Combined allergic rhinitis and asthma syndrome (CARAS) Paiva Ferreira, Laércia K.D.; Paiva Ferreira, Larissa A.M.; Monteiro, Talissa M. ...
International immunopharmacology,
September 2019, 2019-Sep, 2019-09-00, 20190901, Volume:
74
Journal Article
Peer reviewed
Combined allergic rhinitis and asthma syndrome (CARAS) is a concept of “one airway – one disease” or “unified airway disease “. The upper and lower airway inflammation characterizes allergic rhinitis ...and asthma, respectively and both diseases have shown an intimate connection in their genesis, coexistence and similarities as triggered by the same etiological agents; the same inflammatory cell profile and share therapeutic treatment. This review highlights the concept of CARAS by its phenotype, endotype and biomarker classification. Indeed, rhinitis is divided into four major phenotypes: allergic rhinitis; infectious rhinitis; non-infective/non-allergic rhinitis and mixed rhinitis. On the other hand, asthma has no common consensus yet; however, the most accepted classification is based on the stage of life (early- or late- onset asthma) in which the clinical symptoms are presented. Experimental researches where animals develop a syndrome similar to CARAS have been contributed to better understand the pathogenesis of the syndrome. Therefore, the aim of this review is to clarify current terms related to CARAS as definition, phenotypes, endotypes/biomarkers, physiopathology and treatments.
•CARAS is characterized by type 2 immune response.•Allergic rhinitis and asthma share the same pathophysiology and therapies.•Phenotypes, endotypes and biomarkers are pointed for both diseases.•Immunoregulation and experimental protocols are described to characterize CARAS.
Ticks are obligate blood feeding ectoparasites that transmit a wide variety of pathogenic microorganisms to their vertebrate hosts.
is vector of
, the causative agent of Rocky Mountain spotted fever ...(RMSF), the most lethal rickettsiosis that affects humans. It is known that the transmission of pathogens by ticks is mainly associated with the physiology of the feeding process. Pathogens that are acquired with the blood meal must first colonize the tick gut and later the salivary glands (SG) in order to be transmitted during a subsequent blood feeding via saliva. Tick saliva contains a complex mixture of bioactive molecules with anticlotting, antiplatelet aggregation, vasodilatory, anti-inflammatory, and immunomodulatory properties to counteract both the hemostasis and defense mechanisms of the host. Besides facilitating tick feeding, the properties of saliva may also benefits survival and establishment of pathogens in the host. In the current study, we compared the sialotranscriptome of unfed
ticks and those fed for 72 h on rabbits using next generation RNA sequencing (RNA-seq). The total of reads obtained were assembled in 9,560 coding sequences (CDSs) distributed in different functional classes. CDSs encoding secreted proteins, including lipocalins, mucins, protease inhibitors, glycine-rich proteins, metalloproteases, 8.9 kDa superfamily members, and immunity-related proteins were mostly upregulated by blood feeding. Selected CDSs were analyzed by real-time quantitative polymerase chain reaction preceded by reverse transcription (RT-qPCR), corroborating the transcriptional profile obtained by RNA-seq. Finally, high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analysis revealed 124 proteins in saliva of ticks fed for 96-120 h. The corresponding CDSs of 59 of these proteins were upregulated in SG of fed ticks. To the best of our knowledge, this is the first report on the proteome of
saliva. The functional characterization of the identified proteins might reveal potential targets to develop vaccines for tick control and/or blocking of
transmission as well as pharmacological bioproducts with antihemostatic, anti-inflammatory and antibacterial activities.
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•CARAS is a serious health problem all over the world generating negative economic and social impacts.•4-carvomenthenol (Carvo), an essential oil, reduces airway mucus ...production.•Carvo is a potent immunomodulatory molecule by decreasing IL-13 and increasing IL-10 into the airway.•The mechanism of action of Carvo is related, at least, with the p38MAPK / NF-κB (p65) signaling pathway inhibition.
The aim of this study was to analyze the 4-carvomenthenol (carvo) oral treatment on the experimental model of the combined allergic rhinitis and asthma syndrome (CARAS). BALB/c mice were OVA-sensitized on day zero and 7th (50 μg/mL OVA in 10 mg/mL Al (OH)3) and OVA-challenged (5 mg/mL, 20 μL/animal) for three weeks. In the last week, the animals were dally challenged with aerosol of OVA and the carvo treatment (12.5, 25 or 50 mg/kg) occurred one hour before each OVA-challenge. Data were analyzed and p < 0.05 was considered significant. Carvo (12.5–50 mg/kg) decreased significantly the eosinophil migration into the nasal (NALF) and bronchoalveolar (BALF) cavities as well as on the nasal and lung tissues of sick animals. The treatment also decreased mucus production on both tissue sections stained with PAS (periodic acid-Schiff satin). In addition, the histological analyzes demonstrated that sick mice presented hyperplasia and hypertrophy of the lung smooth muscle layer followed by increasing of extracellular matrix and carvo (50 mg/kg) inhibited these asthmatic parameters. We analyzed the allergic rhinitis signals as nasal frictions and sneezing and observed that carvo decreased these two signals as well as serum OVA-specific IgE titer, type 2 cytokine synthesis, mainly IL-13, with increasing of IL-10 production. Decreasing of IL-13 production corroborated with decreasing of mucus production and these effects were dependent on p38MAPK/NF-κB(p65) signaling pathway inhibition. Therefore, these data demonstrated that a monoterpene of essential oils presents anti-allergic property on an experimental model of CARAS suggesting a new drug prototype to treat this allergic syndrome.
