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1.
In Vivo ; 35(6): 3245-3251, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34697155

RESUMO

BACKGROUND/AIM: Using a rat model of collagen-induced arthritis (CIA), we evaluated the therapeutic effects of HM71224 (BTKi), as well as the drug-drug interactions in combined therapy with methotrexate (MTX) based on both drugs' pharmacological role in immune regulation and antiinflammation. MATERIALS AND METHODS: Arthritis in rats was induced using type II collagen and incomplete Freund's adjuvant. The therapeutic effects of HM71224 (alone or in combination with MTX) were evaluated by arthritis score, paw volume, body weight, and histopathological examination (H&E and Safranin-O staining). The drug-drug interactions between HM71224 and MTX were investigated by measuring plasma, liver enzyme and creatinine levels and blood cell counts. RESULTS: HM71224 reduced the clinical signs of arthritis, paw volume, and body weight loss in CIA rats. ED50 and ED90 were 1.0 and 2.5 mg/kg, respectively. HM71224 combined with MTX decreased the arthritis score, bone erosion, synovitis, and cartilage degradation without apparent interaction. CONCLUSION: The combination of HM71224 and MTX improved the therapeutic effect with no drug-drug interactions in RA.


Assuntos
Artrite Experimental , Metotrexato , Animais , Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Quimioterapia Combinada , Metotrexato/farmacologia , Metotrexato/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Ratos
2.
Mol Syst Biol ; 17(11): e10396, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34709727

RESUMO

Treatment options for COVID-19, caused by SARS-CoV-2, remain limited. Understanding viral pathogenesis at the molecular level is critical to develop effective therapy. Some recent studies have explored SARS-CoV-2-host interactomes and provided great resources for understanding viral replication. However, host proteins that functionally associate with SARS-CoV-2 are localized in the corresponding subnetwork within the comprehensive human interactome. Therefore, constructing a downstream network including all potential viral receptors, host cell proteases, and cofactors is necessary and should be used as an additional criterion for the validation of critical host machineries used for viral processing. This study applied both affinity purification mass spectrometry (AP-MS) and the complementary proximity-based labeling MS method (BioID-MS) on 29 viral ORFs and 18 host proteins with potential roles in viral replication to map the interactions relevant to viral processing. The analysis yields a list of 693 hub proteins sharing interactions with both viral baits and host baits and revealed their biological significance for SARS-CoV-2. Those hub proteins then served as a rational resource for drug repurposing via a virtual screening approach. The overall process resulted in the suggested repurposing of 59 compounds for 15 protein targets. Furthermore, antiviral effects of some candidate drugs were observed in vitro validation using image-based drug screen with infectious SARS-CoV-2. In addition, our results suggest that the antiviral activity of methotrexate could be associated with its inhibitory effect on specific protein-protein interactions.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Descoberta de Drogas , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Proteoma/efeitos dos fármacos , SARS-CoV-2/fisiologia , COVID-19/virologia , Reposicionamento de Medicamentos , Humanos , Espectrometria de Massas , Metotrexato/farmacologia , Proteômica , Replicação Viral/efeitos dos fármacos
3.
Int J Mol Sci ; 22(17)2021 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-34502521

RESUMO

BACKGROUND: Sepsis is a serious, heterogeneous clinical entity produced by a severe and systemic host inflammatory response to infection. Methotrexate (MTX) is a folate-antagonist that induces the generation of adenosine and also inhibits JAK/STAT pathway; MTX it is widely used as an anti-inflammatory drug to control the immune system. OBJECTIVE: The aim of this study was to assess the beneficial effects of a single and low dose of MTX in the systemic response and acute lung injury (ALI) induced by sepsis. As in the clinics, we treated our animals with antibiotics and fluids and performed the source control to mimic the current clinic treatment. METHODS AND MAIN RESULTS: Sepsis was induced in rats by a cecal ligation puncture (CLP) procedure. Six hours after induction of sepsis, we proceeded to the source control; fluids and antibiotics were administered at 6 h and 24 h after CLP. MTX (2.5 mg/Kg) was administered 6 h after the first surgery in one CLP experimental group and to one Sham group. A protective effect of MTX was observed through a significant reduction of pro-inflammatory cytokines and a decrease infiltration of inflammatory cells in the lung. In addition, we found a regulation in adenosine receptor A2aR and the metalloproteinases by MTX. CONCLUSION: A single, low dose of MTX attenuates sepsis lung-associated damage by decreasing pro-inflammatory response, infiltration of pro-inflammatory cells and avoiding defective tissue lung remodeling.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Metotrexato/farmacologia , Sepse/tratamento farmacológico , Animais , Anti-Inflamatórios/uso terapêutico , Ceco/patologia , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Ligadura , Pulmão/efeitos dos fármacos , Masculino , Metotrexato/metabolismo , Punções , Ratos , Ratos Sprague-Dawley , Sepse/fisiopatologia
4.
RMD Open ; 7(3)2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34588273

