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1.
J Anal Toxicol ; 44(7): 734-740, 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33043985

RESUMO

The historical practice of brewing poppy tea for its opioid-like effects is reoccurring with modern-day substance users. We present four postmortem cases with toxicology results that serve as case studies for the potential hazards of poppy tea ingestion. There is limited information regarding the risks of this practice due to the variability of the morphine content of the opium exuded from the plant. While internet tea recipes offer guidance, differences in poppy cultivation, washing, and infusing time are some of the reasons why the beverage may contain inconsistent and clinically significant alkaloid concentrations for each preparation. Variability in opioid tolerance along with additional drugs taken will impact the overall degree of toxicity experienced from the opiates in the tea. Advancements in the genetic modification of the poppy plant could greatly alter the ratio of alkaloids seen in biological fluids and will be highly dependent on the source of the poppy product. The blood concentrations of free morphine and free codeine in cases 1-3 where the toxicity from the tea was considered the primary cause of death were 0.94 and 0.11 mg/L, 0.62 and 0.034 mg/L, and 0.16 and 0.010 mg/L, respectively. The urine concentrations of morphine and codeine were 13 and 0.94 mg/L in case 1 and 16 and 1.6 mg/L in case 2, respectively. The opium alkaloids thebaine and laudanosine were identified qualitatively by our routine organic base/neutral drug detection procedure.


Assuntos
Overdose de Drogas , Extratos Vegetais/envenenamento , Chás de Ervas , Analgésicos Opioides , Tolerância a Medicamentos , Humanos , Morfina , Papaver
2.
Nat Commun ; 11(1): 4864, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978392

RESUMO

The synthesis of customized glycoconjugates constitutes a major goal for biocatalysis. To this end, engineered glycosidases have received great attention and, among them, thioglycoligases have proved useful to connect carbohydrates to non-sugar acceptors. However, hitherto the scope of these biocatalysts was considered limited to strong nucleophilic acceptors. Based on the particularities of the GH3 glycosidase family active site, we hypothesized that converting a suitable member into a thioglycoligase could boost the acceptor range. Herein we show the engineering of an acidophilic fungal ß-xylosidase into a thioglycoligase with broad acceptor promiscuity. The mutant enzyme displays the ability to form O-, N-, S- and Se- glycosides together with sugar esters and phosphoesters with conversion yields from moderate to high. Analyses also indicate that the pKa of the target compound was the main factor to determine its suitability as glycosylation acceptor. These results expand on the glycoconjugate portfolio attainable through biocatalysis.


Assuntos
Tolerância a Medicamentos/fisiologia , Fungos/enzimologia , Fungos/metabolismo , Xilosidases/química , Xilosidases/metabolismo , Biocatálise , Domínio Catalítico , Fungos/efeitos dos fármacos , Glicoconjugados/metabolismo , Glicosídeo Hidrolases/metabolismo , Glicosídeos/química , Glicosilação , Concentração de Íons de Hidrogênio , Cinética , Modelos Moleculares , Mutagênese , Especificidade por Substrato , Talaromyces/enzimologia , Talaromyces/genética , Xilosidases/genética
3.
Nephrol Dial Transplant ; 35(8): 1346-1353, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32844224

RESUMO

BACKGROUND: Haemodialysis patients are at risk of developing severe forms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: coronavirus disease 2019 (COVID-19). In March 2020, hydroxychloroquine (HCQ) and azithromycin (AZI) were proposed as potential treatments of COVID-19, but with warnings concerning their possible toxicity. No data are available regarding the toxicity of this treatment in haemodialysis patients. METHODS: We report the use of HCQ and AZI in a cohort of COVID-19 haemodialysis patients with focus on safety concerns. RESULTS: Twenty-one patients received 200 mg HCQ thrice daily during 10 days, and AZI 500 mg on Day 1, and 250 mg on the four following days. HCQ plasma concentrations were within the recommended range (0.1-1.0 µg/mL) in all patients except one, in which maximum concentration was 1.1 µg/mL. HCQ concentration raised until the third day and remained stable thereafter. No cardiac event occurred in spite of progressive lengthening of corrected QT interval (QTc) during the treatment. One patient experienced a long QTc syndrome (QTc >500 ms) without any arrhythmia episode, although HCQ concentration was in the target range. Five (23.8%) patients experienced hypoglycaemia, a well-known HCQ side-effect. SARS-CoV-2 RNA remained detectable in nasopharyngeal swabs for a long time in haemodialysis patients (mean time 21 days). CONCLUSIONS: HCQ and AZI are safe in haemodialysis patients at these doses but can lead to long QTc syndrome and hypoglycaemia. HCQ concentrations were not correlated with side effects. We recommend monitoring of the QTc length throughout treatment, as well as glycaemia. SARS-CoV-2 could persist for longer in haemodialysis patients than in the general population.