The cytotoxic activity of (−)‐chlorizidine A, a marine alkaloid containing a unique fusion between a pyrroloisoindolone and dehydropyrrolizine, was explored by using a combination of cellular and ...molecular methods. Our studies began by applying preliminary SAR evidence gathered from semisynthetic bioactivity evaluations to prepare an active immunoaffinity fluorescent (IAF) probe. This probe was then used to identify two cytosolic proteins, GAPDH and hENO1, as the targets of (−)‐chlorizidine A.
Cellular and molecular biological studies have identified that the chlorinated marine alkaloid (−)‐chlorizidine A targets the cytosolic proteins GAPDH and ENO1, two multifunctional proteins associated with the glycolytic pathway and implicated in multiple diseases, including metastatic cancer, autoimmune disorders, neurological disorders, and bacterial infections.
The Na+/K+- ATPase acts as an ion pump maintaining the essential plasma membrane potential in all mammalian cell types, and is essential for many cellular functions. There are four α isoforms (α1, ...α2, α3 and α4) with distinct expression patterns, kinetic properties and substrate affinity. The α2-isoform is encoded by ATP1A2 and evidence supports its utmost importance in Cl− homeostasis in neurons, and in the function of respiratory neurons at birth. Monallelic pathogenic variants in ATP1A2 are associated with familial hemiplegic migraine type 2 (FHM2) and on rare occasions with alternating hemiplegia of childhood 1 (AHC1). To date, no instances of biallelic loss of function variants have been reported in humans. However, Atp1a2 homozygous loss of function knockout mice (α2−/− mice) show severe motor deficits, with lack of spontaneous movements, and are perinatally lethal due to absent respiratory activity. In this report we describe three newborns from two unrelated families, who died neonatally, presenting in utero with an unusual form of fetal hydrops, seizures and polyhydramnios. At birth they had multiple joint contractures (e.g. arthrogryposis), microcephaly, malformations of cortical development, dysmorphic features and severe respiratory insufficiency. Biallelic loss of function variants in ATP1A2, predicted to be pathogenic were found on whole exome sequencing. We propose that this is a distinctive new syndrome caused by complete absence of Na+/K+- ATPase α2-isoform expression.
Cognitive dysfunction is often reported in patients with post-coronavirus disease 2019 (COVID-19) syndrome, but its underlying mechanisms are not completely understood. Evidence suggests that severe ...acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein or its fragments are released from cells during infection, reaching different tissues, including the CNS, irrespective of the presence of the viral RNA. Here, we demonstrate that brain infusion of Spike protein in mice has a late impact on cognitive function, recapitulating post-COVID-19 syndrome. We also show that neuroinflammation and hippocampal microgliosis mediate Spike-induced memory dysfunction via complement-dependent engulfment of synapses. Genetic or pharmacological blockage of Toll-like receptor 4 (TLR4) signaling protects animals against synapse elimination and memory dysfunction induced by Spike brain infusion. Accordingly, in a cohort of 86 patients who recovered from mild COVID-19, the genotype GG TLR4-2604G>A (rs10759931) is associated with poor cognitive outcome. These results identify TLR4 as a key target to investigate the long-term cognitive dysfunction after COVID-19 infection in humans and rodents.
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•Spike protein infusion into mouse brain induces late cognitive dysfunction•Spike protein induces late hippocampal microgliosis and synapse loss•Blockage of TLR4 renders mice resistant to Spike-induced cognitive dysfunction•TLR4-2604G>A GG genotype was related to poor cognitive outcome in COVID-19 patients
Cognitive impairment is frequent in post-COVID-19 syndrome patients, but its underlying mechanisms are unclear. Fontes-Dantas et al. show that Spike brain infusion in mice induces late neuroinflammation and synapse loss, leading to long-term cognitive impairment mediated by TLR4 signaling. In patients, genotype GG TLR4-2604G>A was associated with poor cognitive outcome.
Zinc oxide (ZnO) was surface treated using argon plasma at 5 and 15 min, using maleic anhydride (MA) in solid state as the functionalizing agent. The samples were characterized by X‐ray photoelectron ...spectroscopy, Fourier‐transform infrared spectroscopy, and thermogravimetric analysis. The results indicate that ZnO surface modification occurs through two main routes: the decomposition of MA and the plasma‐induced formation of C–Zn bonds, with 15 min being the most favorable time span. Poly(lactic acid) (PLA) and ZnO were processed in an internal chamber mixer, which was coupled with a torque rheometer and characterized by the Melt Flow Index. Composites containing treated ZnO present fluidity indices closer to those of pure PLA, indicating the functionalization contribution to control the degradation of the polymer matrix.