RESUMO

OBJECTIVES: In the past, the human microbiome has consistently been associated with rheumatoid arthritis (RA) and disease activity. Here, we investigate the antimicrobial activity of disease-modifying antirheumatic drugs (DMARDs) against typical representatives of the oral microflora that have been associated with RA. METHODS: DMARDs were screened for antimicrobial activity against bacteria that are associated with the pathogenesis of the disease and/or frequently isolated from the oral microflora of patients with RA. Screening was done by an agar diffusion assay and minimum inhibitory concentrations (MICs) of antimicrobial active substances were then determined by broth dilution. RESULTS: Aurothiomalate and sulfasalazine demonstrated broad-spectrum antimicrobial activity, but with MICs ranging from 18 to >280 µg/mL and 150 to >600 µg/mL, respectively, only at supratherapeutic concentrations. Methotrexate showed antimicrobial activity only against Fusobacterium nucleatum and Viridans streptococci. The corresponding MICs were 3.75 to >30 µg/mL and 0.5-15 µg/mL, respectively, thus at least for streptococci, within the therapeutically achievable range. No other DMARD tested showed antimicrobial activity in the agar diffusion screening assay. CONCLUSION: Methotrexate, sulfasalazine and aurothiomalate showed antimicrobial activity against a broad spectrum of RA associated pathogens of the oral microflora. While methotrexate showed relevant antimicrobial activity, and to a more limited extent aurothiomalate, sulfasalazine was active only at far supratherapeutic systemic concentrations. Nevertheless, given the highly species-dependent antimicrobial activity and the multiple ways it can affect the human microbiome, our results suggest a link between antimicrobially active antirheumatic drugs and their potential effect in the treatment of RA.


Assuntos
Antirreumáticos , Artrite Reumatoide , Microbiota , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Humanos , Metotrexato/farmacologia , Metotrexato/uso terapêutico , Sulfassalazina/farmacologia , Sulfassalazina/uso terapêutico
5.
Molecules ; 26(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203991

RESUMO

Unlike other widely known Aloe species used for treatment of rheumatoid arthritis, this species suffers from a lack of sufficient studies on its biological and chemical characters. This is what drove us to perform this work to evaluate the in vivo anti-arthritic potential of its leaf ethanolic extract. The in vivo anti-arthritic activity of the leaf ethanolic extract at 100 and 200 mg/kg/day b.wt. was evaluated alone and in combination with methotrexate (MTX) using complete Freund's adjuvant. Serum levels of rheumatoid factor, anti-cyclic citrullinated peptide (anti-CCP), cytokines pro-inflammatory marker, inflammatory mediator serum levels, and oxidative stress mediators were analyzed, in addition to liver function. Orientin, isoorientin, ß-sitosterol, its palmitate and its glucoside were isolated. The combined therapy of MTX and the leaf ethanolic extract (especially at 200 mg/kg b.wt.) group showed better activity compared to MTX alone. Moreover, the combined therapy provided additional benefits in lowering the liver toxicity by comparison to MTX alone. We concluded that a synergetic combination of the leaf ethanolic extract and MTX is beneficial in the management of rheumatoid arthritis with fewer side effects on liver function, as well as the possibility of the leaf extract to stand alone as an effective natural anti-arthritic agent.


Assuntos
Aloe/metabolismo , Artrite/tratamento farmacológico , Extratos Vegetais/farmacologia , Animais , Antioxidantes/farmacologia , Antirreumáticos/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Adjuvante de Freund/efeitos adversos , Masculino , Metotrexato/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Folhas de Planta/metabolismo , Ratos , Ratos Wistar
6.
Colloids Surf B Biointerfaces ; 206: 111952, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34273810

RESUMO

Rheumatoid arthritis (RA) is the most common inflammatory rheumatic disease, affecting almost 1% of the world population. It is a long-lasting autoimmune disease, which mainly affects the joints causing inflammation and swelling of the synovial joint. RA has a significant impact on the ability to perform daily activities including simple work and household chores. Nonetheless, due to the long periods of pain and the continuous use of anti-inflammatory drugs, RA can debilitate the quality of life and increases mortality. Current therapeutic approaches to treat RA aim to achieve prolonged activity and early and persistent remission of the disease, with the gradual adoption of different drugs available. In this study, we developed a novel hydroxychloroquine and methotrexate co-loaded Pluronic® F-127 nanomicelle and evaluated its therapeutic effects against RA. Our results showed that drug-loaded nanomicelles were capable of modulating the inflammatory process of RA and reducing osteoclastogenesis, edema, and cell migration to the joint. Overall, compared to the free drugs, the drug-loaded nanomicelles showed a 2-fold higher therapeutic effect.


