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1.
Molecules ; 29(2)2024 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-38257311

RESUMO

This review presents a comprehensive evaluation for the manufacture of organic molecules via efficient microfluidic synthesis. Microfluidic systems provide considerably higher control over the growth, nucleation, and reaction conditions compared with traditional large-scale synthetic methods. Microfluidic synthesis has become a crucial technique for the quick, affordable, and efficient manufacture of organic and organometallic compounds with complicated characteristics and functions. Therefore, a unique, straightforward flow synthetic methodology can be developed to conduct organic syntheses and improve their efficiency.

2.
Bioconjug Chem ; 33(6): 1011-1034, 2022 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34793138

RESUMO

Immunotherapy has revolutionized the modality for establishing a firm immune response and immunological memory. However, intrinsic limitations of conventional low responsive poor T cell infiltration and immune related adverse effects urge the coupling of cancer nanomedicines with immunotherapy for boosting antitumor response under ultrasound (US) sensitization to mimic dose-limiting toxicities for safe and effective therapy against advanced cancer. US is composed of high-frequency sound waves that mediate targeted spatiotemporal control over release and internalization of the drug. The unconventional US triggered immunogenic nanoengineered arena assists the limited immunogenic dose, limiting toxicities and efficacies. In this Review, we discuss current prospects of enhanced immunotherapy using nanomedicine under US. We highlight how nanotechnology designs and incorporates nanomedicines for the reprogramming of systematic immunity in the tumor microenvironment. We also emphasize the mechanical and biological potential of US, encompassing sonosensitizer activation for enhanced immunotherapeutic efficacies. Finally, the smartly converging combinational platform of US stimulated cancer nanomedicines for amending immunotherapy is summarized. This Review will widen scientists' ability to explore and understand the limiting factors for combating cancer in a precisely customized way.


Assuntos
Neoplasias , Humanos , Fatores Imunológicos/farmacologia , Imunoterapia , Nanomedicina , Nanotecnologia , Neoplasias/patologia , Microambiente Tumoral
3.
Cytokine ; 158: 155993, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36007427

RESUMO

Allele bias is an epigenetic mechanism wherein only the maternal- or paternal-derived allele of a gene is preferentially expressed. Allele bias is used by T cells to regulate expression of numerous genes, including those which govern their development and response to cytokines. Here we demonstrate that human TH cell expression of the cytokine receptor gene IL12RB1 is subject to allele bias, and the extent to which this bias occurs is influenced by cells' differentiation status and two polymorphic sites in the IL12RB1 3'UTR. The single nucleotide polymorphisms (SNPs) at these sites, rs3746190 and rs404733, function to increase expression of their encoding allele. Modeling suggests this is due to a stabilizing effect of these SNPs on the predicted mRNA secondary structure. The SNP rs3746190 is also proximal to the predicted binding site of microRNA miR-1277, raising the possibility that miR-1277 cannot exert suppression in the presence of rs3746190. Functional experiments demonstrate, however, that miR-1277 suppression of IL12RB1 3'UTR expression-which itself has not been previously reported-is nevertheless independent of rs3746190. Collectively, these data demonstrate that rs3746190 and rs404733 are functional SNPs which regulate IL12RB1 allele bias in human TH cells.


Assuntos
Regiões 3' não Traduzidas , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina-12 , Linfócitos T Auxiliares-Indutores , Regiões 3' não Traduzidas/genética , Alelos , Sítios de Ligação , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Receptores de Interleucina-12/genética
4.
Molecules ; 27(18)2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36144499

RESUMO

Protein corona composition and precise physiological understanding of differentially expressed proteins are key for identifying disease biomarkers. In this report, we presented a distinctive quantitative proteomics table of molecular cell signaling differentially expressed proteins of corona that formed on iron carbide nanoparticles (NPs). High-performance liquid chromatography/electrospray ionization coupled with ion trap mass analyzer (HPLC/ESI-Orbitrap) and MASCOT helped quantify 142 differentially expressed proteins. Among these proteins, 104 proteins showed upregulated behavior and 38 proteins were downregulated with respect to the control, whereas 48, 32 and 24 proteins were upregulated and 8, 9 and 21 were downregulated CW (control with unmodified NPs), CY (control with modified NPs) and WY (modified and unmodified NPs), respectively. These proteins were further categorized on behalf of their regularity, locality, molecular functionality and molecular masses using gene ontology (GO). A STRING analysis was used to target the specific range of proteins involved in metabolic pathways and molecular processing in different kinds of binding functionalities, such as RNA, DNA, ATP, ADP, GTP, GDP and calcium ion bindings. Thus, this study will help develop efficient protocols for the identification of latent biomarkers in early disease detection using protein fingerprints.


