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1.
Biomed Chromatogr ; 38(8): e5899, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38797863

RESUMO

Nanoliposomes (NLs) are ideal carriers for delivering complex molecules and phytochemical products, but ginger by-products, despite their therapeutic benefits, have poor bioavailability due to their low water solubility and stability. Crude ginger extracts (CGEs) and 6-gingerol were individually encapsulated within NLs for in vitro activity assessment. In vitro evaluation of anti-proliferative and anti-inflammatory properties of encapsulated 6-gingerol and CGE was performed on healthy human periodontal ligament (PDL) fibroblasts and MDA-MB-231 breast cancer cells. Encapsulation efficiency and loading capacity of 6-gingerol reached 25.23% and 2.5%, respectively. NLs were found stable for up to 30 days at 4°C with a gradual load loss of up to 20%. In vitro cytotoxic effect of encapsulated 6-gingerol exceeded 70% in the MDA-MB-231 cell line, in a comparable manner with non-encapsulated 6-gingerol and CGE. The effect of CGE with an IC50 of 3.11 ± 0.39, 7.14 ± 0.80, and 0.82 ± 0.55 µM and encapsulated 6-gingerol on inhibiting IL-8 was evident, indicating its potential anti-inflammatory activity. Encapsulating 6-gingerol within NLs enhanced its stability and facilitated its biological activity. All compounds, including vitamin C, were equivalent at concentrations below 2 mg/mL, with a slight difference in antioxidant activity. The concentrations capable of inhibiting 50% of 2,2-diphenyl-1-picrylhydrazyl (DPPH) substrate were comparable.


Assuntos
Anti-Inflamatórios , Catecóis , Álcoois Graxos , Lipossomos , Zingiber officinale , Álcoois Graxos/química , Álcoois Graxos/farmacologia , Humanos , Catecóis/química , Catecóis/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacocinética , Lipossomos/química , Linhagem Celular Tumoral , Zingiber officinale/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Nanopartículas/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Interleucina-8/metabolismo , Proliferação de Células/efeitos dos fármacos
2.
AAPS PharmSciTech ; 25(4): 86, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38605192

RESUMO

The common disorders irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) can modify the drugs' pharmacokinetics via their induced pathophysiological changes. This work aimed to investigate the impact of these two diseases on pravastatin oral bioavailability. Rat models for IBS and IBD were used to experimentally test the effects of IBS and IBD on pravastatin pharmacokinetics. Then, the observations made in rats were extrapolated to humans using a mechanistic whole-body physiologically-based pharmacokinetic (wbPBPK) model. The rat in vivo studies done herein showed that IBS and IBD decreased serum albumin (> 11% for both), decreased PRV binding in plasma, and increased pravastatin absolute oral bioavailability (0.17 and 0.53 compared to 0.01) which increased plasma, muscle, and liver exposure. However, the wbPBPK model predicted muscle concentration was much lower than the pravastatin toxicity thresholds for myotoxicity and rhabdomyolysis. Overall, IBS and IBD can significantly increase pravastatin oral bioavailability which can be due to a combination of increased pravastatin intestinal permeability and decreased pravastatin gastric degradation resulting in higher exposure. This is the first study in the literature investigating the effects of IBS and IBD on pravastatin pharmacokinetics. The high interpatient variability in pravastatin concentrations as induced by IBD and IBS can be reduced by oral administration of pravastatin using enteric-coated tablets. Such disease (IBS and IBD)-drug interaction can have more drastic consequences for narrow therapeutic index drugs prone to gastric degradation, especially for drugs with low intestinal permeability.


Assuntos
Doenças Inflamatórias Intestinais , Síndrome do Intestino Irritável , Humanos , Animais , Ratos , Síndrome do Intestino Irritável/tratamento farmacológico , Pravastatina , Doenças Inflamatórias Intestinais/tratamento farmacológico , Projetos de Pesquisa
3.
Toxicol Appl Pharmacol ; 465: 116451, 2023 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-36894070

