Marco Ruggiero

University of Florence, Florens, Tuscany, Italy

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Publications (140)401.64 Total impact

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    James J. Bradstreet · Marco Ruggiero · Stefania Pacini

    Preview · Article · Dec 2015 · Frontiers in Neuroscience
  • Jacopo J. V. Branca · Stefania Pacini · Marco Ruggiero
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    ABSTRACT: Background: A woman, mother of one at the age of 19 years, was diagnosed with mammary adenocarcinoma in the right breast in 1985 at the age of 37 years. The patient underwent surgery (quadrantectomy), lymphadenectomy and radiotherapy. In 1999, an adenocarcinoma was diagnosed in the left breast, followed by adequate resection, radiotherapy and anti-oestrogen receptor treatment for 6 years. In March 2014, an infiltrating adenocarcinoma was diagnosed in the remaining part of the right breast that had been operated on and irradiated in 1985. Case Report: The pre-surgical biopsy, showed weak positivity for progesterone receptor (PgR) (<1%), high positivity for oestrogen receptor (ER) (90%), high positivity for human epidermal growth factor receptor (HER2) (>10%, score 2+), and high positivity for the nuclear protein Ki67 (30%). In the three weeks between diagnosis and operation, when no other treatment had been planned, the patient decided to self-administer high doses of oral vitamin D3 (10,000 IU/day), and to follow a strict ketogenic diet. Results: Following right mastectomy, analysis of the surgical specimen showed no positivity for HER2 expression (negative, score 0), and significant increase in positivity of PgR (20%). Positivity for ER and Ki67 were unaltered. Conclusion: This observation indicates that a combination of high-dose vitamin D3 and ketogenic diet leads to changes in some biological markers of breast cancer, i.e. negativization of HER2 expression and increased expression of PgR.
    No preview · Article · Oct 2015 · Anticancer research
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    ABSTRACT: Ultrasounds, besides their well-established medical imaging role, influence the homeostasis of complex anatomical systems including the physiology of neurons and glia and the permeability of the blood brain barrier. In this study, neurons and microglial cells were treated with ultrasounds (commonly used in diagnostics) and differences in cell proliferation and morphology were evaluated in comparison to control, untreated cells. Cell proliferation was evaluated by standard viability assessment, while the quantitative analysis of cell morphology, usually performed by edge and line detection algorithms, required the development of a new special algorithm. In fact, traditional software methodologies do not provide the appropriate tools for morphological analysis of neurons and microglial cells, typically characterized by a roughly triangular body and numerous elongations of different lengths resulting in a complex neuron–microglia network. This new method, based on a modified Hough Transform algorithm using a matching operator instead of the common gradient filter, enabled the automatic identification of cell elongations and branches, the extraction of related information, and the comparison of the data between control and treated neurons, as well as microglial cells.
    No preview · Article · Sep 2015 · Biomedical Signal Processing and Control
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    ABSTRACT: The biological properties and characteristics of microglia in rodents have been widely described, but little is known about these features in human microglia. Several murine microglial cell lines are used to investigate neurodegenerative and neuroinflammatory conditions; however, the extrapolation of the results to human conditions is frequently met with criticism because of the possibility of species-specific differences. This study compares the effects of oxaliplatin and of oleic acid Gc-protein-derived macrophage-activating factor (OA-GcMAF) on two microglial cell lines, murine BV-2 cells and human C13NJ cells. Cell viability, cAMP levels, microglial activation, and vascular endothelial growth factor (VEGF) expression were evaluated. Our data demonstrate that oxaliplatin induced a significant decrease in cell viability in BV-2 and in C13NJ cells and that this effect was not reversed with OA-GcMAF treatment. The signal transduction pathway involving cAMP/VEGF was activated after treatment with oxaliplatin and/or OA-GcMAF in both cell lines. OA-GcMAF induced a significant increase in microglia activation, as evidenced by the expression of the B7-2 protein, in BV-2 as well as in C13NJ cells that was not associated with a concomitant increase in cell number. Furthermore, the effects of oxaliplatin and OA-GcMAF on coculture morphology and apoptosis were evaluated. Oxaliplatin-induced cell damage and apoptosis were nearly completely reversed by OA-GcMAF treatment in both BV-2/SH-SY5Y and C13NJ/SH-SY5Y cocultures. Our data show that murine and human microglia share common signal transduction pathways and activation mechanisms, suggesting that the murine BV-2 cell line may represent an excellent model for studying human microglia. