Oxysterols are oxidized derivatives of cholesterol produced by enzymatic activity or non-enzymatic pathways (auto-oxidation). The oxidation processes lead to the synthesis of about 60 different ...oxysterols. Several oxysterols have physiological, pathophysiological, and pharmacological activities. The effects of oxysterols on cell death processes, especially apoptosis, autophagy, necrosis, and oxiapoptophagy, as well as their action on cell proliferation, are reviewed here. These effects, also observed in several cancer cell lines, could potentially be useful in cancer treatment. The effects of oxysterols on cell differentiation are also described. Among them, the properties of stimulating the osteogenic differentiation of mesenchymal stem cells while inhibiting adipogenic differentiation may be useful in regenerative medicine.
Iron is an essential metal for cell survival that is regulated by the peptide hormone hepcidin. However, its influence on certain diseases is directly related to iron metabolism or secondary to ...underlying diseases. Genetic alterations influence the serum hepcidin concentration, which can lead to an iron overload in tissues, as observed in haemochromatosis, in which serum hepcidin or defective hepcidin synthesis is observed. Another genetic imbalance of iron is iron-refractory anaemia, in which serum concentrations of hepcidin are increased, precluding the flow and efflux of extra- and intracellular iron. During the pathogenesis of certain diseases, the resulting oxidative stress, as well as the increase in inflammatory cytokines, influences the transcription of the HAMP gene to generate a secondary anaemia due to the increase in the serum concentration of hepcidin. To date, there is no available drug to inhibit or enhance hepcidin transcription, mostly due to the cytotoxicity described in the in vitro models. The proposed therapeutic targets are still in the early stages of clinical trials. Some candidates are promising, such as heparin derivatives and minihepcidins. This review describes the main pathways of systemic and genetic regulation of hepcidin, as well as its influence on the disorders related to iron metabolism.
Aging is defined as the accumulation of progressive organ dysfunction. There is much evidence linking the involvement of oxidative stress in the pathogenesis of aging. With increasing age, ...susceptibility to the development of diseases related to lipid peroxidation and tissue injury increases, due to chronic inflammatory processes, and production of reactive oxygen species (ROS) and free radicals. The paraoxonase (PON) gene family is composed of three members (
,
,
) that share considerable structural homology and are located adjacently on chromosome 7 in humans. The most studied member product is PON1, a protein associated with high-density lipoprotein with paraoxonase/esterase activity. Nevertheless, all the three proteins prevent oxidative stress. The major aim of this review is to highlight the importance of the role of PON enzymes in the aging process, and in the development of the main diseases present in the elderly: cardiovascular disease, diabetes mellitus, neurodegenerative diseases, and cancer.
•Silver (∼ 33 nm) and gold (∼ 18 nm) nanoparticles with aminolevulinic acid (ALA) synthesized using photoreduction method.•Zeta potential values: -27.1 mV for gold and -36.6 mV for silver ...nanoparticles.•Higher efficiency in the delivery of ALA occurred by gold nanoparticles.•-ALA embedded in the nanoparticles surface was converted to Protoporphyrin X.•When activated by light or ultrasound produces reactive oxygen species leading to cell death.
Nanoparticles show promise for theranostic applications in cancer. The metal-based nanoparticles can be used both as photosensitizers and delivery vehicles. In bimetallic particles based on gold or silver and iron, a combination of the plasmonic features of the gold or silver components with the magnetic properties of the iron makes these hybrid nanomaterials suitable for both imaging and therapeutic applications. Herein, we discuss toxicity and cell internalization of metallic (silver and gold) and bimetallic (silver-iron, gold-iron, and silver-gold) aminolevulinic acid (ALA) nanoparticles. ALA can control the production of an intracellular photosensitizer, protoporphyrin IX (PpIX), commonly used in photodynamic therapy.
Nanoparticles were synthesized by photoreduction method and characterized by UV/Vis spectra, Zeta potential, FTIR, XRD, and transmission electron microscopy. The amount of singlet oxygen generation by a yellow LED, and ultrasound was studied for gold, gold-iron, and silver-gold nanoparticles. Cytotoxicity assays of MCF-7 in the presence of nanoparticles were performed, and PpIX fluorescence was quantified by high content screening (HCS).
Red fluorescence observed after 24 h of nanoparticles incubation on MCF-7 cells, indicated that the ALA in surface of nanoparticles was efficiently converted to PpIX. The best results for singlet oxygen generation with LED or ultrasound irradiation were obtained with ALA:AgAuNPs.
The studied nanoparticles present the potential to deliver aminolevulinic acid to breast cancer cells efficiently, generate singlet oxygen, and convert ALA into PpIX inside the cells allowing photodiagnosis and therapies such as photodynamic and sonodynamic therapies.
