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1.
Rinsho Ketsueki ; 62(10): 1499-1504, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34732623

RESUMO

A 67-year-old woman diagnosed with adult T-cell leukemia/lymphoma received an induction chemotherapy and showed a partial response. She then underwent allogeneic peripheral blood stem cell transplantation from an HLA-identical sibling donor. Although cyclosporine (CS) was stopped at 120 days after transplantation, chronic graft-versus-host disease (cGVHD) of the skin developed. She was treated with a topical steroid, without exacerbation of the GVHD. She was admitted to our hospital due to the sudden development of pancytopenia at 212 days after the transplantation. She had an EB virus-associated post-transplant lymphoproliferative disorder (PTLD) in the hilum of the lung. The cGVHD of the skin resolved after the administration of prednisolone and CS. However, pancytopenia and PTLD persisted. Treatment with four cycles of rituximab (4×375 mg/m2/week) led to the complete resolution of PTLD, but transfusion-dependent cytopenia did not improve. Secondary engraftment failure was diagnosed, and granulocyte colony-stimulating factor (G-CSF) and eltrombopag (100 mg/day) were administered, leading to gradual improvement of pancytopenia. It was observed that persistent pancytopenia was caused by secondary engraftment failure due to cGVHD in this case. This case suggested that the treatment with G-CSF and eltrombopag is effective for cGVHD-associated secondary engraftment failure.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma de Células T do Adulto , Linfoma , Transplante de Células-Tronco de Sangue Periférico , Idoso , Benzoatos , Transplante de Medula Óssea , Feminino , Doença Enxerto-Hospedeiro/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Hidrazinas , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Pirazóis , Transplante Homólogo
2.
Molecules ; 26(20)2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34684722

RESUMO

Avobenzone, one of the most commonly used UV filters in topical sunscreens, is susceptible to photodegradation with a consequential reduction of its UV absorbing properties. This loss of function may lead to skin irritation, photodermatosis, and photoallergic reactions caused by photodegradation byproducts. In this work, we aim to address this issue with a substance named methoxy-monobenzoylmethane (MeO-MBM), which is neither a UVB nor a UVA filter, but which converts to avobenzone, a known and approved UVA filter, under mainly UVB light irradiation. The antioxidant and intracellular radical formation properties of MeO-MBM were compared to the ones of avobenzone. The UV irradiation of MeO-MBM led to an increase in UV absorption primarily in the UVA range after conversion, both in vitro and in vivo. HPTLC and UHPLC studies illustrate the conversion of MeO-MBM to avobenzone in vitro after irradiation at 250 kJ/m2, reaching a conversion rate of 48.8%. A stable molecular antioxidant activity was observed, since 100-µM MeO-MBM was measured to be 11.2% in the DPPH assay, with a decrease to 9.7% after irradiation. In comparison, the molecular antioxidant activity of 100-µM avobenzone was determined to be 0.8%. In keratinocytes, MeO-MBM reduces the intracellular ROS by 90% and avobenzone by 75% with tBHP as the inducer and by 53% and 57%, respectively, when induced by pyocyanin, indicating the redox scavenging capacity of both these molecules. These results indicate that MeO-MBM functions initially as an antioxidant material and as a photoantioxidant during its conversion process to avobenzone. This research provides insight into the development of active ingredients for topical applications with dynamic functionalities. Using this approach, we demonstrate the possibility to extend the UV protection offered to skin cells while combating cellular stress in parallel.


Assuntos
Benzoatos/farmacologia , Metano/análogos & derivados , Protetores Solares/farmacologia , Antioxidantes , Estabilidade de Medicamentos , Humanos , Queratinócitos/efeitos dos fármacos , Metano/farmacologia , Fotólise , Propiofenonas/química , Propiofenonas/farmacologia , Substâncias Protetoras , Pele/efeitos dos fármacos , Protetores Solares/química , Raios Ultravioleta
3.
Invest Ophthalmol Vis Sci ; 62(13): 12, 2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34661609