Assuntos
Nanopartículas , Coroa de Proteína , Difosfato de Adenosina , Trifosfato de Adenosina , Cálcio , Compostos Inorgânicos de Carbono , Análise por Conglomerados , Guanosina Trifosfato , Compostos de Ferro , Nanopartículas/química , Coroa de Proteína/química , Proteínas/metabolismo , Proteômica/métodos , RNA
5.
J Environ Manage ; 278(Pt 2): 111302, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33152547

RESUMO

The water reservoirs are getting polluted due to increasing amounts of micropollutants such as pharmaceuticals, organic polymers and suspended solids. Powdered activated carbon (PAC) has been proved to be a promising solution for the purification of water without having harmful impacts on the environment. Parameters such as PAC dosing, wastewater hardness, the effect of coagulant and flocculant were evaluated in a batch scale study. These parameters were further applied on a pilot plant scale for the performance evaluation of PAC based removal of micropollutants concerning the contact time and PAC dosing with main focus on recirculation of PAC sludge. The obtained optimum dose was 10-20 mg/L providing 84.40-91.30% removal efficiency of suspended solid micropollutants (MPs) and this efficiency increased to 88.90-93.00% along with coagulant which further raised by the addition of polymer and recirculation process at batch scale. On pilot plant scale, the concentration in contact reactor and PAC removal effectiveness of dissolved air flotation, lamella separator and sedimentation tank were compared. Constant optimisation resulted in a concentration ranging from 2.70 to 3.40 g/L at dosing of PAC 10 mg/L, coagulant 2.00 mg/L and polymer 0.50 mg/L. PAC doses of 10-20 mg/L with 15-30 min contact time proved best for above 70-80% elimination. The recirculation system has also proved an efficient technique because the PAC's adsorption capacity was practically completely used. Small PAC dosages yielded high micropollutants elimination.


Assuntos
Poluentes Químicos da Água , Purificação da Água , Adsorção , Carvão Vegetal , Eliminação de Resíduos Líquidos , Águas Residuárias , Poluentes Químicos da Água/análise
6.
Acta Neuropathol ; 140(3): 317-339, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32577828

RESUMO

Dysfunctional RNA-binding proteins (RBPs) have been implicated in several neurodegenerative disorders. Recently, this paradigm of RBPs has been extended to pathophysiology of Alzheimer's disease (AD). Here, we identified disease subtype specific variations in the RNA-binding proteome (RBPome) of sporadic AD (spAD), rapidly progressive AD (rpAD), and sporadic Creutzfeldt Jakob disease (sCJD), as well as control cases using RNA pull-down assay in combination with proteomics. We show that one of these identified proteins, splicing factor proline and glutamine rich (SFPQ), is downregulated in the post-mortem brains of rapidly progressive AD patients, sCJD patients and 3xTg mice brain at terminal stage of the disease. In contrast, the expression of SFPQ was elevated at early stage of the disease in the 3xTg mice, and in vitro after oxidative stress stimuli. Strikingly, in rpAD patients' brains SFPQ showed a significant dislocation from the nucleus and cytoplasmic colocalization with TIA-1. Furthermore, in rpAD brain lesions, SFPQ and p-tau showed extranuclear colocalization. Of note, association between SFPQ and tau-oligomers in rpAD brains suggests a possible role of SFPQ in oligomerization and subsequent misfolding of tau protein. In line with the findings from the human brain, our in vitro study showed that SFPQ is recruited into TIA-1-positive stress granules (SGs) after oxidative stress induction, and colocalizes with tau/p-tau in these granules, providing a possible mechanism of SFPQ dislocation through pathological SGs. Furthermore, the expression of human tau in vitro induced significant downregulation of SFPQ, suggesting a causal role of tau in the downregulation of SFPQ. The findings from the current study indicate that the dysregulation and dislocation of SFPQ, the subsequent DNA-related anomalies and aberrant dynamics of SGs in association with pathological tau represents a critical pathway which contributes to rapid progression of AD.


Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/patologia , Fator de Processamento Associado a PTB/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/metabolismo , Síndrome de Creutzfeldt-Jakob/metabolismo , Citoplasma/metabolismo , Regulação para Baixo/fisiologia , Humanos , Camundongos Transgênicos , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo
7.
Inorg Chem ; 59(20): 14879-14890, 2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-33003697

RESUMO

Ispinesib is a potent inhibitor of kinesin spindle protein (KSP), which has been identified as a promising target for antimitotic anticancer drugs. Herein, we report the synthesis of half-sandwich complexes of Ru, Os, Rh, and Ir bearing the ispinesib-derived N,N-bidentate ligands (R)- and (S)-2-(1-amino-2-methylpropyl)-3-benzyl-7-chloroquinazolin-4(3H)-one and studies on their chemical and biological properties. Using the enantiomerically pure (R)- and (S)-forms of the ligand, depending on the organometallic moiety, either the SM,R or RM,S diastereomers, respectively, were observed in the molecular structures of the Ru- and Os(cym) (cym = η6-p-cymene) compounds, whereas the RM,R or SM,S diastereomers were found for the Rh- and Ir(Cp*) (Cp* = η5-pentamethylcyclopentadienyl) derivatives. However, density functional theory (DFT) calculations suggest that the energy difference between the diastereomers is very small, and therefore a mixture of both will be present in solution. The organometallics exhibited varying antiproliferative activity in a series of human cancer cell lines, with the complexes featuring the (R)-enantiomer of the ligand being more potent than the (S)-configured counterparts. Notably, the Rh and Ir complexes demonstrated high KSP inhibitory activity, even at 1 nM concentration, which was independent of the chirality of the ligand, whereas the Ru and especially the Os derivatives were much less active.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Complexos de Coordenação/farmacologia , Cinesinas/antagonistas & inibidores , Quinazolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antioxidantes/síntese química , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Benzamidas/síntese química , Benzamidas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/síntese química , Complexos de Coordenação/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Cinesinas/metabolismo , Ligantes , Metais Pesados/química , Simulação de Acoplamento Molecular , Ligação Proteica , Quinazolinas/síntese química , Quinazolinas/metabolismo , Estereoisomerismo
8.
Molecules ; 25(15)2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32751780

RESUMO

Withania coagulans contains a complex mixture of various bioactive compounds. In order to reduce the complexity of the plant extract to purify its phytochemical biomolecules, a novel fractionation strategy using different solvent combination ratios was applied to isolate twelve bioactive fractions. These fractions were tested for activity in the biogenic synthesis of cobalt oxide nanoparticles, biofilm and antifungal activities. The results revealed that plant extract with bioactive fractions in 30% ratio for all solvent combinations showed more potent bioreducing power, according to the observed color changes and the appearance of representative absorption peaks at 500-510 nm in the UV-visible spectra which confirm the synthesis of cobalt oxide nanoparticles (Co3O4 NPs). XRD diffraction was used to define the crystal structure, size and phase composition of the products. The fractions obtained using 90% methanol/hexane and 30% methanol/hexane showed more effectiveness against biofilm formation by Pseudomonas aeruginosa and Staphylococcus aureus so these fractions could potentially be used to treat bacterial infections. The 90% hexane/H2O fraction showed excellent antifungal activity against Aspergillus niger and Candida albicans, while the 70% methanol/hexane fraction showed good antifungal activity for C. albicans, so these fractions are potentially useful for the treatment of various fungal infections. On the whole it was concluded that fractionation based on effective combinations of methanol/hexane was useful to investigate and study bioactive compounds, and the active compounds from these fractions may be further purified and tested in various clinical trials.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Biofilmes/efeitos dos fármacos , Cobalto/química , Nanopartículas Metálicas/química , Óxidos/química , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Withania/química , Aspergillus niger/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Fracionamento Químico/métodos , Hexanos/química , Metanol/química , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa/efeitos dos fármacos , Solventes/química , Staphylococcus aureus/efeitos dos fármacos
9.
Angew Chem Int Ed Engl ; 59(34): 14609-14614, 2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32431061

