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1.
Nat Commun ; 13(1): 5401, 2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36104354

RESUMO

FLT3 is an attractive therapeutic target in acute lymphoblastic leukemia (ALL) but the mechanism for its activation in this cancer is incompletely understood. Profiling global gene expression in large ALL cohorts, we identify over-expression of FLT3 in ZNF384-rearranged ALL, consistently across cases harboring different fusion partners with ZNF384. Mechanistically, we discover an intergenic enhancer element at the FLT3 locus that is exclusively activated in ZNF384-rearranged ALL, with the enhancer-promoter looping directly mediated by the fusion protein. There is also a global enrichment of active enhancers within ZNF384 binding sites across the genome in ZNF384-rearranged ALL cells. Downregulation of ZNF384 blunts FLT3 activation and decreases ALL cell sensitivity to FLT3 inhibitor gilteritinib in vitro. In patient-derived xenograft models of ZNF384-rearranged ALL, gilteritinib exhibits significant anti-leukemia efficacy as a monotherapy in vivo. Collectively, our results provide insights into FLT3 regulation in ALL and point to potential genomics-guided targeted therapy for this patient population.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Transativadores , Compostos de Anilina , Epigênese Genética , Fusão Gênica , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pirazinas , Transativadores/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo
2.
Org Lett ; 24(36): 6686-6691, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36053069

RESUMO

The synthesis of aniline derivatives, common building blocks in many pharmaceuticals, agrochemicals, dyes or polymers, has been limited to reactions based on benzene-toluene-xylene derivatives (BTX) due to their ample availability. Despite the large number of existing methodologies, the synthesis of chiral 4-(sec-alkyl)anilines has not been accomplished so far. In this work, a tandem strategy based on the generation of a reactive aza-p-quinone methide (aza-p-QM) intermediate followed by Cu(I)-catalyzed addition of Grignard reagents has been developed.


Assuntos
Benzeno , Xilenos , Agroquímicos , Compostos de Anilina , Catálise , Corantes , Indicadores e Reagentes , Indolquinonas , Preparações Farmacêuticas , Polímeros , Tolueno
3.
Arthritis Res Ther ; 24(1): 223, 2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36115996

RESUMO

BACKGROUND: Subchondral bone plays an important role in the pathogenesis of radiographic osteoarthritis (OA). However, the bony changes that occur in hand OA (HOA) are much less understood. This study aimed to describe the association between radiographic HOA and high-resolution peripheral quantitative computed tomography (HRpQCT) measures of the hand and radius in a population-based sample. METHODS: A total of 201 participants (mean age 72, 46% female) from the Tasmanian Older Adult Cohort (TASOAC) study underwent HRpQCT assessment of the 2nd distal and proximal interphalangeal (DIP, PIP), 1st carpometacarpal (CMC) joint, and distal radius. Radiographic HOA was assessed at the 2nd DIP, PIP joints, and the 1st CMC joint using the OARSI atlas. RESULTS: Proximal osteophyte and joint space narrowing (JSN) scores were consistently more strongly associated with HRpQCT measures compared to the distal site with positive associations for indices of bone size (total and trabecular bone area and cortical perimeter but inconsistent for cortical area) and negative associations for volumetric bone mineral density (vBMD). There was a decrease in trabecular number and bone volume fraction with increasing osteophyte and JSN score as well as an increase in trabecular separation and inhomogeneity. Osteophyte and JSN scores in the hand were not associated with HRpQCT measures at the distal radius. CONCLUSIONS: This hypothesis generating data suggests that bone size and trabecular disorganization increase with both osteophyte formation and JSN (proximal more than distal), while local vBMD decreases. This process appears to be primarily at the site of pathology rather than nearby unaffected bone.