RESUMO

The toxic effects of alcohol consumption on population health are significant worldwide and the synergistic toxic effects of concurrent intake of Acetaminophen and alcohol is of clinical concern. The understanding of molecular mechanisms beneath such synergism and acute toxicity may be enhanced through assessing underlying metabolomics changes. The molecular toxic activities of the model hereby, is assessed though metabolomics profile with a view to identifying metabolomics targets which could aid in the management of drug-alcohol interactions. In vivo exposure of C57/BL6 mice to APAP (70 mg/kg), single dose of ethanol (6 g/kg of 40%) and APAP after alcohol consumption was employed. Plasma samples were prepared and subjected to biphasic extraction for complete LC-MS profiling, and tandem mass MS2 analysis. Among the detected ions, 174 ions had significant (VIP scores >1 and FDR <0.05) changes between groups and were selected as potential biomarkers and significant variables. The presented metabolomics approach highlighted several affected metabolic pathways, including nucleotide and amino acid metabolism; aminoacyl-tRNA biosynthesis as well as bioenergetics of TCA and Krebs cycle. The impact of APAP on the concurrent administration of alcohol showed great biological interactions in the vital ATP and amino acid producing processes. The metabolomics changes show distinct metabolites which are altered to alcohol-APAP consumption while presenting several unneglectable risks on the vitality of metabolites and cellular molecules which shall be concerned.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Doença Hepática Induzida por Substâncias e Drogas , Camundongos , Animais , Acetaminofen/toxicidade , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Fígado , Metabolômica , Biomarcadores , Aminoácidos/metabolismo , Consumo de Bebidas Alcoólicas/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Camundongos Endogâmicos C57BL
4.
Mol Cell Biochem ; 478(9): 1949-1960, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36583794

RESUMO

Cell stress transcribing genes provide a diverse platform of molecular mediators that vary in response to toxicity. Common drug-induced liver injury (DILI) biomarkers are usually expressed in mild toxicity and limited to confirming it rather than categorizing its intensity. Thus, new parametric biomarkers are needed to be explored. Classifying the toxicological response based on the dose-level and severity of stimuli will aid in the evaluation and approach against drug exposure. The present research explored the involvement of gene expression of potential biomarkers as a severity-specific hallmark in different acetaminophen (APAP)-induced hepatotoxicity levels in C57BL/6 mice. The differentially expressed genes were annotated and analyzed using bioinformatics tools to predict canonical pathways altered by DILI. The results revealed alteration in genes encoding for antioxidant enhancement; Slc7a11, bile efflux; MDR4, fatty acid metabolism and transcriptional factors namely Srebf1 and Pparα. Potential APAP toxicity biomarkers included Adh1 and thrombin, and other DNA damage and stress chaperones which were changed at least fourfold between control and the three tested severity models. The current investigation demonstrates a dose-mediated association of several hallmark genes in APAP-induced liver damage and addressed the involvement of uncommonly studied molecular responses. Such biomarkers can be further developed into predictive models, translated for risk assessment against drug exposure and guide in building theragnostic targets.


Assuntos
Acetaminofen , Doença Hepática Induzida por Substâncias e Drogas , Camundongos , Animais , Acetaminofen/toxicidade , PPAR alfa/genética , PPAR alfa/metabolismo , Álcool Desidrogenase/metabolismo , Trombina/metabolismo , Camundongos Endogâmicos C57BL , Fígado/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Biomarcadores/metabolismo , Dano ao DNA , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
5.
Molecules ; 28(5)2023 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-36903651

RESUMO

Deep eutectic solvents (DESs) and ionic liquids (ILs) offer novel opportunities for several pharmaceutical applications. Their tunable properties offer control over their design and applications. Choline chloride (CC)-based DESs (referred to as Type III eutectics) offer superior advantages for various pharmaceutical and therapeutic applications. Here, CC-based DESs of tadalafil (TDF), a selective phosphodiesterase type 5 (PDE-5) enzyme inhibitor, were designed for implementation in wound healing. The adopted approach provides formulations for the topical application of TDF, hence avoiding systemic exposure. To this end, the DESs were chosen based on their suitability for topical application. Then, DES formulations of TDF were prepared, yielding a tremendous increase in the equilibrium solubility of TDF. Lidocaine (LDC) was included in the formulation with TDF to provide a local anaesthetic effect, forming F01. The addition of propylene glycol (PG) to the formulation was attempted to reduce the viscosity, forming F02. The formulations were fully characterised using NMR, FTIR and DCS techniques. According to the obtained characterisation results, the drugs were soluble in the DES with no detectable degradation. Our results demonstrated the utility of F01 in wound healing in vivo using cut wound and burn wound models. Significant retraction of the cut wound area was observed within three weeks of the application of F01 when compared with DES. Furthermore, the utilisation of F01 resulted in less scarring of the burn wounds than any other group including the positive control, thus rendering it a candidate formula for burn dressing formulations. We demonstrated that the slower healing process associated with F01 resulted in less scarring potential. Lastly, the antimicrobial activity of the DES formulations was demonstrated against a panel of fungi and bacterial strains, thus providing a unique wound healing process via simultaneous prevention of wound infection. In conclusion, this work presents the design and application of a topical vehicle for TDF with novel biomedical applications.


