[Show abstract][Hide abstract] ABSTRACT: Kaposi's sarcoma-associated herpes virus is associated with primary effusion lymphoma and multicentric Castleman's disease.
Seropositivity to lytic and latent Kaposi's sarcoma herpes virus (KSHV) antigens were examined in 2083 lymphomas and 2013 controls from six European countries.
Antibodies against KSHV latent and lytic antigens were detectable in 4.5% and 3.4% of controls, respectively, and 3.6% of cases (P>0.05). The KSHV seropositivity was associated with splenic marginal zone lymphoma (SMZL) (odds ratio (OR)=4.11, 95% confidence interval (CI)=1.57-10.83) and multiple myeloma (OR=0.31, 95% CI=0.11-0.85).
The KSHV is unlikely to contribute importantly to lymphomagenesis among immunocompetent subjects. However, the observed association with SMZL may underline a chronic antigen mechanism in its aetiology.
Full-text · Article · Sep 2011 · British Journal of Cancer
[Show abstract][Hide abstract] ABSTRACT: Our studies on the role of cholesterol in prion infection/replication showed that brains and peripheral cells of sheep susceptible-to
or suffering-from Scrapie were characterized by an altered cholesterol homeostasis, and that drugs affecting cholesterol ester
pool were endowed with selective anti-prion activity in N2a cell lines infected with the 22L and RML prion strains. In these
prion-infected N2a cell lines, we now report increased anti-prion activity of dual-drug combinations consisting of cholesterol
ester modulators associated with prion inhibitors. Synergism was obtained with the cholesterol ester modulators everolimus,
pioglitazone, progesterone, and verapamil associated with the anti-prion chlorpromazine, and with everolimus and pioglitazone
associated with the anti-prion quinacrine. In addition, comparative lipid analyses in prion-infected vs. uninfected N2a cells, demonstrated a derangement of type and distribution of cholesterol ester, free cholesterol, and triglyceride
pools in the infected cells. Single-drug treatments differently affected synthesis of the various lipid forms, whereas combined
drug treatments appeared to restore a lipid profile similar to that of the untreated-uninfected cells. We conclude that the
anti-prion synergistic effects of cholesterol ester modulators associated with the cholesterol-interfering anti-prion drugs
chlorpromazine and quinacrine may arise from the ability of combined drugs to re-establish lipid homeostasis in the prion-infected
cells. Overall, these data suggest that inhibition of prion replication can be readily potentiated by combinatorial drug treatments
and that steps of cholesterol/cholesterol ester metabolism may represent suitable targets.
KeywordsPrions-Cholesterol metabolism-Cholesterol esters-Prion inhibitors-Drug combinations
Full-text · Article · Apr 2010 · Central European Journal of Biology
[Show abstract][Hide abstract] ABSTRACT: Alzheimer's disease is the most common progressive neurodegenerative disease. In recent years, numerous progresses in the discovery of novel Alzheimer's disease molecular biomarkers in brain as well as in biological fluids have been made. Among them, those involving lipid metabolism are emerging as potential candidates. In particular, an accumulation of neutral lipids was recently found by us in skin fibroblasts from Alzheimer's disease patients. Therefore, with the aim to assess whether peripheral alterations in cholesterol homeostasis might be relevant in Alzheimer's disease development and progression, in the present study we analyzed lipid metabolism in plasma and peripheral blood mononuclear cells from Alzheimer's disease patients and from their first-degree relatives.
Blood samples were obtained from 93 patients with probable Alzheimer's disease and from 91 of their first-degree relatives. As controls we utilized 57, cognitively normal, over-65 year-old volunteers and 113 blood donors aged 21-66 years, respectively. Data are reported as mean +/- standard error. Statistical calculations were performed using the statistical analysis software Origin 8.0 version. Data analysis was done using the Student t-test and the Pearson test.
