Maria Rachele Ceccarini

Why high cholesterol levels help hematological malignancies: role of nuclear lipid microdomains

BackgroundDiet and obesity are recognized in the scientific literature as important risk factors for cancer development and progression. Hypercholesterolemia facilitates lymphoma lymphoblastic cell growth and in time turns in hypocholesterolemia that is a sign of tumour progression. The present study examined how and where the cholesterol acts in cancer cells when you reproduce in vitro an in vivo hypercholesterolemia condition.MethodsWe used non-Hodgkin’s T cell human lymphoblastic lymphoma (SUP-T1 cell line) and we studied cell morphology, aggressiveness, gene expression for antioxidant proteins, polynucleotide kinase/phosphatase and actin, cholesterol and sphingomyelin content and finally sphingomyelinase activity in whole cells, nuclei and nuclear lipid microdomains.ResultsWe found that cholesterol changes cancer cell morphology with the appearance of protrusions together to the down expression of β-actin gene and reduction of β-actin protein. The lipid influences SUP-T1 cell aggressiveness since stimulates DNA and RNA synthesis for cell proliferation and increases raf1 and E-cadherin, molecules involved in invasion and migration of cancer cells. Cholesterol does not change GRX2 expression but it overexpresses SOD1, SOD2, CCS, PRDX1, GSR, GSS, CAT and PNKP. We suggest that cholesterol reaches the nucleus and increases the nuclear lipid microdomains known to act as platform for chromatin anchoring and gene expression.ConclusionThe results imply that, in hypercholesterolemia conditions, cholesterol reaches the nuclear lipid microdomains where activates gene expression coding for antioxidant proteins. We propose the cholesterolemia as useful parameter to monitor in patients with cancer.

Inhibitory effects of agmatine on monoamine oxidase (MAO) activity: Reconciling the discrepancies

Abstract Agmatine has been functionally characterized as an important hormone and co-neurotransmitter in mammals. Given its ability in binding Imidazoline sites, a regolatory site of monoaminoxydase, it has been suggested to be involved in many neurological aspects. However, its inhibitory effect on this enzyme still remains an unanswered question. This present study is aimed to asses whether different experimental conditions could affect the agmatine action on monoaminoxydase activity. We demonstrate that the monoaminoxydase inhibition by agmatine is obtained under alkaline conditions and a long time of incubation. No inhibitiory action was found for shorter times of reaction at elevated pH, or at neutral condition and long time of incubation. No inhibition was also detected by substituting the monoamineoxydase substrate tyramine with kynuramine, however, while in these conditions a remarkable inhibition was shown by two aminoxydase inhibitors tranylcypromine and idazoxan. Herein, we discuss a mechanism model and the functional consequences of agmatine action on monoaminoxydase.

Dietary effects of oregano (Origanum vulgaris L.) plant or sweet chestnut (Castanea sativa Mill.) wood extracts on microbiological, chemical-physical characteristics and lipid oxidation of cooked ham during storage

The aim of this study was to evaluate the dietary effect of feeding pigs with diets enriched with sweet chestnut wood (Castanea sativa Mill.) or oregano (Origanum vulgaris L.) extract on the microbiological and chemical characteristics of cooked pork ham. Three groups of 10 pigs were fed with a control diet (CTRL), with the CTRL diet enriched with 0.2% of oregano extract (OR) and with the CTRL diet enriched with 0.2% of sweet chestnut wood extract (SCW), respectively. Six cooked hams per group were produced, sliced and packaged under a modified atmosphere (N2:CO2=80:20) and stored at refrigeration temperature (4±1°C). Three packages per cooked ham were sampled for analyses at three different storage times (0, 10 and 20 days). At day 0 time, antioxidant capacity of the products (ORACFL assay) and chemical composition were performed. At each sampling time, from all the samples the following analyses were performed: total microbial count (TMC), lactic acid bacteria count (LAB), Enterobacteriaceae count, Listeria monocytogenes, pH value, colour coordinates (L*, a*, b*), total basic volatile nitrogen (TBVN) and thiobarbituric reactive substances (TBARs) determinations. No differences in TMC, LAB and Enterobacteriaceae count, pH, TBVN, chemical composition and L* values were registered between the three groups at all the sampling times considered. No Listeria monocytogenes was detected in the samples tested. Significant differences were registered for ORACFL at 0 days, a* and b* values and TBARs value at 10 and 20 days of storage, with higher values for ORACFL, a* and b* values and lower values for TBARs in SCW and OR than CTRL. No antimicrobial effect could be recorded for OR and SCW but a higher oxidative stability, also highlighted by the colour maintenance, was observed in both OR and SCW.

