Kinin B1 receptor deficiency promotes enhanced adipose tissue thermogenic response to ß3-adrenergic stimulation.

OBJECTIVE AND DESIGN: Kinin B1 receptor (B1R) has a key role in adipocytes to protect against obesity and glycemic metabolism, thus becoming a potential target for regulation of energy metabolism and adipose tissue thermogenesis. MATERIAL OR SUBJECTS: Kinin B1 knockout mice (B1KO) were subjected to acute induction with CL 316,243 and chronic cold exposure. METHODS: Metabolic and histological analyses, gene and protein expression and RNA-seq were performed on interscapular brown adipose tissue (iBAT) and inguinal white adipose tissue (iWAT) of mice. RESULTS: B1KO mice, under acute effect of CL 316,243, exhibited increased energy expenditure and upregulated thermogenic genes in iWAT. They were also protected from chronic cold, showing enhanced non-shivering thermogenesis with increased iBAT mass (~ 90%) and recruitment of beige adipocytes in iWAT (~ 50%). Positive modulation of thermogenic and electron transport chain genes, reaching a 14.5-fold increase for Ucp1 in iWAT. RNA-seq revealed activation of the insulin signaling pathways for iBAT and oxidative phosphorylation, tricarboxylic acid cycle, and browning pathways for iWAT. CONCLUSION: B1R deficiency induced metabolic and gene expression alterations in adipose tissue, activating thermogenic pathways and increasing energy metabolism. B1R antagonists emerge as promising therapeutic targets for regulating obesity and associated metabolic disorders, such as inflammation and diabetes.

Evidence of plastics contamination and sewage-derived residues in a Brazilian Hope Spot for conservation of marine biodiversity - Cagarras Islands and surrounding waters.

Cagarras Islands Archipelago, a no-take MPA in Southeast Brazil, was designated as Natural Monument (MONA Cagarras) and, more recently, recognized as Hope Spot for biodiversity conservation. This study aimed to assess plastic contamination by analyzing marine litter and microplastics in MONA Cagarras and surrounding waters. Marine litter (34.12 kg) was caught by artisanal fishermen in MONA Cagarras proximities, and plastics represented ∼79 %. Personal hygiene items and strains of hair were found, suggesting sewage-derived contamination from Ipanema SSO. Microplastics were detected in MONA Cagarras surface waters. Fragments and black particle were the most frequently found microplastic shape and color, respectively. µ-FTIR analysis identified, in descending order of occurrence, polystyrene-PS, polyethylene-PE, polyvinyl chloride-PVC, polypropylene-P, and polyamide-PA. Our integrated results of macro and microplastic contamination highlight an issue of effective conservation and health of marine biodiversity in MONA Cagarras and surrounding waters and a concern for better management of Brazilian MPAs.

ß-Caryophyllene Inhibits Oxaliplatin-Induced Peripheral Neuropathy in Mice: Role of Cannabinoid Type 2 Receptors, Oxidative Stress and Neuroinflammation.

Peripheral neuropathy is an important adverse effect caused by some chemotherapeutic agents, including oxaliplatin (OXA). OXA-induced peripheral neuropathy (OIPN) is a challenging condition due to diagnostic complexities and a lack of effective treatment. In this study, we investigated the antiallodynic effect of ß-caryophyllene (BCP), a cannabinoid type 2 (CB2) receptor agonist, in a mouse model of OIPN. BCP treatment inhibited OXA-induced mechanical and cold allodynia in both preventive and therapeutic drug treatment regimens. Experiments with the CB2 receptor agonist GW405833 confirmed the role of CB2 receptors in OIPN. The CB2 antagonist SR144528 abrogated the anti-nociceptive effect of BCP on mechanical allodynia, without impacting OXA-induced sensitivity to cold. BCP decreased neuroinflammation, as inferred from TNF, IL-1ß, IL-6, and IL-10 profiling, and also reduced ROS production, lipid peroxidation, and 4-hydroxynonenal protein adduct formation in the spinal cords of OXA-treated mice. BCP did not affect the antitumor response to OXA or its impact on blood cell counts, implying that the cytotoxicity of OXA was preserved. These results underscore BCP as a candidate drug for OIPN treatment via CB2 receptor-dependent mechanisms, and anti-inflammatory and antioxidant responses in the spinal cord.