Data reported here show high neutral lipid levels and increased ACAT-1 protein in about 85% of peripheral blood mononuclear cells freshly isolated (ex vivo) from patients with probable sporadic Alzheimer's disease compared to about 7% of cognitively normal age-matched controls. A significant reduction in high density lipoprotein-cholesterol levels in plasma from Alzheimer's disease blood samples was also observed. Additionally, correlation analyses reveal a negative correlation between high density lipoprotein-cholesterol and cognitive capacity, as determined by Mini Mental State Examination, as well as between high density lipoprotein-cholesterol and neutral lipid accumulation. We observed great variability in the neutral lipid-peripheral blood mononuclear cells data and in plasma lipid analysis of the subjects enrolled as Alzheimer's disease-first-degree relatives. However, about 30% of them tend to display a peripheral metabolic cholesterol pattern similar to that exhibited by Alzheimer's disease patients.
We suggest that neutral lipid-peripheral blood mononuclear cells and plasma high density lipoprotein-cholesterol determinations might be of interest to outline a distinctive metabolic profile applying to both Alzheimer's disease patients and asymptomatic subjects at higher risk of disease.
[Show abstract][Hide abstract] ABSTRACT: Intracellular cholesterol metabolism was reported to modulate amyloid-beta (Abeta) generation in Alzheimer's disease (AD). Results presented herein demonstrated that, like brain cells, cultured skin fibroblasts from AD patients contained more cholesterol esters than fibroblasts from healthy subjects. Particularly, Oil Red-O, Nile Red, and filipin staining highlighted higher levels of neutral lipids which responded to inhibitors of acyl-coenzyme A:cholesterol acyl-transferase (ACAT-1), associated with an increase in free cholesterol. ACAT-1 mRNA levels increased significantly in AD fibroblasts, whereas those of sterol regulatory element binding protein-2, neutral cholesterol ester hydrolase, and ATP-binding cassette transporter member 1 were markedly down-regulated. Instead, mRNA levels of low-density lipoprotein receptor, hydroxy-methyl-glutaryl-coenzyme A reductase, caveolin-1, and amyloid-beta protein precursor (AbetaPP) were virtually unchanged. Notably, mRNA levels of both beta-site AbetaPP-cleaving enzyme 1 (BACE1) and neprilysin were significantly down-regulated. An increase in Abeta(40) and Abeta(42) immunostaining and a decrease in BACE1 active form were also found in AD versus control fibroblasts. Altogether, these findings support the hypothesis that the derangement of cholesterol homeostasis is a systemic alteration involving central but also peripheral cells of AD patients, and point to cholesterol ester levels in AD fibroblasts as an additional metabolic hallmark useful in the laboratory and clinical practice.
[Show abstract][Hide abstract] ABSTRACT: This study aimed to investigate the mechanisms of action of WEB-2170, an inverse agonist of platelet-activating factor receptor, capable of inducing apoptosis in human acute myelogenous leukemia (AML) cells.
Gene expression profiling followed by cytofluorimetric, morphologic, and biologic analyses were used to monitor WEB-2170 effects in AML cell lines (ie, NB4, KG1, NB4-MR4, THP1, and U937) and blasts from patients with different AML (M0-M5) subtypes. PTEN silencing with small interfering RNA was also performed.
We have demonstrated that drug-mediated cytostasis/apoptosis in NB4 cells is characterized by upregulation of cyclin G2, p21/WAF1, NIX, TNF-alpha, and PTEN expression, and downregulation of cyclin D2 and BCL2 expression. We observed an increase in PTEN protein accompanied by a decrease in phospho-extracellular signal-regulated kinase 2 (ERK2) and phospho-AKT, and by forkhead box O3a (FOXO3a) cytoplasmic-nuclear translocation; the mitochondrial cytochrome C release and PARP cleavage marked the late apoptotic steps. We have found that WEB-2170 triggered apoptosis in NB4, KG1, and NB4-MR4 cells where PTEN was expressed, but not in THP1 and U937 cells where PTEN was absent. Finally, we show that PTEN silencing in NB4 cells by PTEN-specific small interfering RNA resulted in a significant reduction of drug-induced apoptosis.
We demonstrated that WEB-2170 is a powerful antileukemic agent with interesting translational opportunities to treat AML and described mechanisms of drug-induced intrinsic and extrinsic apoptosis both in AML cell lines and blasts from AML patients by addressing PTEN as the master regulator of the whole process.
Full-text · Article · Aug 2009 · Experimental hematology
[Show abstract][Hide abstract] ABSTRACT: Lymphomas are a heterogeneous group of immune-cell malignancies. Immunology-related conditions are among the few factors for which consistent evidence exists relating them to lymphoma risk.