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    No preview · Article · Mar 2015 · Journal of Neuroscience Research
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    ABSTRACT: Background. Overall, the comparative data available on the timing of metopic suture closure in present-day and fossil members of human lineage, as well as great apes, seem to indicate that human brain evolution occurred within a complex network of fetopelvic constraints, which required modification of frontal neurocranial ossification patterns, involving delayed fusion of the metopic suture. It is very interesting that the recent sequencing of the Neanderthal genome has revealed signs of positive selection in the modern human variant of the RUNX2 gene, which is known to affect metopic suture fusion in addition to being essential for osteoblast development and proper bone formation. It is possible that an evolutionary change in RUNX2, affecting aspects of the morphology of the upper body and cranium, was of importance in the origin of modern humans. Thus, to contribute to a better understanding of the molecular evolution of this gene probably implicated in human evolution, we performed a comparative bioinformatic analysis of the coding sequences of RUNX2 in Homo sapiens and other non-human Primates. Results. We found amino-acid sequence differences between RUNX2 protein isoforms of Homo sapiens and the other Primates examined, that might have important implications for the timing of metopic suture closure. Conclusions. Further studies are needed to clear the potential distinct developmental roles of different species-specific RUNX2 N-terminal isoforms. Meantime, our bioinformatic analysis, regarding expression of the RUNX2 gene in Homo sapiens and other non-human Primates, has provided a contribution to this important issue of human evolution.
    No preview · Article · Jan 2015
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    ABSTRACT: Oxaliplatin-based regimens are effective in metastasized advanced cancers. However, a major limitation to their widespread use is represented by neurotoxicity that leads to peripheral neuropathy. In this study we evaluated the roles of a proven immunotherapeutic agent [Gc-protein-derived macrophage activating factor (GcMAF)] in preventing or decreasing oxaliplatin-induced neuronal damage and in modulating microglia activation following oxaliplatin-induced damage. The effects of oxaliplatin and of a commercially available formula of GcMAF [oleic acid-GcMAF (OA-GcMAF)] were studied in human neurons (SH-SY5Y cells) and in human microglial cells (C13NJ). Cell density, morphology and viability, as well as production of cAMP and expression of vascular endothelial growth factor (VEGF), markers of neuron regeneration [neuromodulin or growth associated protein-43 (Gap-43)] and markers of microglia activation [ionized calcium binding adaptor molecule 1 (Iba1) and B7-2], were determined. OA-GcMAF reverted the damage inflicted by oxaliplatin on human neurons and preserved their viability. The neuroprotective effect was accompanied by increased intracellular cAMP production, as well as by increased expression of VEGF and neuromodulin. OA-GcMAF did not revert the effects of oxaliplatin on microglial cell viability. However, it increased microglial activation following oxaliplatin-induced damage, resulting in an increased expression of the markers Iba1 and B7-2 without any concomitant increase in cell number. When neurons and microglial cells were co-cultured, the presence of OA-GcMAF significantly counteracted the toxic effects of oxaliplatin. Our results demonstrate that OA-GcMAF, already used in the immunotherapy of advanced cancers, may significantly contribute to neutralizing the neurotoxicity induced by oxaliplatin, at the same time possibly concurring to an integrated anticancer effect. The association between these two powerful anticancer molecules would probably produce the dual effect of reduction of oxaliplatin-induced neurotoxicity, together with possible synergism in the overall anticancer effect.