Assuntos
Azitromicina/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Tolerância a Medicamentos , Hidroxicloroquina/uso terapêutico , Falência Renal Crônica/terapia , Pneumonia Viral/tratamento farmacológico , Diálise Renal/métodos , Idoso , Antibacterianos/uso terapêutico , Antimaláricos/uso terapêutico , Comorbidade , Infecções por Coronavirus/epidemiologia , Feminino , França/epidemiologia , Humanos , Falência Renal Crônica/epidemiologia , Masculino , Pandemias , Pneumonia Viral/epidemiologia
4.
Bioresour Technol ; 315: 123855, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32707506

RESUMO

In this study, Bacillus coagulans CC17A with highly tolerant to hydrolysate was obtained through adaptive evolution. After 63 generations, the strain CC17A was stably in 45% (v/v) hydrolysate media and could digest multiple inhibitors in the hydrolysate. Based on its promising features, a one-pot process was developed to produce lactic acid (LA) from wheat straw. After dilute acid pretreatment of wheat straw, simultaneous saccharification and co-fermentation was conducted using CC17A without any solid-liquid separation and pre-detoxification. Total 35.50 g LA was produced from 80 g raw substrate and the production yield was as high as 70.9% of theoretical. To elucidate the tolerance mechanism, transcriptomic profiling of CC17A was studied. The highly up-regulated oxidoreductases and phenolic acid decarboxylase are considered to be involved with the inhibitors-tolerance of B. coagulans CC17A.


Assuntos
Bacillus coagulans , Tolerância a Medicamentos , Fermentação , Hidrólise , Ácido Láctico , Triticum
5.
Proc Natl Acad Sci U S A ; 117(32): 19528-19537, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32723821

RESUMO

Zinc starvation in mycobacteria leads to remodeling of ribosomes, in which multiple ribosomal (r-) proteins containing the zinc-binding CXXC motif are replaced by their motif-free paralogues, collectively called C- r-proteins. We previously reported that the 70S C- ribosome is exclusively targeted for hibernation by mycobacterial-specific protein Y (Mpy), which binds to the decoding center and stabilizes the ribosome in an inactive and drug-resistant state. In this study, we delineate the conditions for ribosome remodeling and hibernation and provide further insight into how zinc depletion induces Mpy recruitment to C- ribosomes. Specifically, we show that ribosome hibernation in a batch culture is induced at an approximately two-fold lower cellular zinc concentration than remodeling. We further identify a growth phase in which the C- ribosome remains active, while its hibernation is inhibited by the caseinolytic protease (Clp) system in a zinc-dependent manner. The Clp protease system destabilizes a zinc-bound form of Mpy recruitment factor (Mrf), which is stabilized upon further depletion of zinc, presumably in a zinc-free form. Stabilized Mrf binds to the 30S subunit and recruits Mpy to the ribosome. Replenishment of zinc to cells harboring hibernating ribosomes restores Mrf instability and dissociates Mpy from the ribosome. Finally, we demonstrate zinc-responsive binding of Mpy to ribosomes in Mycobacterium tuberculosis (Mtb) and show Mpy-dependent antibiotic tolerance of Mtb in mouse lungs. Together, we propose that ribosome hibernation is a specific and conserved response to zinc depletion in both environmental and pathogenic mycobacteria.


Assuntos
Mycobacterium tuberculosis/metabolismo , Ribossomos/metabolismo , Zinco/deficiência , Animais , Antibióticos Antituberculose/farmacologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Tolerância a Medicamentos/genética , Endopeptidase Clp/genética , Endopeptidase Clp/metabolismo , Camundongos , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/crescimento & desenvolvimento , Processamento de Proteína Pós-Traducional , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , Subunidades Ribossômicas/metabolismo , Zinco/análise , Zinco/metabolismo
6.
Proc Natl Acad Sci U S A ; 117(32): 19517-19527, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32727901

