1,721,016 research outputs found
Geraniol rescues inflammation in cellular and animal models of mevalonate kinase deficiency
No full textThe inhibition of the mevalonate pathway through genetic defects such as mevalonate kinase deficiency (MKD) or pharmacological drugs such as aminobisphosphonates causes a shortage of intermediate compounds, in particular geranylgeranyl-pyrophosphate (GGPP), which is associated with the consequent augmented IL-1β release in monocytes. Considering that, due to its biochemical structure, isoprenoid geraniol enters the mevalonate pathway and may revert the genetic or pharmacological inhibition, the present study tested isoprenoid geraniol in cellular and animal MKD models obtained through the use of aminobisphosphonate pamidronate
Evolution of the hepcidin gene in primates
Full text linkAbstract Background Hepcidin/LEAP-1 is an iron regulatory hormone originally identified as an antimicrobial peptide. As part of a systematic analysis of the evolution of host defense peptides in primates, we have sequenced the orthologous gene from 14 species of non-human primates. Results The sequence of the mature peptide is highly conserved amongst all the analyzed species, being identical to the human one in great apes and gibbons, with a single residue conservative variation in Old-World monkeys and with few substitutions in New-World monkeys. Conclusion Our analysis indicates that hepcidin's role as a regulatory hormone, which involves interaction with a conserved receptor (ferroportin), may result in conservation over most of its sequence, with the exception of the stretch between residues 15 and 18, which in New-World monkeys (as well as in other mammals) shows a significant variation, possibly indicating that this structural region is involved in other functions.</p
Polymorphisms in TREX1 and susceptibility to HIV-1 infection.
No full textTREX-1 is a restriction factor against HIV-1. The coding sequence of TREX1 gene was analysed in HIV+ subjects searching for genetic variations possibly associated with the susceptibility to HIV infection. The single nucleotide polymorphism rs3135945 was significantly associated with HIV infection, emphasizing the involvement of TREX-1 in the anti-HIV response
NALP1/NLRP1 genetic variants are associated with Alzheimer disease.
No full textAlzheimer disease (AD) is a complex neurodegenerative disease. Genetic and molecular studies have confirmed that in the human brain, amyloid-β fibrils can induce, through the activation of NALP1 inflammosome, inflammatory and apoptotic responses involved in the pathogenesis of AD. Considering that AD pathogenesis is multifactorial, we hypothesized that NALP1/NLRP1 could be a susceptibility gene involved in the devolvement of the disease. The possible association between 9 selected polymorphisms in the NALP1/NLRP1 gene and AD was evaluated by comparing their frequency distribution in an Italian cohort of AD patients (AD, n = 276) and in a group of Italian sex-matched and age-matched healthy controls without dementia (HC, n = 266). Our study, evidences the association of 4 nonsynonymous polymorphisms in the NLRP1 gene (rs2137722, rs34733791, rs11657747, rs11651595) with AD. The major alleles of all 4 single nucleotide polymorphisms and the corresponding homozygote genotypes were more frequent in AD patients than in healthy controls, suggesting an association of these variants in the predisposition versus the development of the disease. These findings seem to support the previously reported role of NALP1 in neuronal damage, and provide evidence of an association between single nucleotide variations in the NLRP1 gene and AD
Host genomic HIV restriction factors modulate the response to dendritic cell-based treatment against HIV-1.
No full textHost genome is still poorly investigated in the context of vaccine or immunotherapy, however recently findings emphasized that it may affect the response to those treatments. In our retrospective study we evaluated the effect of HIV-1 genetic restriction factors on the response to dendritic cell (DC)-based immunotherapy in a Brazilian cohort of HIV positive (HIV+) patients that underwent a phase I clinical trial in 2004. Genomic DNA from 18 HIV+ individuals that underwent DC-based immunotherapy was analyzed for selected polymorphisms known to be associated with susceptibility to HIV-1 infection and/or AIDS progression. Allelic and genotypic distribution of the 22 polymorphisms was evaluated considering the response to the treatment.: The rs11884476 SNP in PARD3B resulted associated with good response to the immune treatment according to an over-dominant model. Even if functional effect of this variation is still unknown, our data suggested that it could play a role in the control of viral replication.: Our findings, being aware of the limitation represented by the small number of subjects analyzed, suggest that genetic factors involved in AIDS progression could affect the response to immunotherapy, reinforcing the idea that deeper investigation on host genetic variations will be fundamental for a rational vaccine development
Decreased cholesterol levels reflect a consumption of anti-inflammatory isoprenoids associated with an impaired control of inflammation in a mouse model of mevalonate kinase deficiency.