Do feeding responses of a non-native bivalve outperform the native one in a coastal lagoon? A possible explanation for the invasion success of the dark false mussel Mytilopsis leucophaeata.

The present study aimed to evaluate and compare feeding responses of the non-native and native bivalves, the dark false mussel Mytilopsis leucophaeata and the scorched mussel Brachidontes darwinianus, respectively, by offering different concentrations of seston from the coastal lagoon where these species coexist after dark false mussel introduction (Rodrigo de Freitas Lagoon, Rio de Janeiro-Brazil). For this purpose, independent laboratory experiments were carried out under five concentrations of seston to test the differences in clearance and ingestion rates of bivalves as a function of increasing concentrations of suspended particulate matter (SPM) on seston. In addition, from the integrated analysis of data obtained in experiments, it can be inferred about the efficiency levels of these species to remove SPM from seston and their effects on water turbidity and nutrient concentrations (total carbon, nitrogen, and phosphorus). Our hypothesis was that the non-native bivalve is more efficient to clear and ingest SPM from seston compared to the native one, which may lead to competitive advantages to the successful invasion of M. leucophaeata in coastal lagoons. Native species did not show a significant difference in clearance and ingestion rates with increasing concentrations of seston. Whereas the non-native bivalve showed a slight tendency to increase its clearance and ingestion rates with the increase in seston concentrations, evidencing its plasticity to adjust its feeding responses. The native bivalve was significantly more efficient to clear and ingest SPM at the lower seston concentration (i.e., close to natural concentrations found in the lagoon) compared to the non-native bivalve, which, on the other hand, showed a significant increase in its ingestion rates at the higher concentration tested (140 mg SPM L-1). Thus, the present results did not suggest food competition between the non-native M. leucophaeata and the native B. darwinianus in the introduced system. However, M. leucophaeata increased its feeding response with experimental increment in seston concentration, which suggests species ability to benefit from conditions of increased inputs of organic matter and higher primary production that could mediate its establishment in introduced systems.

ACE2, ACE, DPPIV, PREP and CAT L enzymatic activities in COVID-19: imbalance of ACE2/ACE ratio and potential RAAS dysregulation in severe cases.

OBJECTIVE AND DESIGN: Circulating enzymatic activity and RAAS regulation in severe cases of COVID-19 remains unclear, therefore we measured the serum activity of several proteases as potential targets to control the SARS-CoV-2 infection. MATERIAL OR SUBJECTS: 152 patients with COVID-19-like symptoms were grouped according to the severity of symptoms (COVID-19 negative, mild, moderate and severe). METHODS: Serum samples of COVID-19 patients and controls were subjected to biochemical analysis and enzymatic assays of ACE2, ACE, DPPIV, PREP and CAT L. One-way ANOVA and multivariate logistic regression analysis were used. Statistical significance was accepted at p < 0.05. RESULTS: We detected a positive correlation among comorbidities, higher C-reactive protein (CRP) and D-dimer levels with disease severity. Enzymatic assays revealed an increase in serum ACE2 and CAT L activities in severe COVID-19 patients, while ACE, DPPIV and PREP activities were significantly reduced. Notably, analysis of ACE2/ACE activity ratio suggests a possible imbalance of ANG II/ANG(1-7) ratio, in a positive association with the disease severity. CONCLUSION: Our findings reveal a correlation between proteases activity and the severity of COVID-19. These enzymes together contribute to the activation of pro-inflammatory pathways, trigger a systemic activation of inflammatory mediators, leading to a RAAS dysregulation and generating a significant damage in several organs, contributing to poor outcomes of severe cases.

Phthalates contamination in the coastal and marine sediments of Rio de Janeiro, Brazil.

