66 research outputs found
Responses to sulfated steroids of female mouse vomeronasal sensory neurons
No full textThe rodent vomeronasal organ plays an important role in many social behaviors. Using the calcium imaging technique with the dye fluo-4 we measured intracellular calcium concentration changes induced by the application of sulfated steroids to neurons isolated from the vomeronasal organ of female mice. We found that a mix of 10 sulfated steroids from the androgen, estrogen, pregnanolone, and glucocorticoid families induced a calcium response in 71% of neurons. Moreover, 31% of the neurons responded to a mix composed of 3 glucocorticoid-derived compounds, and 28% responded to a mix composed of 3 pregnanolone-derived compounds. Immunohistochemistry showed that neurons responding to sulfated steroids expressed phosphodiesterase 4A, a marker specific for apical neurons expressing V1R receptors. None of the neuron that responded to 1 mix responded also to the other, indicating a specificity of the responses. Some neurons responded to more than 1 individual component of the glucocorticoid-derived mix tested at high concentration, suggesting that these neurons are broadly tuned, although they still displayed strong specificity, remaining unresponsive to high concentrations of the ineffective compounds. © The Authors 2012. Published by Oxford University Press. All rights reserved
Mevalonate Pathway Blockade, Mitochondrial Dysfunction and Autophagy: A Possible Link
No full textThe mevalonate pathway, crucial for cholesterol synthesis, plays a key role in multiple cellular processes. Deregulation of this pathway is also correlated with diminished protein prenylation, an important post-translational modification necessary to localize certain proteins, such as small GTPases, to membranes. Mevalonate pathway blockade has been linked to mitochondrial dysfunction: especially involving lower mitochondrial membrane potential and increased release of pro-apoptotic factors in cytosol. Furthermore a severe reduction of protein prenylation has also been associated with defective autophagy, possibly causing inflammasome activation and subsequent cell death. So, it is tempting to hypothesize a mechanism in which defective autophagy fails to remove damaged mitochondria, resulting in increased cell death. This mechanism could play a significant role in Mevalonate Kinase Deficiency, an autoinflammatory disease characterized by a defect in Mevalonate Kinase, a key enzyme of the mevalonate pathway. Patients carrying mutations in the MVK gene, encoding this enzyme, show increased inflammation and lower protein prenylation levels. This review aims at analysing the correlation between mevalonate pathway defects, mitochondrial dysfunction and defective autophagy, as well as inflammation, using Mevalonate Kinase Deficiency as a model to clarify the current pathogenetic hypothesis as the basis of the disease
"Hyper-IgD syndrome" or "mevalonate kinase deficiency": an old syndrome needing a new name?
No full textWe suggest that the use of HIDs name is obsolete, while MKD definition could suit better to the description of the disease
Knockdown of MVK does not lead to changes in NALP3 expression or activation
No full textMutations in the Mevalonate Kinase gene (MVK) are causes of a rare autoinflammatory disease: Mevalonate Kinase Deficiency and its more acute manifestation, Mevalonic Aciduria. The latter is characterized, among other features, by neuroinflammation, developmental delay and ataxia, due to failed cerebellar development or neuronal death through chronic inflammation. Pathogenesis of neuroinflammation in Mevalonate Kinase Deficiency and Mevalonic Aciduria has not yet been completely clarified, however different research groups have been suggesting the inflammasome complex as the key factor in the disease development. A strategy to mimic this disease is blocking the mevalonate pathway, using HMG-CoA reductase inhibitors (Statins), while knock-out mice for Mevalonate Kinase are non-vital and their hemyzygous (i.e only one copy of gene preserved) littermate display almost no pathological features
Non-classical MHC-I human leukocyte antigen (HLA-G) in hepatotropic viral infections and in hepatocellular carcinoma
No full textThe human leukocyte antigen (HLA)-G is a ‘‘nonclassical’’ major histocompatibility complex (MHC) class
Ib gene, located at chromosome 6, in the 6p21.3 region.
The HLA-G presents immunomodulatory functions essential in pregnancy for the tolerance of the
semi-allogenic fetus, but an abnormal expression of HLA-G has been observed in numerous pathological
conditions, such as tumors, autoimmune diseases and viral infections. In recent years, numerous studies
have assessed the clinical relevance of HLA-G expression in different types of cancer: in general, a higher
HLA-G expression correlates with a lower survival rate or a shorter disease-free survival.
Altered expression of HLA-G has been found in both HCV and HBV infection, and some genetic polymorphisms
have been associated with altered susceptibility/disease development for these infections,
however, whether the biologic role of HLA-G in HCV and HBV infection is beneficial or hazardous, it is
not completely clear. In the context of hepatocellular carcinoma, HLA-G has shown a potential diagnostic
role, moreover a prognostic value in HCC patients has been also attributed to HLA-G molecules.