RESUMO

Oxidative damage to DNA is a threat to the genomic integrity and coding accuracy of the chromosomes of all living organisms. Guanine is particularly susceptible to oxidation, and 8-oxo-dG (OG), when produced in situ or incorporated by DNA polymerases, is highly mutagenic due to mispairing with adenine. In many bacteria, defense against OG depends on MutT enzymes, which sanitize OG in the nucleotide pool, and the MutM/Y system, which counteracts OG in chromosomal DNA. In Escherichia coli, antibiotic lethality has been linked to oxidative stress and the downstream consequences of OG processing. However, in mycobacteria, the role of these systems in genomic integrity and antibiotic lethality is not understood, in part because mycobacteria encode four MutT enzymes and two MutMs, suggesting substantial redundancy. Here, we definitively probe the role of OG handling systems in mycobacteria. We find that, although MutT4 is the only MutT enzyme required for resistance to oxidative stress, this effect is not due to OG processing. We find that the dominant system that defends against OG-mediated mutagenesis is MutY/MutM1, and this system is dedicated to in situ chromosomal oxidation rather than correcting OG incorporated by accessory polymerases (DinB1/DinB2/DinB3/DnaE2). In addition, we uncover that mycobacteria resist antibiotic lethality through nucleotide sanitization by MutTs, and in the absence of this system, accessory DNA polymerases and MutY/M contribute to antibiotic-induced lethality. These results reveal a complex, multitiered system of OG handling in mycobacteria with roles in oxidative stress resistance, mutagenesis, and antibiotic lethality.


Assuntos
Antibacterianos/metabolismo , Cromossomos Bacterianos/metabolismo , Reparo do DNA/genética , Mycobacterium/genética , Estresse Oxidativo , 8-Hidroxi-2'-Desoxiguanosina/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Dano ao DNA , Tolerância a Medicamentos , Mutagênese , Mutação , Mycobacterium/crescimento & desenvolvimento , Mycobacterium/metabolismo , Oxirredução
7.
Spine (Phila Pa 1976) ; 45(14): 968-975, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32604353

RESUMO

STUDY DESIGN: Retrospective study. OBJECTIVE: The aim of this study was to determine risk factors for prolonged opioid use and to investigate whether opioid-tolerance affects patient-reported outcomes following anterior cervical discectomy and fusion (ACDF) surgery. SUMMARY OF BACKGROUND DATA: There is a lack of consensus on risk factors that can affect continued opioid use after cervical spine surgery and the influence of opioid use on patient-reported outcomes. METHODS: Ninety-two patients who underwent ACDF for degenerative cervical pathologies were retrospectively identified and their opioid usage before surgery was investigated using a state-sponsored prescription drug monitoring registry. Opioid-naïve and opioid tolerant groups were defined using criteria most consistent with the Federal Drug Administration (FDA) definition. Patient-reported outcomes were then collected, including the Short Form-12 (SF-12) Physical Component (PCS-12) and Mental Component (MCS-12), the Neck Disability Index (NDI), the Visual Analogue Scale Neck (VAS neck) and the Visual Analogue Scale Arm (VAS Arm) pain scores. Logistic regression was used to determine predictors for prolonged opioid use following ACDF. Univariate and multivariate analyses were conducted to compare change in outcomes over time between the two groups. RESULTS: Logistic regression analysis demonstrated that opioid tolerance was a significant predictor for prolonged opioid use after ACDF (odds ratio [OR]: 18.2 [1.46, 226.4], P = 0.02). Duration of usage was also found to be a significant predictor for continued opioid use after surgery (OR: 1.10 [1.0, 1.03], P = 0.03). No other risk factors were found to be significant predictors. Both groups overall experienced improvements in patient-reported outcomes after surgery. Multiple linear regression analysis, controlling for patient demographics, demonstrated that opioid-tolerant user status positively affected change in outcomes over time for NDI (ß = -13.7 [-21.8,-5.55], P = 0.002) and PCS-12 (ß = 6.99 [2.59, 11.4], P = 0.003) but no other outcomes measured. CONCLUSION: Opioid tolerance was found to be a significant predictor for prolonged opioid use after ACDF. Additionally, opioid-naïve and opioid-tolerant users experienced overall improvements across PROMs following ACDF. Opioid-tolerance was associated with NDI and PCS-12 improvements over time compared to opioid-naïve users. LEVEL OF EVIDENCE: 4.


