Deepak Kaul
Dr. Deepak Kaul
Ph.D(AIIMS); FRCPath (Lond.); FNA; FWAAS
Founder- Professor “Molecular Biology Unit”
&
Head , Experimental Medicine & Biotechnology Department
Postgraduate Institute Of Medical Education & Research
Chandigarh - 160012 (India).
Ph.D(AIIMS); FRCPath (Lond.); FNA; FWAAS
Founder- Professor “Molecular Biology Unit”
&
Head , Experimental Medicine & Biotechnology Department
Postgraduate Institute Of Medical Education & Research
Chandigarh - 160012 (India).
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Papers by Deepak Kaul
There exists a general recognition of the fact that mitochondrial remodelling as a result of aerobic glycolysis ensures human somatic cells to revert to a more primitive-form exhibiting stem-like phenotype. The present study is an attempt to demonstrate that miR-2909 RNomics
within human peripheral blood mononuclear cells (PBMCs) has the inherent capacity to re-program these cells to exhibit mitochondrial remodelling paralleled by aerobic glycolysis together with intracellular lipid inclusions. Such re-programmed PBMCs also expressed genes having ability to sustain their de-differentiation state and survival.
Material and methods
Human PBMCs were programed to ectopically express miR-2909. Expression levels of genes including glucose transporter-1 (Glut-1), hexokinase (HK), hypoxia inducia factor-1 (HIF-1α), c-Myc, p53,mechanistic target of rapamycin complex (mTORC1), polycombcomplex protein (Bmi-1), Notch,Nanog,Tie-2, Oct-4,CD59, p53, CD34, B-cell lymphoma-2 (Bcl2),sterol regulatory element-binding protein2 (SREBP2), peroxisome proliferator-activated receptor gamma (PPARγ) nuclear respiratory factor 1 (NRF1), mitochondrial transcription
factor A (Tfam), peroxisome proliferator-activated receptor gamma coactivator 1- alpha (PGC1α) within miR-2909 expression vector transfected human PBMCs as well as PBMCs transfected with control vector containing scrambled sequence after 48h post-transfection
using RT-qPCR and cellular ultrastructural features induced by miR-2909 ectopic expression were observed using transmission electron microscopy and morphometric analysis of an electron micrograph.
Results
Ectopic expression of miR-2909 within human PBMCs resulted in their reprogramming into stem-like phenotype indicated by mitochondrial globular shaped coupled with cristae-poor morphology. Nuclear to cytoplasmic ratio (N/C), quantification of ATP levels, GSSG/GSH
ratio, mitochondrial cytochrome c oxidase activity, secreted lactate concentrations, activity of antioxidant enzymes, levels of esterified cholesterol and triglycerides and flow-cytometric detection of apoptosis confirmed the compromised nature of mitochondrial function induced
by ectopic miR-2909 expression in human PBMCs.
has emerged to regulate genes involved in oncogenesis and immunity, the present study was addressed to reveal the nature of miR‐2909 expression within cancer cells of different tissue origin and its incorporation into exosomes secreted by these cells. Post‐transcriptional modification, especially 3′‐end adenylation and uridylation of miR‐2909, exerts opposing effects that may contribute to direct its sorting into exosomes secreted by cancer cells. Our study also revealed
that selective partitioning of adenosine kinase, between cancer cells and their secreted exosomes, may be responsible for the nature of post‐transcriptional modification of miR‐2909 observed within these cells.
has the inherent capacity to ensure sustained co‐amplification of PVT‐1 gene locus together with c‐Myc gene. Based upon these results, we propose thatmiR‐2909 RNomics pathway may play a crucial role in the regulation of tumorigenic PVT‐1 gene locus.
and exosome secretion are two coordinated mechanisms responsible
for the cellular defense against any kind of stress [14]. Consequently, it
is reasonable to assume that for HIV-1 to sustain its replication cycle,
the host cellular autophagic process has to be considerably reduced to
allow release of exosomes (hiv1-miR-H1) to initiate death within HIVuninfected
bystander CD4+ T-cells through the down-regulation of
AATF gene expression (Figure 1) leading to AIDS disease. Such a
phenomenon would have been impossible to achieve if the HIV-1
encoded hiv1-miR-H1 was not able to exploit miR-2909 RNomics
(Figure 1) to regulate host cellular autophagic process. This view is in
conformity with the finding that revealed higher expression of both
AATF and miR-2909 within lymphocytes from asymptomatic AIDS
subjects as compared to lymphocytes from the symptomatic AIDS
subjects [10]. There is reason to believe that HIV-1 has evolved strategy
to up-regulate cellular miR-2909 RNomics for the sustenance of its
replication cycle and to down-regulate miR-2909 RNomics within
uninfected bystander CD4+ cells exposed to exosomes (enriched with
hiv1-miR-H1) secreted by viral infected immune cells.Hence, it would be pertinent to explore if antagomiR-against hiv1-miR-H1 could be used as a therapeutic strategy against the AIDS pathogenesis.