RESUMO

The combination of more than one bioactive moiety in a multitargeted anticancer agent may result in synergistic activity of its components. Using this concept, bioorganometallic compounds were designed to feature a metal center, a 2-pyridinecarbothioamide (PCA), and a hydroxamic acid, which is found in the anticancer drug vorinostat (SAHA). The organometallics showed inhibitory activity in the nanomolar range against histone deacetylases (HDACs) as the key target for SAHA. In particular, the Rh complex was a potent inhibitor of HDAC6 over HDAC1 and HDAC8. Whereas this complex was highly cytotoxic in human cancer cells, it showed low toxicity in hemolysis studies and zebrafish, demonstrating the role of the metal center. For this complex a slightly reduced expression of vascular endothelial growth factor receptor 2 (VEGFR2) was established, which was upregulated by SAHA. This finding indicates that the new organometallics display different modes of action than their bioactive components.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Compostos Organometálicos/farmacologia , Ródio/farmacologia , Vorinostat/farmacologia , Linhagem Celular Tumoral , Humanos
10.
Inorg Chem ; 57(22): 14427-14434, 2018 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-30406647

RESUMO

The promise of the metal(arene) structure as an anticancer pharmacophore has prompted intensive exploration of this chemical space. While N-heterocyclic carbene (NHC) ligands are widely used in catalysis, they have only recently been considered in metal complexes for medicinal applications. Surprisingly, a comparatively small number of studies have been reported in which the NHC ligand was coordinated to the RuII(arene) pharmacophore and even less with an OsII(arene) pharmacophore. Here, we present a systematic study in which we compared symmetrically substituted methyl and benzyl derivatives with the nonsymmetric methyl/benzyl analogues. Through variation of the metal center and the halido ligands, an in-depth study was conducted on ligand exchange properties of these complexes and their biomolecule binding, noting in particular the stability of the M-CNHC bond. In addition, we demonstrated the ability of the complexes to inhibit the selenoenzyme thioredoxin reductase (TrxR), suggested as an important target for anticancer metal-NHC complexes, and their cytotoxicity in human tumor cells. It was found that the most potent TrxR inhibitor diiodido(1,3-dibenzylbenzimidazol-2-ylidene)(η6-p-cymene)ruthenium(II) 1bI was also the most cytotoxic compound of the series, with the antiproliferative effects in general in the low to middle micromolar range. However, since there was no clear correlation between TrxR inhibition and antiproliferative potency across the compounds, TrxR inhibition is unlikely to be the main mode of action for the compound type and other target interactions must be considered in future.


Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Complexos de Coordenação/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Benzimidazóis/síntese química , Benzimidazóis/química , Benzimidazóis/toxicidade , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , Citocromos c/química , DNA/química , Estabilidade de Medicamentos , Feminino , Humanos , Camundongos Endogâmicos BALB C , Simulação de Dinâmica Molecular , Estrutura Molecular , Osmio/química , Rutênio/química , Relação Estrutura-Atividade , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Ubiquitina/química
11.
Bioorg Med Chem ; 26(15): 4470-4480, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30076000

RESUMO

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a repair enzyme for stalled DNA-topoisomerase 1 (Top 1) cleavage complexes and other 3'-end DNA lesions. Tdp1 is a promising target for anticancer therapy, since it can repair DNA lesions caused by Top1 inhibitors leading to drug resistance. Hence, Tdp1 inhibition should result in synergistic effect with Top1 inhibitors. Twenty nine derivatives of (+)-usnic acid were tested for in vitro Tdp1 inhibitory activity using a fluorescent-based assay. Excellent activity was obtained, with derivative 6m demonstrating the lowest IC50 value of 25 nM. The established efficacy was verified using a gel-based assay, which gave close results to that of the fluorescent assay. In addition, molecular modeling in the Tdp1 substrate binding pocket suggested plausible binding modes for the active analogues. The synergistic effect of the Tdp1 inhibitors with topotecan, a Top1 poison in clinical use, was tested in two human cell lines, A-549 and HEK-293. Compounds 6k and 6x gave very promising results. In particular, 6x has a low cytotoxicity and an IC50 value of 63 nM, making it a valuable lead compound for the development of potent Tdp1 inhibitors for clinical use.