Multidrug resistance (MDR) is the major cause of cancer treatment failure. The ATP-binding cassette-B1 (ABCB1) transporter, also known as MDR1 or P-glycoprotein, is thought to promote the efflux of ...drugs from cells. MDR is also associated with the multidrug resistance-associated protein 1 (ABCC1) and the lung resistance-related protein (LRP), a human major vault protein. Moreover, MDR has a complex relationship with lipids. The ABCB1 has been reported to modulate cellular cholesterol homeostasis. Conversely, cholesterol has been reported to modulate multidrug transporters. However, results reported to date are contradictory and confusing. The aim of this study was to investigate whether LDL, HDL, and serum deprivation could influence ABCB1, ABCC1, and LRP expression in a human doxorubicin-resistant uterine sarcoma cell line.
ABCB1 and ABCC1 expression increased after 24 h of serum deprivation, and expression returned to basal levels after 72 h. LDL, depending on concentration, increased ABCB1, ABCC1, and LRP expression. ABCB1 expression increased at low HDL, and decreased at high HDL concentrations.
We demonstrated that serum deprivation and lipoproteins, particularly LDL, modulated ABCB1 expression and, to a lesser extent, ABCC1 expression. This finding may link the phenomena of drug transport, cholesterol metabolism and cancer.
•LDL, HDL, and serum deprivation modulate ABCB1, ABCC1, and LRP expression.•ABCB1 and ABCC1 expression increase after 24 h of serum deprivation, returning to basal levels after 72 h.•LDL increases ABCB1, ABCC1, and LRP expression.•HDL increases ABCB1 expression at low concentrations, while decreases at high concentrations.
Oxysterols and mesenchymal stem cell biology Levy, Débora; de Melo, Thatiana Correa; Ruiz, Jorge L.M. ...
Chemistry and physics of lipids,
October 2017, 2017-10-00, 20171001, Letnik:
207, Številka:
Pt B
Journal Article
Recenzirano
•Oxysterols plays several roles in pathophysiological processes.•Mesenchymal stem cells (MSCs) have properties of differentiation into other cell types.•The effects of oxysterols on MSCs ...differentiation into osteoblasts and adipocytes are reviewed.•The main pathways involved in these effects are evaluated.
Oxysterols are oxidized products of cholesterol that play several roles in various pathophysiological processes, including the control of lipid metabolism, immunological processes, and cytotoxicity. Mesenchymal stem cells are multipotent cells with properties of self-renewal and the ability to differentiate into other cell types, including osteoblasts and adipocytes. Here, we review the literature regarding the effects of oxysterols on mesenchymal stem cell differentiation and the main signaling pathways involved in this process.
Nodal peripheral T-cell lymphomas (nPTCL) encompass a heterogeneous group of mature and aggressive lymphoid malignancies, including peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS), ...angioimmunoblastic T-cell lymphoma (AITL) and anaplastic large cell lymphoma (ALCL) ALK-positive and ALK-negative. Their differential diagnosis and prognosis are an issue in clinical practice. Accurate biomarkers to define the different subtypes of nPTCL and to stratify their prognosis are essential to improve their treatment approach. The aim of this study was to test the prognostic impact of GATA-3 gene expression, and its capability to discriminate the different subtypes of nPTCL.
We retrospectively assessed GATA-3 gene expression by quantitative real time PCR (qRT-PCR) from neoplastic biopsies in Formalin-Fixed Paraffin-Embedded samples (FFPE) of 80 patients with nPTCL that were admitted in a single cancer treatment center from 2000 to 2017.
Median age was 49 years-old (IqR 34–59), 43/80 (53.7%) were male. Median follow-up was 1.72 years, 36.3% were classified as PTCL, NOS, 31.2% as ALK-negative ALCL, 21.2% as ALK-positive ALCL and 11.3% as AITL. The majority of cases had advanced stage cancer (III/IV). Two-year estimated overall survival (OS) and progression-free survival (PFS) were 52.2% and 39.5%, respectively. The median GATA-3 gene expression level was 0.49 (range 0 – 7.07) in all cohort, with 0.11 for ALK-positive ALCL, 0.46 for ALK-negative ALCL, 0.86 for PTCL, NOS and 0.67 for AITL. The difference of GATA-3 gene expression among distinct variants of nPTCL was statistically significant (p < 0.001). GATA-3 gene expression levels ≥ 0.71 discriminate PTCL, NOS from ALK-negative ALCL and AITL with sensitivity of 62.0% and specificity of 80.3%. GATA-3 gene expression level ≥ median was associated with poor 2-year OS for PTCL, NOS (46.7% versus 21.4%, p = 0.04) and ALK-negative ALCL (85.7% versus 54.5%, p = 0.04). In multivariate analysis, GATA-3 expression ≥ median was an independent factor associated with poor OS in nPTCL (HR: 2.34, 95% CI: 1.12–4.39, p = 0.041).
GATA-3 gene overexpression may be an important biomarker associated with poor prognosis in PTCL, NOS and ALK-negative ALCL. Moreover, it may also discriminate different subtypes of nPTCL. Further studies with larger series of patients should confirm our findings.