Assuntos
Artrite Reumatoide , Metotrexato , Artrite Reumatoide/tratamento farmacológico , Humanos , Hidroxicloroquina/farmacologia , Articulações , Metotrexato/farmacologia , Qualidade de Vida
7.
Carbohydr Polym ; 269: 118325, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34294337

RESUMO

To improve the efficacy of chemotherapy and relieve the pain associated with colorectal cancer, a dual-drug delivery system (DDDS) is proposed. In this system, methotrexate (MTX) loaded CaCO3 (CaCO3/MTX) and aspirin (Asp) are co-entrapped in the hydrogels of alginate (Alg) and sodium carboxymethyl cellulose (CMC) crosslinked with Ca2+. The hydrogels can protect the anti-cancer drug of MTX from being absorbed in stomach and small intestine and ensure their efficacy at the target site of colorectum. More importantly, dual pH-responsive drug delivery can be achieved by the DDDS. Because the pH varies at small intestine and colorectum of human body, dual pH-responsive delivery of Asp and MTX can be achieved at the two organs, respectively, in response to ambient pH. These finding are of significant importance for medical science and pharmaceutics.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Portadores de Fármacos/química , Hidrogéis/química , Metotrexato/farmacologia , Alginatos/química , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/química , Aspirina/química , Aspirina/farmacologia , Carbonato de Cálcio/química , Carboximetilcelulose Sódica/química , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Metotrexato/química
8.
Int J Mol Sci ; 22(14)2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34299347

RESUMO

Efflux transporters, namely ATP-binding cassette (ABC), are one of the primary reasons for cancer chemoresistance and the clinical failure of chemotherapy. Ganciclovir (GCV) is an antiviral agent used in herpes simplex virus thymidine kinase (HSV-TK) gene therapy. In this therapy, HSV-TK gene is delivered together with GCV into cancer cells to activate the phosphorylation process of GCV to active GCV-triphosphate, a DNA polymerase inhibitor. However, GCV interacts with efflux transporters that are responsible for the resistance of HSV-TK/GCV therapy. In the present study, it was explored whether GCV and its more lipophilic derivative (1) could inhibit effluxing of another chemotherapeutic, methotrexate (MTX), out of the human breast cancer cells. Firstly, it was found that the combination of GCV and MTX was more hemocompatible than the corresponding combination with compound 1. Secondly, both GCV and compound 1 enhanced the cellular accumulation of MTX in MCF-7 cells, the MTX exposure being 13-21 times greater compared to the MTX uptake alone. Subsequently, this also reduced the number of viable cells (41-56%) and increased the number of late apoptotic cells (46-55%). Moreover, both GCV and compound 1 were found to interact with breast cancer resistant protein (BCRP) more effectively than multidrug-resistant proteins (MRPs) in these cells. Since the expression of BCRP was higher in MCF-7 cells than in MDA-MB-231 cells, and the cellular uptake of GCV and compound 1 was smaller but increased in the presence of BCRP-selective inhibitor (Fumitremorgin C) in MCF-7 cells, we concluded that the improved apoptotic effects of higher MTX exposure were raised mainly from the inhibition of BCRP-mediated efflux of MTX. However, the effects of GCV and its derivatives on MTX metabolism and the quantitative expression of MTX metabolizing enzymes in various cancer cells need to be studied more thoroughly in the future.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Ganciclovir/farmacologia , Metotrexato/farmacologia , Proteínas de Neoplasias/metabolismo , Antivirais/farmacologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Células MCF-7 , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo
9.
Virus Res ; 302: 198469, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34090962

