ABSTRACT
In recent years, the incidence of metabolic syndrome (MS) has increased due to lifestyle-related factors in developed countries. MS represents a group of conditions that increase the risk of diabetes, cardiovascular diseases, and other severe health problems. Low-grade chronic inflammation is now considered one of the key aspects of MS and could be defined as a new cardiovascular risk factor. Indeed, an increase in visceral adipose tissue, typical of obesity, contributes to the development of an inflammatory state, which, in turn, induces the production of several proinflammatory cytokines responsible for insulin resistance. Psoriasis is a chronic relapsing inflammatory skin disease and is characterized by the increased release of pro-inflammatory cytokines, which can contribute to different pathological conditions within the spectrum of MS. A link between metabolic disorders and Psoriasis has emerged from evidence indicating that weight loss obtained through healthy diets and exercise was able to improve the clinical course and therapeutic response of Psoriasis in patients with obesity or overweight patients and even prevent its occurrence. A key factor in this balance is the gut microbiota; it is an extremely dynamic system, and this makes its manipulation through diet possible via probiotic, prebiotic, and symbiotic compounds. Given this, the gut microbiota represents an additional therapeutic target that can improve metabolism in different clinical conditions.
Subject(s)
Gastrointestinal Microbiome , Inflammation , Metabolic Syndrome , Psoriasis , Psoriasis/microbiology , Psoriasis/metabolism , Psoriasis/complications , Humans , Metabolic Syndrome/microbiology , Metabolic Syndrome/metabolism , Metabolic Syndrome/complications , Inflammation/metabolism , Animals , Obesity/complications , Obesity/microbiology , Obesity/metabolismABSTRACT
The human retina is a complex anatomical structure that has no regenerative capacity. The pathogenesis of most retinopathies can be attributed to inflammation, with the activation of the inflammasome protein platform, and to the impact of oxidative stress on the regulation of apoptosis and autophagy/mitophagy in retinal cells. In recent years, new therapeutic approaches to treat retinopathies have been investigated. Experimental data suggest that the secretome of mesenchymal cells could reduce oxidative stress, autophagy, and the apoptosis of retinal cells, and in turn, the secretome of the latter could induce changes in mesenchymal cells. Other studies have evidenced that noncoding (nc)RNAs might be new targets for retinopathy treatment and novel disease biomarkers since a correlation has been found between ncRNA levels and retinopathies. A new field to explore is the interaction observed between the ocular and intestinal microbiota; indeed, recent findings have shown that the alteration of gut microbiota seems to be linked to ocular diseases, suggesting a gut-eye axis. To explore new therapeutical strategies for retinopathies, it is important to use proper models that can mimic the complexity of the retina. In this context, retinal organoids represent a good model for the study of the pathophysiology of the retina.
Subject(s)
Gastrointestinal Microbiome , Retinal Diseases , Humans , Retina/metabolism , Retinal Diseases/metabolism , Inflammation/metabolismABSTRACT
The high serum concentrations of TNF-α characterize acute graft-versus-host disease (aGVHD), for which infliximab treatment may be beneficial. In 28 pediatric patients, four doses of 10 mg/kg infliximab every seven days were administered after steroid failure (Standard Group, n = 14) or as a first-line therapy (Early Group, n = 14). Population pharmacokinetic analyses and evaluation of serum cytokines were performed. After two months of treatment, complete response in gastrointestinal and liver aGVHD was achieved in 43% and 100% of patients in the Standard and Early groups, respectively. During follow-up, four patients in the Standard Group (but none in the Early Group) experienced an aGVHD recurrence. Viral infections occurred more frequently in the Standard Group after the fifth dose. Infliximab clearance did not differ between groups or according to treatment outcome for each organ involved in aGVHD, whereas serum levels of cytokines significantly differed. Therefore, present findings show that use of first-line, TDM-driven infliximab to treat aGVHD in children may result in better clinical outcomes and tolerability, with a different pattern of cytokines generated according to the moment of beginning of treatment.