particular is nucleolus, a dynamic sub-cellular organelle that employs
the apoptosis-antagonizing transcription factor (AATF) as its
surveillance sensor. It is in this context the AATF RNome, that holds
AATF coding transcript and regulatory non-coding miR-2909 within
its fold, assumes importance because of its ability to tailor cellular
response against a given sensed viral-dependent host-cell nucleoli
subversion. This phenomenon is exemplified by the ability of HIV-1 to
conspicuously target AATF RNome that ensures cellular antiviral
defense through the initiation of CCL5 and RIG-1 signaling response
as well as by regulating chromatin dynamics to restrict HIV-1 latency.
Promastigotes of Leishmania are internalized by macrophages and transformed into
amastigotes in phagosomes, and replicate in phagolysosomes. Phagosomal maturation
arrest is known to play a crucial role in the survival of pathogenic Leishmania within
activated macrophages. Recently, tryptophan–aspartate containing coat (TACO) gene
has been recognized as playing a central role in the survival of Mycobacterium
tuberculosis within human macrophages by arresting the phagosome maturation
process. We postulated that a similar association of TACO gene with phagosomes
would prevent the vacuole from maturation in the case of Leishmania. In this study
we attempted to define the effect of TACO gene downregulation on the entry/survival
of Leishmania donovani intracellularly, by treatment with Vitamin D3 (Vit.D3)/Retinoic
acid (RA) and chenodeoxycholic acid (CDCA)/RA combinations in human THP-1
macrophages (in vitro). Treatment with these molecules downregulated the TACO gene
in macrophages, resulting in reduced parasite load and marked reduction of disease
progression in L. donovani infected macrophages. Taken together, these results suggest
that TACO gene downregulation may play a role in subverting macrophage machinery
in establishing the L. donovani replicative niche inside the host. Our study is the first to
highlight the important role of the TACO gene in Leishmania entry, survival and to identify
TACO gene downregulation as potential drug target against leishmaniasis.
degenerative diseases in general and cancer in particular. Recent findings have added a newdimension to arsenic
biology by revealing thatmost of the arsenic epigenomic effects are mediated through its ability to induce cellular
miR-2909 expression at low doses. The present study was addressed to explore the molecular link that might
exist between arsenic exposure, miR-2909 RNomics involving immunomodulatory genes and effector IgA class
switching, revealed that arsenic-exposed Balb/c mice exhibited predominant Th1 immune response coupled
with effector IgA class switching thereby tailoring their immune system to ensure increased risk to infections
and chronic diseases like cancer.
There exists a general recognition of the fact that mitochondrial remodelling as a result of aerobic glycolysis ensures human somatic cells to revert to a more primitive-form exhibiting stem-like phenotype. The present study is an attempt to demonstrate that miR-2909 RNomics
within human peripheral blood mononuclear cells (PBMCs) has the inherent capacity to re-program these cells to exhibit mitochondrial remodelling paralleled by aerobic glycolysis together with intracellular lipid inclusions. Such re-programmed PBMCs also expressed genes having ability to sustain their de-differentiation state and survival.
Material and methods
Human PBMCs were programed to ectopically express miR-2909. Expression levels of genes including glucose transporter-1 (Glut-1), hexokinase (HK), hypoxia inducia factor-1 (HIF-1α), c-Myc, p53,mechanistic target of rapamycin complex (mTORC1), polycombcomplex protein (Bmi-1), Notch,Nanog,Tie-2, Oct-4,CD59, p53, CD34, B-cell lymphoma-2 (Bcl2),sterol regulatory element-binding protein2 (SREBP2), peroxisome proliferator-activated receptor gamma (PPARγ) nuclear respiratory factor 1 (NRF1), mitochondrial transcription
factor A (Tfam), peroxisome proliferator-activated receptor gamma coactivator 1- alpha (PGC1α) within miR-2909 expression vector transfected human PBMCs as well as PBMCs transfected with control vector containing scrambled sequence after 48h post-transfection
using RT-qPCR and cellular ultrastructural features induced by miR-2909 ectopic expression were observed using transmission electron microscopy and morphometric analysis of an electron micrograph.