Assuntos
Benzofuranos/química , Inibidores de Fosfodiesterase/síntese química , Diester Fosfórico Hidrolases/química , Regulação Alostérica , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzofuranos/síntese química , Sítios de Ligação , Sobrevivência Celular/efeitos dos fármacos , DNA/química , DNA/metabolismo , Furanos/química , Células HEK293 , Humanos , Simulação de Acoplamento Molecular , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/genética , Diester Fosfórico Hidrolases/metabolismo , Estrutura Terciária de Proteína , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Relação Estrutura-Atividade , Especificidade por Substrato
12.
Bioorg Chem ; 76: 392-399, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29248742

RESUMO

The ability of a number of nitrogen-containing compounds that simultaneously carry the adamantane and monoterpene moieties to inhibit Tdp1, an important enzyme of the DNA repair system, is studied. Inhibition of this enzyme has the potential to overcome chemotherapeutic resistance of some tumor types. Compound (+)-3c synthesized from 1-aminoadamantane and (+)-myrtenal, and compound 4a produced from 2-aminoadamantane and citronellal were found to be most potent as they inhibited Tdp1 with IC50 values of 6 and 3.5 µM, respectively. These compounds proved to have low cytotoxicity in colon HCT-116 and lung A-549 human tumor cell lines (CC50 > 50 µM). It was demonstrated that compound 4a at 10 µM enhanced cytotoxicity of topotecan, a topoisomerase 1 poison in clinical use, against HCT-116 more than fivefold and to a lesser extent of 1.5 increase in potency for A-549.


Assuntos
Adamantano/análogos & derivados , Adamantano/farmacologia , Antineoplásicos/farmacologia , Monoterpenos/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Adamantano/síntese química , Adamantano/química , Aminas/síntese química , Aminas/química , Aminas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Sítios de Ligação , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Células HCT116 , Humanos , Simulação de Acoplamento Molecular , Monoterpenos/síntese química , Monoterpenos/química , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Diester Fosfórico Hidrolases/química , Estereoisomerismo , Topotecan/farmacologia
13.
Molecules ; 23(10)2018 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-30261631

RESUMO

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a DNA repair enzyme that mends topoisomerase 1-mediated DNA damage. Tdp1 is a current inhibition target for the development of improved anticancer treatments, as its inhibition may enhance the therapeutic effect of topoisomerase 1 poisons. Here, we report a study on the development of a novel class of Tdp1 inhibitors that is based on the octahydro-2H-chromene scaffold. Inhibition and binding assays revealed that these compounds are potent inhibitors of Tdp1, with IC50 and KD values in the low micromolar concentration range. Molecular modelling predicted plausible conformations of the active ligands, blocking access to the enzymatic machinery of Tdp1. Our results thus help establish a structural-activity relationship for octahydro-2H-chromene-based Tdp1 inhibitors, which will be useful for future Tdp1 inhibitor development work.


Assuntos
Benzopiranos/química , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/química , Diester Fosfórico Hidrolases/metabolismo , Humanos , Modelos Moleculares , Relação Estrutura-Atividade
14.
Molecules ; 23(1)2018 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-29324695

RESUMO

It is now established that the thieno[2,3-b]pyridines are a potent class of antiproliferatives. One of the main issues encountered for their clinical application is their low water solubility. In order to improve this, two strategies were pursued. First, a morpholine moiety was tethered to the molecular scaffold by substituting the sulphur atom with nitrogen, resulting in a 1H-pyrrolo[2,3-b]pyridine core structure. The water solubility was increased by three orders of magnitude, from 1.2 µg/mL (1-thieno[2,3-b]pyridine) to 1.3 mg/mL (3-pyrrolo[2,3-b]pyridine), however, it was only marginally active against cancer cells. The second strategy involved loading a very potent thieno[2,3-b]pyridine derivative (2) into a cholesteryl-poly(allylamine) polymer matrix for water solubilisation. Suppression of human pancreatic adenocarcinoma (BxPC-3) viability was observed to an IC50 value of 0.5 µg/mL (1.30 µM) in conjunction with the polymer, which is a five-fold (×5) increase in potency as compared to the free drug alone, demonstrating the utility of this formulation approach.