RESUMO

Purpose: The purpose of this study was to develop a preclinical compound, ITRI-E-(S)4046, a dual synergistic inhibitor of myosin light chain kinase 4 (MYLK4) and Rho-related protein kinase (ROCK), for reducing intraocular pressure (IOP). Methods: ITRI-E-(S)4046 is an amino-pyrazole derivative with physical and chemical properties suitable for ophthalmic formulation. In vitro kinase inhibition was evaluated using the Kinase-Glo Luminescent Kinase Assays. A comprehensive kinase selectivity analysis of ITRI-E-(S)4046 was performed using the KINOMEscan assay from DiscoverRx. The IOP reduction and tolerability of ITRI-E-(S)4046 were assessed in ocular normotensive rabbits, ocular normotensive non-human primates, and ocular hypertensive rabbits. In vivo studies were conducted to assess drug concentrations in ocular tissue. The adverse ocular effects of rabbit eyes were evaluated following the OECD405 guidelines. Results: ITRI-E-(S)4046 showed highly selective kinase inhibitory activity against ROCK1/2, MYLK4, and mitogen-activated protein kinase kinase kinase 19 (MAP3K19), with high specificity against protein kinase A, G, and C families. In ocular normotensive rabbits and non-human primates, the mean IOP reductions of 0.1% ITRI-E-(S)4046 eye drops were 29.8% and 28.5%, respectively. In hypertonic saline-induced and magnetic beads-induced ocular hypertensive rabbits, the mean IOP reductions of ITRI-E-(S)4046 0.1% eye drops were 46.9% and 22.0%, respectively. ITRI-E-(S)4046 was well tolerated with only temporary and minor signs of hyperemia. Conclusions: ITRI-E-(S)4046 is a novel type of highly specific ROCK1/2 and MYLK4 inhibitor that can reduce IOP in normotensive and hypertensive animal models. It has the potential to become an effective and well-tolerated treatment for glaucoma.


Assuntos
Benzoatos/farmacologia , Proteínas de Ligação ao Cálcio/antagonistas & inibidores , Pressão Intraocular/efeitos dos fármacos , Isoquinolinas/farmacologia , Quinase de Cadeia Leve de Miosina/antagonistas & inibidores , Hipertensão Ocular/tratamento farmacológico , Sulfonamidas/farmacologia , beta-Alanina/análogos & derivados , Animais , Modelos Animais de Doenças , Humanos , Macaca , Masculino , Hipertensão Ocular/fisiopatologia , Coelhos , Tonometria Ocular , beta-Alanina/farmacologia , Quinases Associadas a rho/antagonistas & inibidores
4.
Blood Adv ; 5(19): 3799-3806, 2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34605871

RESUMO

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder with isolated thrombocytopenia and risk of hemorrhage. Treatment with eltrombopag increases and maintains hemostatic platelet counts; however, to date, long-term data are lacking on the outcome of children with ITP who are treated with eltrombopag. This prospective, observational, longitudinal cohort study evaluated the efficacy and safety of eltrombopag in pediatric patients with persistent or chronic ITP. For the 116 pediatric patients enrolled, duration of eltrombopag treatment was at least 3 months. Median effective dose was 25 mg/day, 50 mg/day, and 50 mg/day, respectively, for children age 5 years or younger, 6 to 11 years, or 12 years or older. In all, 89 patients (76.7%) achieved overall response, 53 (45.7%) achieved complete response, and 36 (31.0%) achieved response. Median platelet counts increased by week 1 and were sustained throughout the treatment period. During treatment with eltrombopag, the proportion of patients with grade 1 to 4 bleeding symptoms decreased from 83.61% at baseline to 9.88% at 6 months when only grade 1 was reported. Forty-three patients (37.1%) reported using concomitant medications at study entry, which was reduced to 1 patient (2.5%) who needed concomitant medications at 12 months. All adverse events were grade 1 or 2 according to Common Terminology Criteria for Adverse Events. No serious adverse events, cataracts, malignancies, or thromboses were reported during the study. Long-term treatment with eltrombopag was generally safe, well tolerated, and effective in maintaining platelet counts and reducing bleeding in most pediatric patients with persistent or chronic ITP. Combined with future studies, these findings will help establish how eltrombopag should best be used in the management of pediatric patients with East Asian ancestry.


Assuntos
Púrpura Trombocitopênica Idiopática , Trombocitopenia , Benzoatos/efeitos adversos , Criança , Pré-Escolar , China , Humanos , Hidrazinas , Estudos Longitudinais , Estudos Prospectivos , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis , Resultado do Tratamento
5.
Anal Chem ; 93(41): 13835-13843, 2021 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-34623138