Assuntos
Analgésicos Opioides , Tolerância a Medicamentos/fisiologia , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/uso terapêutico , Humanos , Dor Pós-Operatória/tratamento farmacológico , Medidas de Resultados Relatados pelo Paciente , Estudos Retrospectivos , Fatores de Risco , Fusão Vertebral/efeitos adversos
8.
Ecotoxicol Environ Saf ; 202: 110854, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32585484

RESUMO

Atrazine as a kind of herbicide could cause damage to the sensitive plants. Though plant growth promoting rhizobacteria (PGPR) have been proven with the potential to enhance the resistance of plants against various abiotic stresses, whether it could alleviate phytotoxicity caused by atrazine is sill unclear. In present study, the effects of strain Pseudomonas chlororaphis PAS18, a kind of PGPR enable to produce indole-3-acetic acid (IAA), on the growth and physiological responses of Pennisetum americanum (L.) K.Schum seedlings were investigated under three different levels (0, 20 and 100 mg kg-1) of atrazine in pot experiment. The results suggest that strain PAS18 could alleviate the growth and physiological interference caused by 20 mg kg-1 of atrazine. Physiological analysis showed strain PAS18 could further decrease the damaged extent of photosystem II, superoxide radical level and malondialdehyde content of test plant via up-regulating psbA expression, enhancing superoxide dismutase activity and reducing atrazine accumulation in the test plant. Moreover, ion flux measurements suggest that IAA could alleviate the Ca2+ exflux state of the test plant which caused by atrazine stress. Hence, it is plausible that strain PAS18 could alleviate atrazine-induced stress to P. americanum by enhancing the photosystem II repair and antioxidant defense ability as well as balancing the Ca2+ flux.


Assuntos
Atrazina/toxicidade , Ácidos Indolacéticos/metabolismo , Pennisetum/fisiologia , Pseudomonas chlororaphis/fisiologia , Antioxidantes/metabolismo , Atrazina/metabolismo , Tolerância a Medicamentos , Herbicidas/metabolismo , Malondialdeído/metabolismo , Pennisetum/efeitos dos fármacos , Fotossíntese , Pseudomonas chlororaphis/metabolismo , Plântula/efeitos dos fármacos , Estresse Fisiológico
9.
Mar Pollut Bull ; 156: 111260, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32510402

RESUMO

Differential response of Bruguiera cylindrica to individual (CuSO4) and combined (CuSO4 NaCl) effect was evaluated. The plantlets were treated with control, 0.15 mM CuSO4, 400 mM NaCl and 0.15 mM CuSO4 + 400 mM NaCl. Under combined stress, higher accumulation of Cu in the roots indicate that the roots are the primary site of Cu accumulation and thus the plant perform as an excluder and photosynthetic efficiency reduced drastically and significant enhancement in the superoxide and hydroxyl free radicals which increase membrane lipid peroxidation, leading to cellular damage and destruction. As evidenced from SEM-EDXMA, increase in Cu and Na+ levels in xylem and pith regions of leaf and stem and the presence of deeply stained structures, denoting the probable formation of complex containing the metal. Increased CaOx crystal forming cells (crystal idioblasts) reveals the regulation of bioaccumulated Cu and Na+ by complexing with CaOx. Thus the study suggested that, 400 mM NaCl and 0.15 mM CuSO4 treatments does not have negative impact on plant growth, the NaCl tolerance potential compromised in the presence of mild CuSO4 concentration during combined stress.


Assuntos
Rhizophoraceae , Cloreto de Sódio , Tolerância a Medicamentos , Folhas de Planta , Raízes de Plantas
10.
Lancet Gastroenterol Hepatol ; 5(9): 829-838, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32553151