•GATA-3 gene overexpression by RT-PCR in FFPE samples may be an important biomarker associated with poor-prognosis in nPTCL.•Tissue levels of the GATA-3 gene expression may help to discriminate the histological variants of nPTCL.•High tumor expression of the GATA-3 gene was associated with poor OS in patients with PTCL, NOS and ALK negative ALCL.•GATA-3 overexpression was associated with B-symptoms, high-risk PIT, poor ORR and high-mortality in PTCL, NOS.•Overexpression of the GATA-3 gene was an independent factor associated with decreased OS in nPTCL Latin American patien.
Background
PCNSL is a rare extranodal NHL with poor prognosis. Tumorigenesis has been associated with hyperactivation of BCR downstream and NFkB pathways. We studied the prognosis of the relative ...expression profile of target genes of NFkB pathway (MYC, BCL2), the essential transcriptional regulator in hematopoiesis LMO2, the checkpoint regulation pathway MGMT, the transcription factor POU2F1, the immune checkpoint gene PDCD1, and the proto‐oncogene and transcriptional repressor gene BCL6 and its proteins in PCNSL.
Methods
This study is a retrospective cohort study; 35 immunocompetent PCNSL‐DLBCL patients had their gene expression (RT‐qPCR) normalized to internal control gene GUSB.
Results
Median patient age was 62 years, median OS was 42.6 months (95% CI: 26.6–58.6), PFS was 41 months (95% CI: 19.7–62.4), and DFS was 59.2 months (95% CI 31.9–86.6). A moderate correlation was found between the gene/protein expressions of MYC (kappa = 0.596, p = .022) and of BCL2 (kappa = 0.426, p = .042). Relative gene expression of MYC ≥ 0.201 (HR 6.117; p = .003) was associated with worse 5‐year OS. Relative gene expression of MYC ≥ 0.201 (HR 3.96; p = .016) and MGMT ≥ 0.335 (HR 3.749; p = .056) was associated with worse PFS. Age > 60 years and IELSG score moderate/high were also associated with worse prognosis.
Conclusions
Overexpression of MYC and overexpression of MGMT were prognostic markers associated with unfavorable clinical outcomes in PCNSL.
In this study, we evaluated the expression of target genes of NFkB pathway (MYC, BCL2), the essential transcriptional regulator in hematopoiesis (LMO2), the checkpoint regulation pathway MGMT, the transcription factor POU2F1, and the immune checkpoint gene PDCD1 in patients with PCNSL.
Abstract
Here we define a ~200 Kb genomic duplication in 2p14 as the genetic signature that segregates with postlingual progressive sensorineural autosomal dominant hearing loss (HL) in 20 affected ...individuals from the DFNA58 family, first reported in 2009. The duplication includes two entire genes, PLEK and CNRIP1, and the first exon of PPP3R1 (protein coding), in addition to four uncharacterized long non-coding (lnc) RNA genes and part of a novel protein-coding gene. Quantitative analysis of mRNA expression in blood samples revealed selective overexpression of CNRIP1 and of two lncRNA genes (LOC107985892 and LOC102724389) in all affected members tested, but not in unaffected ones. Qualitative analysis of mRNA expression identified also fusion transcripts involving parts of PPP3R1, CNRIP1 and an intergenic region between PLEK and CNRIP1, in the blood of all carriers of the duplication, but were heterogeneous in nature. By in situ hybridization and immunofluorescence, we showed that Cnrip1, Plek and Ppp3r1 genes are all expressed in the adult mouse cochlea including the spiral ganglion neurons, suggesting changes in expression levels of these genes in the hearing organ could underlie the DFNA58 form of deafness. Our study highlights the value of studying rare genomic events leading to HL, such as copy number variations. Further studies will be required to determine which of these genes, either coding proteins or non-coding RNAs, is or are responsible for DFNA58 HL.
Although papillary thyroid carcinoma (PTC) has a good prognosis, 20-90% of patients show metastasis to regional lymph nodes and 10-15% of patients show metastasis to distant sites. Metastatic disease ...represents the main clinical challenge that impacts survival rate. We previously showed that LIMD2 was a novel metastasis-associated gene. In this study, to interrogate the role of LIMD2 in cancer invasion and metastasis, we used CRISPR-mediated knockout (KO) of LIMD2 in PTC cells (BCPAP and TPC1). Western blot and high-content screening (HCS) analysis confirmed functional KO of LIMD2. LIMD2 KO reduced in vitro invasion and migration. Ultrastructural analyses showed that cell polarity and mitochondria function and morphology were restored in LIMD2 KO cells. To unveil the signals supervising these phenotypic changes, we employed phospho-protein array. Several members of the MAPK superfamily showed robust reduction in phosphorylation. A Venn diagram displayed the overlap of kinases with reduced phosphorylation in both cell lines and showed that they were able to initiate or sustain the epithelial-mesenchymal transition (EMT) and DNA damage checkpoint. Flow cytometry and HCS validation analyses further corroborated the phospho-protein array data. Collectively, our findings show that LIMD2 enhances phosphorylation of kinases associated with EMT and invasion. Through cooperation with different kinases, it contributes to the increased genomic instability that ultimately promotes PTC progression.
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