    Full-text · Article · Oct 2014 · Anti-Cancer Drugs
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    ABSTRACT: Aim: Aim of the present study was to prevent overtraining and to ensure that the athletic training program will result in performance improvements, regular performance tests as well as heart rate evaluation and questionnaires are necessary. However, none of them are routinely performed on regular basis mainly for their interference with the session training, thus leading to the risk of an over-reaching which in turn may result in an overtraining. In this study we evaluate the possibility to monitor the development of the training program of high level rugby players by a simple, non-invasive and fast salivary testosterone and cortisol measure. Methods: Testosterone and cortisol samplings were performed in several moments of the preseason training program. Measures were correlated with anthropometric evaluations performed by bioelectrical impedance analysis before and after the training program. To assess a potential role of genetic, athletes were also genotyped for ACTN3 and ACE gene polymorphisms. Results: Data from this study show that hormone salivary measures correlate with changes in anthropometric values during the training program. No correlations were observed between genotypes and variations in hormone levels; however, ACE genotype correlates with the differerìt team position of rugby players. Conclusion: Hormone salivary measures represent a valid, fast, non-invasive and stress-free system of monitoring the athletic preparation.
    No preview · Article · Sep 2014 · Medicina dello sport; rivista di fisiopatologia dello sport
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    ABSTRACT: Background: Oleic Acid (OA) has been shown to have anticancer properties mediated by interaction with proteins such as α-lactalbumin and lactoferrins. Therefore, we synthesized complexes of OA and Gc protein-derived macrophage activating factor (GcMAF) that inhibits per se cancer cell proliferation and metastatic potential. We hypothesised that OA-GcMAF complexes could exploit the anticancer properties of both OA and GcMAF in a synergistic manner. We postulated that the stimulating effects of GcMAF on macrophages might lead to release of nitric oxide (NO). Patients and methods: Patients with advanced cancer were treated at the Immuno Biotech Treatment Centre with OA-GcMAF-based integrative immunotherapy in combination with a low-carbohydrate, high-protein diet, fermented milk products containing naturally-produced GcMAF, Vitamin D3, omega-3 fatty acids and low-dose acetylsalicylic acid. Results: Measuring the tumour by ultrasonographic techniques, we observed a decrease of tumour volume of about 25%. Conclusion: These observations demonstrate that OA, GcMAF and NO can be properly combined and specifically delivered to advanced cancer patients with significant effects on immune system stimulation and tumour volume reduction avoiding harmful side-effects.
    No preview · Article · Jul 2014 · Anticancer research
  • M. Ruggiero · S. Pacini · J. J. Bradstreet
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    ABSTRACT: Background: We and others demonstrated that non-thermal ultrasounds (US) used for diagnostic imaging in transcranial ultrasonography (TUS), improve mental states, reduce chronic pain and anxiety, modulate neurotransmission, and have positive effects on heart frequency, blood pressure and muscle strength (Brain Stimul. 2013 May;6(3):409-15. Neuropsychobiology. 2012;65(3):153-60. The Journal of IiME, vol. 6 (1), p 23-28, 2012). Therefore, it can be hypothesized that TUS might be useful in the treatment of some of the most disturbing symptoms of autism. However, the precise mechanism of action of US on neurons and microglia cells has not been elucidated as yet. Objectives: We decided to treat human neurons and microglia cells in culture with US identical to those used in TUS, and to evaluate whether the changes observed in vitro were consistent with the observations reported in vivo. Methods: Human neuronal cells SH-SY5Y, and microglia cells were obtained from the Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia-Romagna, Brescia, Italy. Cells were routinely maintained at 37°C in a humidified atmosphere of 5% CO2 in Eagle’s minimum essential medium in Earle’s Balanced salt solution (45%), Ham’s F12 medium (45%), foetal bovine serum (FBS) 10%. Cells were treated with US using an Esaote MyLabFive system. A linear probe for TUS was applied onto the Petri dishes for 1 min after having assessed that US were able to cross the plastic well and penetrate the cell monolayer. Immediately thereafter, living cells were observed by phase contrast microscopy without any type of fixation or staining. Results: After 1 min US treatment, a significant change in neuronal cell morphology and cell-to-cell connectivity could be observed. US-treated neurons showed a more elongated shape; numerous cytoplasmic bridges between cells could be observed. The increase in neuronal connectivity could be clearly appreciated in those naked areas of the well where thin cytoplasmic elongations connected distant cells. The number of such connections was greatly increased in US-treated neurons. Untreated microglia cells in culture were constantly activated by the presence of serum, and showed the typical round shape that is observed in pathologic, pro-inflammatory microglia activation. After 1 min US treatment, however, microglia cells reverted to the so called ramified state that indicates quiescence and is associated with the lack of production of neurotoxic factors and pro-inflammatory signaling molecules. Conclusions: Although TUS is not yet part of autism therapeutic protocols, its effectiveness in areas such as neurological/psychiatric intervention, long-term alertness/wakefulness, behavioural reinforcement, anxiety/stress reduction, cognitive enhancement and pain intervention, suggests that it might be useful in autism treatment as well. Since decreased neuronal connectivity and microglia activation are common neuro-pathological findings in autism (PLoS One. 2013 Jun 18;8(6):e67329), our results demonstrate that the observed effects of TUS can be ascribed to restoration of neuronal connectivity and inhibition of pro-inflammatory microglia activation.