Coastal and marine environments have been strongly influenced by anthropogenic activities, which may lead to high concentrations of different pollutants in sediments. Our study aimed to assess sediment contamination by polycyclic aromatic hydrocarbons (PAHs), phthalates (PAEs) and bisphenol A (BPA) in nine coastal and marine environments at Rio de Janeiro-Brazil. Physical and chemical water variables, grain-size parameters, moisture, and organic-matter content in sediments were assessed by sampling station. Multivariate analysis evidenced environmental differences between coastal lagoon and oceanic beaches, mostly influenced by marine waters. Differences among bay's beaches were mostly evidenced by sediment characteristics. PAHs and BPA were not detected in samples. For the first time, PAEs were found in sediments at Rio de Janeiro coast (South Atlantic). DEHP was detected in all coastal and marine environments, DBP was found in coastal lagoon and three marine environments. DnOP and DINP were solely found in the coastal lagoon.

Expression of thimet oligopeptidase (THOP) modulated by oxidative stress in human multidrug resistant (MDR) leukemia cells.

Thimet oligopeptidase (THOP) is a cytosolic metallopeptidase known to regulate the fate of post-proteasomal peptides, protein turnover and peptide selection in the antigen presentation machinery (APM) system. Oxidative stress influences THOP expression and regulates its proteolytic activity, generating variable cytosolic peptide levels, possibly affecting the immune evasion of tumor cells. In the present work, we examined the association between THOP expression/activity and stress oxidative resistance in human leukemia cells using the K562 cell line, a chronic myeloid leukemia (CML), and the multidrug-resistant (MDR) Lucena 1 (K562-derived MDR cell line) as model. The Lucena 1 phenotype was validated under vincristine treatment and the relative THOP1 mRNA levels and protein expression compared to K562 cell line. Our data demonstrated increased THOP1 gene and protein levels in K562 cells in contrast to the oxidative-resistant Lucena 1, even after H2O2 treatment, suggesting an oxidative stress dependence in THOP regulation. Further, it was observed higher basal levels of reactive oxygen species (ROS) in K562 compared to Lucena 1 cell line using DHE fluorescent probe. Since THOP activity is dependent on its oligomeric state, we also compared its proteolytic activity under reducing agent treatment, which demonstrated that its function modulation with respect to changes in redox state. Finally, the mRNA expression and FACS analyses demonstrated a reduced expression of MHC I only in K562 cell line. In conclusion, our results highlight THOP redox modulation, which could influence antigen presentation in multidrug resistant leukemia cells.

Omics-based identification of an NRF2-related auranofin resistance signature in cancer: Insights into drug repurposing.

Auranofin is a thioredoxin reductase-1 inhibitor originally approved for the treatment of rheumatoid arthritis. Recently, auranofin has been repurposed as an anticancer drug, with pharmacological activity reported in multiple cancer types. In this study, we characterized transcriptional and genetic alterations associated with auranofin response in cancer. By integrating data from an auranofin cytotoxicity screen with transcriptome profiling of lung cancer cell lines, we identified an auranofin resistance signature comprising 29 genes, most of which are classical targets of the transcription factor NRF2, such as genes involved in glutathione metabolism (GCLC, GSR, SLC7A11) and thioredoxin system (TXN, TXNRD1). Pan-cancer analysis revealed that mutations in NRF2 pathway genes, namely KEAP1 and NFE2L2, are strongly associated with overexpression of the auranofin resistance gene set. By clustering cancer types based on auranofin resistance signature expression, hepatocellular carcinoma, and a subset of non-small cell lung cancer, head-neck squamous cell carcinoma, and esophageal cancer carrying NFE2L2/KEAP1 mutations were predicted resistant, whereas leukemia, lymphoma, and multiple myeloma were predicted sensitive to auranofin. Cell viability assays in a panel of 20 cancer cell lines confirmed the augmented sensitivity of hematological cancers to auranofin; an effect associated with dependence upon glutathione and decreased expression of NRF2 target genes involved in GSH synthesis and recycling (GCLC, GCLM and GSR) in these cancer types. In summary, the omics-based identification of sensitive/resistant cancers and genetic alterations associated with these phenotypes may guide an appropriate repurposing of auranofin in cancer therapy.