RESUMO

The search for successful therapies of infections with the coronavirus SARS-CoV-2 is ongoing. We tested inhibition of host cell nucleotide synthesis as a promising strategy to decrease the replication of SARS-CoV-2-RNA, thus diminishing the formation of virus progeny. Methotrexate (MTX) is an established drug for cancer therapy and to induce immunosuppression. The drug inhibits dihydrofolate reductase and other enzymes required for the synthesis of nucleotides. Strikingly, the replication of SARS-CoV-2 was inhibited by MTX in therapeutic concentrations around 1 µM, leading to more than 1000-fold reductions in virus progeny in Vero C1008 (Vero E6) and ~100-fold reductions in Calu-3 cells. Virus replication was more sensitive to equivalent concentrations of MTX than of the established antiviral agent remdesivir. MTX strongly diminished the synthesis of viral structural proteins and the amount of released virus RNA. Virus replication and protein synthesis were rescued by folinic acid (leucovorin) and also by inosine, indicating that purine depletion is the principal mechanism that allows MTX to reduce virus RNA synthesis. The combination of MTX with remdesivir led to synergistic impairment of virus replication, even at 100 nM MTX. The use of MTX in treating SARS-CoV-2 infections still awaits further evaluation regarding toxicity and efficacy in infected organisms, rather than cultured cells. Within the frame of these caveats, however, our results raise the perspective of a two-fold benefit from repurposing MTX for treating COVID-19. Firstly, its previously known ability to reduce aberrant inflammatory responses might dampen respiratory distress. In addition, its direct antiviral activity described here would limit the dissemination of the virus.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Antagonistas do Ácido Fólico/farmacologia , Metotrexato/farmacologia , SARS-CoV-2/efeitos dos fármacos , Monofosfato de Adenosina/farmacologia , Alanina/farmacologia , Animais , COVID-19/virologia , Técnicas de Cultura de Células , Chlorocebus aethiops , Humanos , RNA Viral/genética , SARS-CoV-2/fisiologia , Células Vero , Replicação Viral/efeitos dos fármacos
10.
J Nanobiotechnology ; 19(1): 184, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34130695

RESUMO

Gestational trophoblastic tumors seriously endanger child productive needs and the health of women in childbearing age. Nanodrug-based therapy mediated by transporters provides a novel strategy for the treatment of trophoblastic tumors. Focusing on the overexpression of human equilibrative nucleoside transporter 1 (ENT1) on the membrane of choriocarcinoma cells (JEG-3), cytarabine (Cy, a substrate of ENT1)-grafted liposomes (Cy-Lipo) were introduced for the targeted delivery of methotrexate (Cy-Lipo@MTX) for choriocarcinoma therapy in this study. ENT1 has a high affinity for Cy-Lipo and can mediate the endocytosis of the designed nanovehicles into JEG-3 cells. The ENT1 protein maintains its transportation function through circulation and regeneration during endocytosis. Therefore, Cy-Lipo-based formulations showed high tumor accumulation and retention in biodistribution studies. More importantly, the designed DSPE-PEG2k-Cy conjugation exhibited a synergistic therapeutic effect on choriocarcinoma. Finally, Cy-Lipo@MTX exerted an extremely powerful anti-choriocarcinoma effect with fewer side effects. This study suggests that the overexpressed ENT1 on choriocarcinoma cells holds great potential as a high-efficiency target for the rational design of active targeting nanotherapeutics.


Assuntos
Citarabina/uso terapêutico , Lipossomos/uso terapêutico , Metotrexato/farmacologia , Proteínas de Transporte de Nucleosídeos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Coriocarcinoma/tratamento farmacológico , Coriocarcinoma/patologia , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Endocitose , Transportador Equilibrativo 1 de Nucleosídeo/química , Transportador Equilibrativo 1 de Nucleosídeo/metabolismo , Feminino , Células Hep G2 , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Nus , Tamanho da Partícula , Ratos Sprague-Dawley , Distribuição Tecidual
11.
PLoS One ; 16(6): e0252859, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34153036

RESUMO

Patients with rheumatoid arthritis (RA) experience a higher prevalence of periodontitis. This study aimed to examine the variation of periodontitis experienced with different serotypes suffered by RA patients and to examine the relationship between the different medications taken for RA that may influence this relationship. Two hundred and sixty RA and control participants underwent standardized periodontal examinations. Medical, serological and radiological (Sharp/van der Heijde) records were assessed. Functional status was assessed using the administered Health Assessment Questionnaire. Moreover, disease parameters, including disease activity (DAS28-ESR) and anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF) seropositivity were evaluated. Periodontitis was higher in RA (71.54%) compared with controls (54.62%). The stage of periodontitis experienced by ACPA-positive participants were higher than APCA-negative participants. The probing pocket depth and recession experienced by RF-positive participants were higher than those who were RF-negative. RA participants on methotrexate had lower clinical attachment loss and lower periodontal probing depth compared with participants on a combination methotrexate and other disease-modifying antirheumatic drugs. Participants taking corticosteroids had lower gingival index scores. The association between seropositivity and the type of medications taken with periodontal health parameters in this group of patients suggests that both seropositivity and medications taken are important modifiers in the relationship between periodontitis and RA.