We used the data from the European case-control study Epilymph on 2,362 lymphoma cases and 2,458 controls to investigate associations between a medical history of infectious and non-infectious diseases with overall and subentity-specific lymphoma risk.
As key results, we observed an increased odds ratio (OR) for self-reported infections with hepatitis B virus (HBV, OR = 1.91, 95% CL = 1.24-2.94) and a null result for rheumatoid arthritis. Additionally, we found an increased OR for infectious mononucleosis (OR = 1.68, 95% CL = 1.14-2.48), an inverse association to frequency of sickness in childhood (OR = 0.68, 95% CL = 0.55-0.84), and-as casual finding-an increased OR with acetaminophen intake (OR = 2.29, 95% CL = 1.49-3.51).
Our results are consistent with the current knowledge about the association with mononucleosis as indicator of Epstein-Barr-virus infection, suggest serological study of the association to HBV infection and do not support the view of a positive association between rheumatoid arthritis and lymphoma risk.
Full-text · Article · Mar 2009 · Journal of Cancer Research and Clinical Oncology
[Show abstract][Hide abstract] ABSTRACT: Background. Our studies on the role of cholesterol in prion infection/replication showed that brains and peripheral cells of sheep susceptible to or suffering from Scrapie were characterized by an altered cholesterol homeostasis compared to animals with a scrapie-resistant genotype, and that drugs influencing cholesterol esterification were endowed with selective anti-prion activity in N2a cell lines infected with the 22L and RML prion strains.
Results. In prion-infected N2a cell lines we now report increased anti-prion activity of dual-drug combinations consisting of cholesterol ester modulators associated with prion inhibitors Synergism was obtained with the cholesterol ester modulators everolimus, pioglitazone, progesterone, and verapamil associated with the anti-prion chlorpromazine, and with everolimus and pioglitazone associated with the anti-prion quinacrine. Comparative lipid analyses in prion-infected and non-infected N2a cells by colorimetric, enzymatic, and chemical means, clearly demonstrated a derangement of type and distribution of cholesterol esters, free cholesterol, and triglycerides in the infected N2a cells. Although single-drug treatments influenced lipid syntheses, only the combined-drug treatments appeared to restore a lipid profile similar to that of untreated-uninfected cells.
Conclusions. We conclude that the anti-prion synergistic effect of cholesterol ester modulators with the cholesterol metabolism interfering anti-prion drugs chlorpromazine and quinacrine may arise from the ability of combined drugs to re-establish the intracellular lipid profile of untreated-uninfected cells. Overall, these data suggest that inhibition of prion replication can be readily potentiated by combinatorial drug treatments, and that steps of cholesterol/cholesterol ester metabolism may represent suitable targets.
[Show abstract][Hide abstract] ABSTRACT: Three recent studies have reported a decreased risk of non-Hodgkin lymphoma (NHL) for high ultraviolet (UV) radiation exposure.
We conducted a multicentre case-control study during 1998-2004 in France, Germany, Ireland, Italy and Spain, comprising 1518 cases of NHL, 268 cases of Hodgkin lymphoma, 242 cases of multiple myeloma and 2124 population or hospital controls. We collected information on sensitivity to sun and personal exposure to UV radiation in childhood and adulthood via interview, and assessed occupational exposure to UV radiation from the occupational history.
The risk of Hodgkin and NHL was increased for increasing skin sensitivity to the sun [odds ratio (OR) for no suntan vs very brown 2.35, 95% CI 0.94-5.87 and 1.39, 95% CI 1.03-1.87, respectively]. The risk of diffuse large B-cell lymphoma was reduced for increasing adult personal (OR for highest vs lowest quartile of exposure in free days 0.62, 95% CI 0.44-0.87) and for occupational exposure to UV radiation (OR for highest vs lowest exposure tertile 0.63, 95% CI 0.37-1.04). The risk of multiple myeloma was increased for personal exposure to UV radiation during adulthood (OR for highest vs lowest quartile of exposure in free days 1.49, 95% CI 0.88-2.50). A protective effect was observed for use of sun lamps for diffuse large B-cell lymphoma (OR for 25+ times vs never 0.63, 95% CI 0.38-1.03).