ABSTRACT
Convolvulus pluricaulis (CP) is a common Indian herb, largely employed in Ayurvedic medicine and known for its neuroprotective and neuroinflammatory action. Its effectiveness against several pathologic/sub-pathologic conditions is widely accepted, but it is not yet completely chemically characterized. In recent years, several researchers have pointed out the involvement of CP and other Convolvulaceae in lipidic and glucidic metabolism, particularly in the control of hyperlipidaemia and diabetic conditions. In this scenario, the aim of the study was to chemically characterize the medium polarity part of the CP whole plant and its fractions and to shed light on their biological activity in adipocyte differentiation using the 3T3-L1 cell model. Our results demonstrated that the CP extract and fractions could upregulate the adipocyte differentiation through the modulation of the nuclear receptor PPARγ (Peroxisome Proliferator-Activated Receptor γ), broadly recognized as a key regulator of adipocyte differentiation, and the glucose transporter GLUT-4, which is fundamental for cellular glucose uptake and for metabolism control. CP also showed the ability to exert an anti-inflammatory effect, downregulating cytokines such as Rantes, MCP-1, KC, eotaxin, and GM-CSF, which are deeply involved in insulin resistance and glucose intolerance. Taken together, these data suggest that CP could exert a potential beneficial effect on glycemia and could be employed as an anti-diabetic adjuvant or, in any case, a means to better control glucose homeostasis.
Subject(s)
Convolvulus , Mice , Animals , Convolvulus/chemistry , Convolvulus/metabolism , 3T3-L1 Cells , Cell Differentiation , Adipocytes , Plant Extracts/pharmacology , Plant Extracts/metabolism , PPAR gamma/metabolismABSTRACT
Despite advances in acute graft-versus-host disease (aGVHD) prophylaxis, current pharmacological approaches fail to prevent aGVHD. The protective effect of defibrotide on GVHD incidence and GVHD-free survival has not been sufficiently studied. 91 pediatric patients included in this retrospective study were divided into two groups based on defibrotide use. We compared the incidence of aGVHD and chronic GVHD-free survival between the defibrotide and control groups. The incidence and severity of aGVHD were significantly lower in patients who received defibrotide prophylactic administration than in the control group. This improvement was observed in the liver and intestinal aGVHD. No defibrotide prophylaxis benefit was observed in the prevention of chronic GVHD. The pro-inflammatory cytokine levels were significantly higher in the control group. Our findings suggest that prophylactic administration of defibrotide in pediatric patients significantly reduces the incidence and severity of aGVHD, with a modification of cytokine pattern, both strongly coherent with the protective drug's action. This evidence adds to pediatric retrospective studies and preclinical data suggesting a possible defibrotide role in this setting.
Subject(s)
Bronchiolitis Obliterans Syndrome , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Humans , Child , Incidence , Retrospective Studies , Graft vs Host Disease/epidemiology , Graft vs Host Disease/prevention & control , Cytokines , Hematopoietic Stem Cell Transplantation/adverse effectsABSTRACT
Neurodegenerative diseases comprise a wide spectrum of pathologies characterized by progressive loss of neuronal functions and structures. Despite having different genetic backgrounds and etiology, in recent years, many studies have highlighted a point of convergence in the mechanisms leading to neurodegeneration: mitochondrial dysfunction and oxidative stress have been observed in different pathologies, and their detrimental effects on neurons contribute to the exacerbation of the pathological phenotype at various degrees. In this context, increasing relevance has been acquired by antioxidant therapies, with the purpose of restoring mitochondrial functions in order to revert the neuronal damage. However, conventional antioxidants were not able to specifically accumulate in diseased mitochondria, often eliciting harmful effects on the whole body. In the last decades, novel, precise, mitochondria-targeted antioxidant (MTA) compounds have been developed and studied, both in vitro and in vivo, to address the need to counter the oxidative stress in mitochondria and restore the energy supply and membrane potentials in neurons. In this review, we focus on the activity and therapeutic perspectives of MitoQ, SkQ1, MitoVitE and MitoTEMPO, the most studied compounds belonging to the class of MTA conjugated to lipophilic cations, in order to reach the mitochondrial compartment.
