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Recent studies showed that angiotensin-(1-7) has cerebroprotective actions in stroke. In the present study, we aim to test whether tissue overexpression of Angiotensin-(1-7), mainly in the brain provides neuroprotection in a model of ischemia/reperfusion by bilateral common carotid arteries occlusion/reperfusion (BCCAo/R). Evaluation of neurological deficit scores and bilateral asymmetry test (BAT) were performed seven days after transient BCCAo/R in transgenic rats (TG-7371) overexpressing Angiotensin-(1-7) and Sprague-Dawley (SD) rats. To assess blood-brain barrier (BBB) permeability Evans blue dye (EB) was intravenously injected. Cytokine levels were quantified in the whole brain through Elisa assay and oxidative stress was measured 7 days after ischemia. The expression of AT 1 and Mas receptors and inducible nitric oxide synthase (iNOS) was evaluated by RT-PCR. Neurological deficits were observed in both SD-BCCAo/R and TG-BCCAo/R, contrasting to sham-operated groups. However, TG-BCCAo/R showed a significant lower neurological score and latency in BAT when compared with SD-BCCAo/R. BBB integrity in TG-BCCAo/R was improved, since these animals showed lower extravasation of EB than SD-BCCAo/R. Interestingly, TG-BCCAo/R presented lower levels of pro-inflammatory cytokines when compared to SD-BCCAo/R. Levels of IL-10 were higher in SD-BCCAo/R than in SD control and even higher in TG-BCCAo/R. TG-BCCAo/R animals presented decreased levels of TBARS and increase in SOD activity and GSH levels when compared to SD sham rats. RT-PCR results showed higher levels of AT 1 receptor and iNOS in SD-BCCAo/R compared to TG-BCCAo/R, but no difference was observed for Mas receptor. The present study shows that lifetime increase in cerebral expression of an Ang-(1-7)-producing fusion protein induces neuroprotection in experimental global cerebral ischemia and reperfusion, reassuring that, pharmacological strategies leading to increase in Ang-(1-7) can be an additional tool for stroke therapy., Competing Interests: Conflict of interest There are no conflicts of interest or disclosures., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Uremic toxins (UTs) accumulate in the circulation of patients with chronic kidney disease (CKD). High volume hemodiafiltration (HDF) improves clearance of low and medium molecular weight UTs compared to HD. The present study is a post-hoc analysis comparing the metabolomic profile in serum from patients under high flux HD (hf-HD) and HDF in HDFIT, a multicentric randomized controlled trial (RCTs). Per protocol, serum samples were collected pre- and post- dialysis treatments at randomization (baseline) and at the end of the follow up (6 months) and stored in a biorepository. Random (pre- and post-dialysis) samples from nine patients in study arm were selected at baseline and at the end of the follow up. To compare the samples, 26 possibly matching metabolites were identified by a t-test among the four groups using 1 H nuclear magnetic resonance (NMR). To evaluate the comparison between the modalities is a single treatment session, the clearance rates (CRs) of each metabolite were calculated based on pre-dialysis and post-dialysis samples. In addition, to evaluate to effect of UT removal during the trial follow up period, the pre-dialysis metabolite concentrations at the baseline and at 6 months were compared among the two arms of the study. There was no significant difference between in the single session CRs of metabolites when hf-HD and HDF were compared. On the other hand, the comparison between baseline and 6-month (long-term evolution) led to the identification of 16 metabolites that differentiated the hf-HD and the HDF evolutions. Most of these 16 metabolites are involved in several important metabolic pathways, such as metabolism of phenylalanine and biosynthesis of phenylalanine, tyrosine, and tryptophan, which are related to UTs and cardiovascular disease development. Although no difference was observed between hf-HD and HDF samples before and after a single session, concentrations of CKD-relevant metabolites and associated pathologies were stable in the HDF samples, but not in the hf-HD samples, over the six-month period, suggesting that HDF enhances long-term stability., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Roberto Pecoits-Filho received research grants from Fresenius Medical Care, received consulting fees from Astra Zeneca, Bayer, Novo Nordisk, Boeringer-Lilly, and Rethrophin, and performed voluntary work for ISN and KDIGO. The other authors declare no conflicts of interest. Conflicts of Interest