First Record of Microplastic Contamination in the Non-Native Dark False Mussel Mytilopsis leucophaeata (Bivalvia: Dreissenidae) in a Coastal Urban Lagoon.

Microplastic contamination is a global concern due to its conspicuous presence in aquatic ecosystems and its toxic nature to environmental and human health. False mussels are among the most notable fresh- and brackish water invaders. The invasive Mytilopsis leucophaeata in Rodrigo de Freitas Lagoon-RFL (Rio de Janeiro, Brazil) is the most abundant macrofaunal invertebrate, widely established and distributed throughout the lagoon. This study aimed to assess microplastic contamination in this invasive filter feeder and evaluate its potential use as a bioindicator. Agglomerates (~100 mussels) were manually collected using a stainless-steel spatula in ten sampling areas distributed throughout the whole lagoon and kept frozen. In the laboratory, 60 individuals were sorted by area for soft-tissue digestion. Each pool of 10 soft-tissue mussels (n = 6 by area) was wet-weighted and then placed in a 150-mL decontaminated glass beaker with 50 mL of 10% KOH. Samples were heated (40 °C) for 48 h, and digested samples were filtered in glass-fiber membranes. Microplastics were found in all samples of mussels (n = 60) from RFL; the particles were mostly lower than 100 µm with a mean concentration (±SD) of 35.96 ± 47.64 MPs g wet-weight-1. Microplastics were distinguished in seven shapes with different occurrences in samples (%): fiber (43.3%); fragment (34.3%); film (16.3%); sponge/foam (4.9%); pellet (0.57%), rope/filaments (0.17%); and undefined (0.4%). Thirteen colors of microplastics were found, but transparent (54.94%), black (10.77%), and white (9.36%) were the most common. Mytilopsis leucophaeata were useful to assess microplastic contamination in RFL and might be preferentially used in other invaded brackish systems instead of native and often threatened bivalves. Our results confirm the effective application of bivalves as an indicator of coastal microplastic pollution.

Exercise Induced-Cytokines Response in Marathon Runners: Role of ACE I/D and BDKRB2 +9/-9 Polymorphisms.

Renin-angiotensin system (RAS) and kallikrein-kinin system (KKS) have a different site of interaction and modulate vascular tone and inflammatory response as well on exercise adaptation, which is modulated by exercise-induced cytokines. The aim of the study was to evaluate the role of ACE I/D and BDKRB2 +9/-9 polymorphism on exercise-induced cytokine response. Seventy-four male marathon finishers, aged 30 to 55 years, participated in this study. Plasma levels of exercise-induced cytokines were determined 24 h before, immediately after, and 24 h and 72 h after the São Paulo International Marathon. Plasma concentrations of MCP-1, IL-6 and FGF-21 increased after marathon in all genotypes of BDKRB2. IL-10, FSTL and BDNF increased significantly after marathon in the genotypes with the presence of the -9 allele. FSTL and BDNF concentrations were higher in the -9/-9 genotype compared to the +9/+9 genotype before (p = 0.006) and after the race (p = 0.023), respectively. Apelin, IL-15, musclin and myostatin concentrations were significantly reduced after the race only in the presence of -9 allele. Marathon increased plasma concentrations of MCP1, IL-6, BDNF and FGF-21 in all genotypes of ACE I/D polymorphism. Plasma concentrations of IL-8 and MIP-1alpha before the race (p = 0.015 and p = 0.031, respectively), of MIP-1alpha and IL-10 after the race (p = 0.033 and p = 0.047, respectively) and VEGF 72 h after the race (p = 0.018) were lower in II homozygotes compared to runners with the presence of D allele. One day after the race we also observed lower levels of MIP-1alpha in runners with II homozygotes compared to DD homozygotes (p = 0.026). Before the marathon race myostatin concentrations were higher in DD compared to II genotypes (p = 0.009). Myostatin, musclin, IL-15, IL-6 and apelin levels decreased after race in genotypes with the presence of D allele. After the race ACE activity was negatively correlated with MCP1 (r = -56, p < 0.016) and positively correlated with IL-8, IL-10 and MIP1-alpha (r = 0.72, p < 0.0007, r = 0.72, p < 0.0007, r = 0.47, p < 0.048, respectively). The runners with the -9/-9 genotype have greater response in exercise-induced cytokines related to muscle repair and cardioprotection indicating that BDKRB2 participate on exercise adaptations and runners with DD genotype have greater inflammatory response as well as ACE activity was positively correlated with inflammatory mediators. DD homozygotes also had higher myostatin levels which modulates protein homeostasis.