RESUMO

The chemical derivatization of multiple lipid classes was developed using benzoyl chloride as a nonhazardous derivatization agent at ambient conditions. The derivatization procedure was optimized with standards for 4 nonpolar and 8 polar lipid classes and measured by reversed-phase ultrahigh-performance liquid chromatography-tandem mass spectrometry. The derivatization and nonderivatization approaches were compared on the basis of the calibration curves of 22 internal standards from 12 lipid classes. The new method decreased the limit of detection 9-fold for monoacylglycerols (0.9-1.0 nmol/mL), 6.5-fold for sphingoid base (0.2 nmol/mL), and 3-fold for diacylglycerols (0.9 nmol/mL). The sensitivity expressed by the ratio of calibration slopes was increased 2- to 10-fold for almost all investigated lipid classes and even more than 100-fold for monoacylglycerols. Moreover, the benzoylation reaction produces a more stable derivative of cholesterol in comparison to the easily in-source fragmented nonderivatized form and enabled the detection of fatty acids in a positive ion mode, which does not require polarity switching as for the nonderivatized form. The intralaboratory comparison with an additional operator without previous derivatization experiences shows the simplicity, robustness, and reproducibility. The stability of the derivatives was determined by periodical measurements during a one month period and five freeze/thaw cycles. The fully optimized derivatization method was applied to human plasma, which allows the detection of 169 lipid species from 11 lipid classes using the high confidence level of identification in reversed-phase (RP)-ultra high performance liquid chromatography (UHPLC)/mass spectrometry (MS). Generally, we detected more lipid species for monoacylglycerols, diacylglycerols, and sphingoid bases in comparison with previously reported papers without the derivatization.


Assuntos
Lipídeos , Espectrometria de Massas em Tandem , Benzoatos , Cromatografia Líquida de Alta Pressão , Humanos , Reprodutibilidade dos Testes
6.
Anal Chem ; 93(40): 13658-13666, 2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34591463

RESUMO

Currently, gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-MS (LC-MS) are the primary methods used to detect pesticides and their metabolites for biomonitoring of exposure. Although GC-MS and LC-MS can provide accurate and sensitive measurements, these techniques are not suitable for point-of-care or in-field biomonitoring applications. The objective of this work is to develop a smartphone-based dual-channel immunochromatographic test strip (ICTS) for on-site biomonitoring of exposure to cypermethrin by simultaneous detection of cypermethrin and its metabolite, 3-phenoxybenzoic acid (3-PBA). Polymer carbon dots (PCDs) with ultrahigh fluorescent brightness were synthesized and used as a signal amplifier in ICTS assay. Cypermethrin (a representative pyrethroid pesticide) and its major metabolite 3-PBA were simultaneously detected to provide more comprehensive analysis of cypermethrin exposure. After competitive immunoreactions between the target sample and the coating antigens preloaded on the test line, the tracer antibody (PCD-conjugated antibody) was quantitatively captured on the test lines. The captured PCDs were inversely proportional to the amount of the target compound in the sample. The red fluorescence on the test line was then recorded using a smartphone-based device capable of conducting image analysis and recording. Under optimal conditions, the sensor showed excellent linear responses for detecting cypermethrin and 3-PBA ranging from 1 to 100 ng/mL and from 0.1 to 100 ng/mL, respectively, and the limits of detection were calculated to be ∼0.35 ng/mL for cypermethrin and ∼0.04 ng/mL for 3-PBA. The results demonstrate that the ICTS device is promising for accurate point-of-care biomonitoring of pesticide exposure.


Assuntos
Piretrinas , Pontos Quânticos , Benzoatos , Polímeros , Smartphone
7.
J Biosci Bioeng ; 132(6): 621-629, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34583900

RESUMO

Cyclohexanecarboxylate (CHCA) is formed by oxidative microbial degradation of n-alkylcycloparaffins and anaerobic degradation of benzoate, and also known to be a synthetic intermediate or the starter unit of biosynthesis of cellular constituents and secondary metabolites. Although two degradation pathways have been proposed, genetic information has been limited to the ß-oxidation-like pathway. In this study, we identified a gene cluster, designated chcC1XTC2B1B2RAaAbAc, that is responsible for the CHCA aromatization pathway in Sinomonas (formerly Corynebacterium) cyclohexanicum strain ATCC 51369. Reverse transcription-PCR analysis indicated that the chc gene cluster is inducible by CHCA and that it consists of two transcriptional units, chcC1XTC2B1B2R and chcAaAbAc. Overexpression of the various genes in Escherichia coli, and purification of the recombinant proteins led to the functional characterization of ChcAaAbAc as subunits of a cytochrome P450 system responsible for CHCA hydroxylation; ChcB1 and ChcB2 as trans-4-hydroxyCHCA and cis-4-hydroxyCHCA dehydrogenases, respectively; ChcC1 was identified as a 4-oxoCHCA desaturase containing a covalently bound FAD; and ChcC2 was identified as a 4-oxocyclohexenecarboxylate desaturase. The binding constant of ChcAa for CHCA was found to be 0.37 mM. Kinetic parameters established for ChcB1 indicated that it has a high catalytic efficiency towards 4-oxoCHCA compared to trans- or cis-4-hydroxyCHCA. The Km and Kcat values of ChcC1 for 4-oxoCHCA were 0.39 mM and 44 s-1, respectively. Taken together with previous work on the identification of a pobA gene encoding a 4-hydroxybenzoate hydroxylase, we have now localized the remaining set of genes for the final degradation of protocatechuate before entry into the tricarboxylic acid cycle.