Roberto Pecoits-Filho received research grants from Fresenius Medical Care, received consulting fees from Astra Zeneca, Bayer, Novo Nordisk, Boeringer-Lilly, and Rethrophin, and performed voluntary work for ISN and KDIGO. The other authors declare no conflicts of interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Maintaining islet cell viability in vitro, although challenging, appears to be a strategy for improving the outcome of pancreatic islet transplantation. We have shown that prolactin (PRL) leads to beta-cell cytoprotection against apoptosis, an effect mediated by heat shock protein B1 (HSPB1). Since the role of HSPB1 in beta-cells is still unclear and the hormone concentration used is not compatible with clinical applications because of all the side effects displayed by the hormone in other tissues, we explored the molecular mechanisms by which HSPB1 mediates beta-cell cytoprotection. Lysates from PRL- and/or cytokine-treated MIN6 beta-cells were subjected to HSPB1 immunoprecipitation followed by identification through mass spectrometry. PRL-treated cells presented an enrichment of several proteins co-precipitating with HSPB1. Of note were oxidative stress resistance-, protein degradation- and carbohydrate metabolism-related proteins. Wild type, HSPB1 silenced or overexpressing MIN6 cells were exposed to menadione and hydrogen peroxide and analysed for several oxidative stress parameters. HSPB1 knockdown rendered cells more sensitive to oxidative stress and led to a reduced antioxidant capacity, while prolactin induced an HSPB1-mediated cytoprotection against oxidative stress. HSPB1 overexpression, however, led to opposite effects. PRL treatment, HSPB1 silencing or overexpression did not change the expression nor activities of antioxidant enzymes, it also did not lead to a modulation of total glutathione levels nor G6PD expression. However, HSPB1 levels are related to a modulation of GSH/GSSG ratio, G6PD activity and NADPH/NADP  +  ratio. We have shown that HSPB1 is important for pro-survival effects against oxidative stress-induced beta-cell death. These results are in accordance with PRL-induced enrichment of HSPB1-interacting proteins related to protection against oxidative stress. Finally, our results outline the need of further studies investigating the importance of HSPB1 for beta-cell viability, since this could lead to the mitigation of beta-cell death through the up-regulation of an endogenous protective pathway., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Epilepsy is a neurological disease related to the occurrence of pathological oscillatory activity, but the basic physiological mechanisms of seizure remain to be understood. Our working hypothesis is that specific sensory processing circuits may present abnormally enhanced predisposition for coordinated firing in the dysfunctional brain. Such facilitated entrainment could share a similar mechanistic process as those expediting the propagation of epileptiform activity throughout the brain. To test this hypothesis, we employed the Wistar audiogenic rat (WAR) reflex animal model, which is characterized by having seizures triggered reliably by sound. Sound stimulation was modulated in amplitude to produce an auditory steady-state-evoked response (ASSR; -53.71Hz) that covers bottom-up and top-down processing in a time scale compatible with the dynamics of the epileptic condition. Data from inferior colliculus (IC) c-Fos immunohistochemistry and electrographic recordings were gathered for both the control Wistar group and WARs. Under 85-dB SLP auditory stimulation, compared to controls, the WARs presented higher number of Fos-positive cells (at IC and auditory temporal lobe) and a significant increase in ASSR-normalized energy. Similarly, the 110-dB SLP sound stimulation also statistically increased ASSR-normalized energy during ictal and post-ictal periods. However, at the transition from the physiological to pathological state (pre-ictal period), the WAR ASSR analysis demonstrated a decline in normalized energy and a significant increase in circular variance values compared to that of controls. These results indicate an enhanced coordinated firing state for WARs, except immediately before seizure onset (suggesting pre-ictal neuronal desynchronization with external sensory drive). These results suggest a competing myriad of interferences among different networks that after seizure onset converge to a massive oscillatory circuit., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