Subject(s)
Antioxidants , Neurodegenerative Diseases , Humans , Antioxidants/metabolism , Mitochondria/metabolism , Neurodegenerative Diseases/metabolism , Oxidative Stress , Organophosphorus Compounds/metabolism , Cations/metabolism , Ubiquinone/metabolismABSTRACT
The cholesterol biosynthesis represents a crucial metabolic pathway for cellular homeostasis. The end products of this pathway are sterols, such as cholesterol, which are essential components of cell membranes, precursors of steroid hormones, bile acids, and other molecules such as ubiquinone. Furthermore, some intermediates of this metabolic system perform biological activity in specific cellular compartments, such as isoprenoid molecules that can modulate different signal proteins through the prenylation process. The defects of prenylation represent one of the main causes that promote the activation of inflammation. In particular, this mechanism, in association with oxidative stress, induces a dysfunction of the mitochondrial activity. The purpose of this review is to describe the pleiotropic role of prenylation in neuroinflammation and to highlight the consequence of the defects of prenylation.
Subject(s)
Mevalonic Acid , Neuroinflammatory Diseases , Cholesterol/metabolism , Humans , Mevalonic Acid/metabolism , Oxidative Stress , PrenylationABSTRACT
Early post-transplant is the critical phase for the success of hematopoietic stem cell transplantation (HSCT). New viral infections and the reactivations associated with complete ablation of the recipient's T-cell immunity and inefficient reconstitution of the donor-derived system represent the main risks of HSCT. To date, the pharmacological treatments for post-HSCT viral infection-related complications have many limitations. Adoptive cell therapy (ACT) represents a new pharmacological strategy, allowing us to reconstitute the immune response to infectious agents in the post-HSC period. To demonstrate the potential advantage of this novel immunotherapy strategy, we report three cases of pediatric patients and the respective central nervous system complications after donor lymphocyte infusion.
Subject(s)
Communicable Diseases , Hematopoietic Stem Cell Transplantation , Neoplasms , Virus Diseases , Cell- and Tissue-Based Therapy/adverse effects , Child , Communicable Diseases/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Immunotherapy/adverse effects , Immunotherapy, Adoptive/adverse effects , Lymphocytes , Neoplasms/etiology , Virus Diseases/etiology , Virus Diseases/therapyABSTRACT
Janus kinases (JAK) are a family of tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) that transduce cytokine-mediated signals through the JAK-STAT metabolic pathway. These kinases act by regulating the transcription of specific genes capable of inducing biological responses in several immune cell subsets. Inhibition of Janus kinases interferes with the JAK-STAT signaling pathway. Besides being used in the treatment of cancer and inflammatory diseases, in recent years, they have also been used to treat inflammatory conditions, such as graft-versus-host disease (GVHD) and cytokine release syndrome as complications of allogeneic hematopoietic stem cell transplantation and cell therapy. Recently, the FDA approved the use of ruxolitinib, a JAK1/2 inhibitor, in the treatment of acute steroid-refractory GVHD (SR-aGVHD), highlighting the role of JAK inhibition in this immune deregulation. Ruxolitinib was initially used to treat myelofibrosis and true polycythemia in a high-dose treatment and caused hematological toxicity. Since a lower dosage often could not be effective, the use of ruxolitinib was suspended. Subsequently, ruxolitinib was evaluated in adult patients with SR-aGVHD and was found to achieve a rapid and effective response. In addition, its early low-dose use in pediatric patients affected by GVHD has proved effective, safe, and reasonably preventive. The review aims to describe the potential properties of ruxolitinib to identify new therapeutic strategies.
