, 1996 and Turk et al., 2000). The activation peptide length varied from 94 to 110 amino acids in insect cathepsin L sequences analyzed in the present study. After cleavage, these peptides act as cathepsin L inhibitors, playing an important role in the activity regulation Stem Cell Compound Library clinical trial of these digestive enzymes ( Coulombe et al., 1996 and Cygler and Mort, 1997). Considering the ERFNIN and GCNGG motifs, important for the globular folding of the N-terminus of the activation peptide ( Coulombe et al., 1996), the T. infestans cathepsin L sequence (ERYNIN, GCDGG) differed from that of T. brasiliensis

and R. prolixus (ERFNIN, GCEGG). The GNFD motif was more variable, modified to KNFD in TBCATL-2 and T. infestans cathepsin L, MNFD in TBCATL-1 and KNLF in the R. prolixus cathepsin L amino acid sequence ( Lopez-Ordoñez et al., 2001 and Kollien et al., 2004). The initial amino acids of the mature enzyme (Leu-Pro), the

number of disulfide bridge forming cysteine residues, the active site and S2 residues were identical in all four triatomine cathepsin L sequences. Both mature T. brasiliensis cathepsin L amino acid sequences had a closer identity with cathepsin L of R. prolixus than that of T. infestans. Therefore the sequence of T. infestans was separated from the other three triatomine cathepsins in the dendrogram. This result indicates the occurrence of, at least, two cathepsin L subgroups in triatomines. T. brasiliensis and T. infestans are phylogenetically closer than T. brasiliensis and R. prolixus, therefore TBCATL-1 and TBCATL-2 should cluster together with the amino acid sequence Alectinib in vivo of T. infestans. Since this is not the case, we can conclude that TBCATL-1/-2 and R. prolixus cathepsin L encoding genes might be orthologous counterparts, whereas the more distant T. infestans cathepsin L belongs to a second triatomine cathepsin L the group. If we include different cathepsin B, cathepsin D, carboxy- and amino-peptidase isoforms, so far identified at DNA and protein level, the complexity of the triatomine digestive system

becomes clearer. Expression analyses by RT-PCR and northern blotting have shown high cathepsin L transcript abundance in the posterior intestine (small intestine) of R. prolixus whereas in the crop (stomach) cathepsin L mRNA was absent ( Lopez-Ordoñez et al., 2001). These authors also have shown high cathepsin L transcript abundance in second instar nymphs, lower in unfed first instar nymphs and in fed first, third and fourth instars nymphs but absent in fifth instars. These findings are surprising as the last nymphal stage is also strongly dependent on blood digestion in view of nutrient demand for the metamorphosis to adults and because in adult R. prolixus, cathepsin L mRNA has been detected by northern blotting. By contrast, in the present study both cathepsin L transcripts were highly abundant in the small intestine of fifth instar nymphs.

Since the body weight (bw) of SHR was reduced when compared to Wistar rats, the SFR was normalized to the weight of the animals. Increased SFR ( Fig. 1) was observed in 12-week-old when compared to 4-week-old Wistar rats. Any alteration on SFR was observed between 4 and 12 weeks SHR. SHR at 12-week-old showed a reduced SFR than Wistar rat at same age. A slight increase in saliva pH value in SHR 12 weeks old rats was observed when compared to Wistar rat at same age (Table 1). As body weight and SFR were reduced in SHR, all results of biochemical analysis were normalized to the SFR based on body weight. A reduced SBC was

observed only in 12-weeks-old Wistar rats when compared Lenvatinib ic50 to other groups (Table 1). The saliva IgA concentration was not different between groups (Table 1). Protein concentration in the saliva and specific amylase activity were not altered by growth in Wistar group (Fig. 2 and Fig. 3). In SHR, the total protein concentration in saliva showed a threefold increase in 12-week-olds when compared with 4-week-olds (Fig. 2), associated