Short bowel syndrome is a severe malabsorption disorder, and prolonged parenteral nutrition is essential for survival in some cases. Among the undesirable effects of long-term parenteral nutrition is an increase in proinflammatory cytokines. The aim of the present study was to measure the serum levels of interleukin-6, interleukin-10, tumor necrosis factor alpha, and transforming growth factor beta, in patients with short bowel syndrome on cyclic parenteral nutrition and patients who had previously received but no longer require parenteral nutrition. The study was cross-sectional and observational. Three groups were studied as follows: Parenteral nutrition group, 9 patients with short bowel syndrome that receive cyclic parenteral nutrition; Oral nutrition group, 10 patients with the same syndrome who had been weaned off parenteral nutrition for at least 1 year prior to the study; Control group, 13 healthy adults, matched for age and sex to parenteral and oral groups. The following data were collected: age, tobacco use, drug therapies, dietary intake, body weight, height, blood collection. All interleukins were significantly higher in the parenteral group compared with the control group as follows: interleukin-6: 22 ± 19 vs 1.5 ± 1.4 pg/mL, P= .0002; transforming growth factor β: 854 ± 204 vs 607 ± 280 pg/mL, P= .04; interleukin-10: 8 ± 37 vs 0.6 ± 4, P= .03; tumor necrosis factor α: 20 ± 8 vs 8 ± 4 pg/mL, P< .0001. We concluded that parenteral nutrition in short bowel syndrome patients, regardless of its duration, increases serum proinflammatory cytokines., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Galanin is a peptide that is present in the central nervous system in mammals, including rodents and humans. The actions of galanin are mediated by three types of metabotropic receptors: GAL1, GAL2, and GAL3. GAL1 and GAL3 increase K(+) efflux, and GAL2 increases intracellular Ca(2+) levels. The distribution of galanin and its receptors suggests its involvement in fear and/or anxiety. The periaqueductal gray matter (PAG) is a key mediator of defensive behaviors that is both targeted by galaninergic projections and supplied with GAL1 receptors and, less markedly, GAL2 receptors. We examined the effects of galanin microinjections in the dorsal PAG (dPAG) on the performance of rats in different models of anxiety. Male Wistar rats (n=7-12) were implanted with guide cannulae in the dPAG. They received microinjections of either galanin (0.3, 1.0, and 3.0 nmol) or vehicle and were tested in the Vogel conflict test (VCT), elevated plus maze (EPM), and elevated T-maze (ETM). Rats that were tested in the ETM were further evaluated for exploratory activity in the open field test (OFT). Galanin microinjections had no effects on anxiety-like behavior in the EPM or VCT or exploratory activity in the EPM or OFT. In the ETM, however, microinjections of 3 nmol galanin impaired learned anxiety (i.e., avoidance of the open arms) without changing unconditioned fear (i.e., escape from the open arms). The present data suggest that galanin transmission in the dPAG inhibits the acquisition of anxiety-like responses in the ETM., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aripiprazole is an antipsychotic that acts by multiple mechanisms, including partial agonism at dopamine D2 and serotonin 5-HT1A receptors. Since these neurotransmitters also modulate pain and analgesia, we tested the hypothesis that systemic or local administration of aripiprazole induces antinociceptive responses. Systemic aripiprazole (0.1-10 mg/kg; i.p.) injection in mice inhibited formalin-induced paw licking and PGE2-induced hyperalgesia in the paw pressure test. This effect was mimicked by intra-plantar administration (12.5-100 µg/paw) in the ipsi, but not contralateral, paw. The peripheral action of aripiprazole (100 µg/paw) was reversed by haloperidol (0.1-10 µg/paw), suggesting the activation of dopamine receptors as a possible mechanism. Accordingly, quinpirole (25-100 µg/paw), a full agonist at D2/D3 receptors, also reduced nociceptive responses.. In line with the partial agoniztic activity of aripiprazole, low dose of this compound inhibited the effect of quinpirole (both at 25 µg/paw). Finally, peripheral administration of NAN-190 (0.1-10 μg/paw), a 5-HT1A antagonist, also prevented aripiprazole-induced antinociception. In conclusion, systemic or local administration of aripiprazole induces antinociceptive effects. Similar to its antipsychotic activity, the possible peripheral mechanism involves dopamine D2 and serotoninergic 5-HT1A receptors. Aripiprazole and other dopaminergic modulators should be further investigated as new treatments for certain types of pain., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Foamy viruses infect