26 research outputs found
Interleukin-17A (IL-17A): A silent amplifier of COVID-19
One of the hallmarks of COVID-19 is the cytokine storm that provokes primarily
pneumonia followed by systemic inflammation. Emerging evidence has identified a
potential link between elevated interleukin-17A (IL-17A) levels and disease
severity and progression. Considering that per se, IL-17A can activate several
inflammatory pathways, it is plausible to hypothesize an involvement of this
cytokine in COVID-19 clinical outcomes. Thus, IL-17A could represent a marker of
disease progression and/or a target to develop therapeutic strategies. This
hypothesis paper aims to propose this "unique" cytokine as a silent amplifier of
the COVID-19 immune response and (potentially) related therapy
IL-17A neutralizing antibody regulates monosodium urate crystal-induced gouty inflammation
Gout is a paradigm of acute, self-limiting inflammation caused by the deposition of monosodium urate (MSU) crystals within intra-and/or peri-articular areas, leading to excruciating pain, joint swelling and stiffness. The infiltration of leukocytes drives the inflammatory response and remains an attractive target for therapeutic intervention. In this context, emerging evidence supports the view that systemic differentiation of Th17 cells and their in situ infiltration as one of the potential mechanisms by which these cells, and their main product IL-17, causes damage to target tissues. To test if IL-17 was having a detrimental role in gouty onset and progression we targeted this cytokine, using a neutralizing antibody strategy, in an experimental model of gout. Joint inflammation was induced in CD-1 mice by the intra-articular (i.a.) administration of MSU crystals (200 μg/20 μl). Animals from IL-17Ab-treated groups received 1, 3 and 10 μg (i.a.) in 20 μl of neutralizing antibody after MSU crystals administration. Thereafter, joints were scored macroscopically, and knee joint oedema determined with a caliper. Histological analysis, myeloperoxidase assay and western blots analysis for COX-2/mPGEs-1/IL-17R pathway were conducted at 18 h (peak of inflammation) to evaluate leukocytes infiltration and activation, followed by the analysis, in situ, of pro/anti-inflammatory cytokines and chemokines. Flow cytometry was also used to evaluate the modulation of infiltrated inflammatory monocytes and systemic Th17 and Treg profile. Treatment with IL-17Ab revealed a dose-dependent reduction of joint inflammation scores with maximal inhibition at 10 μg. The neutralizing antibody was also able to significantly reduce leukocytes infiltration and MPO activity as well the expression of JE, IL-1α, IL-1β, IL-16, IL-17, C5a, BLC and, with a less extent IP-10, Rantes, KC, TIMP-1, SDF-1 and metalloproteinases in inflamed tissues. Biochemical analysis also revealed that IL-17Ab treatment modulated COX-2/mPGEs-1 pathway (and related PGE2 production) without interfering with IL-17R expression. Furthermore, flow cytometry analysis highlighted a selective modulation of infiltrating inflammatory monocytes (B220-/GR1hi-F480hi/CD115+) and circulating Th17, but not Treg, cells after IL-17Ab treatment. Collectively the results of this study report for the first time, that i.a. injection of MSU crystals stimulates in vivo production of Th17 cells and Th17-related inflammatory cyto-chemokines. In addition, we have demonstrated that the administration of a neutralizing antibody against IL-17 attenuates joint symptoms, swelling and leukocytes infiltration to the inflamed tissue, possibly providing a new strategy for the treatment of gouty inflammation and/or arthritis
Cyclic Vomiting Syndrome in Children
Cyclic Vomiting Syndrome (CVS) is an underdiagnosed episodic syndrome characterized
by frequent hospitalizations, multiple comorbidities, and poor quality of life. It is often
misdiagnosed due to the unappreciated pattern of recurrence and lack of confirmatory
testing. CVS mainly occurs in pre-school or early school-age, but infants and elderly onset
have been also described. The etiopathogenesis is largely unknown, but it is likely to be
multifactorial. Recent evidence suggests that aberrant brain-gut pathways, mitochondrial
enzymopathies, gastrointestinal motility disorders, calcium channel abnormalities, and
hyperactivity of the hypothalamic-pituitary-adrenal axis in response to a triggering
environmental stimulus are involved. CVS is characterized by acute, stereotyped and
recurrent episodes of intense nausea and incoercible vomiting with predictable periodicity
and return to baseline health between episodes. A distinction with other differential