We revise here the role of HLA-G in hepatotropic HBV/HCV infections and in hepatocellular carcinoma
(HCC)
Alendronate treatment induces IL-1B expression and apoptosis in glioblastoma cell line
No full textAlendronate (ALD), one among the nitrogen-containing bisphosphonates (NBPs), is currently used for the treatment of many pathological conditions. Unfortunately, although generally tolerated, NBPs treatment has been associated with central nervous system (CNS) adverse outcomes, such as amnesia, hallucinations and visual disturbances. So, we analyzed the effect of ALD treatment in glial cells, the main sources of cholesterol for neurons and principal cells involved in the immunological defense of the brain. We treated a glial cell line (U87-MG) with increasing doses of ALD (0.1, 1, 10, 25, 50 μM) for 48 h, aimed at evaluating the influence of this drug treatment on IL-1B expression, NLRP3 and CASP1 expression, mitochondrial activity and apoptotic cell death. We observed that ALD treatment, at the higher concentrations, induced a significant increase of IL-1B, NLRP3, CASP1 expression, provoked apoptosis and also mitochondrial damage in U87-MG. Considering the reported CNS adverse outcomes of NBPs treatment, our results confirm ALD side-effects on glial cell model
sensory neurons
No full textPhotobiomodulation therapy (PBMT) is known as a complementary tool to alleviate pain sensation in patients, nevertheless, there is still a gap of knowledge on its mechanism of action, thus limiting its clinical employment. In this study, a possible molecular mechanism of the 905 nm PBMT (0.25 W/cm2; 3, 6, 12, and 18 J/cm2, 5 Hz) analgesic effect was tested on 50B11 cells, by investigating its impact on mitochondria. A decrement of adenosine triphosphate was detected, moreover, an increment of total reactive oxygen species and mitochondrial superoxide anion was found after PBMT with all protocols tested. PBMT at 18 J diminished the mitochondrial membrane potential, and influenced mitochondrial respiration, decreasing the oxygen consumption rate. Finally, a decrement of extracellular signal-regulated kinase 1/2 phosphorylation was observed with the protocol using 12 J. Taken together these findings highlighted the intracellular effects, mainly correlated to mitochondrial, induced by 905 nm PBMT in sensory neurons, indicating the central role of this organelle in the cellular response to 905 nm near-infrared laser light. (Figure presented.).This work was supported by the Italian Ministry of Health, through the contribution given to the Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy (RC 15/17 and RC 29/23)
Prolonged treatment with mevalonolactone induces oxidative stress response with reactive oxygen species production, mitochondrial depolarization and inflammation in human glioblastoma U-87 MG cells
No full textMevalonate pathway impairment has been observed in diverse diseases, including Mevalonate Kinase Deficiency
(MKD). MKD is a hereditary auto-inflammatory disorder, due to mutations at mevalonate kinase gene (MVK),
encoding mevalonate kinase (MK) enzyme. To date, the most accredited MKD pathogenic hypothesis suggests
that the typical MKD phenotypes might be due to a decreased isoprenoid production rather than to the excess
and accumulation of mevalonic acid, as initially supported. Nevertheless, recent studies provide clear evidences
that accumulating metabolites might be involved in MKD pathophysiology by exerting a toxic effect. Our work
aims at describing the effects of accumulating mevalonolactone, mostly produced by a dehydration reaction due
to mevalonic acid accumulation, using an in vitro cellular model mimicking the glial component of the central
nervous system (human glioblastoma U-87 MG cells). In order to mimic its progressive increase, occurring
during the disease, U-87 MG cells have been treated repeatedly with growing doses of mevalonolactone, followed
by the assessment of oxidative stress response (evaluated by measuring SOD2 and HemeOX expression
levels), ROS production, mitochondrial damage and inflammatory response (evaluated by measuring IL1B expression
levels). Our results suggest that protracted treatments with mevalonolactone induce oxidative stress
with augmented ROS production and mitochondrial damage accompanied by membrane depolarization.
Furthermore, an increment in IL1B expression has been observed, thus correlating the accumulation of the
metabolite with the development of a neuroinflammatory response.
Our experimental work suggests to reconsider the presence of a possible synergy between the two major MKD
pathogenic hypotheses in attempt of unravelling the different pathogenic pathways responsible for the disease
Comment to Santos et. al., "Hyper-IgD and periodic fever syndrome: a new MVK mutation (p.R277G) associated with a severe phenotype"
No full textWe performed molecular modeling analysis onto a novel mutation in the gene MVK, described by Santos et al., found to be causative of a severe form of Hyper-IgD/Mevalonate Kinase Deficiency. The mutation p.R277G, in our analysis, lowers the binding affinity for some enzyme's substrates. Interestingly, we found that p.R277G mutation inhibits binding of Isopentenyl Pyrophosphate (IPP) (binding free energy = 0 Kcal/mol), one of isoprenoids responsible for feedback-inhibition of MVK. IPP is known to be an activator of a specific class of T-cells and we can hypothesize that increased levels of this metabolite generates an aberrant immune system response. Indeed other experiments are needed to verify this hypothesis; however, this work demonstrates usefulness of molecular modeling in generating novel pathogenic hypothesis
HLA-G and susceptibility to develop celiac disease
No full textThe Human Leukocyte Antigen-G has immunomodulatory function and its expression has been associated with several diseases. In our study we analyzed HLA-G polymorphisms in order to evaluate their possible association with susceptibility to celiac disease development. A total of 420 celiac patients and 509 controls were genotyped for HLA-G polymorphisms. We sequenced 800bp upstream the ATG codon (5' upstream regulatory region) and the whole 3' untranslated region of the HLA-G gene, whereas the ΔC deletion at exon 3 was detected by RFLP-PCR. Five polymorphisms (namely -477 C>G, -369 C>A, 14bp del/ins, 3187 A>G, 3196 C>G) and one haplotype (TCGGTACGAAITCCCGAG) were significantly more frequent in celiac patients than controls and associated with increased disease susceptibility. The 14bp I/I, 3187 G/G, 3196 G/G genotypes and TCGGTACGAAITCCCGAG haplotype, were still significantly associated with increased disease susceptibility (and in addition also the 3003 C/C genotype) when the analysis was restricted to patients and controls presenting the DQ2.5 or DQ8 HLA-DQ celiac disease risk haplotypes. Our findings indicate an association between HLA-G gene polymorphisms and susceptibility to celiac disease development, suggesting that HLA-G molecule is possibly involved in the pathogenesis of the disease
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