188 research outputs found
Nuclear inositides: PI-PLC signaling in cell growth, differentiation and pathology
No full textThe existence of phospholipids in chromosomes has been suggested by the work of La Cour et al.
(1958). In the 1970s, Manzoli and colleagues demonstrated that addition of phospholipids to purified
nuclei could influence in vitro transcription (Manzoli et al., 1978). The same group demonstrated that
negatively charged lipids led to chromatin decondensation, while positive charged lipids had the
opposite effect. In 1987, the first demonstration came from a work by Cocco et al., that a nuclear PI
metabolism exists and it is regulated during Friend cells differentiation (Cocco et al., 1987). Since then,
progress has been made on the regulation of nuclear phosphoinositides (PI), as well as their role in
cellular functions, i.e. growth and differentiation. Nevertheless, much still needs to be understood
about the function, regulation and physical properties of this nuclear component. For example, while it
is clear that these PIs are not part of the nuclear envelope but they reside within the nuclear domains,
the physicochemical form of nuclear lipids still needs to be clarified (Irvine, 2006).
We know that inositol lipid signaling molecules are essential components of the extremely
complicated, multistep process that allows one extracellular signal to be transduced inside the cell, to
the nucleus. In the nuclear compartment, lipid second messengers elicit reactions that regulate gene
transcription, DNA replication or repair, and DNA cleavage, eventually resulting in cellular differentiation,
proliferation, apoptosis and other cell functions. Inositol-containing phospholipids are the most
intensively studied lipid second messengers. Albeit most of the research on signal transduction
pathways based on PI has been devoted to phenomena that take place at the cell periphery and plasma
membrane, it has become clear that the nuclear PI cycle is regulated in a totally independent manner
from that at the plasma membrane level. This suggests that nuclear inositol lipids themselves can
modulate nuclear processes, as important as transcription and pre-mRNA splicing, growth, proliferation,
cell cycle regulation and differentiation
The potential of the nutraceutical berberine in the treatment of hepatocellular carcinoma and other liver diseases such as NAFLD and NASH
No full textHepatocellular carcinoma (HCC) is a common cancer which unfortunately has poor outcomes. Common anti-cancer treatments such as chemotherapy and targeted therapy have not increased patient survival significantly. A common treatment for HCC patients is transplantation, however, it has limitations and complications. Novel approaches are necessary to more effectively treat HCC patients. Berberine (BBR) is a nutraceutical derived from various fruits and trees, which has been used for centuries in traditional medicine to treat various diseases such as diabetes and inflammation. More recently, the anti-proliferation effects of BBR have been investigated in the treatment of patients with various cancers, especially colorectal cancer, and in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). In this review, we will focus on studies with BBR in liver diseases
PLCB1 (phospholipase C, beta 1 (phosphoinositide-specific)
No full textdescription, expression and localization of human PLCB1 gen
The physiological roles of primary phospholipase C
No full textThe roles of phosphoinositide-specific phospholipase C (PLC) have been extensively investigated in diverse cell lines and pathological conditions. Among the PLC isozmes, primary PLCs, PLC-β and PLC-γ, are directly activated by receptor activation, unlike other secondary PLCs (PLC-ɛ, PLC-δ1, and PLC-η1). PLC-β isozymes are activated by G protein couple receptor and PLC-γ isozymes are activated by receptor tyrosine kinase (RTK). Primary PLCs are differentially expressed in different tissues, suggesting their specific roles in diverse tissues and regulate a variety of physiological and pathophysiological functions. Thus, dysregulation of phospholipases contributes to a number of human diseases and primary PLCs have been identified as therapeutic targets for prevention and treatment of diseases. Here we review the roles of primary PLCs in physiology and their impact in pathology
Role of inositide signalling regulation in higher-risk MDS patients during epigenetic therapy
No full textBackground: Inositide signalling pathways are involved in cell
growth, differentiation and apoptosis and play a role in
the progression of myelodysplastic syndromes (MDS) towards
acute myeloid leukemia (AML). The combination of the DNA
methyltransferase inhibitor azacitidine (AZA) and the HDAC inhibitor
valproic acid (VPA) in patients with IPSS intermediate-2/high-risk
MDS has been demonstrated to be active and associated with a high
response rate in patients with MDS and unfavourable prognosis
(Voso MT et al, 2009).
Introduction: In the last few years, our group demonstrated not
only that phosphoinositide-phospholipase C beta1 (PI-PLCbeta1)
promoter gene is hyper-methylated in higher-risk MDS, but also that is affected by epigenetic therapy (Follo MY et al, PNAS 2009; Follo
MY et al. Leukemia 2010). Indeed, AZA, alone or in combination with
VPA was able to induce PI-PLCbeta1 demethylation and expression.
Purpose: In this study we further investigated the role of lipid
signalling pathways during epigenetic therapy, focusing on the
functional effect of AZA and VPA on PI-PLCbeta1 promoter in highrisk
MDS patients.