Assuntos
Anti-Infecciosos , Queimaduras , Líquidos Iônicos , Anti-Infecciosos/farmacologia , Colina/química , Cicatriz , Líquidos Iônicos/química , Preparações Farmacêuticas , Inibidores da Fosfodiesterase 5/farmacologia , Solventes/química , Tadalafila/farmacologia , Cicatrização , Animais
6.
Molecules ; 28(19)2023 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-37836770

RESUMO

The current work was aimed at the development of a topical drug delivery system for azelaic acid (AzA) for acne treatment. The systems tested for this purpose were deep eutectic systems (DESs) prepared from choline chloride (CC), malonic acid (MA), and PEG 400. Three CC to MA and eight different MA: CC: PEG400 ratios were tested. The physical appearance of the tested formulations ranged from solid and liquid to semisolid. Only those that showed liquid formulations of suitable viscosity were considered for further investigations. A eutectic mixture made from MA: CC: PEG400 1:1:6 (MCP 116) showed the best characteristics in terms of viscosity, contact angle, spreadability, partition coefficient, and in vitro diffusion. Moreover, the MCP116 showed close rheological properties to the commercially available market lead acne treatment product (Skinorin®). In addition, the formula showed synergistic antibacterial activity between the MA moiety of the DES and the AzA. In vitro diffusion studies using polyamide membranes demonstrated superior diffusion of MCP116 over the pure drug and the commercial product. No signs of skin irritation and edema were observed when MCP116 was applied to rabbit skin. Additionally, the MCP116 was found to be, physically and chemically, highly stable at 4, 25, and 40 °C for a one-month stability study.


Assuntos
Acne Vulgar , Fármacos Dermatológicos , Animais , Coelhos , Ácidos Dicarboxílicos/química , Fármacos Dermatológicos/uso terapêutico , Pele , Preparações Farmacêuticas , Colina/química , Acne Vulgar/tratamento farmacológico , Solventes/química
7.
Mol Biol Rep ; 49(5): 4039-4053, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35020121

RESUMO

The Nrf2-ARE transcriptional pathway plays an important role amongst cellular defence systems regulating and ensuring adequacy of redox responses and oxidant signalling factors. Hepatocyte cellular death and injury is a prominent feature underlying liver pathologies. Diverse endogenous molecules and targets contribute to the outcome of cell survival and the consequent mode of cell death. Several research efforts focused on the confirmation of Nrf2 presence in cell death and its vital necessity against cell compromise, however, little they comprehend of such participation. Hepatocyte cell death modes discussed in this review including autophagy, apoptosis, necrosis, ferroptosis, pyroptosis, fibrosis and others, vary in response of the stimuli burdened. The current review presents a handful of highlights and crosstalk involved in the communication of Nrf2 signalling network with the "up to date" reported hepatocyte cell death modes and their underling mechanisms, and addressing key cellular networks of hepatocyte fate, through a perspective of Nrf2 as a critical transcriptional factor. Collectively, labelling the cross-transduction of Nrf2-ARE axis with key cell execution pathways could provide insights to therapeutic interventions and better research outcomes.