to an increase of the specific amylase activity (Fig. 3) in these animals.[Ca++] was increased in the saliva of 12-week-old Wistar when compared to 4-week-old rats (Fig. 4). A reduced [Ca++] was observed in SHR when compared to Wistar at 12 weeks (Fig. 4). The [F−] was PF-562271 supplier higher in 12 than 4 weeks old Wistar rats and in SHR group (Fig. 5). The fluoride concentration in water and food was 0.068 ppm (mg F/L, average of samples) and 18.21 mg F/kg, respectively. By assessing the amount of daily fluoride (mg F) intake per body weight (kg) of each animal during 12 weeks, we observed that Wistar and SHR ingested the same quantity of fluoride (Wistar, 1.56 mg F/kg/day; SHR, 1.57 mg F/kg/day). In this study, the SHR was used as experimental model of hypertension, since the haemodynamic characteristics of the SHR are very similar to those of human essential arterial hypertension. These animals are born normotensive with

average arterial pressure around 112 mmHg and develop spontaneously an increase in arterial pressure from the 8th week after birth7 reaching values higher than 150 mmHg at 12 weeks of age. It has been widely accepted that the most appropriate control strain to SHR studies is the Wistar-Kyoto (WKY) rat, to which SHR rats are genetically Thymidylate synthase related. Concerns have been raised about genetic differences8 and biological variability9 between SHR and WKY rats. Moreover, evidence suggest that the WKY strain is not the most suitable for backcross studies because of the incidence of spontaneous hypertension and the somewhat higher levels of blood pressure in these rats.10, 11, 12 and 13 According to several studies,4, 14 and 15 SHRs were compared to Wistar rats, which are safely normotensive and with no genetic alteration that could modulate arterial pressure. In this study, SHR showed lower body weight compared to the normotensive controls, regardless of the age evaluated.

Adult patients with histologically documented NSCLC who received ≥ 1 platinum-based chemotherapy regimen, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, were potentially eligible for this study. Patients were excluded if they had a life expectancy of less than 1 month or had an indication for liver, renal, or heart failure. Thirty-four eligible patients

were enrolled in this study and Cabozantinib price asked for written informed consent. Information collected at baseline included sex, age, ECOG performance status, tumor size, histology, disease stage, lung tumor–related chest pain or dyspnea, time since last chemotherapy (interval from last chemotherapy to inclusion), times of CT-PFNECII, and platinum resistance. Protocol design, data collection, and analysis were solely the responsibility of the authors. Eligible patients were randomly assigned to receive either CT-PFNECII combined with second-line chemotherapy (standard pemetrexed or docetaxel dosing schedule) (combination group, n = 17) or second-line chemotherapy (standard pemetrexed or docetaxel dosing schedule) alone (chemotherapy

group, n = 17). If a patient received prior taxane treatment, such as docetaxel or paclitaxel, pemetrexed was given as second-line chemotherapy. Otherwise, docetaxel was given as second-line chemotherapy. Ethanol-cisplatin (5%) was freshly prepared with 10 mg (2 ml) of cisplatin (Qilu Pharmaceutical Co, Ltd, Shandong, China) dissolved into an ethanol solution Silmitasertib in vitro of 20 to 30 ml Adenosine triphosphate with the final ethanol concentration of 5% (vol/vol). Next, the freshly prepared 20 to 30 ml of 5% ethanol-cisplatin solution was percutaneously injected into the lung tumor individually with a 22-gauge fine needle (Gallini Medical Devices, Via Frattini, Italy) under CT (GE Healthcare, Waukesha, WI) guidance, once a week. This procedure was performed weekly for two consecutive weeks, and a third week with no treatment completed one cycle. Single chemotherapy agent pemetrexed (Alimta; Eli Lilly and Company,

