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Editorial: Advances in stem cell therapy: new applications and innovative therapeutic approaches
No full textNo abstract availabl
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
TRAIL administration down-modulated the acute systemic inflammatory response induced in a mouse model by muramyldipeptide or lipopolysaccharide.
No full textThe potent inducer of apoptosis TRAIL/Apo2 ligand is now under considerations in clinical trials for the treatment of different types of cancer. Since the natural history of cancer is often characterized by microbial infections, we have investigated the effect of recombinant human TRAIL in a mouse model of systemic acute inflammation of microbial origin represented by BALB/c mice treated with either bacterial muramyldipeptide (MDP) or lipopolysaccharide (LPS). When administered intraperitoneally (i.p.), these inflammatory bacterial compounds triggered a severe systemic inflammatory response within 2h, represented by body temperature elevation, increase of circulating serum amyloid-A (SAA) and of the number of leukocytes in the peritoneal cavity. Moreover, both MDP and LPS induced a significant elevation of the circulating levels of several inflammatory cytokines and chemokines. Noteworthy, pre-treatment with recombinant human TRAIL 48 and 72h before administration of either MDP or LPS, significantly counteracted all acute inflammatory responses, including the elevation of key pro-inflammatory cytokines/chemokines such as IL-1α, IL-6, G-CSF, MCP-1. These data demonstrate for the first time that TRAIL has a potent anti-inflammatory activity, which might be beneficial for the anti-tumoral activity of TRAIL
Repositioning Of Tak-475 In Mevalonate Kinase Disease: Translating Theory Into Practice
Full text linkMevalonate Kinase Deficiency (MKD, OMIM #610377) is a rare autosomal recessive metabolic and inflammatory disease. In MKD, defective function of the enzyme mevalonate kinase (MK), due to a mutation in the MVK gene, leads to the shortage of mevalonate-derived intermediates, which results in unbalanced prenylation of proteins and altered metabolism of sterols. These defects lead to a complex multisystem inflammatory and metabolic syndrome. Although biologic therapies aimed at blocking the inflammatory cytokine interleukin-1 (IL-1) can significantly reduce inflammation, they cannot completely control the clinical symptoms that affects the nervous system. For this reason, MKD can still be considered an orphan drug disease. Cellular models for MKD can be obtained by biochemical inhibition of mevalonate-derived isoprenoids. Of note, these cells present an exaggerated response to inflammatory stimuli that can be reduced by treatment with zaragozic acid, an inhibitor of squalene synthase (SQS) able to increase the availability of isoprenoids intermediates upstream the enzymatic block. A similar action might be obtained by lapaquistat acetate (TAK-475, Takeda), a drug that underwent extensive clinical trials as a cholesterol lowering agent 10 years ago, with a good safety profile. Here we describe the preclinical evidence supporting the possible repositioning of TAK-475 from its originally intended use to the treatment of MKD and discuss its potential to modulate the mevalonate pathway in inflammatory diseases
Microcapsule a doppio strato di polisaccaridiutilizzabili come veicoli per la somministrazione oraledi sostanze biologicamente attive
No full textDecreased 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
Rapid recovery of postnivolumab vemurafenib-induced Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome after tocilizumab and infliximab administration
No full textBackground Immune checkpoint inhibitors such as nivolumab and targeted BRAF inhibitors have dramatically altered the treatment outcomes of metastatic melanoma over the past few years. Skin toxicity is the most common adverse event (AE) related to the commonly used BRAF inhibitor vemurafenib, affecting more than 90% of patients. Vemurafenib-related severe AEs with early onset are reported in patients who were previously treated with anti-programmed cell death-1 (anti PD-1) antibodies. A prolonged administration of systemic steroids is the first-line treatment of severe or life-threatening AEs. We report the case of a woman suffering from vemurafenib-related severe, rapidly worsening Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome, resolved in a few hours after single-dose administration of a combination of TNF-α antagonist infliximab with interleukin (IL)-6 receptor antagonist tocilizumab.Case presentation A 41-year-old woman treated with single-agent nivolumab presented with a melanoma progression. Biopsy samples were