Results
Ectopic expression of miR-2909 within human PBMCs resulted in their reprogramming into stem-like phenotype indicated by mitochondrial globular shaped coupled with cristae-poor morphology. Nuclear to cytoplasmic ratio (N/C), quantification of ATP levels, GSSG/GSH
ratio, mitochondrial cytochrome c oxidase activity, secreted lactate concentrations, activity of antioxidant enzymes, levels of esterified cholesterol and triglycerides and flow-cytometric detection of apoptosis confirmed the compromised nature of mitochondrial function induced
by ectopic miR-2909 expression in human PBMCs.
has emerged to regulate genes involved in oncogenesis and immunity, the present study was addressed to reveal the nature of miR‐2909 expression within cancer cells of different tissue origin and its incorporation into exosomes secreted by these cells. Post‐transcriptional modification, especially 3′‐end adenylation and uridylation of miR‐2909, exerts opposing effects that may contribute to direct its sorting into exosomes secreted by cancer cells. Our study also revealed
that selective partitioning of adenosine kinase, between cancer cells and their secreted exosomes, may be responsible for the nature of post‐transcriptional modification of miR‐2909 observed within these cells.
has the inherent capacity to ensure sustained co‐amplification of PVT‐1 gene locus together with c‐Myc gene. Based upon these results, we propose thatmiR‐2909 RNomics pathway may play a crucial role in the regulation of tumorigenic PVT‐1 gene locus.
and exosome secretion are two coordinated mechanisms responsible
for the cellular defense against any kind of stress [14]. Consequently, it
is reasonable to assume that for HIV-1 to sustain its replication cycle,
the host cellular autophagic process has to be considerably reduced to
allow release of exosomes (hiv1-miR-H1) to initiate death within HIVuninfected
bystander CD4+ T-cells through the down-regulation of
AATF gene expression (Figure 1) leading to AIDS disease. Such a
phenomenon would have been impossible to achieve if the HIV-1
encoded hiv1-miR-H1 was not able to exploit miR-2909 RNomics
(Figure 1) to regulate host cellular autophagic process. This view is in
conformity with the finding that revealed higher expression of both
AATF and miR-2909 within lymphocytes from asymptomatic AIDS
subjects as compared to lymphocytes from the symptomatic AIDS
subjects [10]. There is reason to believe that HIV-1 has evolved strategy
to up-regulate cellular miR-2909 RNomics for the sustenance of its
replication cycle and to down-regulate miR-2909 RNomics within
uninfected bystander CD4+ cells exposed to exosomes (enriched with
hiv1-miR-H1) secreted by viral infected immune cells.Hence, it would be pertinent to explore if antagomiR-against hiv1-miR-H1 could be used as a therapeutic strategy against the AIDS pathogenesis.
particular is nucleolus, a dynamic sub-cellular organelle that employs
the apoptosis-antagonizing transcription factor (AATF) as its
surveillance sensor. It is in this context the AATF RNome, that holds
AATF coding transcript and regulatory non-coding miR-2909 within
its fold, assumes importance because of its ability to tailor cellular
response against a given sensed viral-dependent host-cell nucleoli
subversion. This phenomenon is exemplified by the ability of HIV-1 to
conspicuously target AATF RNome that ensures cellular antiviral
defense through the initiation of CCL5 and RIG-1 signaling response
as well as by regulating chromatin dynamics to restrict HIV-1 latency.
Promastigotes of Leishmania are internalized by macrophages and transformed into
amastigotes in phagosomes, and replicate in phagolysosomes. Phagosomal maturation
arrest is known to play a crucial role in the survival of pathogenic Leishmania within
activated macrophages. Recently, tryptophan–aspartate containing coat (TACO) gene
has been recognized as playing a central role in the survival of Mycobacterium
tuberculosis within human macrophages by arresting the phagosome maturation
process. We postulated that a similar association of TACO gene with phagosomes
would prevent the vacuole from maturation in the case of Leishmania. In this study
we attempted to define the effect of TACO gene downregulation on the entry/survival
of Leishmania donovani intracellularly, by treatment with Vitamin D3 (Vit.D3)/Retinoic
acid (RA) and chenodeoxycholic acid (CDCA)/RA combinations in human THP-1
macrophages (in vitro). Treatment with these molecules downregulated the TACO gene
in macrophages, resulting in reduced parasite load and marked reduction of disease
progression in L. donovani infected macrophages. Taken together, these results suggest
that TACO gene downregulation may play a role in subverting macrophage machinery
in establishing the L. donovani replicative niche inside the host. Our study is the first to
highlight the important role of the TACO gene in Leishmania entry, survival and to identify
TACO gene downregulation as potential drug target against leishmaniasis.
degenerative diseases in general and cancer in particular. Recent findings have added a newdimension to arsenic
biology by revealing thatmost of the arsenic epigenomic effects are mediated through its ability to induce cellular
miR-2909 expression at low doses. The present study was addressed to explore the molecular link that might
exist between arsenic exposure, miR-2909 RNomics involving immunomodulatory genes and effector IgA class
switching, revealed that arsenic-exposed Balb/c mice exhibited predominant Th1 immune response coupled
with effector IgA class switching thereby tailoring their immune system to ensure increased risk to infections
and chronic diseases like cancer.