In vitro and in silico trichomonacidal activity of 2,8-bis(trifluoromethyl) quinoline analogs against Trichomonas vaginalis.

Trichomoniasis is a great public health burden worldwide and the increase in treatment failures has led to a need for finding alternative molecules to treat this disease. In this study, we present in vitro and in silico analyses of two 2,8-bis(trifluoromethyl) quinolines (QDA-1 and QDA-2) against Trichomonas vaginalis. For in vitro trichomonacidal activity, up to seven different concentrations of these drugs were tested. Molecular docking, biochemical, and cytotoxicity analyses were performed to evaluate the selectivity profile. QDA-1 displayed a significant effect, completely reducing trophozoites viability at 160 µM, with an IC50 of 113.8 µM, while QDA-2 at the highest concentration reduced viability by 76.9%. QDA-1 completely inhibited T. vaginalis growth and increased reactive oxygen species production and lipid peroxidation after 24 h of treatment, but nitric oxide accumulation was not observed. In addition, molecular docking studies showed that QDA-1 has a favorable binding mode in the active site of the T. vaginalis enzymes purine nucleoside phosphorylase, lactate dehydrogenase, triosephosphate isomerase, and thioredoxin reductase. Moreover, QDA-1 presented a level of cytotoxicity by reducing 36.7% of Vero cells' viability at 200 µM with a CC50 of 247.4 µM and a modest selectivity index. In summary, the results revealed that QDA-1 had a significant anti-T. vaginalis activity. Although QDA-1 had detectable cytotoxicity, the concentration needed to eliminate T. vaginalis trophozoites is lower than the CC50 encouraging further studies of this compound as a trichomonacidal agent.

Impacts of the COVID-19 pandemic restrictions on solid waste pollution in the worldwide iconic Copacabana Beach (Rio de Janeiro, Brazil).

Total and partial restrictions to beach access during COVID-19 pandemic created an opportunity to evaluate its effect on coastal pollution. We aimed to determine the impact of access restrictions on solid waste pollution at Copacabana beach, Brazil. Solid waste amount was analyzed considering beach access restrictions: unrestricted, total closure, partial restriction, new normal. Relationships of atmospheric temperature and precipitation with access restrictions were assessed and confounding effects controlled for further analyses. Beach access restrictions significantly reduced solid waste pollution at Copacabana beach, beach closure reduced waste amount in 72 %. Partial restrictions and new normal periods have significantly reduced solid wastes amount on the beach in 60 % and 36.88 %, respectively. Qualitative data revealed that most of solid wastes were single-use plastics recently disposed at Copacabana beach, reflecting beachgoer's effects on waste left on the beach. A positive impact of COVID-19 pandemic restrictions was detected on solid waste pollution at Copacabana beach.

Thioredoxin reductase-1 levels are associated with NRF2 pathway activation and tumor recurrence in non-small cell lung cancer.