    No preview · Conference Paper · May 2014
  • J. J. Bradstreet · M. Ruggiero · S. Pacini
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    ABSTRACT: Background: Autism spectrum disorders (ASDs) are developmental conditions of uncertain etiology which have now affected more than 1% of the school-age population of children in many developed nations. Cortical abnormalities observed from autopsy specimens, including inflammation and structural aberrations, have been inconsistently reported. Recently, serial brain magnetic resonance imaging studies from near birth to 2 years of age were noted to be highly predictive of autism when increased frontal extra-axial fluid remained persistent. Transcranial ultrasonography (TUS) via the temporal bone acoustical window appeared to be a potential method of investigation to determine the presence of both cortical abnormalities and increased extra-axial fluid (EAF). Objectives: To evaluate the brain of children with autism and their siblings using 2D TUS. Methods: TUS was accomplished using a linear probe typically used for musculoskeletal investigations (10-5 MHz). Multiple images were recorded and real-time measurement of the cortex and extra-axial spaces were accomplished. Specifically, anatomical areas of significance to autism (primary language and auditory cortical locations) are readily imaged with this novel ultrasonographic technique. With this initial cohort, parents volunteered 18 ASD subjects (males =17) for evaluations (all ages < 16, mean = 7.81 years + 2.4 years), and 12 neurotypical siblings were also examined (all ages < 21, mean = 8.89 years + 3.82 years). Childhood Autism Rating Scale, Second Edition, (CARS2®) scores were obtained as a routine in the practice and the ASD score mean was 48.65 + 7.32 (Severe). Results: Comparisons of the extra-axial spaces indicated increases in the ASD subjects. For EAF we scored based on the gyral summit distances between the arachnoid membrane and the cortical pia layer (subarachnoid space): 1) <0.05 cm, 2) 0.05 – 0.07 cm, 3) 0.07 – 0.10 cm, 4) > 0.10 cm. All of the neurotypical siblings scored 1, whereas the ASD mean score was 3.31 + 0.7. We also defined cortical dysplasia as the following: hypoechoic lesions within the substance of the cortex, or disturbed layering within the grey matter. For cortical dysplasia we scored: 1) none observed, 2) rare hypoechogenic lesions and/or mildly atypical cortical layering patterns, 3) more common, but separated areas of cortical hypoechogenic lesions, or more commonly abnormal cortical layering, 4) very common or confluent areas of cortical hypoechogenicity and/or markedly disturbed layering of the cortex. Again all of the neurotypical siblings scored 1, while the ASD subjects’ mean score was 3.0 + 0.92. Conclusions: These initial TUS observations are consistent with and extend the age range of previous MRI observations of increased EAF in ASDs. The new real-time observations of hypoechogenic lesions in the cortical grey matter suggest focal cortical disruption in areas critical to both language and auditory processing (core features of autism). TUS may be a useful screening technique for ASDs which, if confirmed with repeated studies and high resolution MRI, provides rapid, noninvasive qualification of EAF and cortical lesions.