Indianapolis, IN) (500 mg/m2 as a 10-minute IV infusion on day 1 of a 21-day cycle) or docetaxel (Taxotere; Aventis Pharmaceuticals, Bridgewater, NJ) (75 mg/m2 as a 1-hour IV infusion on day 1 of a 21-day cycle) was administered IV 1 day after CT-PFNECII every 3 weeks as a cycle. Each patient in the combination group received one to two cycles of CT-PFNECII and four cycles of pemetrexed/docetaxel, and each patient in the chemotherapy group received four cycles of pemetrexed/docetaxel. Patients on the pemetrexed arm were instructed to take folic acid (350-1000 μg) orally daily beginning approximately 1 to 2 weeks before the first dose of pemetrexed and continuing daily until 3 weeks after the last dose of pemetrexed. A 1000-μg vitamin B12 injection was administered intramuscularly 1 week before the first dose of pemetrexed and was repeated approximately every 9 weeks until after discontinuation.

Isolate B1 was used as a positive control for AVR-Pi9 primers and isolate ZN61 as a positive control for AVR-Pita1 primers [11]. Under a class II type A/B3 flow hood, a filter paper piece from the stored tube containing 5-month-old mycelia and spores was removed and dipped in

a 0.2 mL Eppendorf tube containing 100 μL 10 × (Tris and EDTA, pH 7.5) (Fig. 1). The tube was then heated at 95 °C for 10 min in a thermocycler (PTC-200, MJ Research, Waltham, MA, USA) and centrifuged at 3000 r min− 1 for 1 min. This DNA extracted for 11 min was stored at 4 °C in a refrigerator until use for PCR amplification. Two sets of primers were designed from the AVR-Pi9 gene (B. Zhou, unpublished data). One set was AVR9-BZ forward (5′-CTG CTC CAT CTT 5-Fluoracil mw GTT TGG CC-3′), and AVR9-BZ reverse (5′-CAC TAG TAC AAG CAC TAA CC-3′) amplifying a 1 kb genomic fragment. The other set was AVR9-YJ-forward (5′-ATC CCC ATC CAC AGG ATT Alectinib clinical trial CC-3′) and AVR9-YJ-reverse (5′-GTG CTT ACT ACT TAG TAT AA-3′) amplifying a 660 bp genomic fragment. The latter were designed using PRIMER 3 (http://biotools.umassmed.edu/bioapps/primer3_www.cgi) based on a genomic sequence encompassing the AVR-Pi9 locus ( [10]; Y. Jia and B. Zhou, unpublished data). These primers were known to amplify a fragment of about 660 bp of the AVR-Pi9 coding region. All PCR

reactions were performed using Taq PCR Master Mix (Qiagen Inc., Valencia, CA, USA). Each PCR consisted of the following components: 10 μL of Taq PCR Master Mix (contains 5 U of Taq DNA polymerase, 2 × Qiagen PCR buffer, 3 mmol L− 1 MgCl2, and 400 μmol L− 1 of each dNTP), 0.5 μL of each 100 μmol L− 1 primer, 1 μL fungal genomic DNA solution, and 9 μL distilled water (provided by the Qiagen Kit) in a final reaction volume of 20 μL. Reactions were performed in a thermocycler (PTC-200, MJ Research, Waltham, MA, USA) with the following PCR program: 1 cycle at 95 °C for 3 min for initial denaturation, 29 cycles at 94 °C for 30 s,

55 °C for 30 s, 72 °C for 60 s, and a final extension at 72 °C for 8 min. The PCR products Quinapyramine were separated by 1.0% (w/v) agarose gel electrophoresis in 1 × TAE, and stained with SYBR Green Safe (Invitrogen Inc., Grand Island, NY, USA). The gel was visualized and photographed using a Bio-Rad gel photographic system, Chemi Doc MP (Bio-Rad Laboratories, Inc., Hercules, CA, USA). The size of the amplified fragment was estimated with a Bioline hyperladder 1 kb plus (Bioline USA Inc., Taunton, MA, USA). To evaluate the stability of the DNA extracted directly from inoculated filter paper pieces, PCRs were repeated on days 4, 8, 10, and 18 of refrigerated storage. The tests were performed independently using the same sets of samples following a similar amplification protocol. The same DNA samples were used to amplify AVR-Pita1 using primers YL149/YL169 on day 18 of storage using the protocol described by Dai et al. [11] For a positive control, DNA from ZN61 extracted conventionally was used [12].