ABSTRACT
Innate and adaptive immune responses have a well-known link and represent the distinctive origins of several diseases, many of which may be the consequence of the loss of balance between these two responses. Indeed, autoinflammation and autoimmunity represent the two extremes of a continuous spectrum of pathologic conditions with numerous overlaps in different pathologies. A common characteristic of these dysregulations is represented by hyperinflammation, which is an exaggerated response of the immune system, especially involving white blood cells, macrophages, and inflammasome activation with the hyperproduction of cytokines in response to various triggering stimuli. Moreover, hyperinflammation is of great interest, as it is one of the main manifestations of COVID-19 infection, and the cytokine storm and its most important components are the targets of the pharmacological treatments used to combat COVID-19 damage. In this context, the purpose of our review is to provide a focus on the pathogenesis of autoinflammation and, in particular, of hyperinflammation in order to generate insights for the identification of new therapeutic targets and strategies.
Subject(s)
Adaptive Immunity , Autoimmune Diseases/pathology , Cytokine Release Syndrome/pathology , Immunity, Innate , Autoimmune Diseases/immunology , COVID-19/complications , COVID-19/pathology , COVID-19/virology , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/immunology , Cytokines/metabolism , Humans , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , SARS-CoV-2/isolation & purificationABSTRACT
Mevalonate Kinase Deficiency (MKD) is a rare inborn disease belonging to the family of periodic fever syndromes. The MKD phenotype is characterized by systemic inflammation involving multiple organs, including the nervous system. Current anti-inflammatory approaches to MKD are only partially effective and do not act specifically on neural inflammation. According to the new emerging pharmacology trends, the repositioning of drugs from the indication for which they were originally intended to another one can make mechanistic-based medications easily available to treat rare diseases. According to this perspective, the squalene synthase inhibitor Lapaquistat (TAK-475), originally developed as a cholesterol-lowering drug, might find a new indication in MKD, by modulating the mevalonate cholesterol pathway, increasing the availability of anti-inflammatory isoprenoid intermediates. Using an in vitro model for MKD, we mimicked the blockade of the cholesterol pathway and evaluated the potential anti-inflammatory effect of Lapaquistat. The results obtained showed anti-inflammatory effects of Lapaquistat in association with a low blockade of the metabolic pathway, while this effect did not remain with a tighter blockade. On these bases, Lapaquistat could be configured as an effective treatment for MKD's mild forms, in which the residual enzymatic activity is only reduced and not almost completely absent as in the severe forms.
Subject(s)
Farnesyl-Diphosphate Farnesyltransferase/antagonists & inhibitors , Inflammation/drug therapy , Inflammation/enzymology , Mevalonate Kinase Deficiency/enzymology , Oxazepines/therapeutic use , Piperidines/therapeutic use , Alendronate/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Apoptosis/drug effects , Autophagy/drug effects , Biosynthetic Pathways/drug effects , Cell Death/drug effects , Cell Shape/drug effects , Farnesyl-Diphosphate Farnesyltransferase/metabolism , Interleukin-6/metabolism , Lipopolysaccharides/pharmacology , Macrophages/drug effects , Macrophages/metabolism , Macrophages/ultrastructure , Mevalonic Acid/metabolism , Mice , Mitochondria/drug effects , Mitochondria/pathology , Mitochondria/ultrastructure , Oxazepines/pharmacology , Piperidines/pharmacology , RAW 264.7 Cells , Tumor Necrosis Factor-alpha/metabolismABSTRACT
BACKGROUND: Total body irradiation (TBI) is a mandatory step for patients with acute lymphoblastic leukemia (ALL), undergoing allogeneic hematopoietic stem cell transplantation (HSCT). In the past, amylases have been reported to be a possible sign of TBI toxicity. We investigated the relationship between total amylases (TA) and transplant-related outcomes in pediatric recipients. METHODS: We retrospectively analyzed the medical records of all the patients who underwent allogeneic HSCT between January 2000 and November 2019. The inclusion criteria were the following: recipient's age between 2 and 18, diagnosis of ALL, no previous transplantation, and use of TBI-based conditioning. The serum total amylase and pancreatic amylase were evaluated before, during, and after transplantation. Cytokines and chemokines assays were retrospectively performed. RESULTS: 78 patients fulfilled the inclusion criteria. Fifty-seven patients were treated with fractionated TBI, and 21 with a single-dose regimen. The overall survival (OS) was 62.8%. Elevated values of TA were detected in 71 patients (91%). The TA were excellent in predicting the OS (AUC = 0.773; 95% CI = 0.66-0.86; p < 0.001). TA values below 374 U/L were correlated with a higher OS. The highest mean TA values (673 U/L) were associated with a high disease-progression mortality rate. The TA showed a high predictive performance for disease progression-related death (AUC = 0.865; 95% CI = 0.77-0.93; p < 0.0001). Elevated TA values were also connected with significantly higher levels of proinflammatory cytokines, such as TNF-α, IL-6, and RANTES (p < 0.001). CONCLUSIONS: this study shows that TA is a valuable predictor of post-transplant OS and increased risk of leukemia relapse.