Alpha-Mannosidosis: Therapeutic Strategies

Alpha-mannosidosis (α-mannosidosis) is a rare lysosomal storage disorder with an autosomal recessive inheritance caused by mutations in the gene encoding for the lysosomal α-d-mannosidase. So far, 155 variants from 191 patients have been identified and in part characterized at the biochemical level. Similarly to other lysosomal storage diseases, there is no relationship between genotype and phenotype in alpha-mannosidosis. Enzyme replacement therapy is at the moment the most effective therapy for lysosomal storage disease, including alpha-mannosidosis. In this review, the genetic of alpha-mannosidosis has been described together with the results so far obtained by two different therapeutic strategies: bone marrow transplantation and enzyme replacement therapy. The primary indication to offer hematopoietic stem cell transplantation in patients affected by alpha-mannosidosis is preservation of neurocognitive function and prevention of early death. The results obtained from a Phase I–II study and a Phase III study provide evidence of the positive clinical effect of the recombinant enzyme on patients with alpha-mannosidosis.

Current highlights about the safety of inorganic nanomaterials in healthcare

In recent years inorganic materials are largely present in products intended to health care. Literature gives many examples of inorganic materials used in many health care products, mainly in pharmaceutical field. Silver, zinc oxide, titanium oxide, iron oxide, gold, mesoporous silica, hydrotalcite-like compound and nanoclays are the most common inorganic materials used in nanosized form for different applications in health field. Generally, these materials are employed to realize formulations for systemic use, often with the aim to perform a specific targeting to the pathological site. The nanometric dimensions are often preferred to obtain the cellular internalization when the target is localized in the intracellular space. Some materials are frequently used in topical formulations as rheological agents, adsorbents, mattifying agents, physical sunscreen (e.g. zinc oxide, titanium dioxide), and others. Recent studies highlighted that the use of nanosized inorganic materials can represents a risk for health. The very small dimension (nanometric) until few years ago represented a fundamental requirement however it is currently held as responsible for the inorganic material toxicity. This aspect is very important to be considered as actually numerous inorganic materials can be found in many products available on the market, often dedicated to infants and children. These materials are used without taking into account their dimensional properties with increased risk for the user/patient. This review deals with a deep analysis of current researches documenting the toxicity of nanometric inorganic materials especially those largely used in products available on the market.

Origin of α-mannosidase activity in CSF.

The α-mannosidase activity in human frontal gyrus, cerebrospinal fluid and plasma has been analyzed by DEAE-cellulose chromatography to investigate the origin of the α-mannosidase activity in cerebrospinal fluid (CSF). The profile of α-mannosidase isoenzymes obtained in CSF was similar to that in the frontal gyrus but different from that in human plasma. In particular the two characteristic peaks of lysosomal α-mannosidase, A and B, which have a pH-optimum of 4.5 and are found in human tissues, were present in both the frontal gyrus and CSF. In contrast the majority of α-mannosidase activity in human plasma was due to the so called intermediate form, which has a pH-optimum of 5.5. The results suggest that the intermediate form of α-mannosidase in plasma does not cross the blood-brain barrier and that the α-mannosidase activity present in the cerebrospinal fluid is of lysosomal type and of brain origin. Thus the α-mannosidase activity in cerebrospinal fluid might mirror the brain pathological changes linked to neurodegenerative disorders such as Parkinsons disease.

Lysosomal alpha-mannosidase and alpha-mannosidosis.

Lysosomal alpha-mannosidase with acidic pH optimum is ubiquitous in human tissues where is expressed in two major forms, A and B that are the product of a single gene located on chromosome 19. Mutations in the gene encoding for alpha-mannosidase cause alpha- mannosidosis, an autosomal recessive disease, resulting in the accumulation of unprocessed mannose containing oligosaccharide material. This rare disease has an estimated incidence of 1/500.0.00 live births and clinically is divided into three subgroups. Today the most promising therapy for this disease is the enzyme replacement therapy. To develop this strategy a mouse model for alpha-mannosidosis has been generated and a recombinant human alpha-mannosidase has been produced from Chinese-hamster ovary cells. Interestingly it has been shown that the recombinant enzyme, used in high dose, can cross the blood brain barrier. This recombinant enzyme has been tested in the first randomized study investigating the efficacy of enzyme replacement therapy in patients with alpha-mannosidosis. This review contains the scientific progresses on lysosomal alpha-mannosidase from the cloning to the beginning of the therapy.