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NT157 has antineoplastic effects and inhibits IRS1/2 and STAT3/5 in JAK2^(V617F)-positive myeloproliferative neoplasm cells

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Signal Transduction and Targeted Therapy 2020年第1期5卷 2440-2449页

作者： Bruna alves Fenerich Jaqueline Cristina Fernandes ana paula nunes rodrigues alves Juan Luiz Coelho-Silva Renata Scopim-Ribeiro Priscila Santos Scheucher Christopher A.Eide Cristina E.Tognon Brian J.Druker Eduardo Magalhães Rego João Agostinho Machado-Neto Fabiola Traina Department of Medical Images Hematologyand Clinical OncologyUniversity of Sao Paulo at Ribeirao Preto Medical SchoolRibeirao PretoSao PauloBrazil Center for Cell-Based Therapy Sao Paulo Research FoundationRibeirao PretoSao PauloBrazil Knight Cancer Institute Oregon Health&Science UniversityPortlandORUSA Howard Hughes Medical Institute PortlandORUSA Department of Internal Medicine University of Sao Paulo Medical SchoolSao PauloBrazil Department of Pharmacology Institute of Biomedical Sciences of the University of Sao PauloSao PauloBrazil

Recent data indicate that IGF1R/IRS signaling is a potential therapeutic target in BCR-ABL1-negative myeloproliferative neoplasms(MPN);in this pathway,IRS2 is involved in the malignant transformation induced by JAK2^(V617F),and upregulation of IGF1R signaling induces the MPN ***157,a synthetic compound designed as an IGF1R-IRS1/2 inhibitor,has been shown to induce antineoplastic effects in solid ***,we aimed to characterize the molecular and cellular effects of NT157 in JAK2^(V617F)positive MPN cell lines(HEL and SET2)and primary patient hematopoietic *** JAK2^(V617F)cell lines,NT157 decreased cell viability,clonogenicity,and cell proliferation,resulting in increases in apoptosis and cell cycle arrest in the G2/M phase(p<0.05).NT157 treatment inhibited IRS1/2,JAK2/STAT,and NFκB signaling,and it activated the AP-1 complex,downregulated four oncogenes(CCND1,MYB,WT1,and NFKB1),and upregulated three apoptotic-related genes(CDKN1A,FOS,and JUN)(p<0.05).NT157 induced genotoxic stress in a JAK2/STAT-independent ***157 inhibited erythropoietin-independent colony formation in cells from polycythemia vera patients(p<0.05).These findings further elucidate the mechanism of NT157 action in a MPN context and suggest that targeting IRS1/2 proteins may represent a promising therapeutic strategy for MPN.

关键词： JAK2 IGF1R neoplasms STAT3

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Doxycycline induces bone repair and changes in Wnt signalling

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International Journal of Oral Science 2017年第3期9卷 158-166页

作者： kátia do nascimento gomes ana paula negreiros nunes alves paula góes pinheiro dutra glauce socorro de barros viana faculty of dentistry pharmacy and nursingfederal university of cearáFortalezaBrazil faculty of medicine federal university of cearáFortaleza Brazil

Doxycycline （DOX） exhibits anti-inflammatory and MMP inhibitory properties. The objectives of this study were to evaluate the effects of DOX on alveolar bone repair. Controls （CTL） and DOX-treated （10 and 25 mg. kg- 1） molars were extracted, and rats were killed 7 or 14 days later. The maxillae were processed and subjected to histological and immunohistochemical assays. Hematoxylin-eosin staining （7th day） revealed inflammation in the CTL group that was partly reversed after DOX treatment. On the 14th day, the CTL group exhibited bone neoformation, conjunctive tissue, re-epithelization and the absence of inflammatory infiltrate. DOX-treated groups exhibited complete re-epithelization, tissue remodelling and almost no inflammation. Picrosirius red staining in the DOXlO group （7th and 14th days） revealed an increased percentage of type I and III collagen fibres compared with the CTL and DOX25 groups. The DOXlO and DOX25 groups exhibited increases in osteoblasts on the 7th and 14th days. However, there were fewer osteoclasts in the DOXlO and DOX25 groups on the 7th and 14th days. Wnt-lOb- immunopositive cells increased by 130% and 150% on the 7th and 14th days, respectively, in DOX-treated groups compared with the CTL group. On the 7th day, Dickkopf （Dkk）-I immunostaining was decreased by 63% and 46% in the DOXlO and DOX25 groups, respectively. On the 14th day, 69% and 42% decreases in immunopositive cells were observed in the DOXlO and DOX25 groups, respectively, compared with the CTL group. By increasing osteoblasts, decreasing osteoclasts, activating Wnt lOb and neutralising Dkk, DOX is a potential candidate for bone repair in periodontal diseases.