    No preview · Conference Paper · May 2014
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    ABSTRACT: Background: Autism spectrum disorders (ASDs) are developmental conditions of uncertain etiology which have now affected more than 1% of the school-age population of children in many developed nations. Transcranial ultrasonography (TUS) via the temporal bone appeared to be a potential window of investigation to determine the presence of both cortical abnormalities and increased extra-axial fluid (EAF). Methods: TUS was accomplished using a linear probe (10–5 MHz). Parents volunteered ASD subjects (N = 23; males 18, females 5) for evaluations (mean = 7.46 years ± 3.97 years), and 15 neurotypical siblings were also examined (mean = 7.15 years ± 4.49 years). Childhood Autism Rating Scale (CARS2®) scores were obtained and the ASD score mean was 48.08 + 6.79 (Severe). Results: Comparisons of the extra-axial spaces indicated increases in the ASD subjects. For EAF we scored based on the gyral summit distances between the arachnoid membrane and the cortical pia layer (subarachnoid space): (1) <0.05 cm, (2) 0.05–0.07 cm, (3) 0.08–0.10 cm, (4) >0.10 cm. All of the neurotypical siblings scored 1, whereas the ASD mean score was 3.41 ± 0.67. We also defined cortical dysplasia as the following: hypoechoic lesions within the substance of the cortex, or disturbed layering within the gray matter. For cortical dysplasia we scored: (1) none observed, (2) rare hypoechogenic lesions and/or mildly atypical cortical layering patterns, (3) more common, but separated areas of cortical hypoechogenic lesions, (4) very common or confluent areas of cortical hypoechogenicity. Again all of the neurotypical siblings scored 1, while the ASD subjects’ mean score was 2.79 ± 0.93. Conclusion: TUS may be a useful screening technique for children at potential risk of ASDs which, if confirmed with repeated studies and high resolution MRI, provides rapid, non-invasive qualification of EAF, and cortical lesions.
    Preview · Article · Jan 2014 · Frontiers in Human Neuroscience
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    ABSTRACT: The role of vitamin D in maintaining health appears greater than originally thought, and the concept of the vitamin D axis underlines the complexity of the biological events controlled by biologically active vitamin D (1,25(OH)(2)D3), its two binding proteins that are the vitamin D receptor (VDR) and the vitamin D-binding protein-derived macrophage activating factor (GcMAF). In this study we demonstrate that GcMAF stimulates macrophages, which in turn attack human breast cancer cells, induce their apoptosis and eventually phagocytize them. These results are consistent with the observation that macrophages infiltrated implanted tumors in mice after GcMAF injections. In addition, we hypothesize that the last 23 hydrophobic amino acids of VDR, located at the inner part of the plasma membrane, interact with the first 23 hydrophobic amino acids of the GcMAF located at the external part of the plasma membrane. This al1ows 1,25(OH)(2)D3 and oleic acid to become sandwiched between the two vitamin D-binding proteins, thus postulating a novel molecular mode of interaction between GcMAF and VDR. Taken together, these results support and reinforce the hypothesis that GcMAF has multiple biological activities that could be responsible for its anti-cancer effects, possibly through molecular interaction with the VDR that in turn is responsible for a multitude of non-genomic as well as genomic effects.
    Full-text · Article · Jul 2013 · Nutrients
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    ABSTRACT: Cardiovascular diseases are more prevalent in patients with chronic kidney disease than in the general population and they are considered the leading cause of death in patients with end-stage renal disease. The discovery that vitamin D3 plays a considerable role in cardiovascular protection has led, in recent years, to an increase in the administration of therapies based on the use of this molecule; nevertheless, several studies warned that an excess of vitamin D3 may increase the risk of hypercalcemia and vascular calcifications. In this study we evaluated the effects of vitamin D3, and of its selective analog paricalcitol, on immature cardiomyocytes. Results show that vitamin D3 induces cAMP-mediated cell proliferation and significant intracellular calcification. Paricalcitol, however, induces cell differentiation, morphological modifications in cell shape and size, and no intracellular calcification. Furthermore, vitamin D3 and paricalcitol differently affect cardiomyoblasts responses to acetylcholine treatment. In conclusion, our results demonstrate that the effects of vitamin D3 and paricalcitol on cardiomyoblasts are different and, if these in vitro observations could be extrapolated in vivo, they suggest that paricalcitol has the potential for cardiovascular protection without the risk of inducing intracellular calcification.