Materials and Methods: The study included 20 higher-risk MDS
patients (IPSS risk: intermediate-2 or high): 8 of them were treated
with AZA alone (75 mg/m2/day SC for 7 days/28 days), whereas 6 of
them received the combination of AZA with VPA (600–1500 mg/daily
orally) and the remaining 6 were treated only with best supportive
care. For each patient we analyzed the effect of epigenetic therapy
in correlation to PI-PLCbeta1 signalling, by analyzing the binding
affinity of transcription factors correlated to hematopoietic stem
cell differentiation and proliferation, as well as by quantifyng the
expression of molecules involved in the epigenetic machinery, such
as Class I HDACs.
Results: 8/20 (40%) of our MDS patients showed a favourable
hematologic response to epigenetic therapy and an increase in PIPLCbeta1
expression, as compared with the pre-treatment period,
thus confirming the involvement of this molecule in response
to demethylating agents. Moreover, MDS patients responding to
epigenetic treatment seem to involve the recruitment of specific
transcription factors on PI-PLCbeta1 promoter during the regulation
of methylation processes. Taken together, our data are consistent
with the hypothesis of a correlation between epigenetic treatment
and PI-PLCbeta1 signalling, thus hinting at a role for PI-PLCbeta1 in
monitoring the efficacy of epigenetic therapy and paving the way
for the development of innovative therapeutic strategies in MD
Nuclear phosphoinositide specific phospholipase C (PI-PLC)-beta 1: a central intermediary in nuclear lipid-dependent signal transduction.
No full textB-all complexity: Is targeted therapy still a valuable approach for pediatric patients?
No full textB-cell acute lymphoblastic leukemia (B-ALL) is a hematologic malignancy that arises from the clonal expansion of transformed B-cell precursors and predominately affects childhood. Even though significant progresses have been made in the treatment of B-ALL, pediatric patients’ outcome has to be furtherly increased and alternative targeted treatment strategies are required for younger patients. Over the last decade, novel approaches have been used to understand the genomic landscape and the complexity of the molecular biology of pediatric B-ALL, mainly next generation sequencing, offering important insights into new B-ALL subtypes, altered pathways, and therapeutic targets that may lead to improved risk stratification and treatments. Here, we will highlight the up-to-date knowledge of the novel B-ALL subtypes in childhood, with particular emphasis on altered signaling pathways. In addition, we will discuss the targeted therapies that showed promising results for the treatment of the different B-ALL subtypes
Effect of azacitidine on inositide-dependent signalling pathways in low-risk MDS patients
No full textBackground: Azacitidine is a DNA methyltransferase inhibitor
currently used for the treatment of higher-risk myelodysplastic
syndromes (MDS) which has also been proven an effective treatment
of lower-risk MDS (Silverman LR et al, J Clin Oncol 2002; Musto P
et al, Cancer 2010). Inositide signalling is involved in cell growth,
differentiation and apoptosis, therefore affecting cell processes and
playing a role in the pathogenesis of several malignancies.
Introduction: Our group recently demonstrated that phosphoinositide-phospholipase
C beta1 (PI-PLCbeta1) is involved in the
MDS progression to AML and is affected by epigenetic therapy
(Follo MY et al, J Cell Biochem 2010; Follo MY et al, Leukemia
2010). Namely, PI-PLCbeta1 specifically targets Cyclin D3, which
is in turn implicated in hematopoietic stem cell proliferation and
differentiation.
Purpose: In this study, we analyzed the role of PI-PLCbeta1-
dependent signalling pathways during epigenetic therapy, focusing
on the effect of azacitidine on PI-PLCbeta1 downstream target Cyclin
D3 in lower-risk MDS patients.
Materials and Methods: The analysis included 25 patients (IPSS risk:
low or intermediate-1) treated with azacitidine alone (75 mg/m2
subcutaneous daily for 5 consecutive days every 28 days, for a total
of 8 courses). For each patient we followed the effect of azacitidine
in correlation to both PI-PLCbeta1 and Cyclin D3 expression.
Results: Our results show that 9/25 (36%) of our lower-risk MDS
patients showed a hematologic response to azacitidine (Complete
Remission: 4 patients, Partial Remission: 1 patient, Hematologic
Improvements: 4 patients), as well as an increase in PI-PLCbeta1
expression, as compared with pre-treatment levels. Furthermore,
ongoing analyses are trying to disclose whether Cyclin D3 activation
is also implicated in azacitidine response, therefore affecting
hematopoietic stem cell differentiation processes.
Conclusions: Overall, our data hint at a correlation between
azacitidine therapy and PI-PLCbeta1 signalling, possibly via the
activation of Cyclin D3, even in lower-risk MDS, thus indicating
that PI-PLCbeta1 could be useful not only for evaluating the efficacy
of azacitidine but also for disclosing the molecular mechanisms
underlying this kind of treatment in lower-risk MD
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