a wide range of placental mammals, including primates. However, despite of great diversity of New World primates, only three strains of neotropical simian foamy viruses (SFV) have been described. Only after 40 years since serological characterization, the complete sequence of an SFVcap strain infecting a family of six capuchin monkeys (Sapajus xanthosternos) was obtained. Co-culture of primate peripheral blood mononuclear cells with Cf2Th canine cells was established and monitored for the appearance of cytopathic effects, PCR amplification of integrated SFV proviral genome and viral reverse transcriptase activity. The novel SFVcap was fully sequenced through a next-generation sequencing protocol. Phylogenetic analysis of the complete genome grouped SFVcap and SFVmar, both infecting primate species of the Cebidae family with a genetic similarity of approximately 85%. Similar ORF sizes were observed among SFV from neotropical primates, and env and pol genes were the most conserved. Neotropical SFV presented the smallest LTRs among exogenous mammalians. The novel SFVcap strain provides a valuable research tool for the FV community., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Aripiprazole is an antipsychotic that acts as a partial agonist at dopamine D2 receptors, with a favorable pharmacological profile. Due to its unique mechanism of action, this compound has potential application as a substitutive therapy for drug addiction. Considering that distinct neural systems subserve the addictive and analgesic actions of opioids, we tested the hypothesis that aripiprazole selectively inhibit the abuse-related, but not the antinociceptive, effects of morphine. The drugs were tested in male Swiss mice for their effects on locomotion, conditioned place preference (CPP) and nociception. Morphine (20mg/kg) increased motor activity, whereas aripiprazole (0.1, 1 and 10mg/kg) did not induce any change. This antipsychotic, however, prevented morphine-induced locomotion. In the conditioning box, aripiprazole did not induce either reward or aversion. Yet, it prevented both the acquisition and the expression of morphine-induced CPP. Finally, none of the doses of this antipsychotic interfere with morphine (5mg/kg)-induced antinociception in the tail-flick test. In conclusion, aripiprazole inhibited the abuse-related effects of morphine at doses that do not interfere with basal locomotion, reward or aversion. Also, it did not alter morphine-induced antinociceptive effects. This antipsychotic should be further investigated as a possible substitutive strategy for treating certain aspects of opioid addiction., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The reduced availability of nitric oxide (NO) is associated with cardiovascular diseases. Therefore, NO donors such as organic nitrates are useful for the treatment of these disorders. The 2-nitrate-1,3-dibuthoxypropan (NDBP) is an organic nitrate synthesized from glycerin, which the pharmacological effects have not been investigated. In this study we evaluated the vasorelaxant effect induced by NDBP in superior mesenteric artery from rats. In phenylephrine pre-contracted artery rings, NDBP (10(-8)-10(-4)M) elicited concentration-dependent and endothelium-independent relaxation, which were attenuated by hydroxocobalamin-HDX (30 μM), a NO extracellular scavenger, and 1-H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one-ODQ (10 μM), an inhibitor of soluble guanylyl cyclase (sGC). In addition, the NDBP-induced relaxation was reduced by non-selective K(+) channels blocker KCl (20 mM) or selective K(+) channels blockers such as tetraethylammonium-TEA (B(KCa), 1 mM), charybdotoxin-ChTX (B(KCa), 100 nM), glibenclamide (K(ATP), 1μM) and 4-aminopyridine-4-AP (K(V), 1mM). In preparations with ODQ (10 μM) plus TEA (1 mM), the response was virtually abolished. In rat smooth muscle cells culture, NDBP (10(-6)-10(-4)M) caused concentration-dependent increases in NO levels. These findings suggest that NDBP causes vasorelaxation through NO generation and activation of the sCG/cGMP/PKG pathway., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Human immunodeficiency virus type 1 (HIV-1) subtype B predominates in Brazil, but in the southern region subtype C is the most frequent, followed by subtypes B, F1 and recombinant forms. In southern Brazil, these subtypes co-circulate in subjects with homogeneous demographic and clinical features, enabling a better understanding of the role of HIV-1 subtypes on the characteristics of infection., Objectives: To evaluate the prevalence of different HIV-1 subtypes in subjects with recent diagnosis for HIV infection