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1.
Int J Mol Med ; 47(4): 1, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33537817

RESUMO

Inflammation is the most common cause of most acute and chronic debilitating diseases. Towards unveiling novel therapeutic options for patients with such complications, N­bromotaurine (TauNHBr) has emerged as a potential anti­inflammatory agent; however, its therapeutic efficacy is hindered due to its relatively poor stability. To address this challenge, the present study focused on examining the effects of a stable active bromine compound, named bromamine T (BAT). The present study examined the protective properties of BAT against lipopolysaccharide (LPS)­mediated inflammation in vitro, by using LPS­stimulated murine J774.A1 macrophages (Mφs), as well as in vivo, by using a murine LPS­mediated air­pouch model. Additionally, its efficacy was compared with that of taurine, a known potent anti­inflammatory molecule. In LPS­stimulated J774A.1 Mφs, BAT and taurine were very effective in reducing the secretion of pro­inflammatory mediators. The in vitro experiments indicated that LPS­mediated inflammation was attenuated due to the protective properties of BAT and of taurine, probably through the inhibition of phosphorylated p65 NF­κB subunit (Ser 536) nuclear translocation. The in vivo experiments also revealed that BAT and taurine inhibited LPS­mediated inflammation by reducing total cell/polymorphonuclear cell (PMN) infiltration in the air­pouch and by decreasing pouch wall thickness. The analysis of exudates obtained from pouches highlighted that the inhibitory effects of BAT and taurine on the secretion of pro­inflammatory cytokines were similar to those observed in vitro. Notably, the effect of BAT at the highest concentration tested was superior to that of taurine at the highest concentration. Taken together, the findings of the present study indicate that BAT prevents the LPS­induced inflammatory response both in vitro and in vivo.


Assuntos
Bromo/uso terapêutico , Inflamação/tratamento farmacológico , Sulfonamidas/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Bromo/farmacologia , Linhagem Celular , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Fosforilação/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sulfonamidas/farmacologia , Taurina/farmacologia , Fator de Transcrição RelA/metabolismo , Transcrição Genética/efeitos dos fármacos
2.
Trials ; 22(1): 116, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33546739