They were trained with category structures in which a single feature determined category membership as well ones that required integration of features. Crucially, an executively-demanding concurrent task slowed learning of the single-feature categories but had little effect on the categories that required integration. The authors suggested that learning a single-feature category involved using

executive resources to extract an explicit rule that governs category membership. In contrast, learning of the feature-integration categories Olaparib was assumed to be an implicit stimulus-driven process (see also Ashby & Ell, 2001). Relating these findings to our patient group, it appears that while integration of features was impaired, executively-mediated

rule extraction was intact in most cases, hence their over-learning of a single feature dimension. However, the two most severe patients (N.H. and E.T.) were less successful in acquiring appropriate single-feature information, perhaps indicating a decline learn more in executive processes as the disease progresses. Which regions within the ATLs are critically involved in acquiring and storing coherent concepts? In SD, atrophy affects the entire ATL region, though it is concentrated in polar and ventrolateral regions (Gorno-Tempini et al., 2004 and Mion et al., 2010). Converging evidence from other methodologies has also implicated the ventral Chlormezanone and lateral aspects of the ATLs in the representation of conceptual knowledge (Binney et al., 2010, Marinkovic et al., 2003, Pobric et al., 2007 and Visser and Lambon Ralph, 2011). A parallel line of work has implicated medial anterior temporal regions, particularly the perirhinal cortex, in the perception and learning of novel feature conjunctions, both in humans (Barense et al., 2005 and Taylor et al., 2006) and non-human primates (Bussey et al., 2002 and Murray and Richmond, 2001). Damage to this region is associated with deficits in discriminating between novel stimuli based on conjunctions of their features. Medial and ventrolateral temporal regions also appear to interact in the acquisition and representation

of concepts. For example, neurons in both the perirhinal and ventrolateral ATLs change their response characteristics as monkeys learn novel visual associations, suggesting that both areas are involved (Messinger, Squire, Zola, & Albright, 2001). It is likely that medial temporal regions play a critical role in the perception and initial encoding of new conceptual information, while ventrolateral temporal cortex is necessary for longer-term storage of concepts (Albright, 2012 and Squire et al., 2004). Established theories of learning hold that this division of labour is necessary to avoid catastrophic interference between similar representations (McClelland, McNaughton, & O’Reilly, 1995). It is also consistent with the data observed in this study.

6). Data are shown as mean ± SEM. ANOVA parametric test with Bonferroni correction was used for multiple comparisons. For non-parametric data, we performed Mann–Whitney test. Statistical significance was set at p < 0.05. The authors declare that they have no competing interests. This work was funded by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior

(CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação de Amparo à Pesquisa Trichostatin A purchase do Estado de Minas Gerais (Fapemig), Brazil. “
“The febrile response is a key phenomenon of the acute phase reaction, which is also characterized by changes in several physiological parameters such as the levels of liver proteins, hormones and cells in blood, sleep phases, food intake, and others (Zeisberger, 1999). Due to the

increased body temperature, defense mechanisms are stimulated, making the febrile response relevant to protection AZD6244 cell line of the body’s integrity against invading organisms (Blatteis and Sehic, 1998). The main brain area involved in the control of the body temperature is the anterior hypothalamic pre-optic area (POA), which transduces the information received to a neuronal signal that changes the temperature set point, resulting in fever (Blatteis and Sehic, 1998 and Zeisberger, 1999). The systemic administration of LPS to experimental animals represents one of the classical models of fever induction since it reproduces what naturally occurs during inflammatory and infectious processes. LPS stimulates macrophages, monocytes, and other cells to release cytokines, which can act as endogenous pyrogens to promote fever (Roth and De Souza, 2001). Interleukin (IL)-1β was the first-described endogenous