    Full-text · Article · Jun 2013 · Nutrients
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    ABSTRACT: We developed a modified transcranial sonography technique to study the morphology of the temporal lobe, a brain region involved in language, memory and social functions in humans that can be visualized in correspondence of the acoustic window of the temporal squama. Previous studies raise the possibility that a unique derived feature of Homo sapiens is a relatively larger temporal lobe compared to those of other hominins and apes. Such a brain reorganization might have contributed to the evolution of various "higher" cognitive functions of Homo sapiens, including language. Hence, the importance of further comparative analyses of the temporal region. With the technique that we developed we were able to study the meninges, the subarachnoidal space and the cortex of the human temporal lobe. The spatial resolution and the ability to visualize structures of 200-300 microm size led us to hypothesize that the linear structures parallel to the subarachnoidal space might be referred to the neuronal layers of the cortex. The low cost, simplicity and safety of the procedure suggest that this technique may have a significant potential in the comparative study of the primate temporal lobe. Furthermore, the procedure described here can also be used for the study of vascularization of the meninges, in order to better understand the evolutionary relationships between the neurocranial shape and the middle meningeal vessels in living and fossil human species.
    No preview · Article · Jan 2013 · Italian journal of anatomy and embryology = Archivio italiano di anatomia ed embriologia
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    ABSTRACT: According to the World Health Organization, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a neurological disease characterized by widespread inflammation and multi-systemic neuropathology. Aetiology and pathogenesis are unknown, and several agents have been proposed as causative agents or as factors perpetuating the syndrome. Exposure to heavy metals, with particular reference to mercury and gold in dental amalgams, has been considered among the triggers of ME/CFS. Here we hypothesize that cadmium, a widespread occupational and environmental heavy metal pollutant, might be associated with some of the neurological findings described in ME/CFS. In fact, ME/CFS patients show a decrease of the volume of the gray matter in turn associated with objective reduction of physical activity. Cadmium induces neuronal death in cortical neurons through a combined mechanism of apoptosis and necrosis and it could then be hypothesized that cadmium-induced neuronal cell death is responsible for some of the effects of cadmium on the central nervous system, i.e. a decrease in attention level and memory in exposed humans as well as to a diminished ability for training and learning in rats, that are symptoms typical of ME/CFS. This hypothesis can be tested by measuring cadmium exposure in a cohort of ME/CFS patients compared with matched healthy controls, and by measuring gray matter volume in un-exposed healthy controls, exposed non-ME/CFS subjects, un-exposed ME/CFS patients and exposed ME/CFS patients. In addition, we hypothesize that cadmium exposure could be associated with reduced cerebral blood flow in ME/CFS patients because of the disruptive effects of cadmium on angiogenesis. In fact, cadmium inhibits angiogenesis and low global cerebral flow is associated with abnormal brain neuroimaging results and brain dysfunction in the form of reduced cognitive testing scores in ME/CFS patients. This hypothesis can be tested by measuring cerebral cortex blood flow in un-exposed healthy controls, exposed non-ME/CFS subjects, un-exposed ME/CFS patients and exposed ME/CFS patients. If our hypothesis is demonstrated correct, the consequences could affect prevention, early diagnosis, and treatment of ME/CFS. Implications in early diagnosis could entail the evaluation of symptoms typical of ME/CFS in cadmium-exposed subjects as well as the search for signs of exposure to cadmium in subjects diagnosed with ME/CFS. Nutritional supplementation of magnesium and zinc could then be considered, since these elements have been proposed in the prophylaxis and therapy of cadmium exposure, and magnesium was demonstrated effective on ME/CFS patients' symptom profiles.