RESUMO

OBJECTIVES: Baricitinib is supposed to have a double effect on SARS-CoV2 infection. Firstly, it reduces the inflammatory response through the inhibition of the Januse-Kinase signalling transducer and activator of transcription (JAK-STAT) pathway. Moreover, it reduces the receptor mediated viral endocytosis by AP2-associated protein kinase 1 (AAK1) inhibition. We propose the use of baricinitib to prevent the progression of the respiratory insufficiency in SARS-CoV2 pneumonia in onco-haematological patients. In this phase Ib/II study, the primary objective in the safety cohort is to describe the incidence of severe adverse events associated with baricitinib administration. The primary objective of the randomized phase (baricitinib cohort versus standard of care cohort) is to evaluate the number of patients who did not require mechanical oxygen support since start of therapy until day +14 or discharge (whichever it comes first). The secondary objectives of the study (only randomized phase of the study) are represented by the comparison between the two arms of the study in terms of mortality and toxicity at day+30. Moreover, a description of the immunological related changes between the two arms of the study will be reported. TRIAL DESIGN: The trial is a phase I/II study with a safety run-in cohort (phase 1) followed by an open label phase II randomized controlled trial with an experimental arm compared to a standard of care arm. PARTICIPANTS: The study will be performed at the Institut Català d'Oncologia, a tertiary level oncological referral center in the Catalonia region (Spain). The eligibility criteria are: patients > 18 years affected by oncological diseases; ECOG performance status < 2 (Karnofsky score > 60%); a laboratory confirmed infection with SARS-CoV-2 by means of real -time PCR; radiological signs of low respiratory tract disease; absence of organ dysfunction (a total bilirubin within normal institutional limits, AST/ALT≤2.5 X institutional upper limit of normal, alkaline phosphatase ≤2.5 X institutional upper limit of normal, coagulation within normal institutional limits, creatinine clearance >30 mL/min/1.73 m2 for patients with creatinine levels above institutional normal); absence of HIV infection; no active or latent HBV or HCV infection. The exclusion criteria are: patients with oncological diseases who are not candidates to receive any active oncological treatment; hemodynamic instability at time of study enrollment; impossibility to receive oral medication; medical history of recent or active pulmonary embolism or deep venous thrombosis or patients at high-risk of suffering them (surgical intervention, immobilization); multi organ failure, rapid worsening of respiratory function with requirement of fraction of inspired oxygen (FiO2) > 50% or high-flow nasal cannula before initiation of study treatment; uncontrolled intercurrent illness (ongoing or severe active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements); allergy to one or more of study treatments; pregnant or breastfeeding women; positive pregnancy test in a pre-dose examination. Patients should have the ability to understand, and the willingness to sign, a written informed consent document; the willingness to accept randomization to any assigned treatment arm; and must agree not to enroll in another study of an investigational agent prior to completion of Day +28 of study. An electronic Case Report Form in the Research Electronic Data Capture (REDCap) platform will be used to collect the data of the trial. Removal from the study will apply in case of unacceptable adverse event(s), development of an intercurrent illness, condition or procedural complication, which could interfere with the patient's continued participation and voluntary patient withdrawal from study treatment (all patients are free to withdraw from participation in this study at any time, for any reasons, specified or unspecified, and without prejudice). INTERVENTION AND COMPARATOR: Treatment will be administered on an inpatient basis. We will compare the experimental treatment with baricitinib plus the institutional standard of care compared with the standard of care alone. During the phase I, we will define the dose-limiting toxicity of baricitinib and the dose to be used in the phase 2 part of the study. The starting baricitinib dose will be an oral tablet 4 mg-once daily which can be reduced to 2 mg depending on the observed toxicity. The minimum duration of therapy will be 5 days and it can be extended to 7 days. The standard of care will include the following therapies. Antibiotics will be individualized based on clinical suspicion, including the management of febrile neutropenia. Prophylaxis of thromboembolic disease will be administered to all participants. Remdesivir administration will be considered only in patients with severe pneumonia (SatO2 <94%) with less than 7 days of onset of symptoms and with supplemental oxygen requirements but not using high-flow nasal cannula, non-invasive or invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO). In the randomized phase, tocilizumab or interferon will not be allowed in the experimental arm. Tocilizumab can be used in patients in the standard of care arm at the discretion of the investigator. If it is prescribed it will be used according to the following criteria: patients who, according to his baseline clinical condition, would be an ICU tributary, interstitial pneumonia with severe respiratory failure, patients who are not on mechanical ventilation or ECMO and who are still progressing with corticoid treatment or if they are not candidates for corticosteroids. Mild ARDS (PAFI <300 mmHg) with radiological or blood gases deterioration that meets at least one of the following criteria: CRP >100mg/L D-Dimer >1,000µg/L LDH >400U/L Ferritin >700ng/ml Interleukin 6 ≥40ng/L. The use of tocilizumab is not recommended if there are AST/ALT values greater than 10 times the upper limit of normal, neutrophils <500 cells/mm3, sepsis due to other pathogens other than SARS-CoV-2, presence of comorbidity that can lead to a poor prognosis, complicated diverticulitis or intestinal perforation, ongoing skin infection. The dose will be that recommended by the Spanish Medicine Agency in patients ≥75Kg: 600mg dose whereas in patients <75kg: 400mg dose. Exceptionally, a second infusion can be assessed 12 hours after the first in those patients who experience a worsening of laboratory parameters after a first favourable response. The use of corticosteroids will be recommended in patients who have had symptoms for more than 7 days and who meet all the following criteria: need for oxygen support, non-invasive or invasive mechanical ventilation, acute respiratory failure or rapid deterioration of gas exchange, appearance or worsening of bilateral alveolar-interstitial infiltrates at the radiological level. In case of indication, it is recommended: dexamethasone 6mg/d p.o. or iv for 10 days or methylprednisolone 32mg/d orally or 30mg iv for 10 days or prednisone 40mg day p.o. for 10 days. MAIN OUTCOMES: Phase 1 part: to describe the toxicity profile of baricitinib in COVID19 oncological patients during the 5-7 day treatment period and until day +14 or discharge (whichever it comes first). Phase 2 part: to describe the number of patients in the experimental arm that will not require mechanical oxygen support compared to the standard of care arm until day +14 or discharge (whichever it comes first). RANDOMISATION: For the phase 2 of the study, the allocation ratio will be 1:1. Randomization process will be carried out electronically through the REDcap platform ( https://www.project-redcap.org/ ) BLINDING (MASKING): This is an open label study. No blinding will be performed. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The first part of the study (safety run-in cohort) will consist in the enrollment of 6 to 12 patients. In this population, we will test the toxicity of the experimental treatment. An incidence of severe adverse events grade 3-4 (graded by Common Terminology Criteria for Adverse Events v.5.0) inferior than 33% will be considered sufficient to follow with the next part of the study. The second part of the study we will perform an interim analysis of efficacy at first 64 assessed patients and a definitive one will analyze 128 assessed patients. Interim and definitive tests will be performed considering in both cases an alpha error of 0.05. We consider for the control arm this rate is expected to be 0.60 and for the experimental arm of 0.80. Considering this data, a superiority test to prove a difference of 0.20 with an overall alpha error of 0.10 and a beta error of 0.2 will be performed. Considering a 5% of dropout rate, it is expected that a total of 136 patients, 68 for each study arm, will be required to complete study accrual. TRIAL STATUS: Version 5.0. 14th October 2020 Recruitment started on the 16th of December 2020. Expected end of recruitment is June 2021. TRIAL REGISTRATION: AEMPs: 20-0356 EudraCT: 2020-001789-12, https://www.clinicaltrialsregister.eu/ctr-search/search (Not publically available as Phase I trial) Clinical trials: BARCOVID19, https://www.clinicaltrials.gov/ (In progress) FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol."