Assuntos
Proteínas de Escherichia coli , Genes Bacterianos , Proteínas da Membrana Bacteriana Externa , Sequência de Bases , Benzoatos , Escherichia coli/genética , Família Multigênica
8.
Blood Coagul Fibrinolysis ; 32(7): 519-521, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34520405

RESUMO

Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by isolated thrombocytopenia (platelet count <100 × 109/l) in the absence of other causes or disorders associated. The incidence of ITP in pregnancy is one to two cases per 1000 gestations. ITP could be diagnosed before or during pregnancy; sometimes a relapse of a previously diagnosed ITP can occur. Intravenous immune globulins (IVIg) and corticosteroids are the standard frontline therapy because of their well known safety profile either for the mother or for the neonate. Treatments for refractory patients are limited by potential fetal risk. We report the case of a patient with ITP along pregnancy, refractory to corticosteroids and IVIg, successfully treated with, the thrombopoietin receptor agonist (TPO-RA) eltrombopag. Patient received this compound for almost the whole pregnancy and in particular for the whole first trimester, without any complication for the mother and the neonate. Although transient administration of TPO-RAs in pregnancy seems to be well tolerated, their use during the whole gestation is still controversial; this is the reason of the description of this case, which did not show any complications, and thus it could add useful information on this field.


Assuntos
Benzoatos/uso terapêutico , Hidrazinas/uso terapêutico , Complicações Hematológicas na Gravidez/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis/uso terapêutico , Adolescente , Feminino , Humanos , Recém-Nascido , Contagem de Plaquetas , Gravidez , Receptores de Trombopoetina/agonistas
9.
Hematology ; 26(1): 697-708, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34547980

RESUMO

OBJECTIVE: To assess real-world treatment patterns in patients with immune thrombocytopenia (ITP) who received thrombopoietin receptor agonists (TPO-RAs) in Germany. METHODS: This was a longitudinal, retrospective study using anonymized patient-level data (IQVIA healthcare prescription database, covering 82% of German statutory prescriptions). Eligible patients (aged ≥18 years) had received ≥1 TPO-RA prescription (romiplostim/eltrombopag) from July 2016 to June 2019 (treatment duration ≥30 days). ITP medication use was assessed for 18 months prior to, during and for ≥6 months after TPO-RA treatment. RESULTS: A total of 3553 patients (median age 64 years) were included. Median persistence on TPO-RAs was 12 months (range 1-34). In the periods before, during and after TPO-RA treatment, oral corticosteroids were the most commonly used therapy (64.4%, 43.4% and 36.1% of patients, respectively); median cumulative doses across each period were 2521.9, 2000.0 and 2277.8 mg. The median total duration of corticosteroid use before, during and after TPO-RA therapy was 15, 18 and 32 weeks, respectively. The total median cumulative corticosteroid dose was 6799.7 mg. CONCLUSION: We identified a potential overuse of corticosteroids in patients with ITP in Germany. Earlier use of TPO-RA therapy after a short course of corticosteroids could avoid side effects associated with long-term use.


Assuntos
Benzoatos/administração & dosagem , Bases de Dados Factuais , Prescrições de Medicamentos , Hidrazinas/administração & dosagem , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis/administração & dosagem , Receptores Fc/administração & dosagem , Receptores de Trombopoetina/agonistas , Proteínas Recombinantes de Fusão/administração & dosagem , Trombopoetina/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Alemanha/epidemiologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Púrpura Trombocitopênica Idiopática/epidemiologia , Estudos Retrospectivos
10.
Nat Commun ; 12(1): 5492, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34535643

RESUMO

Soluble guanylate cyclase (sGC) is the receptor for nitric oxide (NO) in human. It is an important validated drug target for cardiovascular diseases. sGC can be pharmacologically activated by stimulators and activators. However, the detailed structural mechanisms, through which sGC is recognized and positively modulated by these drugs at high spacial resolution, are poorly understood. Here, we present cryo-electron microscopy structures of human sGC in complex with NO and sGC stimulators, YC-1 and riociguat, and also in complex with the activator cinaciguat. These structures uncover the molecular details of how stimulators interact with residues from both ß H-NOX and CC domains, to stabilize sGC in the extended active conformation. In contrast, cinaciguat occupies the haem pocket in the ß H-NOX domain and sGC shows both inactive and active conformations. These structures suggest a converged mechanism of sGC activation by pharmacological compounds.