No full textObjective
The aim of this study was to evaluate, in a mouse model of mevalonate kinase deficiency (MKD), the possible link between inflammatory symptoms and serum cholesterol levels.
Materials and methods
Balb/c mice were treated with alendronate and bacterial muramyl dipeptide. Body temperature, interleukin-1β (IL-1β) secretion and serum cholesterol levels were measured.
Results
An increased production of the pro-inflammatory cytokine IL-1β (p < 0.05) and a rise in body temperature (p < 0.05) was observed, while, in parallel, serum cholesterol concentration significantly decreased (p < 0.05). These effects were completely reversed when animals were treated with exogenous isoprenoids.
Conclusions
In the mouse model of MKD, the inflammatory response is associated with a reduction in cholesterol levels, and hence this parameter could be used as an indicator of isoprenoid consumption. In addition, plant derived isoprenoids could represent candidate treatments for this disease
Comments on ''Geranylgeraniol--a new potential therapeutic approach to bisphosphonate associated osteonecrosis of the jaw" by Ziebart T et al. (2011).
No full texttherapeutic approach to bisphosphonate associated osteonecrosis of the jaw’’ in Oral Oncology, by Ziebart T et al., and would like to compare and discuss these results with our recently published data.1 The design of the two studies is very similar: natural isoprenoids have been used to revert the mevalonate pathway inhibition induced by amino-bisphosphonates (N-BPs). Isoprenoid compounds are hypothesized to enter the mevalonate pathway after the N-BPs block, being metabolized as farnesyl-pyrophosphate and bypass the biochemical inhibition mediate by N-BPs on farnesyl- pyrophosphate synthase, restoring the metabolites flux along the pathway.2,3 Ziebart T. et al. empathized that the isoprenoid geranylgeraniol (GGOH) can antagonize the effects of N-BPs in the processes of osteoclast formation, apoptosis, bone resorption and in tumor cells (i.e. prostate cancer cells, human myeloma cells) as previously described in several studies,4,5 suggesting a therapeutic use of GGOH in bisphosphonate associated osteonecrosis of the jaw (BP-ONJ). Recently, our group demonstrated that GGOH and several other isoprenoids (farnesol, geranygeraiol, mentol, limonene) are able to revert the pro-inflammatory effect induced by the combination of N-BPs and bacterial lipoplyshaccaride (LPS) or muramyldipeptide (MDP) both in Balb/c mice and in human and murine monocytes. 2,3,6 We also proposed isoprenoid compounds as eligible treatment for the rare and still orphan disease mevalonate kinase deficiency (MKD, OMIM: 251170), characterized by genetic defect in the second enzyme of the mevalonate pathway. All this considered we would like to discuss the following issues: – We do agree with Ziebart T. et al.1 about the anti-N-BPs effect of geraniol, emphasizing that this effect is not dependent on the N-BP used on the isoprenoids. Ziebart’ group used ibandronate, pamidronate and zoledronate in their model, whereas we treated Balb/c mice and monocytes with alendronate or pamidronate obtaining comparable and reproducible findings. 2,7 Moreover geranylgeraniol, farnesol, menthol and limonene showed a comparable effect in contrasting N-BP action in our models,3 suggesting a common mechanism of action for these compounds in the context of NBP inhibition. – It is interesting to note that GGOH is able to contrast N-BP effect independently of the cellular model implied (osteoblast or monocytes) and the different outcome of N-BP inhibition. Since the block of the mevalonate pathway affects the prenylation of several signalling molecules involved in cell cycle, differentiation and cell response to extracellular stimulus, probably it results in different defects depending on the cell types. – We suggest Ziebart T. et al.1, to test other isoprenoids in addition to GGOH, such as geraniol, farnesol, menthol or limonene, in order to identify the most effective isoprenoids to treat in combination within aminobisphosphonate associated osteonecrosis of the jaw. While the dose/effect of the isoprenoid is comparable within Ziebart T. et al. and our models, additionally we would like to emphasize the importance of the timing in isoprenoid administration. – In our animal model the isoprenoid timing necessary to revert the pro-inflammatory action of alendronate or pamidronate was the critical point, because the isoprenoid must be injected the day before and/or after the N-BP.2,7 – Recently we showed that farnesyltransferase inhibitor (FTI) such as manumycin A, Tipifarnib or Lonafarnib, currently used in clinical trials as anticancer drugs, were able to contrast N-BP effect leading to a redistribution of mevalonate intermediates along its pathway.6 We propose Ziebart T. et al. to evaluate the effects of these pharmacological agents which could be an alternative therapeutic approach in the case of N-BP-induced osteonecrosis of the jaw. In summary, we do agree with the study by Ziebart T. et al., and emphasize the pivotal role of isoprenoid to rescue the phenotype inflammation induced by aminobisphosphonate treatment
Natural isoprenoids inhibit LPS-induced-production of cytokines and nitric oxide in aminobisphosphonate-treated monocytes.