Assuntos
Antivirais/efeitos adversos , Azetidinas/efeitos adversos , Neoplasias Hematológicas/complicações , Purinas/efeitos adversos , Pirazóis/efeitos adversos , Insuficiência Respiratória/prevenção & controle , Sulfonamidas/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , /epidemiologia , /virologia , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Estudos de Coortes , Feminino , Neoplasias Hematológicas/epidemiologia , Neoplasias Hematológicas/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Oxigenoterapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Reação em Cadeia da Polimerase em Tempo Real , Insuficiência Respiratória/epidemiologia , Espanha/epidemiologia , Resultado do Tratamento , Adulto Jovem
3.
Medicine (Baltimore) ; 100(6): e24703, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33578607

RESUMO

RATIONALE: The abnormal expression of B-cell lymphoma-2 (Bcl-2) family members is often associated with the progression of the disease. Bcl-2 inhibitors (eg, venetoclax) were first reported to inhibit the proliferation of malignant lymphocytes and have a significant effect on patients with chronic lymphoblastic leukemia, but research on myeloid tumors is relatively delayed. Venetoclax was approved in 2018 for the treatment of acute myeloid leukemia (AML) patients who were not suitable for high-dose chemotherapy. The approval of venetoclax is an advance in the treatment of hematological tumors. PATIENT CONCERNS: Here we report a 64-year-old male with an increased white blood cell (WBC) count (39.0 × 109/L) and lymphocyte count (30.6 × 109/L) on physical examination in July 2014. The patients were diagnosed with chronic lymphocytic leukemia (CLL) through bone marrow (BM) smears and immunophenotyping without any cytogenetic or molecular abnormalities. Chlorambucil was prescribed, WBC was stable between 15 × 109/L and 25 × 109/L in the past 6 years. He came to the hospital again in May 2020 and complained of fatigue for 2 weeks. WBC (16.7 × 109/L) and lymphocyte (14.76 × 109/L) counts were increased, hemoglobin (HGB) and platelet (PLT) were decreased in peripheral blood, which indicated the progression of the disease. DIAGNOSES: The patient was diagnosed as secondary AML after CLL based on the clinical and laboratory findings. INTERVENTIONS: He achieved a morphological complete remission in both AML and CLL without any adverse reactions after one course of venetoclax monotherapy. OUTCOMES: He received standard daunorubicin and cytarabine combined with venetoclax as consolidation therapy and is now ready for allogeneic-hematopoietic stem cell transplantation. LESSONS: Our case presents a challenge to traditional treatment. New drugs such as venetoclax have shown outstanding effects in this respect. High expression of Bcl-2 can identify the responders of venetoclax. These findings should be validated in future clinical trials. We fully believe that in the near future, the comprehensive use of targeted drugs with different mechanisms will not only improve the quality of life of patients, but also completely change the prognosis of patients with recurrent and refractory hematological malignancies.


Assuntos
Leucemia Linfocítica Crônica de Células B/complicações , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/etiologia , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/uso terapêutico , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Citarabina/administração & dosagem , Citarabina/uso terapêutico , Daunorrubicina/administração & dosagem , Daunorrubicina/uso terapêutico , Progressão da Doença , Transplante de Células-Tronco Hematopoéticas/normas , Humanos , Imunofenotipagem/métodos , Leucemia Linfocítica Crônica de Células B/patologia , Leucemia Mieloide Aguda/patologia , Contagem de Leucócitos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêutico , Resultado do Tratamento
4.
Nat Commun ; 12(1): 76, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397953

RESUMO

Full development of IL-17 producing CD4+ T helper cells (TH17 cells) requires the transcriptional activity of both orphan nuclear receptors RORα and RORγt. However, RORα is considered functionally redundant to RORγt; therefore, the function and therapeutic value of RORα in TH17 cells is unclear. Here, using mouse models of autoimmune and chronic inflammation, we show that expression of RORα is required for TH17 cell pathogenicity. T-cell-specific deletion of RORα reduces the development of experimental autoimmune encephalomyelitis (EAE) and colitis. Reduced inflammation is associated with decreased TH17 cell development, lower expression of tissue-homing chemokine receptors and integrins, and increased frequencies of Foxp3+ T regulatory cells. Importantly, inhibition of RORα with a selective small molecule antagonist mostly phenocopies our genetic data, showing potent suppression of the in vivo development of both chronic/progressive and relapsing/remitting EAE, but with no effect on overall thymic cellularity. Furthermore, use of the RORα antagonist effectively inhibits human TH17 cell differentiation and memory cytokine secretion. Together, these data suggest that RORα functions independent of RORγt in programming TH17 pathogenicity and identifies RORα as a safer and more selective therapeutic target for the treatment of TH17-mediated autoimmunity.