pyrogen (Dinarello, 1984) and despite the subsequent identification of others it probably remains the most studied Carnitine dehydrogenase (Helle et al., 1988, Watanabe, 1992 and Zampronio et al., 1994). A number of mechanisms have been suggested to explain how the peripherally produced endogenous pyrogens exert their effects on the central nervous system (CNS) to produce fever (Banks et al., 1991, Banks et al., 1994, Cao et al., 1996 and Konsman et al., 2004), but it is clear that the synthesis and release of central mediators is required to bring about the necessary changes in the hypothalamic set point. Several central mediators have been proposed including prostaglandins E2 (PGE2) and F2α (PGF2α) (Coelho et al., 1993 and Milton, 1989), corticotrophin releasing factor (CRF) (Rothwell, 1989 and Zampronio et al., 2000), endothelin-1 (ET-1) (Fabricio et al., 1998), endogenous opioids (Benamar et al., 2000 and Fraga et al., 2008), endocannabinoids (Fraga et al., 2009) and also substance P (SP) (Blatteis et al., 1994). Among these, prostaglandins derived from both peripheral and central sources appear to be important (Ivanov et al., 2003 and Steiner et al., 2006).

In all cross-shore gradient-dependent mortality models the mortality function M was determined either by the cross-shore location of the particle (ADG), or by the cross-shore location of the particle and scaled solar insolation (ADGI). The cross-shore dependence of M was similar to the horizontal diffusion function used in all models (Eq. (1)): equation(8) ADG model:M=m1+m0-m121-tanhy-y0yscale equation(9) ADGI model:M=I(t)Imaxm1+m0-m121-tanhy-y0yscalewhere

m0 is surfzone mortality, m1 is offshore mortality, y0 is the offshore edge of the surfzone, and yscale determines the cross-shore scale of the surfzone/offshore transition. Values for y0 and yscale Selleck Ribociclib were 50 m and 5 m, respectively, the same values used to parameterize diffusivity (Eq. (1)). Note that in the ADG and ADGI models, mortality is not an intrinsic property of a given particle (as in the ADS and ADSI models). Instead, particles move through stationary cross-shore mortality gradients and take on different mortality rates based on their cross-shore location within those gradients. TGF-beta inhibitor review All presumptive Enterococcus isolates were found to come from one of nine different groups. Five of

these groups were common fecal (E. faecalis, E. faecium, E. hirae) and plant-associated (E. casseliflavus, E. mundtii) Enterococcus species, and one group contained rare Enterococcus biotypes (“other” Enterococcus). Three additional non-enterococcal groups were also isolated. These organisms grow and produce enterococcus-like reactions on mEI agar (blue halo) but are not Enterococcus. These organisms C1GALT1 were Streptococcus bovis, found in ruminant guts, Aerococcus viridans, and a group of unidentified non-enterococcal organisms collectively called the “not Enterococcus” group. During HB06, E. casseliflavus (∼32%) was the dominant Enterococcus species observed, while E. faecalis (∼22%) and E. faecium (∼15%) were also common ( SI Fig. 2). The dominance of E. casseliflavus during HB06 is notable, as E. casseliflavus is a plant- rather than fecal-associated species. Its dominance in the surfzone at Huntington Beach, and other nearby beaches ( Ferguson

et al., 2005 and Moore et al., 2008), suggests that the use of total Enterococcus counts without subsequent species identification may lead to spurious identification of surfzone fecal pollution. Statistically significant differences were observed in the Enterococcus species composition onshore vs. offshore (Chi-square p-value < 0.01). Onshore, E. casseliflavus, E. faecalis and E. faecium all occurred at high percentages (>17% each), while offshore, concentrations of E. faecium were only ∼8%, reducing it from a major (onshore) to a minor (offshore) constituent. Furthermore, the percentage of E. mundtii was much higher offshore than onshore (14% vs. 7%), and E. hirae, A. viridans, rare Enterococcus biotypes, and non-enterococcal organisms were more prevalent offshore ( Fig.