Assuntos
Antineoplásicos/química , Piridinas/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Polímeros , Piridinas/síntese química , Piridinas/farmacologia , Solubilidade , Relação Estrutura-Atividade
15.
Saudi Pharm J ; 26(4): 453-461, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29844715

RESUMO

Adverse Drug Reactions (ADRs) underreporting is a great challenge to pharmacovigilance. Healthcare professionals should consider ADR reporting as their professional obligation because the effective system of ADR reporting is important to improve patient care and safety. This study was designed to assess the knowledge, attitude, practice and factors associated with ADR reporting by healthcare professionals (physicians and pharmacists) in secondary and tertiary hospitals of Islamabad. A pretested questionnaire comprising of 27 questions (knowledge 12, attitude 4, practice 9 and factors influencing ADR reporting 2) was administered to 384 physicians and pharmacists in public and private hospitals. Respondents were evaluated for their knowledge, attitude and practice related to ADR reporting. Additionally, the factors which encourage and discourage respondents to report ADRs were also determined. The data was analysed by using SPSS statistical software. Among 384 respondents, 367 provided responses to questionnaire, giving a response rate of 95.5%. The mean age was 28.3 (SD = 6.7). Most of the respondents indicated poor ADR reporting knowledge (83.1%). The majority of respondents (78.2%) presented a positive attitude towards ADR reporting and only a few (12.3%) hospitals have good ADR reporting practice. The seriousness of ADR, unusualness of reaction, new drug involvement and confidence in the diagnosis of ADR are the factors which encourage respondents to report ADR whereas lack of knowledge regarding where and how to report ADR, lack of access to ADR reporting form, managing patient is more important than reporting ADR legal liability issues were the major factors which discourage respondents to report ADR. The study reveals poor knowledge and practice regarding ADR reporting. However, most of the respondents have shown a positive attitude towards ADR reporting. There is a serious need for educational training as well as sincere and sustained efforts should be made by Government and Hospital Authorities to ensure proper implementation of ADR reporting system in all of the hospitals.

16.
Molecules ; 22(12)2017 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-29258235

RESUMO

A panel of docking scaffolds was developed for the known molecular targets of the anticancer agents, thieno[2,3-b]pyridines, in order to glean insight into their mechanism of action. The reported targets are the copper-trafficking antioxidant 1 protein, tyrosyl DNA phosphodiesterase 1, the colchicine binding site in tubulin, adenosine A2A receptor, and, finally, phospholipase C-δ1. According to the panel, the A2A receptor showed the strongest binding, inferring it to be the most plausible target, closely followed by tubulin. To investigate whether the thieno[2,3-b]pyridines modulate G protein-coupled receptors (GPCRs) other than A2A, a screen against 168 GPCRs was conducted. According to the results, ligand 1 modulates five receptors in the low µM region, four as an antagonist; CRL-RAMP3 (IC50-11.9 µM), NPSR1B (IC50-1.0 µM), PRLHR (IC50-9.3 µM), and CXCR4 (IC50-6.9 µM). Finally, one agonist, GPRR35, was found (EC50 of 7.5 µM). Molecular modelling showed good binding to all of the receptors investigated; however, none of these surpass the A2A receptor. Furthermore, the newly-identified receptors are relatively modestly expressed in the cancer cell lines most affected by the thieno[2,3-b]pyridines, making them less likely to be the main targets of the mechanism of action for this compound class. Nevertheless, new modulators against GPCRs are of an interest as potential hits for further drug development.


Assuntos
Antineoplásicos/farmacologia , Piridinas/farmacologia , Receptores Acoplados a Proteínas G/química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Ligação Proteica , Conformação Proteica , Piridinas/química , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-Atividade
17.
RSC Adv ; 14(29): 21047-21064, 2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38962094

RESUMO

This review explores recent advancements in synthesizing quinoid heteroaryls, namely quinazoline and quinoline, vital in chemistry due to their prevalence in natural products and pharmaceuticals. It emphasizes the rapid, highly efficient, and economically viable synthesis achieved through gold-catalyzed cascade protocols. By investigating methodologies and reaction pathways, the review underscores exceptional yields attainable in the synthesis of quinoid heteroaryls. It offers valuable insights into accessing these complex structures through efficient synthetic routes. Various strategies, including cyclization, heteroarylation, cycloisomerization, cyclo-condensation, intermolecular and intramolecular cascade reactions, are covered, highlighting the versatility of gold-catalyzed approaches. The comprehensive compilation of different synthetic approaches and elucidation of reaction mechanisms contribute to a deeper understanding of the field. This review paves the way for future advancements in synthesizing quinoid heteroaryls and their applications in drug discovery and materials science.