RESUMO

BACKGROUND: Diacylglycerol-O-acyltransferase 2 (DGAT2) is one of two enzyme isoforms that catalyse the final step in the synthesis of triglycerides. IONIS-DGAT2Rx is an antisense oligonucleotide inhibitor of DGAT2 that is under clinical investigation for the treatment of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). The aim of this trial was to examine the safety, tolerability, and efficacy of IONIS-DGAT2Rx versus placebo in reducing liver fat in patients with type 2 diabetes and NAFLD. METHODS: This double-blind, randomised, placebo-controlled, phase 2 study consisted of a 2-week screening period, a run-in period of up to 4 weeks, a 13-week treatment period of once-weekly dosing, and a 13-week post-treatment follow-up period. The study was done at 16 clinical research sites in Canada, Poland, and Hungary. Eligible participants were aged 18-75 years, had a body-mass index at screening between 27 kg/m2 and 39 kg/m2, haemoglobin A1c (HbA1c) levels from 7·3% to 9·5%, and liver fat content 10% or greater before randomisation, and agreed to maintain a stable diet and exercise routine throughout the study. Enrolled participants were stratified on the basis of liver fat content during the run-in period (<20% or ≥20%) and then centrally randomised (2:1) to receive once weekly subcutaneous injection of 250 mg IONIS-DGAT2Rx or placebo for 13 weeks. Participants, investigators, funder personnel, and the clinical research organisation staff, including central readers of MRI scans, were all masked to treatment identity. The primary endpoints were the safety, tolerability, and pharmacodynamic effect of IONIS-DGAT2Rx on hepatic steatosis, according to absolute reduction from baseline in liver fat percentage as quantified by MRI-estimated proton density fat fraction and assessed in the per-protocol population. Pharmacodynamic performance was determined in the per-protocol population by the change in liver fat content from baseline to 2 weeks after the last dose. The per-protocol population included all randomised participants who received at least ten doses of study drug, with the first four doses administered in the first 5 weeks, did not miss more than three consecutive weekly doses, and who had no protocol deviations that might affect efficacy. All randomised participants who received at least one dose of study drug were included in the safety analysis. This study is registered with ClinicalTrials.gov, NCT03334214. FINDINGS: Between Nov 3, 2017, and Nov 28, 2018, we screened 173 people for eligibility. 44 were enrolled and randomly assigned to receive either IONIS-DGAT2Rx (29 participants) or placebo (15 participants). After 13 weeks of treatment, the mean absolute reduction from baseline was -5·2% (SD 5·4) in the IONIS-DGAT2Rx group compared with -0·6% (6·1) in the placebo group (treatment difference -4·2%, 95% CI -7·8 to -0·5, p=0·026). Reductions in liver fat were not accompanied by hyperlipidaemia, elevations in serum aminotransferases or plasma glucose, changes in bodyweight, or gastrointestinal side-effects compared with placebo. Six serious adverse events occurred in four patients treated with IONIS-DGAT2Rx. No serious adverse events were reported in the placebo group. One of four patients reported three serious adverse events: acute exacerbation of chronic obstructive pulmonary disease, cardiac arrest, and ischaemic cerebral infarction, each considered severe and not related to study drug. Three of four patients reported one serious adverse event of increased blood triglycerides (severe, unrelated to study drug), deep-vein thrombosis (severe, unlikely to be related to study drug), and acute pancreatitis (mild, unrelated to study drug). INTERPRETATION: Our results suggest that DGAT2 antisense inhibition could be a safe and efficacious strategy for treatment of NAFLD and support further investigation in patients with biopsy-proven NASH. Based on the pharmacological target, the response to treatment observed in this study population could extend to the broader population of patients with NAFLD. FUNDING: Ionis Pharmaceuticals.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Oligonucleotídeos Antissenso/antagonistas & inibidores , Idoso , Índice de Massa Corporal , Canadá/epidemiologia , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diacilglicerol O-Aciltransferase/administração & dosagem , Diacilglicerol O-Aciltransferase/efeitos adversos , Diacilglicerol O-Aciltransferase/farmacologia , Método Duplo-Cego , Tolerância a Medicamentos , Feminino , Humanos , Hungria/epidemiologia , Injeções Subcutâneas , Gordura Intra-Abdominal/diagnóstico por imagem , Gordura Intra-Abdominal/efeitos dos fármacos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/patologia , Oligonucleotídeos Antissenso/administração & dosagem , Oligonucleotídeos Antissenso/efeitos adversos , Oligonucleotídeos Antissenso/farmacologia , Placebos/administração & dosagem , Polônia/epidemiologia , Segurança , Resultado do Tratamento
11.
Chemosphere ; 252: 126576, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32443267

RESUMO

Phytoremediation using high production crops could be an alternative for the recovery of metals polluted soils. In this sense, the Arundo donax L. energy crop has shown tolerance to moderate concentrations of heavy metals. The objective of this work was to test the tolerance of micropropagated plants of Arundo donax to increasing concentrations of cadmium, chromium, cooper, nickel and lead, in an in vitro culture medium. Biomass production and concentration of heavy metal in shoots and roots were analyzed. Results showed that heavy metals were accumulated mostly in subterranean organs. The increase in heavy metal concentration was dose dependent and not always follows a linear relationship. Arundo donax showed a broad tolerance to cadmium (0.5 mM), chromium (0.2 mM), cooper (2 mM), nickel (0.5 mM) and lead (1 mM). In relation to cooper, Arundo donax showed a hyperaccumulative potential. These results suggest the potential use of Arundo donax in the phytomanagement of polluted soils although further studies should be carried out using polluted soils.