Assuntos
Articulação da Mão , Osteoartrite , Osteófito , Idoso , Compostos de Anilina , Osso e Ossos/patologia , Feminino , Articulação da Mão/diagnóstico por imagem , Articulação da Mão/patologia , Humanos , Masculino , Osteoartrite/diagnóstico por imagem , Osteoartrite/patologia , Osteófito/diagnóstico por imagem , Osteófito/patologia
4.
Anal Chim Acta ; 1227: 340239, 2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-36089329

RESUMO

A novel screen-printed electrode (SPE) for potentiometric determination of nalbuphine (NAL) is described. Carboxylated multi-walled carbon nano tubes/polyaniline (f-MWCNTs/PANI) nanocomposite is used as an ion-to- electron transducer and is covered by a selective polyvinyl chloride (PVC) membrane incorporated with molecularly imprinted drug polymer (MIP) beads as a recognition receptor for potentiometric determination a synthetic narcotic, nalbuphine (NAL). The SPE displays a Nernstian response with a slope of 60.3 ± 1.2 mV/decade (R2 = 0.999) over the concentration range 2.4 × 10-7 - 5.0 × 10-2 mol/L and a detection limit of 1.1 × 10-7 mol/L (0.04 µg/mL) with response time less than 20 s (<20 s). The interfacial capacitance of the proposed SPE is measured using chronopotentiometry (CP) and electrochemical impedance spectroscopy (EIS). The use of the f-MWCNTs/PANI nanocomposite layer improved the interfacial capacitance reached 52.5 µF. Besides, it eliminated the formation of the undesired thin water-layer between the sensing membrane and the conducting substrate. This prevents membrane delamination and increases potential stability. The obtained high selectivity, sensitivity and potential stability offered a great applicability of the proposed SPE for the determination of nalbuphine in hospitals for rapid diagnosis of overdose patients and for quality control/quality assurance in pharmaceutical industry.


Assuntos
Nalbufina , Nanotubos de Carbono , Compostos de Anilina , Eletrodos , Humanos , Polímeros Molecularmente Impressos , Nanotubos de Carbono/química , Preparações Farmacêuticas , Transdutores
5.
Med Oncol ; 39(12): 195, 2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36071367

RESUMO

Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that is effective against the EGFR T790M mutation in patients with advanced non-small-cell lung cancer (NSCLC). However, acquired resistance appears invariably due to several mechanisms. The strategy of using EGF-targeted nanobodies (Nbs) to block the initial step of the EGFR pathway constitutes a new research area. Nbs offer several advantages compared to traditional mAbs, such as their reduced size, increased stability, and tissue penetration, which provide key advantages for targeting soluble tumoral growth factors. In this study we investigated the efficacy of anti-EGF Nbs to reduce Osimertinib resistance. Two anti-EGF Nbs, generated in our laboratory, were shown to inhibit cell viability and colony formation in PC9 and PC9-derived osimertinib-resistant cell lines. The combination of these Nbs with osimertinib improved the antitumor efficacy of this EGFR-TKI in cell viability and colony formation experiments. In a mechanistic study of the EGFR pathway, the combination treatment dampened the activation of downstream proteins such as Akt and Erk1/2 MAP kinases. In addition, it increased cellular apoptosis and decreased the expression of Hes1, a cancer stem cell marker involved in metastasis and osimertinib resistance. We conclude that the addition of anti-EGF nanobodies enhances the antitumor properties of osimertinib, thus representing a potentially effective strategy for NSCLC patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Anticorpos de Domínio Único , Acrilamidas , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/genética , Humanos , Indóis , Neoplasias Pulmonares/patologia , Mutação , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas , Anticorpos de Domínio Único/genética , Anticorpos de Domínio Único/farmacologia
6.
Praxis (Bern 1994) ; 111(12): 668-673, 2022 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-36102020

RESUMO

Hand Osteoarthritis - Clinical Picture and Current Management Abstract. Finger joint osteoarthritis (HOA) is a common joint disease that increases with age. The cause is polyethiological. The distal joints of the fingers are most frequently affected, followed by the carpometacarpal joint of the thumb, the proximal interphalangeal joints, and the metacarpophalangeal joints. The clinical symptoms of HOA are painful functional restrictions of the hand and fingers. In terms of therapy, lifestyle modifications and exercise are primarily recommended. Only when these measures are inadequate or not helpful drugs will be recommended be recommended. First-choice drugs are non-steroidal anti-inflammatory drugs applied topically or p.o. Pharmaceutically manufactured chondroitin preparations are also helpful. In severely painful or erosive forms of HOA, corticosteroids can be used intra-articularly. The status of laser therapy or fractionated radiation is (still) unclear. Classical disease-modifying drugs such as those used in inflammatory joint diseases have no therapeutic value. Surgical interventions should be considered if conservative treatments are not sufficiently helpful and hand function is significantly impaired.