18.
J Gastrointest Cancer ; 55(4): 1498-1510, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39256264

RESUMO

PURPOSE: This review article summarizes the pathophysiological aspects of interleukins (ILs) including IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, and IL-10 in pancreatic cancer (PC). METHODS: Science Direct, PubMed, and Google Scholar were used for the literature review. The search was conducted until August 12, 2024, and particular keywords such as "Pancreatic Cancer," "Interleukins," "Pathophysiological Aspects," "Immunosuppression," "Invasiveness," and "Metastasis" were used. Focusing on interleukins related to pancreatic cancer, 61 original studies were included: 32 studies for human patients, 16 studies for animal models, and 13 studies for both animal models and human patients. All types of PC were considered. The timeframe of 1991 to 2024 was chosen for clinical studies. RESULTS: In epithelial pancreatic tumors, IL-1 is a major inflammation factor. Serum concentrations of soluble interleukin-2-receptor were considerably greater in patients with PC and chronic pancreatitis than in healthy individuals. In comparison to controls, pancreatic cancer patients had considerably greater levels of macrophage colony-stimulating factor and significantly lower levels of stem cell factor and IL-3. The tissues and cells of pancreatic cancer have higher concentrations of IL-4 receptors. IL-5 has a role in the accumulation of pancreatic fibrosis. For individuals with pancreatic ductal adenocarcinoma (PDAC), a high serum level of IL-6 may be a separate risk factor for the development of widespread liver metastases. PDAC patients' peripheral blood mononuclear cells exhibit a substantial upregulation of IL-7 receptor. The role of IL-8 in the growth and spread of PC in humans. The miR-200a/ß-catenin axis may be the mechanism by which IL-9 stimulates the proliferation and metastasis of PC cells. Blocking IL-10 in the local microenvironment appears to result in a significant reversal of tumor-induced immunosuppression. CONCLUSION: The article concludes that interleukins 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 played significant roles in the pathogenesis of PC.


Assuntos
Interleucinas , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/imunologia , Interleucinas/sangue , Interleucinas/metabolismo , Animais
19.
Artigo em Inglês | MEDLINE | ID: mdl-39252627

RESUMO

INTRODUCTION: Endocrine-disrupting drugs, also called endocrine disruptors or micropollutants, cause serious environmental and public health problems due to their ability to disrupt the endocrine functions of organisms and humans, even at low concentrations. This report provides a summary of current removal techniques, such as activated sludge processes, membrane filtration, adsorption, and membrane bioreactor techniques for endocrine-disrupting chemicals, including their efficiency, limitations, and practical implementation. METHODS: This review evaluates these methods by considering their treatment efficiency, costs, and environmental impact. To curb this menace, several developed countries have distinct strategies, such as physical remediation techniques, biological processes, phytoremediation, and chemical processes to remove endocrine disruptors. RESULTS: In developing nations, most conventional wastewater treatment plants do not even monitor those contaminants due to the low biodegradability and high complexity of such compounds. CONCLUSION: Hence, in this review work, potential endocrine-disrupting chemicals, their impacts, mechanisms of action, consequences for human health, and bio-mitigation strategies reported so far have been discussed in the context of the relevant literature.

20.
RSC Adv ; 14(28): 20365-20389, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38919284

RESUMO

The recent advancements in utilizing organocatalysts for the synthesis of organic compounds have been described in this review by focusing on their simplicity, effectiveness, reproducibility, and high selectivity which lead to excellent product yields. The organocatalytic methods for various derivatives, such as indoles, pyrazolones, anthrone-functionalized benzylic amines, maleimide, polyester, phthalimides, dihydropyrimidin, heteroaryls, N-aryl benzimidazoles, stilbenoids, quinazolines, quinolines, and oxazolidinones have been specifically focused. The review provides more understanding by delving into potential reaction mechanisms. We anticipate that this collection of data and findings on successful synthesis of diverse compound derivatives will serve as valuable resources and stimulating current and future research efforts in organocatalysis and industrial chemistry.

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