    No preview · Article · Jul 2012 · Medical Hypotheses
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    ABSTRACT: In patients with advanced cancer, cachexia correlates with low performance status and poor quality of life. In addition, cachexia may be associated with reduced response to chemoradiotherapy and a poor prognosis in cancer patients. Nearly all forms of cachexia are closely associated with chronic inflammation and elevated levels of inflammatory and pro-inflammatory circulating factors, including C-reactive protein (CRP), which is considered a valid laboratory and clinical marker. Among the different pathways involved in the production of inflammatory cytokines and chemokines, the vitamin D-vitamin D receptor (VDR) axis plays a fundamental role. In this study, we explore the possible association between CRP and key factors pertaining to the vitamin D axis--in particular, VDR gene polymorphisms--in cancer patients with cachexia. Although certain tumor types are more commonly associated with cachexia, even within the same tumor type there are significant differences in the extent and duration of cachexia. Such variations may be due to polymorphisms of the VDR gene that could lead to cachexia-prone genotypes or to cachexia-resistant genotypes. Identification of such genotypes could be very helpful in the management of cancer patients. Forty-three cancer patients were recruited by the Nutritional Unit of the Prato Hospital. Data on age, gender, type of cancer, stage of cancer, and nutritional assessment, as well as transferrin, ferritin, albumin, and CRP levels, were collected. Genomic DNA was extracted from peripheral blood leukocytes and amplified by polymerase chain reaction. BsmI, ApaI, TaqI, and FokI polymorphisms of the VDR gene were investigated using the respective restriction enzymes. For the different VDR polymorphisms, the absence or presence of the restriction sites were designated with capital or small letters, respectively. For example, for the BsmI polymorphism, the presence of the undigested fragment identified the B allele, whereas the presence of the digested fragment identified the b allele. Cancer patients with cachexia have higher CRP levels compared with non-cachectic cancer patients, independently from the genotype. In cachectic patients, the presence of specific VDR BsmI and TaqI alleles was associated with higher CRP levels. In particular, the VDR b and T alleles were more frequent in cachectic cancer patients with elevated CRP levels than in cachectic patients with normal CRP levels. From these results, we hypothesize that there is an association between BsmI and TaqI VDR gene polymorphisms and the cachectic syndrome. In particular, we propose that in cancer patients, the concomitance of b and T alleles with elevated CRP levels may represent an early clinical predictor for the development of a more aggressive form of cachexia.
    No preview · Article · Apr 2012 · Molecular Diagnosis & Therapy
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    ABSTRACT: The ubiquitin-proteasome pathway is a crucial connection between aberrant immune system activation, systemic inflammation and Cancer Anorexia-Cachexia Syndrome (CACS), a syndrome that culminates in hyper-activation of the ubiquitin-proteasome pathway. Angiotensin directly up-regulates this pathway, while vitamin D down-regulates it indirectly through the insulin-like growth factor-1 pathway. We investigated the genetic predisposition towards CACS in a cancer population, examining Insertion/Deletion (I/D) polymorphism of angiotensin-converting enzyme gene and FokI and BsmI polymorphisms of vitamin D receptor gene. Sixty-two cancer patients were recruited and divided into three groups: primary cachectic (C1, n = 14; dysmetabolic body weight loss ≥5% in 6 months); secondary cachectic (C2, n = 34; similar weight loss, mechanic or iatrogenic origin); and non-cachectic (NC, n = 16). C2+NC were merged in the control group. The three groups showed significant differences in average prognostic inflammatory nutritional index (C1: 26.4±23.4; C2: 5.4±5.6; NC: 0.37±0.5), C-reactive protein serum levels (C1: 6.6±2.1; C2: 2.4±2.2; NC: 1.0±2.0 mg/dl), albumin serum levels (C1: 3.1±0.6; C2: 3.5±0.4; NC 3.7±0.6 g/dl), weight loss (C1: 22±8; C2: 15±6.7; NC 5±6%) and life expectancy (C1: 6.4±3.3; C2: 25±28; NC: 45±25 months). However, none of the chosen polymorphisms showed any statistically significant correlation with CACS. The complexity of the changes of the immune system in the chronic inflammation state associated with CACS is far greater than expected and further studies are required to identify genetic independent markers of progression toward CACS.
    No preview · Article · Jan 2012
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    ABSTRACT: Searching for additional therapeutic tools to fight breast cancer, we investigated the effects of vitamin D-binding protein-derived macrophage activating factor (DBP-MAF, also known as GcMAF) on a human breast cancer cell line (MCF-7). The effects of DBP-MAF on proliferation, morphology, vimentin expression and angiogenesis were studied by cell proliferation assay, phase-contrast microscopy, immunohistochemistry and western blotting, and chorioallantoic membrane (CAM) assay. DBP-MAF inhibited human breast cancer cell proliferation and cancer cell-stimulated angiogenesis. MCF-7 cells treated with DBP-MAF predominantly grew in monolayer and appeared to be well adherent to each other and to the well surface. Exposure to DBP-MAF significantly reduced vimentin expression, indicating a reversal of the epithelial/mesenchymal transition, a hallmark of human breast cancer progression. These results are consistent with the hypothesis that the known anticancer efficacy of DBP-MAF can be ascribed to different biological properties of the molecule that include inhibition of tumour-induced angiogenesis and direct inhibition of cancer cell proliferation, migration and metastatic potential.