Assuntos
Inflamação/imunologia , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Células Th17/imunologia , Animais , Autoimunidade/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Doença Crônica , Colo/patologia , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental , Células HEK293 , Humanos , Inflamação/genética , Camundongos Endogâmicos C57BL , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Tamanho do Órgão/efeitos dos fármacos , Índice de Gravidade de Doença , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Tiofenos/química , Tiofenos/farmacologia
5.
Theranostics ; 11(1): 316-329, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33391477

RESUMO

Severe coronavirus disease 2019 (COVID-19) is characterized by systemic hyper-inflammation, acute respiratory distress syndrome, and multiple organ failure. Cytokine storm refers to a set of clinical conditions caused by excessive immune reactions and has been recognized as a leading cause of severe COVID-19. While comparisons have been made between COVID-19 cytokine storm and other kinds of cytokine storm such as hemophagocytic lymphohistiocytosis and cytokine release syndrome, the pathogenesis of cytokine storm has not been clearly elucidated yet. Recent studies have shown that impaired response of type-1 IFNs in early stage of COVID-19 infection played a major role in the development of cytokine storm, and various cytokines such as IL-6 and IL-1 were involved in severe COVID-19. Furthermore, many clinical evidences have indicated the importance of anti-inflammatory therapy in severe COVID-19. Several approaches are currently being used to treat the observed cytokine storm associated with COVID-19, and expectations are especially high for new cytokine-targeted therapies, such as tocilizumab, anakinra, and baricitinib. Although a number of studies have been conducted on anti-inflammatory treatments for severe COVID-19, no specific recommendations have been made on which drugs should be used for which patients and when. In this review, we provide an overview of cytokine storm in COVID-19 and treatments currently being used to address it. In addition, we discuss the potential therapeutic role of extracorporeal cytokine removal to treat the cytokine storm associated with COVID-19.


Assuntos
Anti-Inflamatórios/uso terapêutico , Síndrome da Liberação de Citocina/imunologia , Citocinas/metabolismo , Imunossupressores/uso terapêutico , Anti-Inflamatórios/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Azetidinas/farmacologia , Azetidinas/uso terapêutico , /imunologia , Ensaios Clínicos como Assunto , Síndrome da Liberação de Citocina/tratamento farmacológico , Citocinas/antagonistas & inibidores , Citocinas/imunologia , Humanos , Imunossupressores/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Purinas/farmacologia , Purinas/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Fatores de Transcrição STAT/antagonistas & inibidores , Fatores de Transcrição STAT/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Resultado do Tratamento
6.
Sci Total Environ ; 751: 142217, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-33181985

RESUMO

Global use of antibiotics has exceedingly enhanced in agricultural, veterinary and prophylactic human use in recent days. Hence, these antibiotics can easily be found in the environment. This study revealed the occurrence of emerging MDR and ESBL producing strains, pollution profile, and factors integrons (intI1 and intI2) and environmental factors associated, in the riverine systems under different ecological and geo-climatic zones were investigated. The samples were collected based on anthropogenic intervention such as discharge of domestic wastes, industrial wastes, hospital, and municipal wastes. Among 160bacterial morphotypes, 121 (75.62%) exhibited MDR trait with maximum resistance towards lincosamide (CD = 71.3%), beta-lactams (P = 70.6%; AMX = 66.3%), cephalosporin (CZ = 60.6%; CXM = 34.4%), sulfonamide (COT = 50.6%; TR = 43.8%) followed by macrolide (E = 29.4%), tetracycline (TET = 18.8%), aminoglycosides (S = 18.8%; GEN = 6.3%), fluoroquinolones (NX = 18.1%; OF = 4.4%) and carbapenem (IPM = 5.0%). IntI1 gene was detected in 73 (60.3%) of isolates, whereas intI2 was found in 11 (9.09%) isolates. Eight (6.61%) isolates carried both integron genes (intI1 and intI2). sul1 and dfrA1 genes were detected in 53 (72.6%) and 63 (86.3%) isolates, respectively. A total of 103 (85.1%) were found ESBL positive with the presence of ESBL genes in 100 (97.08%) isolates. In riverine systems most prevalent ESBL gene blaTEM (93.0%) was detected alone as well as in combination with bla genes. The data can be utilized for public awareness and regulation of guidelines by local governing bodies as an alarming threat to look-out against the prevalent resistance in environment thereby assisting in risk management during epidemics. This study is a comprehensive investigation of emerging antibiotic pollutants and its resistance in bacteria associated with factors integrons-integrase responsible for its dissemination. It may also assist in global surveillance of antibiotic resistance and policies to curtail unnecessary antibiotic use.


Assuntos
Integrases , Integrons , Antibacterianos , Humanos , Testes de Sensibilidade Microbiana , Sulfonamidas
7.
Chemosphere ; 262: 128026, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33182090

RESUMO

The objective of the study was to assess the applicability of the mycelium obtained from the in vitro cultures of nontoxic bracket fungus, Pleurotus eryngii, to sulfonamides mycodegradation. Samples containing one of the six selected sulfonamides, sulfanilamide derivatives, were incubated with the mycelium of P. eryngii for 7 and 14 days in vitro. Subsequently, change in the sulfonamide concentration was assessed in the samples using the UPLC-QTof. The transformation products were identified based on monoisotopic molecular mass and fragmentation spectra. The studied sulfonamides did not inhibit the growth of P. eryngii mycelium in the in vitro cultures. In addition, a considerable reduction of sulfonamide concentration was observed in all the incubated samples (from 73.7 ± 8.3% to 99.8 ± 0.3%). In the case of three sulfonamides, the reduction in concentration >90% occurred after 7 days of incubation. However, the transformation of sulfonamides was partially caused by their degradation to simpler organic compounds. After incubation, the products of condensation of sulfonamides with formyl, acyl, and sugar groups, and amino acid-derived compounds were identified in the samples. This indicated the partially reversible nature of the mycodegradation process.