ABSTRACT
Mitoquinone (MitoQ) is a mitochondrial reactive oxygen species scavenger that is characterized by high bioavailability. Prior studies have demonstrated its neuroprotective potential. Indeed, the release of reactive oxygen species due to damage to mitochondrial components plays a pivotal role in the pathogenesis of several neurodegenerative diseases. The present study aimed to examine the impact of the inflammation platform activation on the neuronal cell line (DAOY) treated with specific inflammatory stimuli and whether MitoQ addition can modulate these deregulations. DAOY cells were pre-treated with MitoQ and then stimulated by a blockade of the cholesterol pathway, also called mevalonate pathway, using a statin, mimicking cholesterol deregulation, a common parameter present in some neurodegenerative and autoinflammatory diseases. To verify the role played by MitoQ, we examined the expression of genes involved in the inflammation mechanism and the mitochondrial activity at different time points. In this experimental design, MitoQ showed a protective effect against the blockade of the mevalonate pathway in a short period (12 h) but did not persist for a long time (24 and 48 h). The results obtained highlight the anti-inflammatory properties of MitoQ and open the question about its application as an effective adjuvant for the treatment of the autoinflammatory disease characterized by a cholesterol deregulation pathway that involves mitochondrial homeostasis.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Apoptosis/drug effects , Free Radical Scavengers/pharmacology , Inflammation/drug therapy , Organophosphorus Compounds/pharmacology , Ubiquinone/analogs & derivatives , Cell Line , Humans , Inflammation/metabolism , Mitochondria/metabolism , Neurons/cytology , Neurons/drug effects , Neurons/metabolism , Reactive Oxygen Species/metabolism , Ubiquinone/pharmacologyABSTRACT
BACKGROUND AND AIMS: Cardiovascular disease is the main cause of death worldwide, but the collective efforts to prevent this pathological condition are directed exclusively to individuals at higher risk due to hypercholesterolemia, hypertension, obesity, diabetes. Recently, vitamin D deficiency was identified as a risk factor for cardiovascular disease in healthy people, as it predisposes to different vascular dysfunctions that can result in plaque development and fragility. In this scenario, the fundamental aim of the study was to reproduce a disease model inducing vitamin D deficiency and atheromatosis in ApoE-/- mice and then to evaluate the impact of this vitamin D status on the onset/progression of atheromatosis, focusing on plaque formation and instability. METHODS AND RESULTS: In our murine disease model, vitamin D deficiency was achieved by 3 weeks of vitamin D deficient diet along with intraperitoneal paricalcitol injections, while atheromatosis by western-type diet administration. Under these experimental conditions, vitamin D deficient mice developed more unstable atheromatous plaques with reduced or absent fibrotic cap. Since calcium and phosphorus metabolism and also cholesterol and triglycerides systemic concentration were not affected by vitamin D level, our results highlighted the role of vitamin D deficiency in the formation/instability of atheromatous plaque and, although further studies are needed, suggested a possible intervention with vitamin D to prevent or delay the atheromatous disease. CONCLUSIONS: The data obtained open the question about the potential role of the vitamins in the pharmacological treatments of cardiovascular disorders as coadjutant of the primary drugs used for these pathologies.