Assuntos
Osteoartrite , Compostos de Anilina , Articulações dos Dedos , Humanos , Osteoartrite/diagnóstico , Osteoartrite/terapia , Dor , Radiografia , Polegar
7.
Cells ; 11(17)2022 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-36078163

RESUMO

FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (FLT3-ITD) mutations occur in about 25% of all acute myeloid leukemia (AML) patients and confer a poor prognosis. FLT3 inhibitors have been developed to treat patients with FLT3-mutated AML and have shown promise, though the acquisition of resistance occurs, highlighting the need for combination therapies to prolong the response to FLT3 inhibitors. In this study, we investigated the selective Mcl-1 inhibitor AZD5991 in combination with the FLT3 inhibitors gilteritinib and MRX-2843. The combinations synergistically induce apoptosis in AML cell lines and primary patient samples. The FLT3 inhibitors downregulate c-Myc transcripts through the suppression of the MEK/ERK and JAK2/STAT5 pathways, resulting in the decrease in c-Myc protein. This suppression of c-Myc plays an important role in the antileukemic activity of AZD5991. Interestingly, the suppression of c-Myc enhances AZD5991-inudced cytochrome c release and the subsequent induction of apoptosis. AZD5991 enhances the antileukemic activity of the FLT3 inhibitors gilteritinib and MRX-2843 against FLT3-mutated AML in vitro, warranting further development.


Assuntos
Leucemia Mieloide Aguda , Tirosina Quinase 3 Semelhante a fms , Compostos de Anilina , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirazinas/farmacologia , Tirosina Quinase 3 Semelhante a fms/genética
8.
ACS Appl Mater Interfaces ; 14(36): 40624-40632, 2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36049088

RESUMO

As an energy supplier, ATP plays an important role in various life activities, and there is an urgent need to develop an effective means of detecting ATP. However, the traditional sensors face serious nonspecific adsorption. In this work, an antifouling electrochemical biosensor based on the interpenetrating network of Y-DNA scaffold and polyaniline hydrogel was designed for ATP detection. The polyaniline hydrogel was conducive to the transport of electrons and ions, the structure of Y-DNA cross-linked by ATP aptamers in the polyaniline hydrogel achieved the effect of signal amplification. Super hydrophilic cellulose nanocrystals (CNCs) and zwitterion polypeptide sequence (Pep) were doped to play a synergistic antifouling effect. The hydrogel sensor we have built has a wide linear range of 0.1 pM-1 µM for ATP detection and a low detection limit of 0.025 pM (S/N = 3). For ATP detection in actual serum samples, the recovery of this sensor was 99.5%-106%, and the relative standard deviation was 0.4%-2.88%. It is proven that the sensor has good ATP detection performance, and it will provide a certain reference value for the detection of other biological small molecules.


Assuntos
Incrustação Biológica , Técnicas Biossensoriais , Trifosfato de Adenosina/análise , Compostos de Anilina , Incrustação Biológica/prevenção & controle , DNA/química , Técnicas Eletroquímicas , Hidrogéis , Limite de Detecção
9.
Thorac Cancer ; 13(18): 2641-2649, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36082809