Activating mutations in the KEAP1/NRF2 pathway characterize a subset of non-small cell lung cancer (NSCLC) associated with chemoresistance and poor prognosis. We herein evaluated the relationship between 64 oxidative stress-related genes and overall survival data from 35 lung cancer datasets. Thioredoxin reductase-1 (TXNRD1) stood out as the most significant predictor of poor outcome. In a cohort of NSCLC patients, high TXNRD1 protein levels correlated with shorter disease-free survival and distal metastasis-free survival post-surgery, including a subset of individuals treated with platinum-based adjuvant chemotherapy. Bioinformatics analysis revealed that NSCLC tumors harboring genetic alterations in the NRF2 pathway (KEAP1, NFE2L2 and CUL3 mutations, and NFE2L2 amplification) overexpress TXNRD1, while no association with EGFR, KRAS, TP53 and PIK3CA mutations was found. In addition, nuclear accumulation of NRF2 overlapped with upregulated TXNRD1 protein in NSCLC tumors. Functional cell assays and gene dependency analysis revealed that NRF2, but not TXNRD1, has a pivotal role in KEAP1 mutant cells' survival. KEAP1 mutants overexpress TXNRD1 and are less susceptible to the cytotoxic effects of the TXNRD1 inhibitor auranofin when compared to wild-type cell lines. Inhibition of NRF2 with siRNA or ML-385, and glutathione depletion with buthionine-sulfoximine, sensitized KEAP1 mutant A549 cells to auranofin. NRF2 knockdown and GSH depletion also augmented cisplatin cytotoxicity in A549 cells, whereas auranofin had no effect. In summary, these findings suggest that TXNRD1 is not a key determinant of malignant phenotypes in KEAP1 mutant cells, although this protein can be a surrogate marker of NRF2 pathway activation, predicting tumor recurrence and possibly other aggressive phenotypes associated with NRF2 hyperactivation in NSCLC.

Harmful algal blooms and shellfish in the marine environment: an overview of the main molluscan responses, toxin dynamics, and risks for human health.

Besides human health risks, phycotoxins may cause physiological injuries on molluscan shellfish and, consequently, damages to marine ecosystems and global fisheries production. In this way, this review aimed to present an overview of HABs impacts on marine shellfish by evaluating the effects of cultivated molluscs exposure to microalgae and cyanobacteria that form blooms and/or synthesize toxins. More specifically, it was assessed the main molluscan shellfish responses to harmful algae, trophic transfer and dynamics of phycotoxins, and the risks for human health. Of the 2420 results obtained from literature search, 150 scientific publications were selected after thorough inspections for subject adherence. In total, 70 molluscan species and 37 taxa of harmful algae were assessed from retrieved scientific publications. A significant positive correlation was found between the marine production of molluscs and the number of available studies by molluscan category. Molluscan responses to HABs and phycotoxins were categorized and discussed in three sub-sections: effects on grazing and behavior, metabolic and physiological reactions, and fitness consequences. The main histopathological injuries and toxin concentrations in molluscan tissues were also compiled and discussed. Bivalves often accumulate more toxins than gastropods and cephalopods, occasionally exceeding recommended levels for safe consumption, representing a risk for human health. Harmful algae impact on molluscan shellfish are complex to trace and predict; however, considering the perspective of increase in the occurrence and intensity of HABs, the intensification of efforts to expand the knowledge about HABs impacts on marine molluscs is crucial to mitigate the damages on economy and human health.

Effects of the toxic dinoflagellates Prorocentrum lima and Ostreopsis cf. ovata on immune responses of cultured oysters Crassostrea gasar.

Oyster production in Brazil has been highlighted as an important economic activity and is directly impacted by the quality of the environment, which is largely the result of human interference and climate change. Harmful algal blooms occur in aquatic ecosystems worldwide, including coastal marine environments which have been increasing over the last decades as a result of global change and anthropogenic activities. In this study, the native oysters Crassostrea gasar from Northeast of Brazil were exposed to two toxic benthic dinoflagellate species, Prorocentrum lima and Ostreopsis cf. ovata. Their respective effects on C. gasar physiology and defense mechanisms were investigated. Oyster hemocytes were first exposed in vitro to different concentrations of both dinoflagellate species to assess their effects on hemocyte functions, such as phagocytosis, production of reactive oxygen species, as well as mortality. Results highlighted an alteration of hemocyte phagocytosis and viability in presence of O. cf. ovata, whereas P. lima did not affect the measured hemocyte functions. In a second experiment, oysters were exposed for 4 days in vivo to toxic culture of O. cf. ovata to assess its effects on hemocyte parameters, tissues damages and pathogenic Perkinsus spp. infection. An increase in hemocyte mortality was also observed in vivo, associated with a decrease of ROS production. Histopathological analyses demonstrated a thinning of the epithelium of the digestive tubules of the digestive gland, inflammatory reaction and a significant increase in the level of infection by Perkinsus spp. in oysters exposed to O. cf. ovata. These results indicate that oysters C. gasar seem to be pretty resilient to an exposure to P. lima and may be more susceptible to O. cf. ovata. Furthermore, the latter clearly impaired oyster physiology and defense mechanisms, thus highlighting that harmful algal blooms of O. cf. ovata could potentially lead to increased susceptibility of C. gasar oysters to parasite infections.

