160 research outputs found
Liver X Receptors: Regulators of Cholesterol Metabolism, Inflammation, Autoimmunity, and Cancer
No full textThe interplay between cellular stress and immune response can be variable and sometimes contradictory. The mechanisms by which stress-activated pathways regulate the inflammatory response to a pathogen, in autoimmunity or during cancer progression remain unclear in many aspects, despite our recent knowledge of the signalling and transcriptional pathways involved in these diseases. In this context, over the last decade many studies demonstrated that cholesterol metabolism is an important checkpoint for immune homeostasis and cancer progression. Indeed, cholesterol is actively metabolized and can regulate, through its mobilization and/or production of active derivatives, many aspects of immunity and inflammation. Moreover, accumulation of cholesterol has been described in cancer cells, indicating metabolic addiction. The nuclear receptors liver-X-receptors (LXRs) are important regulators of intracellular cholesterol and lipids homeostasis. They have also key regulatory roles in immune response, as they can regulate inflammation, innate and adaptive immunity. Moreover, activation of LXRs has been reported to affect the proliferation and survival of different cancer cell types that show altered metabolic pathways and accumulation of cholesterol. In this minireview we will give an overview of the recent understandings about the mechanisms through which LXRs regulate inflammation, autoimmunity, and cancer, and the therapeutic potential for future treatment of these diseases through modulation of cholesterol metabolism
Hyperthermia enhances CD95-ligand gene expression in T lymphocytes
No full textHyperthermia represents an interesting therapeutic strategy for the treatment of tumors. Moreover, it is able to regulate several aspects of the immune response. Fas (APO-1/CD95) and its ligand (FasL) are cell surface proteins whose interaction activates apoptosis of Fas-expressing targets. In T cells, the Fas-Fas-L system regulates activation-induced cell death, is implicated in diseases in which lymphocyte homeostasis is compromised, and plays an important role during cytotoxic and regulatory actions mediated by these cells. In this study we describe the effect of hyperthermia on activation of the fas-L gene in T lymphocytes. We show that hyperthermic treatment enhances Fas-L-mediated cytotoxicity,fas-L mRNA expression, and fas-L promoter activity in activated T cell lines. Our data indicate that hyperthermia enhances the transcriptional activity of AP-1 and NF-kappaB in activated T cells, and this correlates with an increased expression/nuclear translocation of these transcription factors. Moreover, we found that heat shock factor-1 is a transactivator of fas-L promoter in activated T cells, and the overexpression of a dominant negative form of heat shock factor-1 may attenuate the effect of hyperthermia on fas-L promoter activity. Furthermore, overexpression of dominant negative mutants of protein kinase Cepsilon (PKCepsilon) and PKCtheta partially inhibited the promoter activation and, more importantly, could significantly reduce the enhancement mediated by hyperthermia, indicating that modulation of PKC activity may play an important role in this regulation. These results add novel information on the immunomodulatory action of heat, in particular in the context of its possible use as an adjuvant therapeutic strategy to consider for the treatment of cancer
Detection and quantitation analysis of cocaine and metabolites in fixed liver tissue and formalin solutions.
No full textThis study reports the results of the detection and quantitation of
cocaine and its metabolites in liver tissues fixed in formalin and in
the formalin solutions in which the same tissues were fixed.
Toxicological analyses were performed on formalin-fixed liver
samples from four cases of death of cocaine abusers and on
formalin solutions (10% buffered, pH 7) in which the samples were
preserved. Analyses carried out at the time of autopsy on body
fluids and tissues allowed identification of cocaine and the
metabolite benzoylecgonine. Liver tissue samples were preserved in formalin solutions for four weeks before analysis. Results only
showed the presence of benzoylecgonine in the studied materials.