RESUMO

BACKGROUND: Real-world application of osimertinib with antiangiogenic agents in non-small cell lung cancer (NSCLC) is common, but the efficacy data are rarely reported. METHODS: To obtain an objective efficacy report of different real-world treatment models of osimertinib and antiangiogenic agents. RESULTS: A total of 54 patients with NSCLC were enrolled into the study. Twelve (22.2%) who received a combination of antiangiogenic agents, when there was a trend of osimertinib resistance but did not reach imageology progressive disease (PD), were assigned to Group A, with a median overall survival (OS) and progression-free survival (PFS) of 48.0 (95% CI, not reached) and 21.0 (95% CI: 16.7-25.3) months, respectively. Thirty (55.6%) who received a combination of antiangiogenic agents when there was imageology PD during treatment with osimertinib were assigned to Group B, with a median OS and PFS of 31.8 (95% CI: 26.6-37.1) and 9.2 (95% CI: 5.9-12.6) months, respectively. Twelve (22.2%) who received a combination of antiangiogenic agents at the initial treatment with osimertinib were assigned to Group C, with a median OS and PFS of 28.5 (95% CI: 15.2-41.8) and 15.3 (95% CI: 7.9-22.7) months, respectively. Patients in Group A achieved a significant prolonged median PFS (p < 0.001) compared with Groups B and C. Absence of epidermal growth factor receptor (EGFR) T790M mutations (p = 0.043; hazard ratio [HR] = 2.124, 95% CI: 1.023-4.413) and no previous antiangiogenic agent application (p = 0.012; HR = 0.362, 95% CI: 0.163-0.863) were the independent prognostic factors of OS. CONCLUSION: The well-timed action to combine antiangiogenic agents was when there was a trend of osimertinib resistance. The absence of EGFR T790M mutations and previous use of antiangiogenic agents were poor prognostic factors.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Acrilamidas , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Receptores ErbB/uso terapêutico , Humanos , Indóis , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas
10.
Molecules ; 27(17)2022 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-36080245

RESUMO

The synthesis of MMT and poly(o-anisidine) (MMT/POA) clay nanocomposites was carried out by using the chemical oxidative polymerization of POA and MMT clay with POA, respectively. By maintaining the constant concentration of POA, different percentage loads of MMT clay were used to determine the effect of MMT clay on the properties of POA. The interaction between POA and MMT clay was investigated by FTIR spectroscopy, and, to reveal the complete compactness and homogeneous distribution of MMT clay in POA, were assessed by using scanning-electron-microscope (SEM) analysis. The UV-visible spectrum was studied for the optical and absorbance properties of MMT/POA ceramic nanocomposites. Furthermore, the horizontal burning test (HBT) demonstrated that clay nanofillers inhibit POA combustion.


Assuntos
Retardadores de Chama , Nanocompostos , Compostos de Anilina , Bentonita/química , Argila , Nanocompostos/química , Compostos Organometálicos
11.
Molecules ; 27(17)2022 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-36080391

RESUMO

A novel polyaniline-modified CNT and graphene-based nanocomposite (2.32-7.34 nm) was prepared and characterized by spectroscopic methods. The specific surface area was 176 m2/g with 0.232 cm3/g as the specific pore volume. The nanocomposite was used to remove zinc and lead metal ions from water; showing a high removal capacity of 346 and 581 mg/g at pH 6.5. The data followed pseudo-second-order, intraparticle diffusion and Elovich models. Besides this, the experimental values obeyed Langmuir and Temkin isotherms. The results confirmed that the removal of lead and zinc ions occurred in a mixed mode, that is, diffusion absorption and ion exchange between the heterogeneous surface of the sorbent containing active adsorption centers and the solution containing metal ions. The enthalpy values were 149.9 and 158.6 J.mol-1K-1 for zinc and lead metal ions. The negative values of free energies were in the range of -4.97 to -26.3 kJ/mol. These values indicated an endothermic spontaneous removal of metal ions from water. The reported method is useful to remove the zinc and lead metal ions in any water body due to the high removal capacity of nanocomposite at natural pH of 6.5. Moreover, a low dose of 0.005 g per 30 mL made this method economical. Furthermore, a low contact time of 15 min made this method applicable to the removal of the reported metal ions from water in a short time. Briefly, the reported method is highly economical, nature-friendly and fast and can be used to remove the reported metal ions from any water resource.


Assuntos
Grafite , Nanocompostos , Poluentes Químicos da Água , Purificação da Água , Adsorção , Compostos de Anilina , Grafite/química , Concentração de Íons de Hidrogênio , Íons , Cinética , Metais , Nanocompostos/química , Termodinâmica , Água/química , Poluentes Químicos da Água/química , Purificação da Água/métodos , Zinco
12.
J Org Chem ; 87(18): 12196-12213, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36007261

RESUMO

A novel carbenoid-mediated approach to thioisomünchnones was developed by intermolecular copper-catalyzed reactions of diazoacetamides with aromatic and heteroaromatic thioamides bearing a pyrrolidine moiety. The direction of the reaction can be switched toward 2-amino-2-heteroarylacrylamides by replacing the pyrrolidine with an aniline group or by the use of 2-cyano-2-diazoacetamides. The proposed mechanism and DFT calculations allowed us to rationalize the effect of substituents on the reaction direction. Effective methods were found for the synthesis of previously unknown both 2-heteroarylthioisomünchones and 2-heteroarylacrylamides, based on a wide scope of available reagents with a similar structure. Some of the synthesized thioisomünchnones exhibited multicolor fluorescence in the solid state and solutions.