Assuntos
Poluentes Ambientais/análise , Modelos Teóricos , Micélio/metabolismo , Pleurotus/metabolismo , Sulfonamidas/análise , Biodegradação Ambiental , Biomassa , Carboidratos/análise , Poluentes Ambientais/metabolismo , Micélio/crescimento & desenvolvimento , Pleurotus/crescimento & desenvolvimento , Sulfonamidas/metabolismo
8.
Food Chem ; 335: 127658, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32731124

RESUMO

Raphanus sativus var. longipinnatus, was exposed under experimental conditions to herbicides: rimsulfuron (RIM), administrated as (1) pure substance, (2) in commercially available formulation (RIMEL), (3) its degradation product: 4,6-dimethoxypyrimidin-2-amine (2ADP), (4) mesotrione (MES), (5) sulcotrione (SUL). Profiling and fingerprinting strategies, conducted by LC-MS/MS-FL, were employed to find markers of plant exposure to herbicide stress. The presence ofRIM metabolite in the tissues of plant exposed to this herbicide proved that it is necessary to determine both parent compound and its by-products to obtain reliable information on plant exposure to agrochemicals. A higher content of normetanephrine (NMN) (18-175%) and lower content of tyramine (TYR) (49-75%) and epinephrine (E) (75-83%) was observed in plant tissues exposed to RIM and 2ADP in comparison to blank sample. Therefore, NMN, TRY and E may be considered as markers of plant response to RIM. Non-target analysis enables to recognize the type of herbicide used during cultivation.


Assuntos
Herbicidas/toxicidade , Resíduos de Praguicidas/análise , Piridinas/toxicidade , Raphanus/química , Raphanus/efeitos dos fármacos , Sulfonamidas/toxicidade , Cromatografia Líquida , Cicloexanonas/farmacocinética , Cicloexanonas/toxicidade , Biomarcadores Ambientais , Epinefrina/análise , Mesilatos/farmacocinética , Mesilatos/toxicidade , Metaboloma , Normetanefrina/análise , Plantas Comestíveis/química , Plantas Comestíveis/efeitos dos fármacos , Piridinas/farmacocinética , Pirimidinas/toxicidade , Raphanus/metabolismo , Sulfonamidas/farmacocinética , Espectrometria de Massas em Tandem , Tiramina/análise
9.
J Environ Manage ; 280: 111749, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33309112

RESUMO

The novel HNO3-modifitied biochar (NBC) was synthesized from walnut shell. The NBC was characterized from scanning electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction, X-ray photoelectron spectroscopy and Raman spectrum. The NBC was then used in the adsorption of sulfadiazine, sulfamethazine and sulfachloropyridazine from aqueous solution. The material surface has carbon/oxygen-contained groups, which is benefit for the adsorption. The results showed the adsorption ability of NBC on three sulfonamides were 32, 46, and 40 mg g-1, respectively. The kinetic was found to follow the Elovich model and the isotherm conformed Freundlich. Adsorption was more favorable at weak acidic solution. The interactions mainly include π-π EDA, electrostatic interaction, Lewis acid-base interaction, hydrophobic interaction and H-bond.


Assuntos
Juglans , Poluentes Químicos da Água , Adsorção , Antibacterianos , Carvão Vegetal , Cinética , Espectroscopia de Infravermelho com Transformada de Fourier , Sulfonamidas , Poluentes Químicos da Água/análise
10.
Chemosphere ; 266: 129194, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33316476

RESUMO

The overuse of antibiotics and subsequent enrichment of antibiotic resistant microbes in the natural and built environments is a severe threat to global public health. In this study, a Phanerochaete chrysosporium fungal-luffa fiber system was found to efficiently biodegrade two sulfonamides, sulfadimethoxine (SDM) and sulfadizine (SDZ), in cow urine wastewater. Biodegradation pathways were proposed on the basis of key metabolites identified using high performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (HPLC-QqTOF-MS). Transcriptomic, metabolomic, and free radical analyses were performed to explore the functional groups and detailed molecular mechanisms of SDM and SDZ degradation. A total of 27 UniGene clusters showed significant differences between luffa fiber and luffa fiber-free systems, which were significantly correlated to cellulose catabolism, carbohydrate metabolism, and oxidoreductase activity. Carbohydrate-active enzymes and oxidoreductases appear to play particularly important roles in SDM and SDZ degradation. Electron paramagnetic resonance (EPR) spectroscopy revealed the generation and evolution of OH and R during the biodegradation of SDM and SDZ, suggesting that beyond enzymatic degradation, SDM and SDZ were also transformed through a free radical pathway. Luffa fiber also acts as a co-substrate to improve the activity of enzymes for the degradation of SDM and SDZ. This research provides a potential strategy for removing SDM and SDZ from agricultural and industrial wastewater using fungal-luffa fiber systems.