The mean levels of recovery of benzoylecgonine in fixed tissues
were 12.31% in liver and 84.47% in formalin from liver. Results
indicated that benzoylecgonine has good stability, even in
biological specimens subjected to chemical fixation
Hair analysis in order to evaluate drug abuse in driver's license regranting procedures
No full textIn Italy, driving under the influence of drugs determines the suspension of the offender’s driver’s license. To regain the license the person must be drug free during an observation period. People whose license has been revoked or suspended can obtain, or re-obtain their driver’s license subject to the judgment of a medical commission. The exclusion of illicit drug use is determined by means of toxicological analysis, mainly on urine or hair matrices. We reported the results of several years of experience of the forensic toxicology laboratory of the University of Macerata in the use of hair analysis for the assessment of past exposure to drugs in people suspected of driving under the influence of drugs. From 2004 to 2013, 8,612 hair samples, were analyzed for opiates, cocaine and delta-9-tetrahydrocannabinol (Δ9-THC) using gas chromatography /mass spectrometry (GC/MS) method. We used a cutoff (SoHT or national guidelines) to determine the positive data, regardless of the hair sample concentrations. 1,213 samples resulted positive, 71.7% were positive for cocaine and metabolites, 19.8 % for morphine and metabolites, 8.5% for delta-Δ9-THC. We also studied the timeframe of the abuse, as well as gender and age distribution of positive subjects. Moreover, we analyzed the possible deterrent effect of the hair analysis on driving under the influence of psychoactive substances
Stability of barbiturates in fixed tissues and in formalin solution
No full textThis study reports the results of the retention and quantitation of
barbiturates in fresh tissue, in liver tissue fixed in formalin, and in
the formalin solutions in which the same tissues were fixed for six
months. Biological materials came from four cases of death due to
phenobarbital and two due to butalbital. Results showed the
presence of barbiturates in all studied materials. Mean recovery
rates of phenobarbital in fixed liver were 57.11% and 30.84% in
formalin from liver; and those of butalbital in fixed liver were
21.66% and 66.56% in formalin from liver. Total sums of recovery
rates in formalin solutions and fixed tissues for phenobarbital
(87.95%) and butalbital (88.22%) were comparable with those of
the extraction efficiency of the method (90.2%) and indicate that
these barbiturates have good stability even in biological specimens
subjected to chemical fixation. This fact may be useful in qualitative evaluation of cases
Hyperthermia enhances CD95-ligand gene expression in T lymphocytes
No full textHyperthermia represents an interesting therapeutic strategy for the treatment of tumors. Moreover, it is able to regulate several aspects of the immune response. Fas (APO-1/CD95) and its ligand (FasL) are cell surface proteins whose interaction activates apoptosis of Fas-expressing targets. In T cells, the Fas-Fas-L system regulates activation-induced cell death, is implicated in diseases in which lymphocyte homeostasis is compromised, and plays an important role during cytotoxic and regulatory actions mediated by these cells. In this study we describe the effect of hyperthermia on activation of the fas-L gene in T lymphocytes. We show that hyperthermic treatment enhances Fas-L-mediated cytotoxicity, fas-L mRNA expression, and fas-L promoter activity in activated T cell lines. Our data indicate that hyperthermia enhances the transcriptional activity of AP-1 and NF-κB in activated T cells, and this correlates with an increased expression/nuclear translocation of these transcription factors. Moreover, we found that heat shock factor-1 is a transactivator of fas-L promoter in activated T cells, and the overexpression of a dominant negative form of heat shock factor-1 may attenuate the effect of hyperthermia on fas-L promoter activity. Furthermore, overexpression of dominant negative mutants of protein kinase Cε (PKCε) and PKCθ partially inhibited the promoter activation and, more importantly, could significantly reduce the enhancement mediated by hyperthermia, indicating that modulation of PKC activity may play an important role in this regulation. These results add novel information on the immunomodulatory action of heat, in particular in the context of its possible use as an adjuvant therapeutic strategy to consider for the treatment of cancer
A case report of positive carbohydrate-deficient transferrin result together with negative ethylglucuronide result in hair.
No full textPost-mortem BAC: confronto tra sangue centrale e sangue periferico.
No full textL’azione depressiva che l’etanolo ha sul Sistema Nervoso Centrale fa sì che la concentrazione di alcool nel sangue (BAC) sia strettamente correlata all'incapacità di guida, e l’assunzione di dosi elevate può causare anche intossicazioni acute fatali. Il sangue è un tessuto eccezionalmente importante nell’ambito della tossicologia forense. La determinazione della BAC viene condotta in Gas Cromatografia con rilevatore di fiamma (GC-FID) mediante la tecnica dello spazio di testa. Quando possibile, sangue post-mortem proveniente da due distretti, cardiaco e periferico, dovrebbe essere prelevato ad ogni autopsia. A causa dell’alta probabilità di contaminazione, il sangue proveniente dalla cavità toracica e addominale dovrebbe essere evitato a meno che non ci sia altra matrice ematica a disposizione. Nelle analisi post-mortem per la determinazione e la quantificazione di sostanze esogene il sangue cardiaco è tendenzialmente più soggetto a redistribuzione rispetto al sangue periferico. La redistribuzione post-mortale (PMR) è un fenomeno per il quale la concentrazione di sostanze esogene subisce delle alterazioni nell’organismo dopo la morte. Il meccanismo alla base è complesso e ancora poco chiaro, inoltre il grado di PMR può variare a seconda dei distretti e dei tessuti coinvolti. Le analisi condotte su sangue periferico (es. femorale) mostrano una maggior affidabilità in termini di risultati rispetto al sangue cardiaco. Il sangue prelevato dal cuore o dalla cavità toracica potrebbe contenere concentrazioni più alte di esogeni rispetto ai vasi periferici. Una possibile spiegazione potrebbe essere il fenomeno della diffusione delle sostanze da altri organi limitrofi
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