Zinc oxide (ZnO) is carbon functionalized with C–Zn bonds and by decomposition of maleic anhydride molecules through maleic anhydride plasma. ZnO with surface modification reduces poly(lactic acid) matrix degradation.
The salivary glands (SG) of ixodid ticks play a pivotal role in blood feeding, producing both the cement and the saliva. The cement is an adhesive substance that helps the attachment of the tick to ...the host skin, while the saliva contains a rich mixture of antihemostatic, anti-inflammatory, and immunomodulatory substances that allow ticks to properly acquire the blood meal. The tick saliva is also a vehicle used by several pathogens to be transmitted to the vertebrate host, including various bacterial species from the genus
.
is a tick-borne obligate intracellular bacterium that causes the severe Rocky Mountain spotted fever. In Brazil, the dog yellow tick
is a vector of
. In the current study, the effects of an experimental infection with
on the global gene expression profile of
SG was determined by next-generation RNA sequencing. A total of 260 coding sequences (CDSs) were modulated by infection, among which 161 were upregulated and 99 were downregulated. Regarding CDSs in the immunity category, we highlight one sequence encoding one microplusin-like antimicrobial peptide (AMP) (Ambaur-69859). AMPs are important effectors of the arthropod immune system, which lack the adaptive response of the immune system of vertebrates. The expression of microplusin was confirmed to be significantly upregulated in the SG as well as in the midgut (MG) of infected
by a quantitative polymerase chain reaction preceded by reverse transcription. The knockdown of the microplusin expression by RNA interference caused a significant increase in the prevalence of infected ticks in relation to the control. In addition, a higher rickettsial load of one order of magnitude was recorded in both the MG and SG of ticks that received microplusin-specific dsRNA. No effect of microplusin knockdown was observed on the
transmission to rabbits. Moreover, no significant differences in tick engorgement and oviposition were recorded in ticks that received dsMicroplusin, demonstrating that microplusin knockdown has no effect on tick fitness. Further studies must be performed to determine the mechanism of action of this AMP against
.
Objective: To report a series of atypical presentations of Aicardi–Goutières syndrome. Methods: Clinical, neuroimaging, and genetic data. Results: We report a series of six unrelated patients (five ...males) with a subacute loss of developmental milestones, pyramidal signs, and regression of communication abilities, with onset at ages ranging from 7 to 20 months, reaching a nadir after 4 to 24 weeks. A remarkable improvement of lost abilities occurred in the follow-up, and they remained with residual spasticity and dysarthria but preserved cognitive function. Immunization or febrile illness occurred before disease onset in all patients. CSF was normal in two patients, and in four, borderline or mild lymphocytosis was present. A brain CT scan disclosed a subtle basal ganglia calcification in one of six patients. Brain MRI showed asymmetric signal abnormalities of white matter with centrum semi-ovale involvement in five patients and a diffuse white matter abnormality with contrast enhancement in one. Four patients were diagnosed and treated for acute demyelinating encephalomyelitis (ADEM). Brain imaging was markedly improved with one year or more of follow-up (average of 7 years), but patients remained with residual spasticity and dysarthria without cognitive impairment. Demyelination relapse occurred in a single patient four years after the first event. Whole-exome sequencing (WES) was performed in all patients: four of them disclosed biallelic pathogenic variants in RNASEH2B (three homozygous p.Ala177Thr and one compound heterozygous p.Ala177Thr/p.Gln58*) and in two of them the same homozygous deleterious variants in RNASEH2A (p.Ala249Val). Conclusions: This report expands the phenotype of AGS to include subacute developmental regression with partial clinical and neuroimaging improvement. Those clinical features might be misdiagnosed as ADEM.
•The P. brownianum extract and its fractions have cytoprotective properties against mercury toxicity.•The P. brownianum extract and its fractions have cytoprotective properties against aluminum ...toxicity.•Mainly, the cytoprotective effect of P. brownianum are related to the antioxidant effects of flavonoids.
This study aimed to verify the chelating, antioxidant and cytoprotective activities of Psidium brownianum Mart. Ex DC against mercury and aluminum. The ethanolic extract, as well as the tannic and flavonoid fractions, were prepared and subjected to liquid chromatography-mass spectrometry analysis. Ferric ion reduction and antioxidant activity measurement using the FRAP method were performed with P. brownianum. After determining the sub-allelopathic doses, germination tests using Lactuca sativa (lettuce) seeds were performed. The main compounds identified in the extract and fractions were: quercetin and its derivatives; myricetin and its derivatives; gallic acid; ellagic acid; quinic acid and gallocatechin. The Minimum Inhibitory Concentration (MIC) for all samples were ≥ 1024 μg/mL. The flavonoid fraction in association with mercury chloride demonstrated cytoprotection (p < 0.001). The sub-allelopathic concentration used was 64 μg/mL. The extract and fractions were cytoprotective for radicles and caulicles when assayed in association with mercury and against aluminum for radicles. This suggests that the P. brownianum extract and its fractions present cytoprotective activity, possibly related to the antioxidant effect of secondary metabolites, especially flavonoids.
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