The hypothesis of a protective effect of UV radiation on lymphoma is supported by our results. The underlying mechanisms might differ from those operating in skin carcinogenesis. The increased risk of multiple myeloma is worth replication.
Full-text · Article · Jun 2008 · International Journal of Epidemiology
[Show abstract][Hide abstract] ABSTRACT: Cytogenetic analysis in myeloma reveals marked chromosomal instability. Both widespread genomic alterations and evidence of
aberrant class switch recombination, the physiological process that regulates maturation of the antibody response, implicate
the DNA repair pathway in disease pathogenesis. We therefore assessed 27 SNPs in three genes (XRCC3, XRCC4 and XRCC5) central
to DNA repair in patients with myeloma and controls from the EpiLymph study and from an Irish hospital registry (n = 306 cases, 263 controls). For the haplotype-tagging SNP (htSNP) rs963248 in XRCC4, Allele A was significantly more frequent
in cases than in controls (86.4 versus 80.8%; odds ratio 1.51; 95% confidence interval 1.10–2.08; P = 0.0133), as was the AA genotype (74 versus 65%) (P = 0.026). Haplotype analysis was performed using Unphased for rs963248 in combination with additional SNPs in XRCC4. The
strongest evidence of association came from the A–T haplotype from rs963248–rs2891980 (P = 0.008). For XRCC5, the genotype GG from rs1051685 was detected in 10 cases from different national populations but in only
one control (P = 0.015). This SNP is located in the 3′-UTR of XRCC5. Overall, these data provide support for the hypothesis that common
variation in the genes encoding DNA repair proteins contributes to susceptibility to myeloma.
Full-text · Article · Jan 2008 · Human Molecular Genetics
[Show abstract][Hide abstract] ABSTRACT: Lymphomas are a heterogeneous group of malignancies of the immune system. Recent studies suggest that immunological conditions which are modulated by lifestyle-dependent environmental determinants might affect lymphoma risk. We used data from Epilymph, a European multi-centric case-control study with 2,480 cases and 2,540 controls, to analyse the relationship between lifestyle-dependent immunological determinants and risk of lymphomas. We found an inverse relationship between risk of lymphoma and allergies, mainly respiratory (OR=0.86, CI=0.89-1.01) and food allergies (OR=0.67, CI=0.52-0.85), a slightly elevated lymphoma risk for first-born children (OR=1.17, CI=0.99-1.39) and only children (OR=1.10, CI=0.86-1.39). The inverse relationship between atopic disorders and risk of lymphomas is consistent with earlier observations. Our findings on birth order and lymphoma increase the inconsistency of findings across studies and suggest a critical reappraisal of potential underlying mechanisms.
No preview · Article · Nov 2007 · Leukemia Research
[Show abstract][Hide abstract] ABSTRACT: Epstein-Barr Virus (EBV) is consistently associated with distinct lymphoproliferative malignancies and aberrant EBV antibody patterns are found in most EBV cancer patients. We evaluate the detection of an abnormal reactive serological pattern to EBV (ab_EBV) infection and the risk of lymphoma in a multicentric case-control study. Serum samples were collected at study entry from 1,085 incident lymphoma cases from Spain, France, Germany, Czech Republic, Italy and 1,153 age, sex and country matched controls. EBV immunoglobulin G (IgG) serostatus was evaluated through a peptide-based ELISA combining immunodominant epitopes of EBNA1 (BKRF1) and VCA-p18 (BFRF3). Further, immunoblot analysis was performed to evaluate distinct antibody diversity patterns to EBV early antigens (EA), besides EBNA1, VCA-p18, VCA-p40 (BdRF1) and Zebra (BZLF1). Patients with chronic active EBV infection and aberrant EBV activity were characterized as having an abnormal reactive pattern (ab_EBV). Ab_EBV was observed in 20.9% of 2,238 included subjects with an increased proportion of cases presenting ab_EBV as compared to the control population (23.9% vs. 18.0% p = 0.001). Ab_EBV positivity was a risk factor for all lymphomas combined (odds ratio [OR] = 1.42, 95% confidence interval [CI]=1.15-1.74), and specifically for chronic lymphocytic leukaemia (OR = 2.96, 95%CI = 2.22-3.95). Lower levels of ab_EBV were observed for follicular lymphoma (OR = 0.38, 95%CI = 0.15-0.98). EBV may be involved in a larger subset of lymphomas among clinically immunocompetent subjects than previously thought, probably explained by an underlying loss of immune control of EBV latent infection. Ab_EBV is a useful tool to explore EBV imbalances preceding or paralleling possible EBV associated oncogenic events.