    No preview · Article · Jan 2012 · Anticancer research
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    ABSTRACT: Mechanical stresses induce variations in tissue tensegrity leading to cell proliferation and differentiation thus contributing to tissue remodelling. Besides mechanical forces, skin remodelling may be induced by the application of plasma, a new type of energy delivery resulting in controlled heat damage. Here we demonstrate that mechanical stress induced by the application of vacuum increases the efficacy of plasma in skin regeneration treatment. Vacuum alone and vacuum plus plasma at different energies were applied to rat skin and biopsies collected at different time intervals after treatments. Skin integrity, collagen arrangement, inflammation and myofibroblast differentiation were assessed by Masson's trichrome staining. Procollagen synthesis was evaluated by immunohistochemistry. Vacuum alone induced significant and temporary alterations in the distribution of collagen bundles, with concomitant procollagen synthesis in the dermis; no myofibroblasts and no signs of inflammation were observed. Vacuum plus plasma determined an important spatial modification of collagen bundles, more intense than vacuum or plasma alone. Significant increase of procollagen synthesis, numerous myofibroblasts but slight sign of inflammation appeared after the treatment. Vacuum mechanically stimulated fibroblasts, producing changes in collagen arrangement and procollagen synthesis. Plasma led to the same effects through thermal damage. Application of a combined treatment consisting in vacuum plus plasma induced more remarkable effects on skin regeneration with relatively low plasma energies and no relevant side effects.
    No preview · Article · Oct 2011 · Skin Research and Technology
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    ABSTRACT: In addition to its role in calcium homeostasis and bone mineralization, vitamin D is involved in immune defence, cardiovascular function, inflammation and angiogenesis, and these pleiotropic effects are of interested in the treatment of chronic kidney disease. Here we investigated the effects of paricalcitol, a nonhypercalcemic vitamin D analogue, on human peripheral blood mononuclear cell proliferation and signaling, and on angiogenesis. These effects were compared with those of a known inhibitor of angiogenesis pertaining to the vitamin D axis, the vitamin D-binding protein-derived Gc-macrophage activating factor (GcMAF). Since the effects of vitamin D receptor agonists are associated with polymorphisms of the gene coding for the receptor, we measured the effects of both compounds on mononuclear cells harvested from subjects harboring different BsmI polymorphisms. Paricalcitol inhibited mononuclear cell viability with the bb genotype showing the highest effect. GcMAF, on the contrary, stimulated cell proliferation, with the bb genotype showing the highest stimulatory effect. Both compounds stimulated 3'-5'-cyclic adenosine monophosphate formation in mononuclear cells with the highest effect on the bb genotype. Paricalcitol and GcMAF inhibited the angiogenesis induced by proinflammatory prostaglandin E1. Polymorphisms of the vitamin D receptor gene, known to be associated with the highest responses to vitamin D receptor agonists, are also associated with the highest responses to GcMAF. These results highlight the role of the vitamin D axis in chronic kidney disease, an axis which includes vitamin D, its receptor and vitamin D-binding protein-derived GcMAF.
    No preview · Article · Sep 2011 · Journal of nephrology

Publication Stats

2k Citations
401.64 Total Impact Points

Institutions

  • 1985-2015
    • University of Florence
      • • Dipartimento di Scienze Biomediche, Sperimentali e Cliniche
      • • Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino
      Florens, Tuscany, Italy
  • 1991
    • National Institutes of Health
      • Laboratory of Cellular and Molecular Biology
      베서스다, Maryland, United States
  • 1988-1990
    • National Cancer Institute (USA)
      • Laboratory of Cellular and Molecular Biology
      베서스다, Maryland, United States