Assuntos
Ativadores de Enzimas/farmacologia , Guanilil Ciclase Solúvel/metabolismo , Animais , Benzoatos/química , Benzoatos/farmacologia , Sítios de Ligação , Linhagem Celular , Microscopia Crioeletrônica , Ativação Enzimática/efeitos dos fármacos , Ativadores de Enzimas/química , Humanos , Indazóis/química , Indazóis/farmacologia , Modelos Moleculares , Óxido Nítrico/farmacologia , Multimerização Proteica , Pirazóis/química , Pirazóis/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Guanilil Ciclase Solúvel/química , Guanilil Ciclase Solúvel/ultraestrutura
11.
J Med Microbiol ; 70(9)2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34491156

RESUMO

Introduction. The increase of invasive fungal infections (IFIs) and associated treatment failure in populations at risk is driving us to look for new treatments.Hypothesis. The CIN-102 compound, derived from cinnamon essential oil, could be a new antifungal class with an activity, in particular, on strains resistant to current antifungals but also on biofilms, a factor of virulence and resistance of fungi.Aim. The aim of this study is to show the activity of CIN-102 on various strains resistant to current antifungals, on the biofilm and to determine the possibility of resistance induced with this compound.Methodology. We studied the MIC of CIN-102 and of current antifungals (voriconazole and amphotericin B) using CLSI techniques against eight different strains of three genera of filamentous fungi involved in IFIs and having resistance phenotypes to current antifungals. We also determined their effects on biofilm formation, and the induced resistance by voriconazole (VRC) and CIN-102.Results. MIC values determined for CIN-102 were between 62.5 and 250 µg ml-1. We demonstrated the antifungal effect of CIN-102 on biofilm, and more particularly on its formation, with 100 % inhibition achieved for most of the strains. CIN-102 at a sub-inhibitory concentration in the medium did not induce resistance in our strains, even after 30 generations.Conclusions. In this study we show that CIN-102 is effective against resistant filamentous fungi and against biofilm formation. In addition, our strains did not acquire a resistance phenotype against CIN-102 over time, unlike with VRC. CIN-102 is therefore an interesting candidate for the treatment of IFIs, including in cases of therapeutic failure linked to resistance, although further studies on its efficacy, safety and mechanism of action are needed.


Assuntos
Antifúngicos/farmacologia , Benzoatos/farmacologia , Biofilmes/efeitos dos fármacos , Cinamatos/farmacologia , Fungos/efeitos dos fármacos , Micoses , Terpenos/farmacologia , Anfotericina B/farmacologia , Combinação de Medicamentos , Humanos , Testes de Sensibilidade Microbiana , Micoses/tratamento farmacológico , Micoses/microbiologia , Voriconazol/farmacologia
12.
Int J Mol Sci ; 22(17)2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34502437

RESUMO

Maize root responds to nitrate by modulating its development through the coordinated action of many interacting players. Nitric oxide is produced in primary root early after the nitrate provision, thus inducing root elongation. In this study, RNA sequencing was applied to discover the main molecular signatures distinguishing the response of maize root to nitrate according to their dependency on, or independency of, nitric oxide, thus discriminating the signaling pathways regulated by nitrate through nitric oxide from those regulated by nitrate itself of by further downstream factors. A set of subsequent detailed functional annotation tools (Gene Ontology enrichment, MapMan, KEGG reconstruction pathway, transcription factors detection) were used to gain further information and the lateral root density was measured both in the presence of nitrate and in the presence of nitrate plus cPTIO, a specific NO scavenger, and compared to that observed for N-depleted roots. Our results led us to identify six clusters of transcripts according to their responsiveness to nitric oxide and to their regulation by nitrate provision. In general, shared and specific features for the six clusters were identified, allowing us to determine the overall root response to nitrate according to its dependency on nitric oxide.


Assuntos
Regulação da Expressão Gênica de Plantas , Nitratos/metabolismo , Raízes de Plantas/metabolismo , Transcriptoma , Zea mays/metabolismo , Benzoatos , Fertilizantes , Imidazóis , Óxido Nítrico/metabolismo
13.
Zhongguo Dang Dai Er Ke Za Zhi ; 23(9): 944-950, 2021.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34535211

RESUMO

OBJECTIVES: To systematically assess the efficacy and safety of eltrombopag in the treatment of children with immune thrombocytopenia (ITP). METHODS: PubMed, Embase, Cochrane Library, Weipu Data, CNKI, and Wanfang Data were searched for studies on eltrombopag used for the treatment of children with ITP. RevMan 5.3 and R version 3.6 were used to perform a Meta analysis of included studies. RESULTS: A total of 11 studies were included, with 2 randomized controlled trials and 9 cohort studies. The Meta analysis of the 9 cohort studies showed that eltrombopag had a response rate of about 70% (95%CI: 65%-76%) in the treatment of children with ITP, with no serious adverse events. The Meta analysis of the randomized controlled trials showed that the eltrombopag group had a higher response rate than the placebo group (RR=2.64, 95%CI: 1.58-4.44, P<0.05), while there was no significant difference in the incidence rates of adverse events and serious adverse events between the two groups (P>0.05). CONCLUSIONS: Eltrombopag has good efficacy and safety as a second-line treatment regimen for children with ITP.