Assuntos
Anticorpos Anti-Proteína Citrulinada/metabolismo , Antirreumáticos/farmacologia , Artrite Reumatoide/fisiopatologia , Osteoartrite/fisiopatologia , Periodontite/epidemiologia , Sorogrupo , Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Estudos de Casos e Controles , Feminino , Humanos , Malásia/epidemiologia , Masculino , Metotrexato/farmacologia , Pessoa de Meia-Idade , Osteoartrite/sangue , Osteoartrite/tratamento farmacológico , Periodontite/metabolismo , Periodontite/patologia
12.
Expert Rev Clin Pharmacol ; 14(9): 1105-1112, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34006152

RESUMO

Introduction: Management of inflammatory rheumatic diseases has evolved based on improved treatment strategies and better management of comorbidities, specifically cardiovascular risk. Methotrexate is one of the first-line treatments in the management of inflammatory rheumatic diseases, but its cardiovascular effects are poorly understood. The purpose of this review is to assess the cardiovascular impact of methotrexate in inflammatory rheumatic disease.Areas covered: Current knowledge about the mechanism of action of methotrexate on cardiovascular tissue is presented. A review of the literature in the Medline, Cochrane and Embase databases was performed. Current data about the cardiovascular effects of methotrexate in rheumatoid arthritis, psoriatic arthritis, and psoriasis are presented.Expert opinion: Mechanism of action of methotrexate is based on the antagonism of purines. It reduces systemic inflammation and oxidative stress and improves the major cardiovascular risk factors. Methotrexate improves cardiovascular risk in rheumatoid arthritis, psoriasis and psoriatic arthritis, but the mechanisms involved are partially identified. Data are controversial regarding its effects on endothelial function and atherosclerosis. Conversely, in the general population and in patients with HIV infection, methotrexate does not modify cardiovascular outcomes. Thus, methotrexate only improves cardiovascular risk by reducing systemic inflammation, and should not be used to prevent cardiovascular events.


Assuntos
Antirreumáticos/administração & dosagem , Doenças Cardiovasculares/prevenção & controle , Metotrexato/administração & dosagem , Animais , Antirreumáticos/farmacologia , Artrite Psoriásica/complicações , Artrite Psoriásica/tratamento farmacológico , Artrite Psoriásica/patologia , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Doenças Cardiovasculares/etiologia , Fatores de Risco de Doenças Cardíacas , Humanos , Inflamação/tratamento farmacológico , Inflamação/patologia , Metotrexato/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Psoríase/complicações , Psoríase/tratamento farmacológico , Psoríase/patologia
13.
Mater Sci Eng C Mater Biol Appl ; 124: 112059, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33947553

RESUMO

Solid dispersion with Pluronic F127 was proposed as alternative approach to modify the pharmacologically relevant properties of methotrexate (MTX). Solid dispersion of MTX with Pluronic F127 was prepared by fusion method and characterized by powder X-ray diffraction, thermal analysis, scanning electron microscopy and FTIR spectroscopy with the aim to elucidate the physical state of the dispersed MTX and the nature of the interactions occurring between MTX and the carrier. Effect of Pluronic F127 on solubility, dissolution rate, membrane permeability, and pharmacokinetic parameters was revealed in vitro and in vivo. It was found that physical interactions of MTX with Pluronic F127 are predominant in the solid dispersion. The effect of Pluronic F127 on the MTX solubility and release rate of MTX from the solid dispersion is pH dependent. Apparent solubility of MTX released from the solid dispersion is increased in the acidic medium and remains unchanged in the alkaline medium. In comparison with the pristine MTX, the release of MTX from the solid dispersion is faster in the acidic medium and slower in the alkaline medium. Influence of Pluronic F127 on the membrane permeability of MTX is insignificant. Bioavailability of orally administrated solid dispersion in increased. Results from in vitro and in vivo studies suggested that the pharmacokinetic properties of MTX can be improved by solid dispersion with Pluronic F127.