Assuntos
Cobre , Tioamidas , Acrilamidas , Compostos de Anilina , Catálise , Cobre/química , Estrutura Molecular , Pirrolidinas , Tioamidas/química
13.
EBioMedicine ; 83: 104200, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35932642

RESUMO

BACKGROUND: The mechanism of missense alteration at EGFR L792F in patients with non-small cell lung cancer resistant to osimertinib has not been sufficiently clarified. We aimed to explore the critical molecular events and coping strategies in osimertinib resistance due to acquired L792F mutation. METHODS: Circulating tumor DNA-based sequencing data of 1153 patients with osimertinib resistance were collected to illustrate the prevalence of EGFR L792F mutation. Sensitivity to osimertinib was tested with constructed EGFR 19Del/T790M-cis-L792F cell lines in vitro and in vivo. The correlation and linked pathways between M2 macrophage polarization and EGFR L792Fcis-induced osimertinib resistance were investigated. Possible interventions to suppress osimertinib resistance by targeting IL-4 or STAT3 were explored. FINDINGS: The concomitant EGFR L792F was identified as an independent mutation following the acquisition of T790M after osimertinib resistance, in that 5 of the 946 patients with osimertinib resistance harbored EGFR T790M-cis-L792F mutation. Transfected EGFR 19Del/T790M-cis-L792F in cell lines had decreased sensitivity to osimertinib and enhanced infiltrating macrophage with M2 polarization. Silico analyses confirmed the role of M2 polarization in osimertinib resistance induced by EGFR T790M-cis-L792F mutation. EGFR T790M-cis-L792F mutation upregulated phosphorylation of STAT3 Tyr705 and promoted its specific binding to IL4 promoter, enhancing IL-4 expression and secretion and inducing macrophage M2 polarization. Furthermore, blockade of STAT3/IL-4 (SH-4-54 or dupilumab) suppressed macrophage M2 polarization and regressed tumor sensitivity to osimertinib. INTERPRETATION: Our results proved that targeting EGFR T790M-cis-L792F/STAT3 Tyr705/IL-4 pathway could be a potential strategy to suppress osimertinib resistance in NSCLC. FUNDING: This work was supported by the National Natural Science Foundation of China (81871889, 82072586, 81902910), Beijing Natural Science Foundation (7212084, 7214249), the China National Natural Science Foundation Key Program (81630071), the National Key Research and Development Project (2019YFC1315704), CAMS Innovation Fund for Medical Sciences (CIFMS 2021-1-I2M-012), Aiyou Foundation (KY201701) and CAMS Key Laboratory of translational research on lung cancer (2018PT31035).


Assuntos
Carcinoma Pulmonar de Células não Pequenas , DNA Tumoral Circulante , Neoplasias Pulmonares , Acrilamidas , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Indóis , Interleucina-4/genética , Interleucina-4/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Macrófagos/metabolismo , Mutação , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo
16.
Food Chem Toxicol ; 168: 113370, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35985363

RESUMO

Pendimethalin is globally registered for control of a wide range of weeds in agriculture and home landscaping. Human exposure to pendimethalin can occur by the oral route through food and other sources. Endothelial function is vital to numerous biological processes, and endothelial dysfunction and poor vascular health is associated with increased atherosclerotic events; however, no study has yet investigated the potential effect of pendimethalin on endothelial function and vasculature formation. The objective of the current study is to investigate if pendimethalin may affect the viability and function of vascular endothelial cells. We observed that pendimethalin significantly repressed viability of human endothelial cells, inducing G1 cell cycle arrest and apoptotic/necrotic cell death. Pendimethalin treatment also activated ER stress and autophagy, leading to loss of mitochondrial membrane potential. In addition, pendimethalin impaired the tube forming and migratory abilities of endothelial cells. This study provides previously unrecognized adverse effects of pendimethalin in vascular endothelial cells, mediated by ER stress-induced mitochondrial dysfunction.