No full textThe inhibition of mevalonate pathway through genetic defects (mevalonate kinase deficiency, MKD) or pharmacologic drugs (aminobisphosphonates) causes a shortage of intermediate compounds and, in particular, of geranylgeranyl-pyrophosphate (GGPP) associated to the activation of caspase-1 and IL-1beta release. Geraniol (GOH), farnesol (FOH), geranylgeraniol (GGOH) and menthol (MOH), due to their isoprenoid structure, are supposed to enter the mevalonate pathway and to by-pass the biochemical block, reconstituting the pathway. Considering the already known side effects of aminobisphosphonates, and the lack of a specific treatment for MKD, we evaluated the impact of these natural isoprenoids compounds in a RAW cell lines chemically treated with the aminobisphosphonate alendronate, and in monocytes isolated from 2 patients affected by MKD. GOH, FOH, GGOH and MOH were all capable to diminish inflammatory marker levels induced by LPS. These natural isoprenoids could be proposed as novel therapeutic approach for the still orphan drug MKD, but also considered for the evaluation of possible inflammatory side effects of aminobisphosphonates
HIV-1 induces NALP3-inflammasome expression and interleukin-1β secretion in dendritic cells from healthy individuals but not from HIV-positive patients.
No full textOBJECTIVE:
NALP3-inflammasome is an innate mechanism, alternative to type-1 interferon, which is able to recognize nucleic acids and viruses in the cytoplasm and to induce pro-inflammatory response. Here, we hypothesized the involvement of inflammasome in the early defense against HIV-1 and in the full maturation of dendritic cells: for this, we evaluated the response of dendritic cells pulsed with HIV-1 in terms of inflammasome activation in healthy donors. Moreover, inflammasome response to HIV was evaluated in HIV-infected individuals.
DESIGN AND METHODS:
Monocyte-derived dendritic cells isolated from 20 healthy individuals (HC-DC) and 20 HIV-1-infected patients (HIV-DC) were pulsed with alditrithiol-2-inactivated HIV-1. We then analyzed inflammasome genes expression and interleukin-1β (IL-1β) secretion.
RESULTS:
In HC-DC, HIV-1 induced higher NLRP3/NALP3 mRNA expression compared with other inflammasome genes such as NALP1/NLRP1 or IPAF/NLRC4 (P < 0.001). This augmented expression was accompanied by CASP1-increased and IL1B-increased mRNA levels and by a significant increment of IL-1β secretion (P < 0.05). Otherwise, HIV-1 failed to activate inflammasome and cytokine production in HIV-DC. HIV-DC showed an increased NLRP3/NALP3 basal expression, suggesting a chronic inflammatory profile of patients' immune cells.
CONCLUSION:
HIV-1 was able to induce a NALP3-inflammasome response in healthy individuals, indicating that this inflammasome could play a role in the first steps of HIV-1 infection; the consequent inflammatory process may be important for directing host immune response against the virus and/or disease progression. HIV-DC seemed to be chronically activated, but unresponsive against pathogens. Our findings could be of interest considering the ongoing research about dendritic cell manipulation and therapeutic strategies for AIDS involving dendritic cell-based immune-vaccines
Exosomes are possibly used as a tool of immune regulation during the dendritic cell-based immune therapy against HIV-I
No full textDendritic cell (DC)-based immune therapy (IT) against HIV showed variable results. It is known that different factors influence host response to DC-IT. Exosomes derived from DC are regulators of the immune system. In this context, here we hypothesize about the role of the DC-derived exosomes on the DC-IT response. Based on data from RT-PCR array genes expression (focused on the TSG101 gene, an exosome marker) and flow cytometry experiments of a DC-IT against HIV-1 clinical trial, we hypothesize that: During the DC-IT exosomes are used as an additional tool for immune system modulation. In addition, we believe that a low release of exosomes can be more beneficial for the DC-IT response than a high release of exosomes. Our data reinforce the concept that exosomes can act as an immune regulatory tool, however not in a generalized manner, but in a highly precise way. Our hypothesis is based in preliminary experimental data, thus, it should be tested using experimental and functional strategies involving a great number of patients. Once the hypothesis confirmed, the immunomodulatory role of the exosomes during DC-IT must be considered as an important factor in the (I) evaluation, (II) modulation, and (III) success of DC-IT against HIV
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