Full-text · Article · Oct 2007 · International Journal of Cancer
[Show abstract][Hide abstract] ABSTRACT: A role for genetic susceptibility in non-Hodgkin lymphoma (NHL) is supported by the accumulating evidence of common genetic variations altering NHL risk. However, the pattern of NHL heritability remains poorly understood. We conducted a pooled analysis of 10 211 NHL cases and 11 905 controls from the International Lymphoma Epidemiology Consortium (InterLymph) to evaluate NHL risk among those with hematopoietic malignancies in first-degree relatives. Odds ratios (ORs) and 95% confidence intervals (CIs) of NHL and its subtypes were estimated from unconditional logistic regression models with adjustment for confounders. NHL risk was elevated for individuals who reported first-degree relatives with NHL (OR = 1.5; 95% CI = 1.2-1.9), Hodgkin lymphoma (OR = 1.6; 95% CI = 1.1-2.3), and leukemia (OR = 1.4; 95% CI = 1.2-2.7). Risk was highest among individuals who reported a brother with NHL (OR = 2.8; 95% CI = 1.6-4.8) and was consistent for all NHL subtypes evaluated. If a first-degree relative had Hodgkin lymphoma, NHL risk was highest if the relative was a parent (OR = 1.7; 95% CI = 1.0-2.9). If a first-degree relative had leukemia, NHL risk was highest among women who reported a sister with leukemia (OR = 3.0; 95% CI = 1.6-5.6). The pattern of NHL heritability appeared to be uniform across NHL subtypes, but risk patterns differed by specific hematopoietic malignancies and the sex of the relative, revealing critical clues to disease etiology.
[Show abstract][Hide abstract] ABSTRACT: Increasing evidence points toward a role of hepatitis C virus (HCV) infection in the etiology of malignant lymphomas. However, previous epidemiologic studies were limited in size to establish an association between HCV infection and specific lymphoma subtypes. We performed a large, multicenter, case-control study to address this question.
The study comprised 5 European countries and included newly diagnosed cases of any lymphoid malignancy recruited between 1998 and 2004. Controls were matched to cases by 5-year age group, sex, and study center. In-person interviews were conducted to collect data on demographic, medical, and family history as well as environmental exposures. Serum samples of 1807 cases and 1788 controls (excluding human immunodeficiency virus-positive and organ-transplantation subjects) were screened for HCV infection using an enzyme immunoassay. Positive as well as randomly selected negative samples were subjected to HCV RNA detection and HCV genotyping.
HCV infection was detected in 53 (2.9%) lymphoma cases and in 41 (2.3%) control subjects (odds ratio [OR], 1.42; 95% confidence interval [CI]: 0.93-2.15). Restricted to individuals who tested positive for HCV-RNA (indicating persistent infection and active viral replication), the OR was 1.82 (95% CI: 1.13-2.91). In subtype-specific analyses, HCV prevalence was associated with diffuse large B-cell lymphoma (OR, 2.19; 95% CI: 1.23-3.91) but not with chronic lymphocytic leukemia or follicular, Hodgkin's, or T-cell lymphoma. The sample size was not sufficient to derive any conclusions for rare lymphoma entities such as splenic marginal zone lymphoma.
These results support a model that chronic HCV replication contributes to lymphomagenesis and establish a specific role of HCV infection in the pathogenesis of diffuse large B-cell lymphoma.