Assuntos
Luffa , Phanerochaete , Biodegradação Ambiental , Phanerochaete/genética , Sulfonamidas , Transcriptoma
11.
Pest Manag Sci ; 77(1): 253-263, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32687689

RESUMO

BACKGROUND: Residual herbicides are an important component in many weed control strategies. Their herbicidal activity depends on their fate in soil, with respect to the required concentration for weed control in space and time. In this study, the effect of weather conditions on sulfosulfuron fate in soil, following pre-planting incorporation, and the predicted control efficacy of Egyptian broomrape in tomato, were analyzed for two sites using simulations in Hydrus-1D modeling software. Simulated concentration was compared to measured data from field experiments. RESULTS: Model evaluation against measured data from two fields, with weakly alkaline clay soils, showed high correlations between simulated and measured sulfosulfuron concentrations (r = 0.98 and 0.89). The ratio of measured to simulated concentration was relatively low (1.03) at the top 10-cm layer, in which the mean measured concentration was high (29.6 ng g-1 ). This ratio was higher (12.5) at the 30-60 cm depth, in which the mean measured concentration was lower (0.3 ng g-1 ). Simulations of sulfosulfuron fate in each site, using weather data from the years 2009 to 2019, revealed substantial variations in transport patterns. Thirty days after treatment, 16 out of the 22 years simulated for the two sites (11 at each site) resulted in concentrations lower than the critical value for Egyptian broomrape control throughout the soil profile. The data indicates that variation in sulfosulfuron fate is mainly due to differences in the cumulative precipitation. According to simulation results, cumulative precipitation above 20 or 10 mm during the first 10 or 20 days after treatment, respectively, is expected to reduce the efficiency of broomrape control. CONCLUSION: Considering weather effects when planning herbicide application could optimize herbicide use efficiency. A decision-support tool is presented, whose factors are the time gap and precipitation amount between sulfosulfuron application and tomato planting.


Assuntos
Herbicidas , Poluentes do Solo , Herbicidas/análise , Pirimidinas/análise , Solo , Poluentes do Solo/análise , Sulfonamidas , Tempo (Meteorologia)
12.
J Environ Sci (China) ; 101: 413-427, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33334535

RESUMO

Passive techniques are a constantly evolving approach to the long-term monitoring of micropollutants, including pharmaceuticals, in the aquatic environment. This paper presents, for the first time, the calibration results of a new CNTs-PSDs (carbon nanotubes used as a sorbent in passive sampling devices) with an examination of the effect of donor phase salinity, water pH and the concentration of dissolved humic acids (DHAs), using both ultrapure and environmental waters. Sampling rates (Rs) were determined for the developed kinetic samplers. It has been observed that the impact of the examined environmental factors on the Rs values strictly depends on the type of the analytes. In the case of ß-blockers, the only environmental parameter affecting their uptake rate was the salinity of water. A certain relationship was noted, namely the higher the salt concentration in water, the lower the Rs values of ß-blockers. In the case of sulfonamides, water salinity, water pH 7-9 and DHAs concentration decreased the uptake rate of these compounds by CNTs-PSDs. The determined Rs values differed in particular when the values obtained from the experiments carried out using ultrapure water and environmental waters were compared. The general conclusion is that the calibration of novel CNTs-PSDs should be carried out under physicochemical conditions of the aquatic phase that are similar to the environmental matrix.


Assuntos
Nanotubos de Carbono , Poluentes Químicos da Água , Calibragem , Monitoramento Ambiental , Sulfonamidas , Água , Poluentes Químicos da Água/análise
13.
Bioresour Technol ; 319: 124160, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33010716

RESUMO

Sulfonamide antibiotics (SMs), as a class of antibiotics commonly used in swine industries, pose a serious threat to animal and human health. This study aims to evaluate the performance of an anaerobic membrane bioreactor (AnMBR) with and without supplying a new pomelo peel derived biochar to treat swine wastewater containing SMs. Results show that 0.5 g/L biochar addition could increase more than 30% of sulfadiazine (SDZ) and sulfamethazine (SMZ) removal in AnMBR. Approximately 95% of chemical oxygen demand (COD) was removed in the AnMBR at an influent organic loading rate (OLR) of 3.27 kg COD/(m3·d) while an average methane yield was 0.2 L/g CODremoved with slightly change at a small dose 0.5 g/L biochar addition. SMs inhibited the COD removal and methane production and increased membrane fouling. The addition of biochar could reduce the membrane fouling by reducing the concentration of SMP and EPS.