关键词： alveolar bone loss bone diseases bone repair doxycycline Dickkopf-1 immunohistochemistry Wnt-lOb

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Agmatine as a novel candidate for rapid-onset antidepressant response

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World Journal of Psychiatry 2021年第11期11卷 981-996页

作者： ana paula Valverde Anderson Camargo ana Lúcia S rodrigues Department of Biochemistry Campus UniversitárioCenter for Biological SciencesUniversidade Federal de Santa CatarinaFlorianópolisSC 88040900Brazil

Major depressive disorder(MDD)is a disabling and highly prevalent mood disorder as well as a common cause of *** stress,inflammation,and intestinal dysbiosis have all been shown to play crucial roles in the pathophysiology of *** conventional antidepressants are widely used in the clinic,they can take weeks to months to produce therapeutic *** discovery that ketamine promotes fast and sustaining antidepressant responses is one of the most important breakthroughs in the pharmacotherapy of ***,the adverse psychomimetic/dissociative and neurotoxic effects of ketamine discourage its chronic ***,agmatine,an endogenous glutamatergic modulator,has been postulated to elicit fast behavioral and synaptogenic effects by stimulating the mechanistic target of rapamycin complex 1 signaling pathway,similar to ***,recent evidence has demonstrated that the modulation of the NLR family pyrin domain containing 3 inflammasome and gut microbiota,which have been shown to play a crucial role in the pathophysiology of MDD,may also participate in the antidepressant-like effects of both ketamine and *** review seeks to provide evidence about the mechanisms that may underlie the fast antidepressant-like responses of agmatine in preclinical *** the anti-inflammatory properties of agmatine,it may also be further investigated as a useful compound for the management of MDD associated with a pro-inflammatory ***,the fast antidepressant-like response of agmatine noted in animal models should be investigated in clinical studies.

关键词： Agmatine Fast-acting antidepressants Ketamine Major depressive disorder Microbiota-gut-brain axis Neuroinflammation

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Differential diagnosis between autism spectrum disorder and other developmental disorders with emphasis on the preschool period

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World Journal of Pediatrics 2023年第8期19卷 715-726页

作者： Taynara Amancio de Lima Patricia Aparecida Zuanetti Marina Estima Neiva nunes ana paula Andrade Hamad Department of Neurosciences and Behavioral Sciences Ribeirão Preto Medical SchoolUniversity of São PauloAv.Bandeirantes3900Monte AlegreRibeirão PretoSP14049-900Brazil University Hospital Ribeirão Preto Medical SchoolUniversity of São Paulo(HCFMRP-USP)Ribeirão PretoSPBrazil

Background Neurodevelopmental disorders are a heterogeneous group of conditions that manifest as delays or deviations in the acquisition of expected developmental milestones and behavioral *** spectrum disorder(ASD)is a neurodevelopmental disorder characterized by deficits in communication and social interaction and by repetitive and restricted patterns of behavior,interests and *** aim of this review is to discuss the clinical features of the differential diagnoses of ASD that are prevalent among preschoolers,focusing on their similarities and *** sources The international medical literature search was conducted using PubMed and was revised regarding the subject using single and/or combined keywords as follows:differential diagnosis,preschoolers,diagnostic challenge,attention deficit hyperactivity disorder,intellectual disability,high abilities/giftedness,childhood apraxia of speech,social communication disorder,Landau–Kleffner syndrome,stereotyped movement disorder and excessive screen *** We describe conditions commonly found in clinical practice,taking ASD as a *** addressed converging and divergent aspects of behavior,cognition,communication,language,speech,socialization,and stereotypes for the diagnosis of ASD and other disorders identified as potential differential or comorbid *** The ranking and characterization of symptoms appear to be essential for better understanding the underlying common ground between children with developmental disorders and children with ASD,thus properly diagnosing and directing social,professional,or medication *** detailed discussion adds to the literature since,although ASD differential diagnoses are frequently mentioned and discussed in textbooks and journal articles,they rarely occupy a prominent place as we aimed herein.