diagnoses is a challenge for clinicians. Although extensive and invasive investigations
should be avoided, baseline testing toward identifying organic causes is recommended
in all children with CVS. The management of CVS requires an individually tailored therapy
Management of acute phase is mainly based on supportive and symptomatic care. Early
intervention with abortive agents during the brief prodromal phase can be used to attempt
to terminate the attack. During the interictal period, non-pharmacologic measures as
lifestyle changes and the use of reassurance and anticipatory guidance seem to be
effective as a preventive treatment. The indication for prophylactic pharmacotherapy
depends on attack intensity and severity, the impairment of the QoL and if attack
treatments are ineffective or cause side effects. When children remain refractory to
acute or prophylactic treatment, or the episode differs from previous ones, the clinician
should consider the possibility of an underlying disease and further mono- or combination
therapy and psychotherapy can be guided by accompanying comorbidities and specific
sub-phenotype. This review was developed by a joint task force of the Italian Society
of Pediatric Gastroenterology Hepatology and Nutrition (SIGENP) and Italian Society
of Pediatric Neurology (SINP) to identify relevant current issues and to propose future
research directions on pediatric CV
New biologic (Ab-IPL-IL-17) for IL-17-mediated diseases:identification of the bioactive sequence (nIL-17) for IL-17A/F function
Febrile infection-related Epilepsy Syndrome (FIRES): a severe encephalopathy with status epilepticus. Literature review and presentation of two new cases
: FIRES is defined as a disorder that requires a prior febrile infection starting between 2 weeks and 24 h before the onset of the refractory status epilepticus with or without fever at the onset of status epilepticus. The patients, previously normal, present in the acute phase recurrent seizures and status epilepticus followed by a severe course with usually persistent seizures and residual cognitive impairment. Boundary with "new onset refractory status epilepticus (NORSE) has not clearly established. Pathogenetic hypothesis includes inflammatory or autoimmune mechanism with a possible genetic predisposition for an immune response dysfunction.Various types of treatment have been proposed for the treatment of the acute phase of the disorder to block the rapid seizures evolution to status epilepticus and to treat status epilepticus itself. Prognosis is usually severe both for control of the seizures and for cognitive involvement.FIRES is an uncommon but severe disorder which must be carefully considered in the differential diagnosis with other epileptic encephalopathy
A N T I - S P I K E D O P O S O M M I N I S T R A Z I O N E D I VA C C I N O A M - R N A I N PA Z I E N T I P O R TATO R I D I T R A P I A N TO R E N A L E , C O N E S E N Z A P R E C E D E N T E I N F E Z I O N E O M A L AT T I A D A S A R S - C O V 2
Indole-3-acetic acid is a physiological inhibitor of TORC1 in yeast.
Indole-3-acetic acid (IAA) is the most common, naturally occurring phytohormone that regulates cell division, differentiation, and senescence in plants. The capacity to synthesize IAA is also widespread among plant-associated bacterial and fungal species, which may use IAA as an effector molecule to define their relationships with plants or to coordinate their physiological behavior through cell-cell communication. Fungi, including many species that do not entertain a plant-associated life style, are also able to synthesize IAA, but the physiological role of IAA in these fungi has largely remained enigmatic. Interestingly, in this context, growth of the budding yeast Saccharomyces cerevisiae is sensitive to extracellular IAA. Here, we use a combination of various genetic approaches including chemical-genetic profiling, SAturated Transposon Analysis in Yeast (SATAY), and genetic epistasis analyses to identify the mode-of-action by which IAA inhibits growth in yeast. Surprisingly, these analyses pinpointed the target of rapamycin complex 1 (TORC1), a central regulator of eukaryotic cell growth, as the major growth-limiting target of IAA. Our biochemical analyses further demonstrate that IAA inhibits TORC1 both in vivo and in vitro. Intriguingly, we also show that yeast cells are able to synthesize IAA and specifically accumulate IAA upon entry into stationary phase. Our data therefore suggest that IAA contributes to proper entry of yeast cells into a quiescent state by acting as a metabolic inhibitor of TORC1