c.), a cannula (PE 50) was inserted retrogradely (1.0 cm) into the portal vein and the vascular mesenteric bed was dissected out at its border with the intestine. The mesenteric venular bed was perfused at a constant rate of 2 mL/min using a peristaltic pump (Miniplus 3, Gilson, France) with Krebs-Henseleit solution, pH 7.4, at 37 °C in the presence of 95% O2 and MK0683 nmr 5% CO2. To confirm the viability of tissues, preparations were exposed to 90 mmol/L KCl for 5 min. After 30 min of washing out the KCl with Krebs solution, Ang II (0.1 nmol) was administered in bolus in a final volume of 100 μL and vascular responses were evaluated as changes

in the perfusion pressure (mmHg) (PowerLab 4S; ADInstruments, Australia). Isolated portal vein ring preparations

were performed according to the method previously described [2]. Rats were anesthetized with chloral hydrate (450 mg/kg, s.c.), the portal vein was excised and connective tissue was removed. Rings of portal veins (3–4 mm length) were mounted under 0.5 g of passive tension in an organ bath (15 mL) containing Krebs-Henseleit solution, pH 7.4, at 37 °C with 95% O2 and 5% CO2. Preparations were allowed to equilibrate for 60 min; during this time, the bath solution was changed every 20 min. To confirm the viability of tissues, the preparations were exposed to 90 mmol/L KCl for 5 min. After 30 min of washing out the KCl with normal Krebs solution, a cumulative-concentration response curve (CCRC) to Ang II (0.1–100 nmol/L) was performed and changes in isometric tension (grams) were recorded (PowerLab 4S, ADInstruments, Australia). CCRC were analyzed by a data analyses JAK inhibitor program (Prism3, GraphPad) Selleck Neratinib to evaluate the EC50 (the concentration of Ang II required to produce 50% maximum response) and maximum response (Emax). Efficacy and sensitivity of portal vein rings preparations in response to Ang II was determined as Emax and pEC50 (−log EC50), respectively. To investigate the mechanisms involved in Ang II-mediated contraction, preparations of mesenteric venous beds

and portal vein rings were incubated with Krebs-Henseleit solution containing losartan (specific AT1R antagonist, 0.1 μmol/L), PD 123319 (specific AT2R antagonist, 0.1 μmol/L), HOE 140 (specific B2R antagonist, 20 nmol/L) [13], indomethacin (COX inhibitor, 10 μmol/L), or L-NAME (inhibitor of NO synthesis, 10 μmol/L) 30 min before Ang II injection. In addition, a group of SHR were treated with celecoxib (specific COX2 inhibitor, 10 mg/kg) [20] administered by gavage 3 h before were killed and the mesenteric venular beds and portal vein rings were prepared. All the concentrations of antagonists/inhibitors used in experiments were based in preliminary studies performed in our laboratory or in the literature, when specified. Total RNA from the portal veins of SHR and Wistar rats was extracted using Trizol reagent (Invitrogen, USA) in accordance with the manufacturer’s protocol.

In addition to co-translational acetylation Unimod and TopFIND report 11 amino-terminal PTMs check details including acetylation, mono-methylation, di-methylation and tri-methylation, formylation, carbamylation, succinylation, cyclization, propionylation, palmitoylation and myristoylation. Among these αN-acetylation

and cyclization are the only two studied in depth at the mechanistic and proteome-wide level. αN-acetylation plays an important regulatory role in protein stability and protein turnover via the N-end rule [32•• and 33]. Initially, only co-translational αN-acetylation was recognized. However, post-translational αN-acetylation is now recognized as widespread PTM occurring in