Subject(s)
Aortic Diseases/etiology , Atherosclerosis/etiology , Vitamin D Deficiency/complications , Vitamin D/analogs & derivatives , Animals , Aorta/metabolism , Aorta/pathology , Aortic Diseases/blood , Aortic Diseases/pathology , Atherosclerosis/blood , Atherosclerosis/pathology , Biomarkers/blood , Diet, High-Fat , Disease Models, Animal , Fibrosis , Lipids/blood , Mice, Knockout, ApoE , Plaque, Atherosclerotic , Rupture, Spontaneous , Vitamin D/blood , Vitamin D Deficiency/bloodABSTRACT
OBJECTIVES: Cytomegalovirus (CMV)-related encephalitis is a rare but potentially life-threatening complication of CMV infection in immunocompromised patients. The high mortality rate is associated with deficient immune system reconstitution after hematopoietic stem cell transplant (HSCT) and poor bioavailability of antiviral drugs in cerebrospinal fluid (CSF). CMV-related central nervous system (CNS) infection may occur with aspecific symptoms, without evidence of either blood viral load or magnetic resonance imaging (MRI) signs of encephalitis. METHODS: Here, we describe a 10-year-old girl who underwent an allogeneic HSCT and subsequently developed CMV encephalitis. Because of the absence of CMV antigen in the blood, the diagnosis of encephalitis was proposed only after a delay, following the onset of immune reconstitution inflammatory syndrome (IRIS). Two months of combined dual antiviral therapy with ganciclovir and foscarnet proved ineffective against CMV and caused significant bone marrow and renal toxicity. To avoid further toxicity, the girl was given daily treatment with CMV-hyperimmune globulins alone. RESULTS: After three weeks, the CSF viral load dropped significantly and was undetectable within three more weeks. In the meantime, the renal impairment resolved, and there was a complete bone marrow recovery. CONCLUSION: We suggest that this patient succeeded in achieving CMV CSF clearance with high dose of CMV-hyperimmune globulin, given alone, because of the ability of immunoglobulins to penetrate the blood-brain barrier (BBB).
ABSTRACT
BACKGROUND: 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.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Drug Hypersensitivity Syndrome/drug therapy , Eosinophilia/drug therapy , Exanthema/drug therapy , Infliximab/therapeutic use , Melanoma/drug therapy , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Dermatologic Agents/therapeutic use , Drug Hypersensitivity Syndrome/etiology , Eosinophilia/chemically induced , Exanthema/chemically induced , Female , Humans , Melanoma/immunology , Nivolumab/administration & dosage , Prognosis , Skin Neoplasms/drug therapy , Skin Neoplasms/immunology , Vemurafenib/administration & dosageABSTRACT
BACKGROUND: The long non-coding RNA (lncRNA) growth arrest-specific transcript 5 (GAS5) seems to be involved in the regulation of mediators of tissue injury, in particular matrix metalloproteinases (MMPs), implicated in the pathogenesis of inflammatory bowel disease (IBD). We investigated the role of GAS5 in regulating MMP2 and MMP9 expression in pediatric patients with IBD and in vitro. METHODS: In total, 25 IBD patients were enrolled: For each patient paired inflamed and non-inflamed biopsies were collected. RNA was extracted and GAS5, MMP2, and MMP9 were quantified by TaqMan assay. The expression of GAS5 and MMPs was also determined in the human monocytic THP1 cells differentiated into macrophages and stimulated with lipopolysaccharide (LPS). The function of GAS5 was assessed by overexpressing the lncRNA and evaluating the MMPs levels. RESULTS: Real-time PCR results demonstrated a downregulation of GAS5 and an upregulation of both MMPs in inflamed tissues. In vitro data confirmed the trend observed in patients for the three genes: The stimulation with LPS promoted a downregulation of GAS5 while an increase of MMPs was observed. Overexpression experiments showed that higher levels of GAS5 lead to a decrease of both enzymes. CONCLUSION: These results provide new information about the role of GAS5 in IBD: The lncRNA could mediate tissue damage by modulating the expression of MMPs.