No preview · Article · Jan 2007 · Gastroenterology
[Show abstract][Hide abstract] ABSTRACT: We analysed the effects of tobacco and alcohol in the aetiology of Hodgkin's lymphoma (HL), based on 340 cases and 2465 controls enrolled in Spain, France, Italy, Germany, Ireland and Czech Republic, between 1998 and 2004. Current smokers showed a significantly increased odds ratio (OR) of HL of 1.39 (95% confidence interval (CI) = 1.04-1.87). Analyses were also conducted separately for subjects younger than 35 years (179 cases) and for older subjects (161 cases). For subjects below age 35, no association was observed between tobacco and HL, whereas for older subjects, ever-smokers experienced a doubled risk of HL as compared to never smokers and the OR of HL for current smoking was 2.35 (95% CI = 1.52-3.61), with suggestion of a dose-response relationship. A protective effect of alcohol was observed in both age groups. The OR for ever-regular drinking was 0.58 (95% CI = 0.38-0.89) for younger subjects and 0.50 (95% CI = 0.34-0.74) for older subjects. There was no evidence of interaction between tobacco and alcohol. Our results are consistent with previous studies, suggesting a protective effect of alcohol on HL. An effect of tobacco was suggested for HL occurring in middle and late age, although this finding might have occurred by chance.
Full-text · Article · Sep 2006 · British Journal of Cancer
[Show abstract][Hide abstract] ABSTRACT: Hair dyes have been evaluated as possibly being mutagenic and carcinogenic in animals. Studies of the association between human cancer risk and use of hair dyes have yielded inconsistent results. The authors evaluated the risk of lymphoid malignancies associated with personal use of hair dyes. The analysis included 2,302 incident cases of lymphoid neoplasms and 2,417 hospital- or population-based controls from the Czech Republic, France, Germany, Ireland, Italy, and Spain (1998-2003). Use of hair dyes was reported by 74% of women and 7% of men. Lymphoma risk among dye users was significantly increased by 19% in comparison with never use (odds ratio (OR) = 1.19, 95% confidence interval (CI): 1.00, 1.41) and by 26% among persons who used hair dyes 12 or more times per year (OR = 1.26, 95% CI: 1.00, 1.60; p for linear trend = 0.414). Lymphoma risk was significantly higher among persons who had started coloring their hair before 1980 (OR = 1.37, 95% CI: 1.09, 1.72) and persons who had used hair dyes only before 1980 (OR = 1.62, 95% CI: 1.10, 2.40). Personal use of hair dyes is associated with a moderate increase in lymphoma risk, particularly among women and persons who used dyes before 1980. Specific compounds associated with this risk remain to be elucidated.
Preview · Article · Aug 2006 · American Journal of Epidemiology
[Show abstract][Hide abstract] ABSTRACT: Statins, drugs used to treat dyslipidemia, may have anticancer properties. We have evaluated lymphoma risk associated with regular statin use in an international case-control study.
This case-control study included 2,362 cases of incident B- and T-cell lymphoma from Czech Republic, France, Germany, Ireland, Italy, and Spain and 2,206 hospital or population controls. Information on drug use, diagnosis at admission (for hospital controls), and putative risk factors for lymphoma was collected with personal interviews. Hospital controls admitted for diseases possibly entailing use of statins were excluded from the analysis.
The odds ratio for regular statin use was 0.61 (95% confidence interval, 0.45-0.84); all major lymphoma subtypes showed similarly decreased risks. Decreased risks were observed in all centers. Duration of statin use was not associated with a greater reduction in the risk of lymphoma. Use of other lipid lowering drugs, such as fibrates, did not significantly modify the risk of lymphoma (odds ratio, 0.75; 95% confidence interval, 0.44-1.27).
Statin use was associated with an important reduction in lymphoma risk, adding to the growing evidence of anticancer properties of this group of drugs. These results are reassuring for the increasing number of patients taking statins on a regular basis.
Full-text · Article · Jun 2006 · Cancer Epidemiology Biomarkers & Prevention
[Show abstract][Hide abstract] ABSTRACT: The effects of ganaxolone, a synthetic analog of the endogenous neuroactive steroid allopregnanolone, on the function and expression of GABA(A) receptors were determined. Electrophysiological recordings demonstrated that ganaxolone potentiated with a potency and efficacy similar to those of allopregnanolone the Cl- currents evoked by GABA at recombinant human GABA(A) receptors (comprising alpha1beta2gamma2L or alpha2beta2gamma2L subunit assemblies) expressed in Xenopus oocytes. Exposure of cultured rat cerebellar granule cells to 1 microM ganaxolone for 5 days had no effect on the abundance of mRNAs encoding the alpha1, alpha2, alpha3, alpha4, alpha5, gamma2L, or gamma2S subunits of the GABA(A) receptor. Withdrawal of ganaxolone after such long-term treatment, however, induced an increase in the abundance of alpha2, alpha4, and alpha5 subunit mRNAs and a decrease in the amounts of alpha1, gamma2L, and gamma2S subunit mRNAs. These changes were maximal 3 to 6 h after drug withdrawal and were reversible, being no longer apparent after 24 h. These results suggest that long-term exposure of cerebellar granule cells to ganaxolone does not affect the sensitivity of the GABA(A) receptor to several positive modulators. Nevertheless, the reduction in the amounts of the alpha1 and gamma2 subunit mRNAs together with the increase in the abundance of the alpha4 subunit mRNA induced by abrupt discontinuation of long-term treatment with ganaxolone suggest that withdrawal of this drug might result in a reduced response to classic benzodiazepines.