vivo [ 6•, 25••, 29••, 34, 35, 36• and 37]. Comprehensive understanding of αN-acetylation also enables the identification of alternate translational start sites utilizing the differential selleck products patterns displayed by co-translational and post-translational αN-acetylation [ 29••]. Chen et al. [ 38] for the first time described a physiological function for terminal methylation. The binding efficiency of regulator of chromatin condensation 1 (RCC1) to H2A and/or H2B depends on its terminal methylation with defective methylation leading to spindle-pole defects. Interestingly recent experiments suggest functional interplay or competition between αN-acetylation and αN-methylation [ 39] and probably also αN-propionylation, which early terminomics studies identified as occurring in vivo [ 34]. Cyclization of a terminal glutaminyl or glutamate residue forming N-pyroglutamate, a process initially believed to occur spontaneously but now recognized to be catalyzed by two glutaminylcyclases [40], attracts interest in Alzheimer’s research following the identification of a toxic pyroglutamate modified APP Aβ species (see below). In vivo sequence specificity for N-terminal cyclization has now been recently determined by TAILS, which enriches for all blocked termini, regardless

of the modification [ 29••]. Finally, attachment of fatty acid Resveratrol or prenyl moieties is not strictly limited to the terminal amino acid, but N-myristoylation and N-palmitoylation are known to mediate signaling and trafficking [ 41 and 42], making their location at a terminus special, as these sites and cell attachment can be lost upon cleavage. While this group of PTMs has been extensively studied by classical biochemical and cell biological approaches its proteome wide relevance remains to be shown. The C terminus of proteins is inherently less reactive than the N terminus. While this may lead to less extensive modification in nature, this too is the very reason for the lack of C-terminal sequencing ability and hence recognition of C terminal modifications, until recently.

, 2009); however, recent studies in murine models of asthma have suggested that AE might have a possible anti-inflammatory effect on chronic allergy airway inflammation (Pastva et al., 2004, Vieira

et al., 2007, Vieira et al., 2011 and Silva et al., 2010). Our group and others have shown some effects FK228 mouse of AE on chronic allergic lung inflammation (Pastva et al., 2004, Vieira et al., 2007, Vieira et al., 2008, Vieira et al., 2011 and Silva et al., 2010). However, many criticisms have been raised concerning the mouse model of asthma involving the use of ovalbumin. Wenzel and Holgate (2006) suggest that mouse models of asthma provide insights into immunologic processes but have shortcomings that continue to limit the understanding and treatment of human asthma. Several reasons are given as limitations: (i) mouse models of asthma require artificial intra-peritoneal allergen sensitization and adjunctive stimulation and provoke a systematic BLU9931 supplier rather than a

pulmonary allergic sensitization, which can even extend to include cardiovascular effects (Bice et al., 2000); (ii) the site of inflammation is mainly located in the parenchyma and the lung vascular vessels instead of the airways as occurs in human asthma (Wenzel and Holgate, 2006); and (iii) mice have lower levels of eosinophils in the airways following antigen challenge compared to guinea pigs and humans with asthma (Korsgren et al., 1997). Our results showed that sensitized guinea pigs submitted to AE training had a reduction in eosinophil migration as well as in the migration of lymphocytes to the airways,

which reinforced previous studies showing that AE reduces eosinophilic inflammation in mouse models of asthma (Pastva et al., 2004 and Vieira et al., 2007). However, the reduction in lymphocyte migration to the airways following AE was previously unknown and is interesting because lymphocytes orchestrate eosinophilic migration. To better understand the effect of AE on reducing eosinophilic migration, we quantified the expression of Th2 cytokines. The results show that AE reversed the OVA-induced expression of IL-4 and IL-13, suggesting an important effect of AE on the pro-inflammatory cytokines involved in Fossariinae allergic airway inflammation. Despite the fact that AE has been shown to reduce IL-4 expression in mouse studies (Pastva et al., 2004, Vieira et al., 2007, Vieira et al., 2008 and Vieira et al., 2011), this is the first study in guinea pigs to show that AE can also reduce the expression of IL-13. IL-13 is an important interleukin in the pathophysiology of asthma that modulates eosinophilic inflammation and mucus hypersecretion (Zhu et al., 1999). In addition, a study by Willis-Karp et al. demonstrated that these pro-asthmatic effects of IL-13 are independent of IgE production (Wills-Karp et al., 1998).