关键词： Autism spectrum disorder Clinical features Differential diagnosis Neurodevelopmental disorders Preschool

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Antioxidant Migration Studies in Chitosan Films Incorporated with Plant Extracts

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Journal of Renewable Materials 2018年第5期6卷 548-558页

作者： Victor Gomes Lauriano Souza Patricia Freitas rodrigues Maria paula Duarte ana Luisa Fernando MEtRiCS Departamento de Ciências e Tecnologia da BiomassaFaculdade de Ciências e Tecnologia(FCT)Universidade NOVA de LisboaCampus da Caparica2829-516 CaparicaPortugal CENIMAT/I3N Departamento de Ciências dos MateriaisFaculdade de Ciências e Tecnologia(FCT)Universidade NOVA de LisboaCampus da Caparica2829-516 CaparicaPortugal

The aim of this work was to develop an active biopolymer based on chitosan by incorporating natural *** essential oils(ginger,rosemary,sage,tea tree and thyme)and six hydro-alcoholic extracts(from ginger,green and black tea,kenaf leaves,rosemary and sage plants)were *** assays were carried out to evaluate the films’activity,and total phenolic content and antioxidant activity were monitored in the simulant during *** between natural compounds and polymeric matrix was evaluated by FTIR *** diffusion of the phenolic compounds was not detected in the films incorporated with hydro-alcoholic extracts(HAEs),indicating their entrapment in the *** was observed in the films with essential oils(EOs),and biobased films incorporated with ginger,sage or rosemary essential oils,presented the highest diffusion and antioxidant activity in the simulant,highlighting their functionality and potential to be used as food active packaging material.

关键词： Active packaging antioxidant activity biopolymers chitosan phenolic content

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A Brazilian experience of the self transglutaminase-based test for celiac disease case finding and diet monitoring

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World Journal of Gastroenterology 2009年第35期15卷 4423-4428页

作者： Lorete Maria da Silva Kotze ana paula Brambila rodrigues Luiz Roberto Kotze Renato Mitsunori Nisihara Gastroenterology and Endoscopy Services Cajuru HospitalPontifical Catholic University of ParanáCEP 80240-220CuritibaParanáBrazil Evangelical University and Laboratory of Immunopathology Clinical HospitalFederalUniversity of ParanáCEP 80240-220CuritibaParanáBrazil

AIM： To evaluate the effectiveness of a rapid and easy fingertip whole blood point-of-care test for celiac disease （CD） case finding and diet monitoring. METHODS： Three hundred individuals, 206 females （68.7%） and 94 males （31.3%）, were submitted to a rapid and easy immunoglobulin-A-dass fingertip whole blood point-of-care test in the doctor＇s office in order to make immediate clinical decisions： 13 healthy controls, 6 with CD suspicion, 46 treated celiacs, 84 relatives of the celiac patients, 69 patients with dyspepsia, 64 with irritable bowel syndrome （IBS）, 8 with Crohn＇s disease and 9 with other causes of diarrhea. RESULTS： Upper gastrointestinal endoscopy with duodenal biopsies was performed in patients with CD suspicion and in individuals with positive test outcome： in 83.3% （5/6） of the patients with CD suspicion, in 100% of the patients that admitted gluten-free diet transgressions （6/6）, in 3.8% of first-degree relatives （3/79） and in 2.9% of patients with dyspepsia （2/69）. In all these individuals duodenal biopsies confirmed CD （Marsh＇s histological classification）. The studied test showed good correlation with serologic antibodies, endoscopic and histological ***： The point-of-care test was as reliable as conventional serological tests in detecting CD cases and in CD diet monitoring.

关键词： Celiac disease Gluten Relatives Dyspepsia Diarrhea

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Medicinal plants from the Brazilian Amazonian region and their antileishmanial activity:a review

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Journal of Integrative Medicine 2018年第4期16卷 211-222页

作者： Bruno Jose Martins Da Silva Amanda anastacia Pinto Hage Edilene Oliveira Silva ana paula Drummond rodrigues Laboratory of Parasitology and Laboratory of Structural Biology Institute of Biological SdencesFederal University of PardBelemPard 66075-110Brazil National Institute of Science and Technology in Structural Biology and Bioimaging Rio de JaneiroRio de Janeiro 21941-901Brazil Laboratory of Electron Microscopy Department of Health SurveillanceMinistry of HealthEvandro Chagas InstituteBelemPard 66087-082Brazil