Assuntos
Metotrexato , Poloxâmero , Disponibilidade Biológica , Portadores de Fármacos , Metotrexato/farmacologia , Solubilidade
14.
J Nanobiotechnology ; 19(1): 143, 2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001161

RESUMO

Breast cancer (BC) is the most frequently diagnosed cancer with a low survival rate and one of the major causes of cancer-related death. Methotrexate (MTX) is an anti-tumor drug used in the treatment of BC. Poor dispersion in water and toxic side effects limit its clinical application. Gold nanoparticles (AuNPs), owing to their specific structures and unique biological and physiochemical properties, have emerged as potential vehicles for tumor targeting, bioimaging and cancer therapy. An innovative nano drug-loading system (Au @PDA-PEG-MTX NPs) was prepared for targeted treatment of BC. Au @PDA-PEG-MTX NPs under near infra-red region (NIR) irradiation showed effective photothermal therapy against MDA-MB-231 human BC cells growth in vitro by inducing apoptosis through triggering reactive oxygen species (ROS) overproduction and generating excessive heat. In vivo studies revealed deep penetration ability of Au @PDA-PEG-MTX NPs under NIR irradiation to find application in cancer-targeted fluorescence imaging, and exhibited effective photothermal therapy against BC xenograft growth by inducing apoptosis. Histopathological analysis, cellular uptake, cytotoxicity assay, and apoptosis experiments indicated that Au @PDA-PEG-MTX NPs possessed a good therapeutic effect with high biocompatibility and fewer side effects. This Au NPs drug-loading system achieved specific targeting of MTX to BC cells by surface functionalisation, fluorescence imaging under laser irradiation, combined photothermal-chemotherapy, and pH- and NIR- triggered hierarchical drug release.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Liberação Controlada de Fármacos , Ouro/química , Nanopartículas Metálicas/química , Metotrexato/farmacologia , Terapia Fototérmica/métodos , Animais , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos Endogâmicos BALB C , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Eur J Pharmacol ; 904: 174131, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-33933464

RESUMO

The safe development of nanotechnology and usage of nanoparticles (NPs) require the cellular toxicity examination of these NPs. Systematic studies are necessary to collect related data and comparison of the physicochemical features of NPs and their effects on cellular viability on model systems. In the present study, we systematically reviewed original studies, which investigated the cytotoxic effects and apoptosis of free NPs (loaded with doxorubicin (Dox)/or methotrexate (MTX)) via in vitro models. Articles were systematically collected by screening the literature published online in the following databases; PUBMED and SCOPUS and Web of Science and EMBASE. 23 in vitro cytotoxicity studies with 8 apoptosis examinations were found on osteosarcoma (OS) cell lines (mostly on MG-63). 43.47% of the synthesized NPs (10 studies) showed no cytotoxicity to OS cells. 39.13% of the synthesized NPs (9 studies) showed time and/or concentration related-cytotoxicity. Potent cytotoxic synthesized NP did not state. Significance difference between the half-maximal inhibitory concentration (IC50) of drug and drug/NP reported in all studies. Involved NPs in this systematic review for delivery of Dox/or MTX to OS cells have higher safety index and biocompatibility, although small and positively charged NPs acted more toxic in comparison to larger and negative ones, apoptosis rate like cytotoxicity index was notable in drug/NP group, to apply them in clinical works. Future studies are required to address the mechanisms involved in cytotoxicity and apoptosis with a special focus on in vivo investigations.


Assuntos
Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Metotrexato/farmacologia , Nanopartículas/química , Animais , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Humanos , Osteossarcoma/tratamento farmacológico
16.
Front Immunol ; 12: 663736, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33897713

RESUMO

Rheumatoid arthritis (RA) is a complex disease with a wide range of underlying susceptibility factors. Recently, dysregulation of microRNAs (miRNAs) in RA have been reported in several immune cell types from blood. However, B cells have not been studied in detail yet. Given the autoimmune nature of RA with the presence of autoantibodies, CD19+ B cells are a key cell type in RA pathogenesis and alterations in CD19+ B cell subpopulations have been observed in patient blood. Therefore, we aimed to reveal the global miRNA repertoire and to analyze miRNA expression profile differences in homogenous RA patient phenotypes in blood-derived CD19+ B cells. Small RNA sequencing was performed on CD19+ B cells of newly diagnosed untreated RA patients (n=10), successfully methotrexate (MTX) treated RA patients in remission (MTX treated RA patients, n=18) and healthy controls (n=9). The majority of miRNAs was detected across all phenotypes. However, significant expression differences between MTX treated RA patients and controls were observed for 27 miRNAs, while no significant differences were seen between the newly diagnosed patients and controls. Several of the differentially expressed miRNAs were previously found to be dysregulated in RA including miR-223-3p, miR-486-3p and miR-23a-3p. MiRNA target enrichment analysis, using the differentially expressed miRNAs and miRNA-target interactions from miRTarBase as input, revealed enriched target genes known to play important roles in B cell activation, differentiation and B cell receptor signaling, such as STAT3, PRDM1 and PTEN. Interestingly, many of those genes showed a high degree of correlated expression in CD19+ B cells in contrast to other immune cell types. Our results suggest important regulatory functions of miRNAs in blood-derived CD19+ B cells of MTX treated RA patients and motivate for future studies investigating the interactive mechanisms between miRNA and gene targets, as well as the possible predictive power of miRNAs for RA treatment response.