Assuntos
Púrpura Trombocitopênica Idiopática , Benzoatos , Criança , Humanos , Hidrazinas/efeitos adversos , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis , Receptores Fc , Trombopoetina
14.
Blood Adv ; 5(17): 3362-3372, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34477819

RESUMO

The use of umbilical cord blood transplant has been substantially limited by the finite number of hematopoietic stem and progenitor cells in a single umbilical cord blood unit. Small molecules that not only quantitatively but also qualitatively stimulate enhancement of hematopoietic stem cell (HSC) self-renewal ex vivo should facilitate the clinical use of HSC transplantation and gene therapy. Recent evidence has suggested that the cyclin-dependent kinase inhibitor, p18INK4C (p18), is a critical regulator of mice HSC self-renewal. The role of p18 in human HSCs and the effect of p18 inhibitor on human HSC expansion ex vivo need further studies. Here we report that knockdown of p18 allowed for an increase in long-term colony-forming cells in vitro. We then identified an optimized small molecule inhibitor of p18, 005A, to induce ex vivo expansion of HSCs that was capable of reconstituting human hematopoiesis for at least 4 months in immunocompromised mice, and hence, similarly reconstituted secondary recipients for at least 4 more months, indicating that cells exposed to 005A were still competent in secondary recipients. Mechanistic studies showed that 005A might delay cell division and activate both the Notch signaling pathway and expression of transcription factor HoxB4, leading to enhancement of the self-renewal of long-term engrafting HSCs and the pool of progenitor cells. Taken together, these observations support a role for p18 in human HSC maintenance and that the p18 inhibitor 005A can enhance the self-renewal of long-term HSCs.


Assuntos
Inibidor de Quinase Dependente de Ciclina p18 , Células-Tronco Hematopoéticas , Animais , Benzoatos , Ciclo Celular , Inibidor de Quinase Dependente de Ciclina p18/genética , Hematopoese , Humanos , Camundongos
15.
Carbohydr Polym ; 270: 118328, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34364591

RESUMO

Here, biomimetic dual esterification strategy was proposed on natural polysaccharides cellulose nanocrystals (CNCs) and galactomannan (GM) in combination with tartaric acid (TA) and benzoic anhydride (BA) respectively. Evaporation-induced self-assembly (EISA) formed the oriented quasinematic structure of the nanocomposites membranes. The CNCs crystallites were modified by TA and intercalated by amorphous polysaccharides, building a complex supramolecular network. Thus, it presents excellent light scattering property with the optical haze of ~90%, which was rarely reported previously. TA and BA simultaneously contributed to satisfying UV adsorption capability for the membranes, showing almost whole-spectra UVA/UVB blocking. Super high mechanical strength (>150 MPa) and toughness (~8 kJ/m3) were revealed by the membranes with high addition amount of BA, together with the efficient antibacterial capability on both Gram-positive and negative bacteria. The diverse optical, mechanical and biological functions displayed by the polysaccharides membranes, propose new horizons on application for packaging, optoelectronic and biomonitoring sensors.


Assuntos
Antibacterianos/química , Benzoatos/química , Celulose/química , Galactose/análogos & derivados , Mananas/química , Nanopartículas/química , Tartaratos/química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Benzoatos/farmacologia , Materiais Biocompatíveis/química , Esterificação , Galactose/química , Galactose/farmacologia , Mananas/farmacologia , Nanocompostos/química , Polissacarídeos/química , Polissacarídeos/farmacologia , Tartaratos/farmacologia , Resistência à Tração , Raios Ultravioleta
16.
Biochem Biophys Res Commun ; 573: 55-61, 2021 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-34388455

RESUMO

Mammary epithelial cells are the only cells in the mammary glands that are capable of lactation and they are ideal for studying cellular and molecular biology mechanisms during growth, development and lactation of the mammary glands. The limiting factors in most of the currently available mammary epithelial cells are low cell viability, transgenerational efficiency and lactation function that renders them unsuitable for subsequent studies on mammary gland's cellular and lactation mechanisms and utilizing them as bioreactors. Hence, new methods are required to obtain mammary epithelial cells with high transgenerational efficiency and lactation function. In this study, transdifferentiation of goat ear fibroblasts (GEFs) into goat mammary epithelial cells (CiMECs) was induced in only eight days by five small molecule compounds, including 500 µg/mL VPA, 10 µM Tranylcypromine, 10 µM Forskolin, 1 µM TTNPB, 10 µM RepSox. Morphological observation, marker genes comparison, specific antigen expression and comparison of gene expression levels by transcriptome sequencing between the two types of cells that led to the primary deduction that CiMECs have similar biological properties to goat mammary epithelial cells (GMECs) and comparatively more lactation capacity. Therefore, we establish a novel reprogramming route to convert fibroblasts into CiMECs under fully chemically conditions. This study is expected to provide an in vitro platform for understanding cellular mechanisms such as mammary epithelial cells' fate determination and developmental differentiation, and also to find a new way to obtain a large number of functional mammary epithelial cells in vitro.