Leishmaniasis, a neglected disease caused by Leishmania protozoans, primarily affects people in tropical and subtropical areas. Chemotherapy based on the use of pentavalent antimonials, amphotericin B, paromomycin, miltefosine and liposomal amphotericin B is currently the only effective treatment. However, adverse effects, long-term treatment and the emergence of parasite resistance have led to the search for alternative treatments. Natural products used in traditional medicine provide an unlimited source of molecules for the identification of new drugs, and the Amazon region has abundant biodiversity that includes several species of plants and animals, providing a rich source of new products and com- pounds. Although the literature describes numerous promising compounds and extracts for combating Leishmania protozoans, the results of such research have not been embraced by the pharmaceutical industry for the development of new drugs. Therefore, this review focused on the antileishmanial activity of extracts, isolated compounds and essential oils commonly used by the local population in the Brazilian Amazonian region to treat several illnesses and described in the literature as promising compounds for combating leishmaniasis.

关键词： Amazonian plants Leishmaniasis treatment Plant compounds Plant extracts Plant oils

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Dealing with Multisource Information for Estuarine Flood Risk Appraisal in Two Western European Coastal Areas

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International Journal of Disaster Risk Science 2022年第2期13卷 199-213页

作者： ana rodrigues Rilo Alexandre Manuel de Oliveira Soares Tavares paula Maria dos Santos Freire José Luis Zêzere Estuarine and Coastal Zones Unit LNEC-National Civil Engineering Laboratory.1700-075 LisbonPortugal Centre of Geographical Studies Institute of Geography and Spatial PlanningUniversidade de Lisboa1700-066 LisbonPortugal Centre for Social Studies and Earth Sciences Department Coimbra University3030-790 CoimbraPortugal

Estuaries are usually affected by compound flooding triggers that cause diverse territorial *** fluvial flood risk assessment frameworks are well established in the literature,integrated management instruments that deal with estuarine flood risk remain incomplete and often *** research presents a methodology to extract relevant information from multiple sources post-event and a database building process that is applied to two contrasting estuaries(the Tagus River estuary in Portugal,and the Shannon River estuary in Ireland)in the Western European coastal ***,a total of 274 documents were analyzed and the information was stored in two *** correspondence analysis was applied to extract the most informative and relevant estuarine flood *** integrated estuarine flood risk assessment framework is presented and discussed based on the extracted *** framework is driven by two distinct dimensions(oceanic and hydrographic)and revealed the transversal position of triggers of estuarine floods,reflecting the compounding effects usually present in these *** results also highlight two levels of flood risk mostly based on damage typology.

关键词： Estuarine floods Estuarine flood indicators Multiple correspondence analysis Post-hazard multisource information Western Europe

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Dietary supplementation with free methionine or methionine dipeptide mitigates intestinal oxidative stress induced by Eimeria spp. challenge in broiler chickens

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Journal of Animal Science and Biotechnology 2019年第4期10卷 1005-1021页

作者： Angélica de Souza Khatlab ana paula Del Vesco Adhemar rodrigues de Oliveira Neto Roberta Pereira Miranda Fernandes Eliane Gasparino Animal Science Department State University of MaringáColombo Avenue5790Jardim UniversitárioMaringáParaná87020-900Brazil Animal Science Department Federal University of SergipeMarechal Rondon AvenueS/NJardim Rosa ElzeSao CristóvaoSergipe 49100-000Brazil EVONIK of Brazil Arquiteto Olavo Redig de Campos Street105Tower ASo PauloSP 04711-904Brazil Physiology Departament Federal University of SergipeMarechal Rondon AvenueS/NJardim Rosa ElzeSao CristóvaoSergipe 49100-000Brazil