Assuntos
Artrite Reumatoide/etiologia , Artrite Reumatoide/metabolismo , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Metotrexato/farmacologia , MicroRNAs/genética , Antígenos CD19/metabolismo , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Biomarcadores , Biologia Computacional/métodos , Gerenciamento Clínico , Suscetibilidade a Doenças , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Metotrexato/uso terapêutico , Interferência de RNA
17.
PLoS Negl Trop Dis ; 15(4): e0009377, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33905412

RESUMO

Our understanding of folate metabolism in Leishmania has greatly benefited from studies of resistance to the inhibitor methotrexate (MTX). Folates are reduced in Leishmania by the bifunctional dihydrofolate reductase thymidylate synthase (DHFR-TS) and by pteridine reductase (PTR1). To further our understanding of folate metabolism in Leishmania, a Cos-seq genome-wide gain of function screen was performed against MTX and against the two thymidylate synthase (TS) inhibitors 5-fluorouracil and pemetrexed. The screen revealed DHFR-TS and PTR1 but also the nucleoside transporter NT1 and one hypothetical gene derived from chromosome 31. For MTX, the concentration of folate in the culture medium affected the enrichment pattern for genes retrieved by Cos-seq. We generated a L. infantum DHFR-TS null mutant that was thymidine auxotroph, a phenotype that could be rescued by the addition of thymidine or by transfection of the flavin dependent bacterial TS gene ThyX. In these DHFR-TS null mutants it was impossible to obtain a chromosomal null mutant of PTR1 except if DHFR-TS or PTR1 were provided episomally. The transfection of ThyX however did not allow the elimination of PTR1 in a DHFR-TS null mutant. Leishmania can survive without copies of either DHFR-TS or PTR1 but not without both. Provided that our results observed with the insect stage parasites are also replicated with intracellular parasites, it would suggest that antifolate therapy in Leishmania would only work if both DHFR-TS and PTR1 would be targeted simultaneously.


Assuntos
Deleção de Genes , Leishmania infantum/efeitos dos fármacos , Leishmania infantum/genética , Metotrexato/farmacologia , Complexos Multienzimáticos/genética , Tetra-Hidrofolato Desidrogenase/genética , Timidilato Sintase/genética , Animais , DNA de Protozoário/genética , DNA Recombinante/genética , Resistência a Medicamentos , Ácido Fólico/metabolismo , Antagonistas do Ácido Fólico/metabolismo , Antagonistas do Ácido Fólico/farmacologia , Leishmania infantum/enzimologia , Metotrexato/metabolismo , Complexos Multienzimáticos/metabolismo , Fenótipo , Tetra-Hidrofolato Desidrogenase/metabolismo , Timidilato Sintase/metabolismo , Transfecção
18.
Mol Immunol ; 135: 36-44, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33857817

RESUMO

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease for which there are currently no effective therapies. Although mesenchymal stem cells (MSCs) can prevent arthritis through immunomodulatory mechanisms, there are several associated risks. Alternatively, MSC-derived small extracellular vesicles (sEVs) can mimic the effects of MSCs, while reducing the risk of adverse events. However, few studies have examined sEVs in the context of RA. Here, we evaluate the immunomodulatory effects of human umbilical cord MSC (hUCMSC)-derived sEVs on T lymphocytes in a collagen-induced arthritis (CIA) rat model to elucidate the possible mechanism of sEVs in RA treatment. We then compare these mechanisms to those of MSCs and methotrexate (MTX). METHODS: The arthritis index and synovial pathology were assessed. T lymphocyte proliferation and apoptosis, Th17 and Treg proportions, and interleukin (IL)-17, IL-10, and transforming growth factor (TGF)-ß expression were detected using flow cytometry. Retinoic acid receptor-related orphan receptor gamma t (RORγt) and forkhead box P3 (FOXP3), which are master transcriptional regulators of Th17 and Treg differentiation, were also assessed using immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: sEV treatment ameliorated arthritis and inhibited synovial hyperplasia in a dose-dependent manner. These effects were mediated by inhibiting T lymphocyte proliferation and promoting their apoptosis, while decreasing Th17 cell proportion and increasing that of Treg cells in the spleen, resulting in decreased serum IL-17, and enhanced IL-10 and TGF-ß expression. Transcriptionally, sEVs decreased RORγt and increased FOXP3 expression in the spleen, and decreased RORγt and FOXP3 expression in the joints. In some aspects sEVs were more effective than MSCs and MTX in treating CIA. CONCLUSIONS: hUCMSC-derived sEVs ameliorate CIA via immunomodulatory T lymphocytes, and might serve as a new therapy for RA.