Assuntos
Biodegradação Ambiental , Poaceae/fisiologia , Poluentes do Solo/metabolismo , Biomassa , Cádmio , Tolerância a Medicamentos , Metais Pesados , Níquel , Raízes de Plantas/química , Solo , Poluentes do Solo/análise
12.
Anesth Analg ; 130(6): 1638-1652, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32384350

RESUMO

One of the most prevalent symptoms after major surgery is pain. When postoperative pain treatment is unsatisfactory, it can lead to poor surgical recovery, decreased quality of life, and increased health care costs. Current analgesics, single or in combination, have limited efficacy due to low potency, limited duration of action, toxicities, and risk of addiction. The lack of nonaddictive strong analgesics along with the over prescription of opioids has led to an opioid epidemic in the United States. Therefore, there is an urgent need for the development of newer analgesics. Microribonucleic acids (miRNAs) are small noncoding RNA molecules that modulate protein synthesis in neurons and supporting cells (glia, leukocytes, and Schwann cells). The literature indicates that miRNA regulation is important in nociception. Here, we summarize the current evidence on the role of miRNAs on mechanisms involved in incisional, inflammatory, neuropathic, and cancer pain. We also discuss the role of modulating miRNA functions as potential therapeutic targets for analgesic use and opioid tolerance. Finally, we propose how the delivery of analog miRNAs (mimic-miRNAs or antago-miRNAs) could be introduced into clinical practice to provide analgesia in the perioperative period.


Assuntos
MicroRNAs/metabolismo , Dor Pós-Operatória/genética , Dor Pós-Operatória/metabolismo , Dor Aguda/genética , Dor Aguda/metabolismo , Dor Aguda/terapia , Analgesia , Analgésicos/administração & dosagem , Analgésicos Opioides/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Dor do Câncer/terapia , Tolerância a Medicamentos , Epigênese Genética , Custos de Cuidados de Saúde , Humanos , Inflamação , Manejo da Dor/métodos , Medição da Dor , Dor Pós-Operatória/terapia , Período Perioperatório , Qualidade de Vida , Medula Espinal/metabolismo
13.
PLoS One ; 15(5): e0233375, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32421756

RESUMO

MYB-related transcription factors play important roles in plant development and response to various environmental stresses. In the present study, a novel MYB gene, designated as BnMYB2 (GenBank accession number: MF741319.1), was isolated from Boehmeria nivea using rapid amplification of cDNA ends (RACE) and RT-PCR on a sequence fragment from a ramie transcriptome. BnMYB2 has a 945 bp open reading frame encoding a 314 amino acid protein that contains a DNA-binding domain and shares high sequence identity with MYB proteins from other plant species. The BnMYB2 promoter contains several putative cis-acting elements involved in stress or phytohormone responses. A translational fusion of BnMYB2 with enhanced green fluorescent protein (eGFP) showed nuclear and cytosolic subcellular localization. Real-time PCR results indicated that BnMYB2 expression was induced by Cadmium (Cd) stress. Overexpression of BnMYB2 in Arabidopsis thaliana resulted in a significant increase of Cd tolerance and accumulation. Thus, BnMYB2 positively regulated Cd tolerance and accumulation in Arabidopsis, and could be used to enhance the efficiency of Cd removal with plants.


Assuntos
Boehmeria/genética , Cádmio/metabolismo , Fatores de Transcrição/fisiologia , Arabidopsis/metabolismo , Cádmio/farmacologia , Tolerância a Medicamentos/genética , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/fisiologia , Proteínas Proto-Oncogênicas c-myb/metabolismo , Proteínas Proto-Oncogênicas c-myb/fisiologia , Estresse Fisiológico/efeitos dos fármacos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
14.
J Vis Exp ; (158)2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32364549

RESUMO

Drosophila melanogaster provides an excellent model to study the genetic underpinnings of alcohol sensitivity. In contrast to studies in human populations, the Drosophila model allows strict control over genetic background, and virtually unlimited numbers of individuals of the same genotype can be reared rapidly under well-controlled environmental conditions without regulatory restrictions and at relatively low cost. Flies exposed to ethanol undergo physiological and behavioral changes that resemble human alcohol intoxication, including loss of postural control, sedation, and development of tolerance. Here, we describe a simple, low-cost, high-throughput assay for assessing alcohol sedation sensitivity in large numbers of single flies. The assay is based on video recording of single flies introduced without anesthesia in 24-well cell culture plates in a set-up that enables synchronous initiation of alcohol exposure. The system enables a single person to collect individual ethanol sedation data on as many as 2,000 flies within an 8 h work period. The assay can, in principle, be extended to assess the effects of exposure to any volatile substance and applied to measure effects of acute toxicity of volatiles on other insects, including other fly species.