Background: This study evaluated the effects of Eimeria spp. challenge and dietary supplementation with free methionine or methionine dipeptide on animal performance;expression of genes associated with the immune system, antioxidant system, and amino acid transport in the jejunum;and redox status of the jejunum of broiler ***: A randomized, 2 × 3 factorial design was used, in which Eimeria spp. challenge was the first factor(Eimeria-challenged, EC, or unchallenged, UC, broilers) and methionine supplementation was the second factor(non-supplemented, NS;free DL-methionine, DL-Met;and methionine dipeptide, DL-methionyl-DL-methionine, DLMMet). At 14 days of age, chickens were inoculated orally with sporulated oocysts of Eimeria acervulina, Eimeria praecox, Eimeria maxima, and Eimeria mitis. Birds were killed by cervical dislocation 144 h post-inoculation(PI), and the jejunum was collected for biochemical and molecular ***: EC broilers had a 13% lower feed intake(FI), 37% lower body weight gain(BWG), and 39% higher feed conversion ratio(FCR) than UC broilers. Chickens fed the DL-Met diet had higher BWG(about 12% higher) and better FCR(about 12% lower) than chickens fed the NS diet. EC chickens had lower relative weight of the bursa of Fabricius(51.8%) and higher relative weights of the spleen and whole intestine(53.6% and 26.3%, respectively) than UC chickens. Eimeria spp. challenge led to an increase in the levels of oxidative substances, such as nitrite and thiobarbituric acid reactive substances(TBARS), in the jejunum of chickens 144 h PI. Among UC chickens, those fed the DL-Met diet had higher total antioxidant capacity(TAC) and lower catalase(CAT) and superoxide dismutase(SOD) activities. EC chickens that received the NS diet had higher carbonylated protein content(CP). This result was associated with their lower TAC and catalase activity. The lower TAC in EC chickens might have been due to reduced expression of catalase(CAT) and superoxide

关键词： Antioxidant Coccidiosis Gut INFG PEPT1

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In vitro antileishmanial effects of Physalis angulata root extract on Leishmania infantum

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Journal of Integrative Medicine 2018年第6期16卷 404-410页

作者： Bruno Jose Martins Da Silva Sandro Wilson Gomes Pereira ana paula Drummond rodrigues Jose Luiz Martins Do Nascimento Edilene Oliveira Silva Laboratory of Structural Biology Institute of Biological SciencesFederal University of PardBelemPard 66075-110Brazil National Institute of Science and Technology in Structural Biology and Bioimaging(INCT-INBEB) Rio de Janeiro 21941-901Brazil Laboratory of Electron Microscopy Department of Health SurveillanceMinistry of HealthEvandro Chagas InstituteBelemPard 66087-082Brazil Laboratory of Molecular and Cellular Neurochemistry Institute of Biological SciencesFederal University of PardBelemPard 66075-110Brazil National Institute of Science and Technology in Neuroimmunomodulation(INCT-NIM) Rio de Janeiro 21040-360Brazil

Objective： In the present study, we evaluated the effects of the aqueous extract of Physalis angulata root （AEPa） on Leishmania infanturn proliferation, morphology, and the driving mechanism in leishmanicidal activity and modulatory action on macrophages. Methods： I., infantum promastigotes were treated with 50 and 100 μg/mL AEPa for 72 h and then antipro- mastigote assay was performed by counts in a Newbauer chamber, morphological changes were analyzed by transmission electron microscopy and the mechanism of the leishmanicidal activity was detected. In addition, macrophages were infected with L. infantum and were used to evaluate anti-amastigote activity of AEPa and effects of AEPa on cytokine secretion after 72-hour treatment. Results： Treatment with AEPa reduced the numbers ofL infantum promastigotes （50% inhibitory concen- tration （ICso） = 65.9μg/mL; selectivity index （SI）= 22.1） and amastigotes （ICso = 37.9 μg/mL; SI = 38.5） compared with the untreated control. Amphotericin B reduced 100% of the promastigote numbers after 72 h of treatment （IC50 = 0.2μg/mL）. AEPa induced several morphological changes and increased the production of reactive oxygen species and apoptotic death in promastigotes after treating for 72 h. AEPa （100 μg/mL） promoted tumor necrosis factor-α secretion in macrophages infected with L. infantum after 72 h of treatment, but did not induce an increase in this cytokine in noninfected macrophages. In addition, AEPa showed no cytotoxic effect on J774-A1 cells （50% cytotoxic concentration 〉1000μg/mL）. Conclusion： AEPa presented antileishmanial activity against the promastigotes and amastigotes of I.. infantum without macrophage cytotoxicity; these results show that natural products such as P. angulata have leishmanicidal potential and in the future may be an alternative treatment for leishmaniasis.

关键词： Leishmanicidal activity Leishmania infantum Reactive oxygen species Apoptosis Physalis angulata

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