Assuntos
Artrite Experimental/terapia , Vesículas Extracelulares/metabolismo , Imunomodulação/imunologia , Células-Tronco Mesenquimais/metabolismo , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Artrite Experimental/induzido quimicamente , Células Cultivadas , Colágeno/toxicidade , Modelos Animais de Doenças , Feminino , Fatores de Transcrição Forkhead/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Imunossupressores/farmacologia , Interleucina-10/imunologia , Interleucina-17/imunologia , Metotrexato/farmacologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Ratos , Ratos Wistar , Membrana Sinovial/patologia , Fator de Crescimento Transformador beta/metabolismo
19.
Nutrients ; 13(4)2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33924354

RESUMO

Anti-inflammatory potential of orally administrated bioflavonoid-robinin, active sub-stance of original drug Flaroninum™ (FL), was investigated in the combination with methotrexate (MTX) and in monotherapy in rats suffering from adjuvant-induced arthritis (AA). Robinin (kaempferol-3-O-robinoside-7-O-rhamnoside) was isolated from the aerial parts of Astragalus falcatus Lam. The monotherapy with robinin was not efficient in alleviating symptoms of AA. The combination of MTX with robinin was similarly active as MTX alone in reducing the hind paw volume and change of body weight during the whole experiment. The combination, however, reduced plasma levels of Interleukin-17Aand activity of gamma-glutamyl transferase in joint more efficiently then MTX alone. Our results demonstrate that the novel combination of robinin and MTX mildly improved the reduction of inflammation in experimental arthritis.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Flavonoides/farmacologia , Metotrexato/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/uso terapêutico , Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Astrágalo (Planta)/química , Sinergismo Farmacológico , Quimioterapia Combinada , Flavonoides/isolamento & purificação , Flavonoides/uso terapêutico , Flores/química , Adjuvante de Freund/administração & dosagem , Adjuvante de Freund/imunologia , Humanos , Lipídeos/administração & dosagem , Lipídeos/imunologia , Masculino , Metotrexato/uso terapêutico , Folhas de Planta/química , Ratos
20.
Molecules ; 26(9)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33925555

RESUMO

Patients with hematologic malignancies require intensive therapies, including high-dose chemotherapy. Antimetabolite-methotrexate (MTX) has been used for many years in the treatment of leukemia and in lymphoma patients. However, the lack of MTX specificity causes a significant risk of morbidity, mortality, and severe side effects that impairs the quality of patients' life. Therefore, novel targeted therapies based on the malignant cells' common traits have become an essential treatment strategy. Glucose transporters have been found to be overexpressed in neoplastic cells, including hematologic malignancies. In this study, we biologically evaluated a novel glucose-methotrexate conjugate (Glu-MTX) in comparison to a free MTX. The research aimed to assess the effectiveness of Glu-MTX on chosen human lymphoma and leukemia cell lines. Cell cytotoxicity was verified by MTT viability test and flow cytometry. Moreover, the cell cycle and cellular uptake of Glu-MTX were evaluated. Our study reveals that conjugation of methotrexate with glucose significantly increases drug uptake and results in similar cytotoxicity of the synthesized compound. Although the finding has been confined to in vitro studies, our observations shed light on a potential therapeutic approach that increases the selectivity of chemotherapeutics and can improve leukemia and lymphoma patients' outcomes.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Linfoma não Hodgkin/tratamento farmacológico , Metotrexato/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citometria de Fluxo , Glucose/farmacologia , Proteínas Facilitadoras de Transporte de Glucose/antagonistas & inibidores , Proteínas Facilitadoras de Transporte de Glucose/genética , Humanos , Imunoconjugados/farmacologia , Linfoma não Hodgkin/genética , Linfoma não Hodgkin/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia
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