Assuntos
Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/genética , Etanol/toxicidade , Animais , Tolerância a Medicamentos/genética , Genótipo , Fatores de Tempo
15.
Lancet Haematol ; 7(6): e490-e497, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32470440

RESUMO

Evaluation of tolerability is increasingly relevant for patients with haematological malignancies treated with chronically administered therapies. Adverse events from these agents might affect the ability of patients to tolerate treatment over time. Conventional toxicity tables that include the incidence of high-grade adverse events, defined by the Common Terminology Criteria for Adverse Events, do not provide information on the time profile of these adverse events or reflect the continuous, lower grade symptomatic toxicities that are particularly relevant to treatment tolerability for patients living with indolent disease. Modern approaches to the evaluation and reporting of toxicity that capture the tolerability of treatment to the patient are imperative. In this Viewpoint, we present a focused, pilot, and longitudinal Toxicity over Time analysis of adverse events from lenalidomide and lenalidomide with rituximab in patients with follicular lymphoma treated in the CALGB 50401 (Alliance; NCT00238238) trial to define the trajectory of adverse events and quantify the burden of continuous, low-grade events. Toxicity over Time analyses provided clinically relevant descriptions of neutropenia and fatigue trajectories caused by lenalidomide that were not identified by standard analysis of the maximum grade events defined by the Common Terminology Criteria for Adverse Events. Systematic, rigorous incorporation of patient-reported outcomes in clinical trials will be crucial to our understanding of the tolerability of chronically administered therapies in patients with haematological malignancies.


Assuntos
Inibidores da Angiogênese/toxicidade , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Neoplasias Hematológicas/tratamento farmacológico , Lenalidomida/toxicidade , Linfoma Folicular/tratamento farmacológico , Inibidores da Angiogênese/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Tolerância a Medicamentos/fisiologia , Fadiga/induzido quimicamente , Fadiga/classificação , Fadiga/epidemiologia , Humanos , Infusões Intravenosas , Lenalidomida/efeitos adversos , Neutropenia/induzido quimicamente , Neutropenia/classificação , Neutropenia/epidemiologia , Rituximab/administração & dosagem , Rituximab/uso terapêutico , Trombose/induzido quimicamente , Trombose/classificação , Trombose/epidemiologia
16.
Nat Commun ; 11(1): 2345, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32393797

RESUMO

The determination of individual cell trajectories through a high-dimensional cell-state space is an outstanding challenge for understanding biological changes ranging from cellular differentiation to epigenetic responses of diseased cells upon drugging. We integrate experiments and theory to determine the trajectories that single BRAFV600E mutant melanoma cancer cells take between drug-naive and drug-tolerant states. Although single-cell omics tools can yield snapshots of the cell-state landscape, the determination of individual cell trajectories through that space can be confounded by stochastic cell-state switching. We assayed for a panel of signaling, phenotypic, and metabolic regulators at points across 5 days of drug treatment to uncover a cell-state landscape with two paths connecting drug-naive and drug-tolerant states. The trajectory a given cell takes depends upon the drug-naive level of a lineage-restricted transcription factor. Each trajectory exhibits unique druggable susceptibilities, thus updating the paradigm of adaptive resistance development in an isogenic cell population.


Assuntos
Tolerância a Medicamentos , Genômica , Melanoma/tratamento farmacológico , Análise de Célula Única , Linhagem Celular Tumoral , Genes Reporter , Proteínas de Fluorescência Verde/metabolismo , Humanos , Metabolômica , Fator de Transcrição Associado à Microftalmia , Modelos Moleculares , Proteômica , Proteínas Proto-Oncogênicas B-raf/genética , Reprodutibilidade dos Testes
17.
Int J Lab Hematol ; 42 Suppl 1: 19-20, 2020 06.
Artigo em Inglês | MEDLINE | ID: covidwho-88479
18.
Life Sci ; 252: 117676, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32304763