Assuntos
Benzoatos/farmacologia , Colforsina/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Retinoides/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Tranilcipromina/farmacologia , Ácido Valproico/farmacologia , Animais , Benzoatos/química , Transdiferenciação Celular/efeitos dos fármacos , Colforsina/química , Relação Dose-Resposta a Droga , Orelha , Células Epiteliais/efeitos dos fármacos , Feminino , Fibroblastos/efeitos dos fármacos , Cabras , Glândulas Mamárias Animais/efeitos dos fármacos , Pirazóis/química , Piridinas/química , Retinoides/química , Bibliotecas de Moléculas Pequenas/química , Tranilcipromina/química , Ácido Valproico/química
17.
Angew Chem Int Ed Engl ; 60(43): 23182-23186, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34399005

RESUMO

The 1,4-diacyloxylation of 1,3-cyclohexadiene (CHD) affords valuable stereochemically defined scaffolds for natural product and pharmaceutical synthesis. Existing cis-selective diacyloxylation protocols require superstoichiometric quantities of benzoquinone (BQ) or MnO2 , which limit process sustainability and large-scale application. In this report, reaction development and mechanistic studies are described that overcome these limitations by pairing catalytic BQ with tert-butyl hydroperoxide as the stoichiometric oxidant. Catalytic quantities of bromide enable a switch from trans to cis diastereoselectivity. A catalyst with a 1:2 Pd:Br ratio supports high cis selectivity while retaining good rate and product yield. Further studies enable replacement of BQ with hydroquinone (HQ) as a source of cocatalyst, avoiding the handling of volatile and toxic BQ in large-scale applications.


Assuntos
Acetatos/química , Benzoatos/síntese química , Cicloexenos/síntese química , Hidroquinonas/química , Compostos Organometálicos/química , Catálise , Paládio/química , Estereoisomerismo
18.
Int J Mol Sci ; 22(15)2021 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-34360675

RESUMO

In recent decades, interest in natural compounds has increased exponentially due to their numerous beneficial properties in the treatment of various acute and chronic diseases. A group of plant derivatives with great scientific interest is terpenic compounds. Among the plants richest in terpenes, the genus Ferula L. is one of the most representative, and ferutinin, the most common sesquiterpene, is extracted from the leaves, rhizome, and roots of this plant. As reported in the scientific literature, ferutinin possesses antioxidant and anti-inflammatory properties, as well as valuable estrogenic properties. Neurodegenerative and demyelinating diseases are devastating conditions for which a definite cure has not yet been established. The mechanisms involved in these diseases are still poorly understood, and oxidative stress is considered to be both a key modulator and a common denominator. In the proposed experimental system, co-cultured human neurons (SH-SY5Y) and human oligodendrocytes (MO3.13) were treated with the pro-inflammatory agent lipopolysaccharide at a concentration of 1 µg/mL for 24 h or pretreated with ferutinin (33 nM) for 24 h and subsequently exposed to lipopolysaccharide 1 µg/mL for 24 h. Further studies would, however, be needed to establish whether this natural compound can be used as a support strategy in pathologies characterized by progressive inflammation and oxidative stress phenomena.


Assuntos
Benzoatos/farmacologia , Cicloeptanos/farmacologia , Inflamação/tratamento farmacológico , Lipopolissacarídeos/toxicidade , Neurônios/efeitos dos fármacos , Oligodendroglia/efeitos dos fármacos , Estresse Oxidativo , Sesquiterpenos/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Linhagem Celular , Técnicas de Cocultura , Escherichia coli , Humanos , Inflamação/induzido quimicamente , Neurônios/metabolismo , Neurônios/patologia , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Substâncias Protetoras/farmacologia
19.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361032