Assuntos
Antibacterianos , Águas Residuárias , Anaerobiose , Animais , Reatores Biológicos , Carvão Vegetal , Membranas Artificiais , Sulfonamidas , Suínos , Eliminação de Resíduos Líquidos
14.
Food Chem ; 339: 127580, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32858380

RESUMO

In this study, a microbiological inhibition method for rapidly screening antibiotics in swine urine was established with an easy sample pre-treatment. The microbiological system consisted of an agar medium mixed with nutrients, sensitizers, a test bacterium (Geobacillus stearothermophilus ATCC12980) and pH indicator (bromocresol purple). It was observed that the detection limits of the test kit for twenty-eight common antimicrobial residues in urine, including ß-lactams, aminoglycosides, tetracyclines, sulfonamides, macrolides, and lincosamides, were less than or equal to the maximum residue limits of the kidney, as determined by the EU and China. Moreover, the false negative rate and the false positive rate, along with other performance indexes such as interassay coefficients of variation and shelf life of the kit, all met the standard requirements of the ISO13969:2003 guidelines. Additionally, our results were consistent with those using the gold-standard physical chemistry method, which suggest the proposed method is suitable for screening antibiotic residues.


Assuntos
Antibacterianos/urina , Resíduos de Drogas/análise , Ensaios de Triagem em Larga Escala/métodos , Drogas Veterinárias/urina , Aminoglicosídeos/farmacologia , Aminoglicosídeos/urina , Animais , Antibacterianos/análise , Antibacterianos/farmacologia , Meios de Cultura , Reações Falso-Negativas , Reações Falso-Positivas , Contaminação de Alimentos/análise , Geobacillus stearothermophilus/efeitos dos fármacos , Limite de Detecção , Macrolídeos/farmacologia , Macrolídeos/urina , Sensibilidade e Especificidade , Sulfonamidas/farmacologia , Sulfonamidas/urina , Suínos , Tetraciclinas/farmacologia , Tetraciclinas/urina , Drogas Veterinárias/farmacologia
15.
Drugs Today (Barc) ; 56(12): 755-768, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33332482

RESUMO

Fedratinib hydrochloride is a selective Janus kinase 2 (JAK2) inhibitor approved by the U.S. Food and Drug Administration (FDA) in August 2019 for intermediate- 2 or high-risk primary or secondary myelofibrosis. The approval of this novel oral agent was based on the phase II and III JAKARTA-2 and JAKARTA trials, which both showed significant reduction in splenomegaly and myelofibrosis symptom burden. The most common adverse effects associated with fedratinib include anemia, gastrointestinal symptoms and elevation in liver transaminases. Early clinical trial data was concerning for an increased incidence of Wernicke's encephalopathy (WE), which led the FDA to place a clinical hold on further drug development. However, upon further investigation it was determined that there was no clear evidence that fedratinib causes WE, and the clinical hold was lifted in 2017. This inclusive review provides insight into the pharmacology, safety and efficacy, and future direction of fedratinib use in myeloproliferative neoplasms.


Assuntos
Mielofibrose Primária , Desenvolvimento de Medicamentos , Humanos , Mielofibrose Primária/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Pirrolidinas , Sulfonamidas
16.
PLoS One ; 15(12): e0232864, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33373369

RESUMO

Activation of the kappa opioid receptor (KOR) contributes to the aversive properties of stress, and modulates key neuronal circuits underlying many neurobehavioral disorders. KOR agonists directly inhibit ventral tegmental area (VTA) dopaminergic neurons, contributing to aversive responses (Margolis et al. 2003, 2006); therefore, selective KOR antagonists represent a novel therapeutic approach to restore circuit function. We used whole cell electrophysiology in acute rat midbrain slices to evaluate pharmacological properties of four novel KOR antagonists: BTRX-335140, BTRX-395750, PF-04455242, and JNJ-67953964. Each compound concentration-dependently reduced the outward current induced by the KOR selective agonist U-69,593. BTRX-335140 and BTRX-395750 fully blocked U-69,593 currents (IC50 = 1.2 ± 0.9 and 1.2 ± 1.3 nM, respectively). JNJ-67953964 showed an IC50 of 3.0 ± 4.6 nM. PF-04455242 exhibited partial antagonist activity asymptoting at 55% blockade (IC50 = 6.7 ± 15.1 nM). In 3/8 of neurons, 1 µM PF-04455242 generated an outward current independent of KOR activation. BTRX-335140 (10 nM) did not affect responses to saturating concentrations of the mu opioid receptor (MOR) agonist DAMGO or the delta opioid receptor (DOR) agonist DPDPE, while JNJ-67953964 (10 nM) partially blocked DAMGO and DPDPE responses. Importantly, BTRX-335140 (10 nM) rapidly washed out with complete recovery of U-69,593 responses within 10 min. Collectively, we show electrophysiological evidence of key differences amongst KOR antagonists that could impact their therapeutic potential and have not been observed using recombinant systems. The results of this study demonstrate the value of characterizing compounds in native neuronal tissue and within circuits implicated in the neurobehavioral disorders of interest.


Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Receptores Opioides kappa/antagonistas & inibidores , Analgésicos Opioides/farmacologia , Animais , Benzamidas/farmacologia , Compostos de Bifenilo/farmacologia , Neurônios Dopaminérgicos/metabolismo , Eletrofisiologia , D-Penicilina (2,5)-Encefalina/farmacologia , Masculino , Mesencéfalo/metabolismo , Antagonistas de Entorpecentes/farmacologia , Oxidiazóis/farmacologia , Técnicas de Patch-Clamp/métodos , Piperidinas/farmacologia , Pirrolidinas/farmacologia , Quinolinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/metabolismo , Sulfonamidas/farmacologia , Área Tegmentar Ventral/efeitos dos fármacos
17.
Nat Commun ; 11(1): 5731, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-33184293

RESUMO

There is increasing evidence that inducing neuronal mitophagy can be used as a therapeutic intervention for Alzheimer's disease. Here, we screen a library of 2024 FDA-approved drugs or drug candidates, revealing UMI-77 as an unexpected mitophagy activator. UMI-77 is an established BH3-mimetic for MCL-1 and was developed to induce apoptosis in cancer cells. We found that at sub-lethal doses, UMI-77 potently induces mitophagy, independent of apoptosis. Our mechanistic studies discovered that MCL-1 is a mitophagy receptor and directly binds to LC3A. Finally, we found that UMI-77 can induce mitophagy in vivo and that it effectively reverses molecular and behavioral phenotypes in the APP/PS1 mouse model of Alzheimer's disease. Our findings shed light on the mechanisms of mitophagy, reveal that MCL-1 is a mitophagy receptor that can be targeted to induce mitophagy, and identify MCL-1 as a drug target for therapeutic intervention in Alzheimer's disease.


Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Mitofagia/efeitos dos fármacos , Mitofagia/fisiologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/efeitos dos fármacos , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proteína 5 Relacionada à Autofagia/economia , Sobrevivência Celular , Modelos Animais de Doenças , Técnicas de Inativação de Genes , Glucose , Células HEK293 , Células HeLa , Ensaios de Triagem em Larga Escala , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteínas de Neoplasias , Proteínas do Tecido Nervoso , Neurônios/metabolismo , Oxigênio , Receptores Citoplasmáticos e Nucleares , Sulfonamidas/farmacologia , Tioglicolatos/farmacologia
18.
BMC Nephrol ; 21(1): 486, 2020 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-33198670

RESUMO

BACKGROUND: Critically ill coronavirus disease 2019 (COVID-19) patients have a high risk of acute kidney injury (AKI) that requires renal replacement therapy (RRT). A state of hypercoagulability reduces circuit life spans. To maintain circuit patency and therapeutic efficiency, an optimized anticoagulation strategy is needed. This study investigates whether alternative anticoagulation strategies for RRT during COVID-19 are superior to administration of unfractionated heparin (UFH). METHODS: Retrospective cohort study on 71 critically ill COVID-19 patients (≥18 years), admitted to intensive care units at a tertiary health care facility in the southwestern part of Germany between February 26 and May 21, 2020. We collected data on the disease course, AKI, RRT, and thromboembolic events. Four different anticoagulatory regimens were administered. Anticoagulation during continuous veno-venous hemodialysis (CVVHD) was performed with UFH or citrate. Anticoagulation during sustained low-efficiency daily dialysis (SLEDD) was performed with UFH, argatroban, or low molecular weight heparin (LMWH). Primary outcome is the effect of the anticoagulation regimen on mean treatment times of RRT. RESULTS: In patients receiving CVVHD, mean treatment time in the UFH group was 21.3 h (SEM: ±5.6 h), in the citrate group 45.6 h (SEM: ±2.7 h). Citrate anticoagulation significantly prolonged treatment times by 24.4 h (P = .001). In patients receiving SLEDD, mean treatment time with UFH was 8.1 h (SEM: ±1.3 h), with argatroban 8.0 h (SEM: ±0.9 h), and with LMWH 11.8 h (SEM: ±0.5 h). LMWH significantly prolonged treatment times by 3.7 h (P = .008) and 3.8 h (P = .002), respectively. CONCLUSIONS: UFH fails to prevent early clotting events in the dialysis circuit during COVID-19. For patients, who do not require effective systemic anticoagulation, regional citrate dialysis is the most effective strategy. For patients, who require effective systemic anticoagulation, the usage of LMWH results in the longest circuit life spans. The proposed anticoagulatory strategies are safe, can easily be monitored, and allow an individualized treatment.


Assuntos
Lesão Renal Aguda/terapia , Anticoagulantes/administração & dosagem , Betacoronavirus , Infecções por Coronavirus/epidemiologia , Pneumonia Viral/epidemiologia , Terapia de Substituição Renal/métodos , Lesão Renal Aguda/sangue , Lesão Renal Aguda/epidemiologia , Adulto , Idoso , Arginina/análogos & derivados , Coagulação Sanguínea , Ácido Cítrico/administração & dosagem , Comorbidade , Infecções por Coronavirus/sangue , Cuidados Críticos , Estado Terminal , Falha de Equipamento , Feminino , Alemanha/epidemiologia , Heparina/administração & dosagem , Heparina de Baixo Peso Molecular/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Ácidos Pipecólicos/administração & dosagem , Pneumonia Viral/sangue , Terapia de Substituição Renal/instrumentação , Estudos Retrospectivos , Sulfonamidas , Centros de Atenção Terciária
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