Subject(s)
Inflammatory Bowel Diseases/pathology , Intestinal Mucosa/metabolism , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , RNA, Long Noncoding/metabolism , Adolescent , Cell Line , Child , Down-Regulation/drug effects , Female , Humans , Inflammatory Bowel Diseases/genetics , Inflammatory Bowel Diseases/metabolism , Lipopolysaccharides/pharmacology , Male , Matrix Metalloproteinase 2/genetics , Matrix Metalloproteinase 9/genetics , Monocytes/cytology , Monocytes/drug effects , Monocytes/metabolism , RNA, Long Noncoding/genetics , Severity of Illness Index , Tetradecanoylphorbol Acetate/pharmacologyABSTRACT
PURPOSE: Idiopathic nephrotic syndrome (INS) is the most frequent form of childhood nephrotic syndrome. Steroids represent the best therapeutic option; however, inter-individual differences in their efficacy and side effects have been reported. To date, there is no way to predict patients' resistance and/or dependence. Alterations in the cytokine profile of INS patients might contribute to proteinuria and glomerular damage and affect drug sensitivity. METHODS: The cytokine plasma levels were measured in 21 INS children at diagnosis to investigate the association among cytokines pattern and clinical response. Patients were selected on the basis of their clinical response: 7 steroid sensitive (SS), 7 dependent (SD), and 7 resistant (SR). Significant results were then analyzed in 41 additional pediatric INS patients. RESULTS: Within the 48 cytokines analyzed, macrophage migration inhibitory factor (MIF) was a good predictor of steroid response. Indeed, SR patients showed significantly higher MIF plasma levels compared with all others (p = 0.022; OR = 4.3, 95%CI = 1.2-25.4): a cutoff concentration of MIF > 501 pg/ml significantly discriminated SR patients (sensitivity = 85.7%, specificity = 71.4%). On the contrary, SD patients showed lower MIF plasma levels compared with others (p = 0.010; OR = 0.12, 95%CI = 9.2 × 10-3-6.7 × 10-1). Significant results were confirmed in the entire cohort. CONCLUSIONS: Our comprehensive cytokine analysis indicates that assessing MIF plasma levels at diagnosis could predict response to glucocorticoids in children with INS.
Subject(s)
Intramolecular Oxidoreductases/blood , Macrophage Migration-Inhibitory Factors/blood , Nephrotic Syndrome/blood , Nephrotic Syndrome/drug therapy , Steroids/therapeutic use , Adolescent , Child , Child, Preschool , Cytokines/blood , Drug Resistance , Female , Humans , Intramolecular Oxidoreductases/genetics , Macrophage Migration-Inhibitory Factors/genetics , Male , Nephrotic Syndrome/genetics , Polymorphism, Genetic , Predictive Value of TestsABSTRACT
Myeloablative conditioning is a well-established procedure that precedes hematopoietic stem cell transplantation (HSCT), particularly in pediatric patients. In the period directly following transplantation, several factors may contribute to complications that lead to the activation or damage of endothelial cells, involved in the pathogenesis of vascular endothelial syndromes (VES). However, to date, sufficiently specific and sensitive diagnostic markers for the various forms of VES have not been identified. This was a retrospective single-center study of patients who underwent allogeneic HSCT. For this cohort of patients, parameters including type of engraftment, donor characteristics, and cytokine production were measured and correlated with a high prevalence of short-term complications after HSCT. The aim of this study was to identify specific parameters useful for improving diagnostics and predicting adverse effects in VES. We confirmed that monocyte-predominant engraftment was related to a higher risk for an early transplant-related complication termed sinusoidal obstruction syndrome (SOS). The increased production of specific cytokines, in particular RANTES, represents a marker associated with prevalent engraftment. In addition, patients undergoing prophylaxis with defibrotide had "classical" engraftment, a common cytokine profile and a lower incidence of life-threatening transplant-related complications. The beneficial effect of defibrotide might be a starting point for developing selective prophylaxis for patients with monocyte engraftment to prevent severe early transplant-related complications.