RESUMO

17,18-Epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic acid (19,20-EDP) are bioactive epoxides produced from n-3 polyunsaturated fatty acid eicosapentaenoic acid and docosahexaenoic acid, respectively. However, these epoxides are quickly metabolized into less active diols by soluble epoxide hydrolase (sEH). We have previously demonstrated that an sEH inhibitor, t-TUCB, decreased serum triglycerides (TG) and increased lipid metabolic protein expression in the brown adipose tissue (BAT) of diet-induced obese mice. This study investigates the preventive effects of t-TUCB (T) alone or combined with 19,20-EDP (T + EDP) or 17,18-EEQ (T + EEQ) on BAT activation in the development of diet-induced obesity and metabolic disorders via osmotic minipump delivery in mice. Both T + EDP and T + EEQ groups showed significant improvement in fasting glucose, serum triglycerides, and higher core body temperature, whereas heat production was only significantly increased in the T + EEQ group. Moreover, both the T + EDP and T + EEQ groups showed less lipid accumulation in the BAT. Although UCP1 expression was not changed, PGC1α expression was increased in all three treated groups. In contrast, the expression of CPT1A and CPT1B, which are responsible for the rate-limiting step for fatty acid oxidation, was only increased in the T + EDP and T + EEQ groups. Interestingly, as a fatty acid transporter, CD36 expression was only increased in the T + EEQ group. Furthermore, both the T + EDP and T + EEQ groups showed decreased inflammatory NFκB signaling in the BAT. Our results suggest that 17,18-EEQ or 19,20-EDP combined with t-TUCB may prevent high-fat diet-induced metabolic disorders, in part through increased thermogenesis, upregulating lipid metabolic protein expression, and decreasing inflammation in the BAT.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Ácidos Araquidônicos/uso terapêutico , Benzoatos/uso terapêutico , Obesidade/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Adipogenia , Tecido Adiposo Marrom/citologia , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Animais , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/farmacologia , Ácidos Araquidônicos/administração & dosagem , Ácidos Araquidônicos/farmacologia , Benzoatos/administração & dosagem , Benzoatos/farmacologia , Glicemia/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Dieta Hiperlipídica , Epóxido Hidrolases/antagonistas & inibidores , Ácidos Graxos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/farmacologia
20.
J Clin Hypertens (Greenwich) ; 23(9): 1664-1674, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34384001

RESUMO

This multicenter, phase 4, Prospective Randomized Open, Blinded End-point (PROBE) study aimed to evaluate safety and efficacy of telmisartan/rosuvastatin single-pill combination (SPC) therapy on lowering central blood pressure (BP) compared with telmisartan monotherapy in hypertensive patients with dyslipidemia in Korea. Study was terminated earlier than planned due to COVID-19 pandemic, thus should be considered as a pilot study. Among 125 patients who met the inclusion criteria of hypertension and dyslipidemia (defined as 10-year Atherosclerotic Cardiovascular Disease risk score over 5%), 80 patients went through 4-week single-group run-in period with telmisartan 40-80 mg, then randomized to telmisartan 80 mg + rosuvastatin (10 or 20 mg) SPC group or telmisartan 80 mg monotherapy group. The central/brachial BP, brachial-ankle pulse wave velocity (baPWV), and augmentation index (AIx) were assessed at baseline and 16 weeks later. Mean brachial SBP changed from 135.80 ± 14.22 mmHg to 130.69 ± 13.23 mmHg in telmisartan/rosuvastatin group and from 134.37 ± 12.50 mmHg to 133.75 ± 12.30 mmHg in telmisartan monotherapy group without significant difference (between-group difference p = .149). Mean central SBP were reduced significantly in the telmisartan/rosuvastatin group with change from 126.72 ± 14.44 mmHg to 121.56 ± 14.56 mmHg while telmisartan monotherapy group showed no significant change (between-group difference p = .028). BaPWV changed from 1672.57 ± 371.72 m/s to 1591.75 ± 272.16 m/s in telmisartan/rosuvastatin group and from 1542.85 ± 263.70 m/s to 1586.12 ± 297.45 m/s in telmisartan group with no significance (between-group difference p = .078). Change of AIx had no significant difference (between-group difference p = .314). Both groups showed excellent compliance rate of 96.9 ± 4.5% with no significant difference in adverse rate. Telmisartan/rosuvastatin SPC therapy was more effective in lowering central BP compared with the telmisartan monotherapy. The results of this study showed benefit of additive statin therapy in hypertensive patients combined with dyslipidemia.


Assuntos
COVID-19 , Dislipidemias , Hipertensão , Índice Tornozelo-Braço , Anti-Hipertensivos/uso terapêutico , Benzoatos , Pressão Sanguínea , Combinação de Medicamentos , Dislipidemias/tratamento farmacológico , Humanos , Hipertensão/tratamento farmacológico , Pandemias , Projetos Piloto , Estudos Prospectivos , Análise de Onda de Pulso , Rosuvastatina Cálcica , SARS-CoV-2 , Telmisartan/farmacologia
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