Full-text · Article · Jan 2003 · Journal of Pharmacology and Experimental Therapeutics
[Show abstract][Hide abstract] ABSTRACT: Recent studies in both animal and cell models of Alzheimer's disease (AD) indicated that sub-cellular cholesterol distribution seems to regulate amyloid-beta (A[beta]) generation in the brain. In particular, cholesterol-esters (CE), rather than total cholesterol levels, appear directly correlated with A[beta] production. Here we observed that, similarly to brain cells, skin fibroblasts obtained from AD patients produce and accumulate more CE than skin fibroblasts from age-matched healthy controls do. AD fibroblasts also exhibited a 2 fold increase in the expression of ACAT1, in addition to lower levels of SREBP2, nCEH, Caveolin-1 and ABCA1 mRNA levels, all of which are involved in the CE cycle. HMGCoA-reductase and LDL-receptor mRNAs levels did not show statistically significant changes in AD, compared to non-AD, cells. Furthermore, although APP mRNA did not significantly vary, neprilysin (NEP), the most important enzyme in the proteolysis of A[beta], was expressed at very low levels in skin fibroblasts of sporadic AD patients. Our results contribute to the concept that AD may be the consequence of a basic and systemic defect in the CE cycle. Moreover, our results identify new possible targets for the diagnosis, prevention, and cure or, at least, amelioration of the symptoms of AD.
[Show abstract][Hide abstract] ABSTRACT: Introduction. Cardiovascular involvement represents a well-known complication and the primary cause of mortality, both in transfusion-dependent beta thalassemia major (β-TM) and in transfusion-independent beta thalassemia intermedia (β-TI). In β-TM, heart iron overload is considered the main cause of this complication. This is likely due to poor adherence to iron-chelating therapy, resulting in the inability of the body to efficiently remove iron excess derived from transfused red blood cell breakdown. Different clinical pictures may instead be evoked in cardiovascular involvement occurring in β-TI; however, until now, no factor has emerged as the major one responsible for these complications.
Design and Methods. In the present study, iron status, and lipid profiles in serum, as well as lipid content in peripheral blood mononuclear cells (PBMCs) were evaluated in 70 adult β-TM and in 22 adult β-TI patients. Ninety-two age-matched blood donors, free from any form of thalassemia, were utilized as controls. The mRNA levels of genes involved in the regulation of iron metabolism, such as interleukine 1 alfa (IL1α), tumor necrosis factor alfa (TNFα), as well as those involved in cholesterol homeostasis, such as acetyl-coenzymeA: cholesterol acyltransferase (ACAT-1), neutral cholesterol ester hydrolase (nCEH), and ATP binding cassette-A (ABCA1), were also evaluated in PBMCs from the above subjects.
Results. In β-TI patients, serum iron, transferrin saturation and erythropoietin levels were higher, while transferrin and hepcidin were lower, compared to both β-TM and controls. Hepcidin and ILα mRNA levels were found to be reduced in β-TI-PBMCs, while those of TNFα were increased. A reduction in total and high density lipoprotein cholesterol (TC and HDL-C) in serum, and an accumulation of neutral lipids (NL), coupled with increased mRNA levels of ACAT-1 and decreased nCEH in PBMCs were also observed in β-TI.
Conclusions. Since most of the parameters found to be altered in β-TI patients have a key role in the initiation and progression of atherosclerosis, we suggest that cardiovascular complications in these patients may be, at least partially, dependent on the occurrence of premature atherosclerotic lesions.