Assuntos
Compostos de Anilina , Apoptose , Compostos de Anilina/toxicidade , Estresse do Retículo Endoplasmático , Células Endoteliais da Veia Umbilical Humana , Humanos , Mitocôndrias/metabolismo
17.
Chem Res Toxicol ; 35(9): 1625-1630, 2022 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-36001821

RESUMO

Several aromatic amine compounds are urinary bladder carcinogens. Activated metabolites and DNA adducts of polycyclic aromatic amines, such as 4-aminobiphenyl, have been identified, whereas those of monocyclic aromatic amines, such as o-toluidine (o-Tol), o-anisidine (o-Ans), and aniline (Ani), have not been completely determined. We have recently reported that o-Tol and o-Ans are metabolically converted in vitro and in vivo to cytotoxic and mutagenic p-semidine-type dimers, namely 2-methyl-N4-(2-methylphenyl) benzene-1,4-diamine (MMBD) and 2-methoxy-N4-(2-methoxyphenyl) benzene-1,4-diamine (MxMxBD), respectively, suggesting their roles in urinary bladder carcinogenesis. In this study, we found that when o-Tol and o-Ans were incubated with S9 mix, MMBD and MxMxBD as well as two isomeric heterodimers, MMxBD and MxMBD, were formed. Therefore, any two of o-Tol, o-Ans, and Ani (10 mM each) were incubated with the S9 mix for up to 24 h and then subjected to LC-MS to investigate their metabolic kinetics. Metabolic conversions to all nine kinds of p-semidine-type homo- and hetero-dimers were observed, peaking at 6 h of incubation with the S9 mix; MxMxBD reached the peak at 6.1 ± 1.4 µM. Homo- and hetero-dimers containing the o-Ans moiety in the diamine structure showed a faster dimerization ratio, whereas levels of these dimers, such as MxMxBD, markedly declined with further incubation. Dimers containing o-Tol and Ani were relatively stable, even after incubation for 24 h. The electron-donating group of the o-Ans moiety may be involved in rapid metabolic conversion. In the cytotoxic assay, dimers with an o-Ans moiety in the diamine structure and MMBD showed approximately two- to four-fold higher cytotoxicity than other dimers in human bladder cancer T24 cells. These chemical and biological properties of homo- and hetero-dimers of monocyclic aromatic amines may be important when considering the combined exposure risk for bladder carcinogenesis.


Assuntos
Benzeno , Adutos de DNA , Aminas , Compostos de Anilina/metabolismo , Carcinogênese , Carcinógenos/toxicidade , Humanos , Fenilenodiaminas , Toluidinas
18.
Water Res ; 223: 118967, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35973248

RESUMO

Dissolved organic matter (DOM), ubiquitous in natural waters, is known to inhibit the degradation of micropollutants in the advanced oxidation processes such as the UV/peroxydisulfate process. However, the quantitative understanding of the inhibitory pathways is missing. In this study, guanosine, aniline and catechol belonging to amines, purines and phenols were first investigated due to their resistance to UV irradiation at 254 nm and similar reactivity with SO4•- and HO•, respectively. The presence of 0.5 mgC L-1 Suwannee River NOM (SRNOM) inhibited their degradation rates by 72.9%, 54.5%, and 32.4%, respectively, despite their similar degradation rates in the absence of SRNOM. The results highlight the importance of reverse reduction of oxidation intermediates to the parent compound by antioxidant moieties in SRNOM besides the inner filtering and radical scavenging effects. The three inhibitory pathways were quantified for 34 common micropollutants. In the presence of 0.5 mgC L-1 SRNOM, inner filtering effect was found to contribute less than 2.8% of the inhibitory percentages (IP). Radical scavenging effects contribute between 10.7% and 38.9% and compounds having lower reactivity with SO4•- (< 4.0 × 109 M-1 s-1) tended to be inhibited more strongly. The IP of reverse reduction effects of SRNOM varied significantly from none up to 70.8%. It was linearly related with a micropollutant's reduction potential. Purines and amines generally exhibited more pronounced reverse reduction inhibition than phenols. The results of this study provide guidance on improving the elimination efficiency of micropollutants.