Mercury concentration in the sentinel fish species Orthopristis ruber: Effects of environmental and biological factors and human risk assessment.

The present study aimed to assess corocoro grunt use as bioindicator of Hg contamination in coastal marine systems by testing environmental (seasons) and biological effects (sexual maturity, size and weight) on THg accumulation and assessing human health risk. Fish was captured in winter and summer seasons at Vermelha Beach, Rio de Janeiro, Southeast Brazil. Adult O. ruber showed significantly higher THg than juveniles, and THg concentrations were positively correlated to fish length and weight. Fish THg concentrations did not differ between seasons and were below the accepted limit for human consumption. Human exposure risk by fish consumption was 0.31 µg MeHg kg-1 week-1 and the hazard quotient was 0.44 (0.11-1.84). Our results confirm the applied use of O. ruber as sentinel species for Hg contamination monitoring and highlight concern for its consumption, especially for local fishermen populations that highly consume this fish and may be more susceptible to Hg adverse effects.

Antioxidants Improve Oxaliplatin-Induced Peripheral Neuropathy in Tumor-Bearing Mice Model: Role of Spinal Cord Oxidative Stress and Inflammation.

Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a common, difficult-to-treat, and dose-limiting side effect associated with Oxaliplatin (OXA) treatment. In this study, we evaluated the effect of three antioxidants - namely N-acetylcysteine, α-lipoic acid and vitamin E - upon nociceptive parameters and antitumor efficacy of OXA in a tumor-bearing Swiss mice model. Oral treatment with antioxidants inhibited both mechanical and cold allodynia when concomitantly administrated with OXA (preventive protocol), as well as in animals with previously established CIPN (therapeutic protocol). OXA increased Reactive Oxygen Species (ROS) production and lipoperoxidation, and augmented the content of pro-inflammatory cytokines (IL-1ß and TNF-α) and expression of the astrocytic marker Gfap mRNA in the spinal cord. Antioxidants decreased ROS production and lipoperoxidation, and abolished neuroinflammation in OXA-treated animals. Toll-like receptor 4 (Tlr4) and inflammasome enzyme caspase-1/11 knockout mice treated with OXA showed reduced levels of pro-inflammatory cytokines (but not oxidative stress) in the spinal cord, which were associated with resistance to OXA-induced mechanical allodynia. Lastly, antioxidants affected neither antitumor activity nor hematological toxicity of OXA in vivo. The herein presented results are provocative for further evaluation of antioxidants in clinical management of chemotherapy-induced peripheral neuropathy. PERSPECTIVE: This study reports preventive and therapeutic efficacy of orally administrated antioxidants (N-acetylcysteine, α-lipoic-acid and Vitamin-E) in alleviating oxaliplatin-induced peripheral neuropathy in tumor-bearing mice. Antioxidants' anti-nociceptive effects are associated with inhibition of ROS-dependent neuroinflammation, and occur at no detriment of OXA antitumor activity, therefore indicating a translational potential of these compounds.

Cathepsin K inhibitors based on 2-amino-1,3,4-oxadiazole derivatives.