RESUMO

AIMS: Many µ-opioid receptor (MOR)-associated proteins can regulate the MOR signaling pathway. Using a bacterial two-hybrid screen, we found that the C-terminal of the MOR associated with heat shock protein 90 isoform ß (Hsp90ß). Here, we explored the effect of Hsp90ß on MOR signaling transduction and function. MAIN METHODS: The interaction of Hsp90ß with MOR was detected by co-immunoprecipitation and immunofluorescence. The effects of Hsp90ß on MOR signaling induced by opioids were studied in vitro and in vivo. The effects of the Hsp90ß inhibitor 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) on morphine tolerance and dependence were studied via a hot plate test and CPP test. KEY FINDINGS: Hsp90ß, instead of Hsp90α, interacted with the MOR in HEK293 cells and SH-SY5Y cells, and the interaction was augmented after morphine pretreatment. The interaction of Hsp90ß and MOR increased the inhibition of cAMP and decreased PKA activity under opioid treatment. The functional Hsp90ß-MOR complex also promoted the phosphorylation and internalization of the MOR induced by DAMGO in MOR-CHO cells. 17-AAG blocked Hsp90ß-MOR interactions and decreased the effect of Hsp90ß on the MOR signal transduction. In C57BL/6 mice, 17-AAG decreased morphine-induced acute anti-nociception in the hot plate test, with an increase in phosphorylated PKA and phosphorylated JNK and a decrease in phosphorylated CREB and phosphorylated ERK in murine brains. Chronic morphine treatment induced tolerance, and dependence was inhibited by 17-AAG co-administration. SIGNIFICANCE: Hsp90ß is a positive co-regulator of the MOR via the activation of a G-protein-dependent and ß-arrestin-dependent pathway. Hsp90ß has the potential to improve the pharmacologic profile of existing opiates. It is conceivable that in future clinical treatments, the Hsp90ß inhibitor, 17-AAG, could decrease the tolerance and dependence in cancer patients induced by opioids.


Assuntos
Analgésicos Opioides/farmacologia , Benzoquinonas/farmacologia , Proteínas de Choque Térmico HSP90/metabolismo , Lactamas Macrocíclicas/farmacologia , Morfina/farmacologia , Receptores Opioides mu/efeitos dos fármacos , Analgésicos Opioides/administração & dosagem , Animais , Células CHO , Cricetinae , Cricetulus , Tolerância a Medicamentos , Feminino , Células HEK293 , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Morfina/administração & dosagem , Nociceptividade/efeitos dos fármacos , Receptores Opioides mu/metabolismo
19.
Int J Lab Hematol ; 42 Suppl 1: 19-20, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32311843
20.
Chemosphere ; 253: 126695, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32278902

RESUMO

Antibiotic pollution has become a hot issue worldwide, which has toxic effects on plants and even threatens human health. As a common wetland plant, the tolerance mechanism of Phragmites australis to antibiotics is rarely reported. In this study, we investigated the enrichment characteristics and biological response of P. australis to sulfamethoxazole (SMZ) and ofloxacin (OFL) residues, which are common in the environment. We found that the simulated concentration of antibiotics far exceeded the current level of antibiotic residues in the water environment, but it did not significantly inhibit the growth of P. australis. At 1 mg L-1, OFL and SMZ significantly increased the biomass of P. australis, which was mainly related to the improvement of root activity and photosynthetic efficiency, but the duplex treatment (SMZ + OFL) did not significantly stimulate the growth of reeds. OFL could significantly reduce the accumulation of reactive oxygen species (ROS) in P. australis. When OFL was 1 mg L-1, compared with control, superoxide anion and H2O2 were reduced by 11.19% and 10.76%, respectively, which was mainly related to the improvement of membrane stability. SMZ and SMZ + OFL had no significant effect on ROS, but they significantly increased antioxidant enzyme activity. SMZ and OFL could increase soil invertase, urease, and protease activities, and the tested antibiotics had no significant effect on the Shannon-Wiener index of soil microorganisms. The accumulation of antibiotics within tissues could be ranked as root > leaf > stem, and the accumulation and transport of OFL were higher than those of SMZ.


Assuntos
Ofloxacino/toxicidade , Poaceae/fisiologia , Sulfametoxazol/toxicidade , Antibacterianos , Biomassa , Tolerância a Medicamentos , Peróxido de Hidrogênio , Fotossíntese , Folhas de Planta , Poaceae/efeitos dos fármacos , Poaceae/crescimento & desenvolvimento , Solo/química , Áreas Alagadas
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