in the extreme south of Brazil, and to study their association with demographic, behavioral, clinical and laboratorial characteristics., Study Design: We have determined the genetic sequence of viral protease and reverse transcriptase (polymerase, connection and RNase H domains) isolated from studied subjects. Viral subtype was inferred by comparison with reference HIV sequences, and recombination was determined with Simplot analysis. The association of HIV-1 subtypes with studied characteristics was evaluated by chi-square, Fisher's exact, Student's t and Kruskal-Wallis tests., Results: Two hundred and forty-five HIV isolates were molecularly characterized, and the association with variables was studied for 233 (95.1%) patients. Of those, 46.8% followed AIDS defining criteria. HIV-1C was responsible for 56.3% of infections, and was associated with heterosexual transmission (p=0.001) and with higher CD4(+) T-cell counts (p=0.02)., Conclusions: The molecular epidemiology of HIV-1 in the southernmost Brazil is currently steady with predominance of HIV-1C. This is the first study showing a robust association of the infection by this subtype and heterosexual transmission in the state of Rio Grande do Sul, Brazil., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Major and accessory drug resistance mutations have been recently characterized in the C-terminal RT subdomains of HIV-1, connection and RNase H. However, their presence in treatment-naïve patients infected with HIV-1 non-B subtypes remains largely unknown., Objectives: To characterize the patterns of primary resistance at the C-terminal RT subdomains of HIV-1 infecting subjects in the southern region of Brazil, where HIV-1 subtypes B and C co-circulate., Study Design: Plasma viral RNA was extracted from patients recently diagnosed for HIV infection (2005-2008). The protease and reverse transcriptase regions were PCR-amplified and sequenced. Infecting HIV subtypes were assigned by phylogenetic inference and drug resistance mutations were determined following the IAS consensus and recent reports on C-terminal RT mutations., Results: The major mutation to NNRTI T369I/V was found in 1.8% of patients, while A376S was present in another 8.3%. In the RNase H domain, the compensatory mutation D488E was more frequently observed in subtype C than in subtype B (p=0.038), while the inverse was observed for mutation Q547K (p<0.001). The calculated codon genetic barrier showed that 22% of subtype B isolates, but no subtype C, carried T360, requiring two transitions to change into the resistance mutation 360V., Conclusions: Major resistance-conferring mutations to NNRTI were detected in 10% of RT connection domain viral sequences from treatment-naïve subjects. We showed for the first time that the presence of specific polymorphisms can constrain the acquisition of definite resistance mutations in the connection and RNase H subdomains of HIV-1 RT., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The goal of this work was to compare the differences between human immunodeficiency virus type 1 (HIV-1) of B and F1 subtypes in the acquisition of major and minor protease inhibitor (PI)-associated resistance mutations and of other polymorphisms at the protease (PR) gene, through a cross sectional study. PR sequences from subtypes B and F1 isolates matched according to PI exposure time from Brazilian patients were included in this study. Sequences were separated in four groups: 24 and 90 from children and 141 and 99 from adults infected with isolates of subtypes F1 and B, respectively. For comparison, 211 subtype B and 79 subtype F1 PR sequences from drug-naïve individuals were included. Demographic and clinical data were similar among B- and F1-infected patients. In untreated patients, mutations L10V, K20R, and M36I were more frequent in subtype F1, while L63P, A71T, and V77I were more prevalent in subtype B. In treated patients, K20M, D30N, G73S, I84V, and L90M, were more prevalent in subtype B, and K20T and N88S were more prevalent in subtype F1. A higher proportion of subtype F1 than of subtype B strains containing other polymorphisms was observed. V82L mutation was present with increased frequency in isolates from children compared to isolates from adults infected with both subtypes. We could observe a faster resistance emergence in children than in adults, during treatment with protease inhibitors. This data provided evidence that, although rates of overall drug resistance do not differ between subtypes B and F1, the former accumulates resistance at higher proportion in specific amino acid positions of protease when compared to the latter.