Two new series of hitherto unknown dipeptides, containing an electrophilic nitrile or a non-electrophilic 2-amino-1,3,4-oxadiazole moiety were synthesized and evaluated in vitro as Cathepsin K (Cat K) inhibitors. From 14 compounds obtained, the oxadiazole derivatives 10a, 10b, 10e, and 10g acted as enzymatic competitive inhibitors with Ki values between 2.13 and 7.33 µM. Molecular docking calculations were carried out and demonstrated that all inhibitors performed hydrogen bonds with residues from the enzyme active site, such as Asn18. The best inhibitors (10a, 10b, 10g) could also perform these bonds with Cys25, and 10a showed the most stabilizing interaction energy (-134.36 kcal mol-1) with the active cavity. For the first time, derivatives based in 2-amino-1,3,4-oxadiazole scaffolds were evaluated, and the results suggested that this core displays a remarkable potential as a building block for Cat K inhibitors.

COX-2 promotes mammary adipose tissue inflammation, local estrogen biosynthesis, and carcinogenesis in high-sugar/fat diet treated mice.

Obesity is a major risk factor for breast cancer, especially in post-menopausal women. In the breast tissue of obese women, cyclooxygenase-2 (COX-2)-dependent prostaglandin E2 (PGE2) production has been correlated with inflammation and local estrogen biosynthesis via aromatase. Using a mouse model of 7,12-dimethylbenz[a]anthracene/medroxyprogesterone-acetate (DMBA/MPA)-induced carcinogenesis, we demonstrated that an obesogenic diet promotes mammary tissue inflammation and local estrogen production, and accelerates mammary tumor formation in a COX-2-dependent manner. High-sugar/fat (HSF) diet augmented the levels of the pro-inflammatory mediators MCP-1, IL-6, COX-2, and PGE2 in mammary tissue, and this was accompanied by crown-like structures of breast (CLS-B) formation and aromatase/estrogen upregulation. Treatment with a COX-2 selective inhibitor, etoricoxib, decreased PGE2, IL-6, MCP-1, and CLS-B formation as well as reduced aromatase protein and estrogen levels in the mammary tissue of mice fed a HSF diet. Etoricoxib-treated mice showed increased latency and decreased incidence of mammary tumors, which resulted in prolonged animal survival when compared to HSF diet alone. Inhibition of tumor angiogenesis also seemed to account for the prolonged survival of COX-2 inhibitor-treated animals. In conclusion, obesogenic diet-induced COX-2 is sufficient to trigger inflammation, local estrogen biosynthesis, and mammary tumorigenesis.

Are invasive species always negative to aquatic ecosystem services? The role of dark false mussel for water quality improvement in a multi-impacted urban coastal lagoon.

The dark false mussel Mytilopsis leucophaeata occurs as non-native species in Asia, Europe and South America. Despite the low population density usually found in its native range, M. leucophaeata forms dense clusters in newly invaded areas which lead to impacts on local organisms and environment. Some of the impacts of non-native species on newly colonized areas may be positive. However, despite the empirical evidences of increase in water transparency by freshwater dresseinids, the hypothesis that dark false mussel enhances the quality of brackish water has never been tested so far. Thus, the present study aimed to determine M. leucophaeata impacts on the water quality of a nutrient-enriched coastal lagoon by (1) analyzing a historical water dataset for pre- and post-invasion at Rodrigo de Freitas Lagoon (Brazil) and (2) experimentally testing dark false mussel direct effects on water quality. Historical field data evidenced significant lower phytoplankton abundance and chlorophyll a, and higher water transparency for the post-invasion period. These pattens were also supported by time-series analyses, which detected a decreasing trend for total coliforms density and an increased trend for dissolved oxygen over time. Moreover, time series indicated a gradual increase in lagoon water level with time, but none or minor changes were evidenced for floodgates operation routine, meteorological variables, and the frequency of sewage input. In microcosms, M. leucophaeata was effective to increase water transparency and decrease E. coli densities. The combination of field and laboratory data partially supported the hypothesis that M. leucophaeata invasion promoted an improvement in lagoon water quality, but increased phosphorus availability through excretion in microcosm assays. Management of dark false mussel populations seems to be a potential strategy for water quality improvement within already invaded systems where high sewage-enriched effluents are released. However, as non-native species often unbalance ecological relationships and functioning of the invaded ecosystems, new introductions of M. leucophaeata must be avoided.