Assuntos
Poluentes Químicos da Água , Purificação da Água , Compostos de Anilina , Antioxidantes , Catecóis , Matéria Orgânica Dissolvida , Guanosina , Cinética , Oxirredução , Fenóis , Purinas , Raios Ultravioleta , Poluentes Químicos da Água/análise , Purificação da Água/métodos
19.
ACS Chem Biol ; 17(9): 2619-2630, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-35969718

RESUMO

Ribosome-inactivating proteins (RIPs) are RNA:adenosine glycosidases that inactivate eukaryotic ribosomes by depurinating the sarcin-ricin loop (SRL) in 28S rRNA. The GAGA sequence at the top of the SRL or at the top of a hairpin loop is assumed to be their target motif. Saporin is a RIP widely used to develop immunotoxins for research and medical applications, but its sequence specificity has not been investigated. Here, we combine the conventional aniline cleavage assay for depurinated nucleic acids with high-throughput sequencing to study sequence-specific depurination of oligonucleotides caused by saporin. Our data reveal the sequence preference of saporin for different substrates and show that the GAGA motif is not efficiently targeted by this protein, neither in RNA nor in DNA. Instead, a preference of saporin for certain hairpin DNAs was observed. The observed sequence-specific activity of saporin may be relevant to antiviral or apoptosis-inducing effects of RIPs. The developed method could also be useful for studying the sequence specificity of depurination by other RIPs or enzymes.


Assuntos
Imunotoxinas , Ricina , Adenosina , Compostos de Anilina , Antivirais/farmacologia , DNA/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Oligonucleotídeos , Proteínas de Plantas/metabolismo , RNA/metabolismo , RNA Ribossômico 28S , Proteínas Inativadoras de Ribossomos , Proteínas Inativadoras de Ribossomos Tipo 1 , Ricina/farmacologia , Saporinas
20.
Colloids Surf B Biointerfaces ; 218: 112763, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35994989

RESUMO

This study was designed to create surface-functionalized bosutinib liposomes that could be used for the management of estrogen-positive cancers. The novelty of this work was the anti-cancer activity of bosutinib-loaded liposomes (Bos-LPs) in estrogen-positive cancer via estrogen response elements, responsible for the malignancy of cancer cells. Biotin effectively delivers active moiety to tumor tissues because it interacts with the biotin receptor and operates through the Sodium-dependent multivitamin transporters (SMVT) transporter. The prepared liposomes had a 257.73 ± 4.50 nm particle size, - 28.07 ± 5.81 mV zeta potential, 87.78 ± 1.16 % encapsulation efficiency and 85.56 ± 0.95 % drug release for 48 h. The surface architecture of biotin-modified bosutinib-loaded liposomes (b-Bos-LPs) was confirmed using scanning electron and transmission electron microscopies. In-vitro experiments revealed that b-Bos-LPs outperformed Bos and Bos-LPs in terms of significantly reduced cell viability in MCF-7 cells. According to biodistribution and pharmacokinetic studies, b-Bos-LPs have a higher Bos concentration in tumor tissues as compared to the other organs and also possess better pharmacokinetic activity, indicating that they can be used to treat carcinogen-induced estrogen-positive cancers. This is the first study to show that b-Bos-LPs can display activity against estrogen-positive cancer via biotin targeting. As evidenced by various parameters, b-Bos-LPs showed improved anticancer targeting, therapeutic safety and efficacy in carcinogen-induced estrogen-positive cancer. The receptor protein estrogen, which is primarily responsible for this cancer was downregulated by b-Bos-LPs in an immunoblotting assay. The results showed that biotinylated distearoylphosphatidylcholine (DSPC) augmented LPs loaded with Bosutinib can cause apoptosis in estrogen-positive breast cancer and be an effective way to treat estrogen-positive cancer.


Assuntos
Compostos de Anilina , Neoplasias da Mama , Lipossomos , Nitrilas , Quinolinas , Compostos de Anilina/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Estrogênios/metabolismo , Feminino , Humanos , Nitrilas/uso terapêutico , Tamanho da Partícula , Quinolinas/uso terapêutico
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