Objectives: To validate C/T(-13910) polymorphism associated with primary hypolactasia for clinical practice., Design and Methods: Lactose breath test and PCR-RFLP for the C/T(-13910) polymorphism were performed., Results: Twenty-seven of 28 patients with genotype CC had positive breath tests; all twenty-two patients with genotypes CT or TT had negative breath tests. Agreement of tests was high (p<0.0001; Kappa Index 0.96)., Conclusion: C/T(-13910) polymorphism detection may be a new tool for primary hypolactasia diagnosis.

Five dihydro-piran-2,4-diones, including 5,6-dimethyl-dihydro-piran-2,4-dione one of the intermediates of the synthesis of caloverticilic acid, were synthesized and submitted to molluscicidal bioassay. The compound's yields varied from moderate to good (42%- 80%) and were achieved through the preparation of the dianion of ethyl acetoacetate, reaction with and aldehyde followed by hydrolysis of the ester (NaOH, H(2)O, 2 h, T.A.) and lactonization in acidic medium (HCl, 0 degrees C). The 5,6-dimethyl-dihydro-piran-2,4-dione and three analogous dihydro-piran-2,4-diones 6-substituted,-phenyl, (4-methoxy-phenyl), and -propenyl, showed significant activities against the Biomphalaria glabrata egg masses, while the analogous 6-(3,4-dimethoxy-phenyl) was inactive as molluscicide. This activity is reported for the first time, extending the range of biological activities of this group.

Abstract-Molluscicidal bioassays and electrochemical studies (measurement of first wave reduction potential, Epcl) were performed on several synthetic nitroaromatics, in relation to possible correlation between biological activity, redox potential and structural effects. Five of them presented a significant molluscicidal activity on Biomphalaria glabrata (LD50 < 20 ppm). The Epc1 values ranged from -0.532 to -0.857 V versus Ag/AgCl (0.1 M) (-0.260 to -0.585 V versus NHE), all of them, in the favorable range for reduction in vivo. Data comparison between Epc1 and molluscicidal activity indicates that the presence of the electroactive nitro group is important for the biological activity. Correlation with redox potential, however, was not evident. Structural effects seem to be the most important parameter. Higher activity is noticeable for phenols, including the para-nitro azo or hydrazo-containing compounds. No activity was observed for compounds having the benzylic substituent in meta position to the nitro group. These results suggest that activity undoubtedly involves more than reduction characteristics and that the possible formation of electrophilic species, after nitro reduction, can play an important role in molluscicidal activity against B. glabrata.

In the search for new molluscicidal agents we tested the activity of lapachol and other 2-hydroxy-3-alkylnaphthoquinones possessing nitrogenated alkyl chains, against the snail Biomphalaria glabrata. Lapachol, isolapachol and nor-lapachol showed strong molluscicidal activity against the adult snail (LD(90)<10 ppm) and significant toxicity against snail egg masses (LD(90)<0.2 ppm). As lapachol is easily extracted, and the derivatives can be synthesised without any difficulty, large-scale synthesis and field tests can be conducted, with a view to large-scale molluscicidal programs.