human Mesenchymal Stem Cells Reveals A Role For Wnt/GSK-3 Signaling In Their Hypoimmunomodulation

Nature Precedings, 2011

Mesenchymal stem cells (MSCs) are gaining importance among clinicians following recent demonstrat... more Mesenchymal stem cells (MSCs) are gaining importance among clinicians following recent demonstration of safe allogeneic transplantation due to their ability to modulate the immune response. However, the molecular machinery regulating the expression of immunomodulatory factors in MSCs is unknown. We, therefore, inhibited glycogen synthase kinase-3 (GSK-3), a Wnt signaling inhibitor, to elucidate the role of Wnt signaling in mediating immunoregulatory effects of human MSCs using gene expression profiling. Our results highlight enhanced ability of GSK-3 inhibitor (lithium) treated MSCs to evade immune response as a result of decreased expression of immune stimulatory cytokines and chemokines.

Research paper thumbnail of Stromal-Derived Factor-1/ CXCR4 Signaling: Indispensable Role in Homing and Engraftment of Hematopoietic Stem Cells in Bone Marrow

Stem Cells and Development, 2011

Homing and engraftment of hematopoietic stem/progenitor cells (HSPCs) in bone marrow is the major... more Homing and engraftment of hematopoietic stem/progenitor cells (HSPCs) in bone marrow is the major determining factor in success of hematopoietic stem cell transplantation. This is a complex, multistep process orchestrated by the coordinated interplay between adhesion molecules, cytokines, growth factors, and regulatory cofactors, many of which remain to be defined. Recent studies have highlighted the pivotal role of unique stromal-derived factor-1 (SDF-1)/CXCR4 signaling in the regulation of HSPC homing and subsequent engraftment. In addition, studies suggest that SDF-1/CXCR4 signaling acts as an essential survival-promoting factor of transplanted HSPCs as well as maintenance of quiescent HSCs in bone marrow niche. These pleiotropic effects exerted by SDF-1/CXCR4 axis make this unique signaling initiator very promising, not only for optimal hematopoietic reconstitution but also for the development of innovative approaches to achieve restoration, regeneration, or repair of other damaged tissues potentially amendable to reversal by stem cell transplantation. This goal can only be achieved when the role of SDF-1/CXCR4 axis in hematopoietic transplantation is clearly defined. Hence, this review presents current knowledge of the mechanisms through which SDF-1/CXCR4 signaling promotes restoration of hematopoiesis by regulating the homing and engraftment of HSPCs.

Research paper thumbnail of Mesenchymal Stem Cells: Molecular Targets for Tissue Engineering

Stem Cells and Development, 2007

the bone marrow, but in a number of tissues, including blood, adipose tissue, muscle, and dermis.... more the bone marrow, but in a number of tissues, including blood, adipose tissue, muscle, and dermis. Their extensive proliferation and transdifferentiation potential makes them best suited for tissue engineering applications. Identification of growth factors and signaling pathways involved in self-renewal and differentiation is important for designing strategies to overcome replicative senescence and attain directed differentiation. Wnt, bone morphogenetic protein (BMP), and Notch pathways have been implicated to play key roles in self-renewal and differentiation of hematopoietic, intestinal, and epidermal stem cells. They are also involved in regulating MSC differentiation. However, MSC self-renewal has not received much attention, with Nucleostemin being the only recently identified proliferation molecule. Although immortalization using viral oncogenes and telomerase has been achieved, transformation in long-term cultures is a potential risk. Understanding of the mechanisms governing osteogenic differentiation of MSCs is expanding with the recent identification of two major transcription factors, Osterix and Runx2. Enhanced expansion as well as osteogenic differentiation of MSCs can be attained using a combinatorial approach involving co-expression of proliferation and differentiation genes. However, a thorough understanding of the molecular mechanism is necessary for enhancing the self-renewal ability and osteogenic potential in vitro.

Research paper thumbnail of Stem Cell c- KIT and HOXB4 Genes: Critical Roles and Mechanisms in Self-Renewal, Proliferation, and Differentiation

Stem Cells and Development, 2006

Hematopoietic stem cells (HSCs) possess a distinct ability to perpetuate through self-renewal and... more Hematopoietic stem cells (HSCs) possess a distinct ability to perpetuate through self-renewal and to generate progeny that differentiate into mature cells of myeloid and lymphoid lineages. A better understanding of the molecular mechanisms by which HSCs replicate and differentiate from the perspective of developing new approaches for HSC transplantation is necessary for further advances. The interaction of the receptor tyrosine kinase-c-KIT-with its ligand stem cell factor plays a key role in HSC survival, mitogenesis, proliferation, differentiation, adhesion, homing, migration, and functional activation. Evidence that activating site-directed point mutations in the c-KIT gene contributes to its ligand-independent constitutive activation, which induces enhanced proliferation of HSCs, is accumulating. Similarly, and equally important, self-renewal is a process by which HSCs generate daughter cells via division. Self-renewal is necessary for retaining the HSC pool. Therefore, elucidating the molecular machinery that governs self-renewal is of key importance. The transcription factor, HOXB4 is a key molecule that has been reported to induce the in vitro expansion of HSCs via self-renewal. However, critical downstream effector molecules of HOXB4 remain to be determined. This concisely reviewed information on c-KIT and HOXB4 helps us to update our understanding of their function and mechanism of action in self-renewal, proliferation, and differentiation of HSCs, particularly modulation by c-KIT mutant interactions, and HOXB4 overexpression showing certain therapeutic implications. 755

Research paper thumbnail of High Throughput Transcriptome Profiling of Lithium Stimulated Human Mesenchymal Stem Cells Reveals Priming towards Osteoblastic Lineage

PLoS ONE, 2013

Human mesenchymal stem cells (hMSCs) present in the bone marrow are the precursors of osteoblasts... more Human mesenchymal stem cells (hMSCs) present in the bone marrow are the precursors of osteoblasts, chondrocytes and adipocytes, and hold tremendous potential for osteoregenerative therapy. However, achieving directed differentiation into osteoblasts has been a major concern. The use of lithium for enhancing osteogenic differentiation has been documented in animal models but its effect in humans is not clear. We, therefore, performed high throughput transcriptome analysis of lithium-treated hMSCs to identify altered gene expression and its relevance to osteogenic differentiation. Our results show suppression of proliferation and enhancement of alkaline phosphatase (ALP) activity upon lithium treatment of hMSCs under non-osteogenic conditions. Microarray profiling of lithium-stimulated hMSC revealed decreased expression of adipogenic genes (CEBPA, CMKLR1, HSD11B1) and genes involved in lipid biosynthesis. Interestingly, osteoclastogenic factors and immune responsive genes (IL7, IL8, CXCL1, CXCL12, CCL20) were also downregulated. Negative transcriptional regulators of the osteogenic program (TWIST1 and PBX1) were suppressed while genes involved in mineralization like CLEC3B and ATF4 were induced. Gene ontology analysis revealed enrichment of upregulated genes related to mesenchymal cell differentiation and signal transduction. Lithium priming led to enhanced collagen 1 synthesis and osteogenic induction of lithium pretreated MSCs resulted in enhanced expression of Runx2, ALP and bone sialoprotein. However, siRNA-mediated knockdown of RRAD, CLEC3B and ATF4 attenuated lithium-induced osteogenic priming, identifying a role for RRAD, a member of small GTP binding protein family, in osteoblast differentiation. In conclusion, our data highlight the transcriptome reprogramming potential of lithium resulting in higher propensity of lithium ''primed'' MSCs for osteoblastic differentiation.