revised, revealing a BRAF V600E mutation. The patient was started on vemurafenib and cobimetinib treatment only 10 days after the last administration of nivolumab. On the third day of anti-BRAF therapy, profound lymphopenia was detected, and maculopapular eruption appeared afterward. Subsequently, the clinical conditions deteriorated further, and the woman was admitted on an emergency basis with high fever, respiratory and cardiocirculatory failure, diffuse rash, generalized edema, and lymphadenopathy. Diagnosis of DRESS syndrome with overexpressed capillary leakage was made. A single dose of tocilizumab was administered with an improvement of cardiocirculatory and renal function in a few hours. Because of worsening of liver function, skin lesions and mucositis, a single dose of infliximab was prescribed, and dramatic improvement was noted over the next 24 hours. Dabrafenib and trametinib were initiated, and coinciding with washout of infliximab from the patient’s blood, the drug toxicity recurred.Conclusion Anti-IL-6 and anti-TNF-α target treatment of very severe AEs may afford an immediate resolution of potentially life-threatening symptoms and reduce the duration and the costs of hospitalization. Maintenance of therapeutic infliximab blood concentrations permits an early switch to dabrafenib after vemurafenib-related AEs
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
Microglia activation and interaction with neuronal cells in a biochemical model of mevalonate kinase deficiency
No full textMevalonate kinase deficiency is a rare disease whose worst manifestation, characterised by severe neurologic impairment, is called mevalonic aciduria. The progressive neuronal loss associated to cell death can be studied in vitro with a simplified model based on a biochemical block of the mevalonate pathway and a subsequent inflammatory trigger. The aim of this study was to evaluate the effect of the mevalonate blocking on glial cells (BV-2) and the following effects on neuronal cells (SH-SY5Y) when the two populations were cultured together. To better understand the cross-talk between glial and neuronal cells, as it happens in vivo, BV-2 and SH-SY5Y were co-cultured in different experimental settings (alone, transwell, direct contact); the effect of mevalonate pathway biochemical block by Lovastatin, followed by LPS inflammatory trigger, were evaluated by analysing programmed cell death and mitochondrial membrane potential, cytokines' release and cells' morphology modifications. In this experimental condition, glial cells underwent an evident activation, confirmed by elevated pro-inflammatory cytokines release, typical of these disorders, and a modification in morphology. Moreover, the activation induced an increase in apoptosis. When glial cells were co-cultured with neurons, their activation caused an increase of programmed cell death also in neuronal cells, but only if the two populations were cultured in direct contact. Our findings, being aware of the limitations related to the cell models used, represent a preliminary step towards understanding the pathological and neuroinflammatory mechanisms occurring in mevalonate kinase diseases. Contact co-culture between neuronal and microglial cells seems to be a good model to study mevalonic aciduria in vitro, and to contribute to the identification of potential drugs able to block microglial activation for this orphan disease. In fact, in such a pathological condition, we demonstrated that microglial cells are activated and contribute to neuronal cell death. We can thus hypothesise that the use of microglial activation blockers could prevent this additional neuronal death
The complex interplay between lipids, immune system and interleukins in cardio-metabolic diseases
Full text linkLipids and inflammation regulate each other. Early studies on this topic focused on the systemic effects that the acute inflammatory response—and interleukins—had on lipid metabolism. Today, in the era of the obesity epidemic, whose primary complications are cardio-metabolic diseases, attention has moved to the effects that the nutritional environment and lipid derangements have on peripheral tissues, where lipotoxicity leads to organ damage through an imbalance of chronic inflammatory responses. After an overview of the effects that acute inflammation has on the systemic lipid metabolism, this review will describe the lipid-induced immune responses that take place in peripheral tissues and lead to chronic cardio-metabolic diseases. Moreover, the anti-inflammatory effects of lipid lowering drugs, as well as the possibility of using anti-inflammatory agents against cardio-metabolic diseases, will be discussed
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