Assuntos
Fator 2 Relacionado a NF-E2 , Transdução de Sinais , Autofagia/fisiologia , Morte Celular , Hepatócitos/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo
8.
Molecules ; 27(23)2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36500674

RESUMO

Capmatinib, a recently approved tyrosine kinase inhibitor, is used for the treatment of non-small cell lung cancer. We describe two new HPLC methods for capmatinib quantification in vivo and in vitro. HPLC with a fluorescence detection method was used to quantify capmatinib in plasma for the first time. The method was successfully applied in a pharmacokinetic study following a 10 mg/kg oral dose of capmatinib given to rats. The chromatographic separation was performed using a Eurospher II 100-3 C18H (50 × 4 mm, 3 µm) column and a mobile phase containing 10 mM of ammonium acetate buffer (pH 5.5): acetonitrile (70:30, v/v), at a flow rate of 2.0 mL min-1. The study also describes the use of HPLC-PDA for the first time for the determination of capmatinib in human liver microsomes and describes its application to study its metabolic stability in vitro. Our results were in agreement with those reported using LC-MS/MS, demonstrating the reliability of the method. The study utilized a Gemini-NX C18 column and a mobile phase containing methanol: 20 mM ammonium formate buffer pH 3.5 (53:47, v/v), delivered at a flow rate of 1.1 mL min-1. These methods are suitable for supporting pharmacokinetic studies, particularly in bioanalytical labs lacking LC-MS/MS capabilities.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Animais , Ratos , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Reprodutibilidade dos Testes , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cromatografia Líquida de Alta Pressão/métodos
9.
J Appl Toxicol ; 39(2): 178-190, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30350376

RESUMO

The urge of identifying new pharmacological interventions to prevent or attenuate liver injury is of critical importance and needs an expanded experimental toolbox. Hepatocyte injury and cellular death is a prominent feature behind the pathology of liver diseases. Several research activities focused on identifying chemicals and hepatotoxicants that induce cell death by apoptosis, in addition to presenting its corresponding signaling pathway. Although such efforts provided further understanding of the mechanisms of cell death, it has also raised confusion concerning identifying the involvement of several modes of cell death including apoptosis, necrosis and fibrosis. The current review highlights the ability of several chemicals and potential hepatotoxicants to induce liver damage in rodents by means of apoptosis while the probable involvement of other modes of cell death is also exposed. Thus, several chemical substances including hepatotoxins, mycotoxins, hyperglycemia inducers, metallic nanoparticles and immunosuppressant drugs are reviewed to explore the hepatic cytotoxic spectrum they could exert on hepatocytes of rodents. In addition, the current review address the mechanism by which hepatotoxicity is initiated in hepatocytes in different rodents aiding the researcher in choosing the right animal model for a better research outcome.


Assuntos
Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/patologia , Hepatócitos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Xenobióticos/toxicidade , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Hepatócitos/patologia , Fígado/patologia , Modelos Biológicos , Roedores
10.
BMC Complement Altern Med ; 19(1): 29, 2019 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-30678660

RESUMO

BACKGROUND: In-depth information of potential drug-herb interactions between warfarin and herbal compounds with suspected anticoagulant blood thinning effects is needed to raise caution of concomitant administration. The current study aimed to investigate the impact of co-administration of pomegranate peel and guava leaves extracts, including their quality markers namely; ellagic acid and quercetin, respectively, on warfarin's in vivo dynamic activity and pharmacokinetic actions, in addition to potential in vitro cytochrome P450 enzymes (CYP) inhibition. METHODS: Influence of mentioned extracts and their key constituents on warfarin pharmacodynamic and kinetic actions and CYP activity were evaluated. The pharmacodynamic interactions were studied in Sprague Dawley rats through prothrombin time (PT) and International Normalized Ratio (INR) measurements, while pharmacokinetic interactions were detected in vivo using a validated HPLC method. Furthermore, potential involvement in CYP inhibition was also investigated in vitro on isolated primary rat hepatocytes. RESULTS: Preparations of pomegranate peel guava leaf extract, ellagic acid and quercetin in combination with warfarin were found to exert further significant increase on PT and INR values (p < 0.01) than when used alone (p < 0.05). Pomegranate peel extract showed insignificant effects on warfarin pharmacokinetics (p > 0.05), however, its constituent, namely, ellagic acid significantly increased warfarin Cmax (p < 0.05). Guava leaves extract and quercetin resulted in significant increase in warfarin Cmax when compared to control (p < 0.01). Furthermore, guava leaves extract showed a significant effect on changing the AUC, CL and Vz. Significant reduction in CYP2C8, 2C9, and 3A4 was seen upon concomitant use of warfarin with ellagic acid, guava leaves and quercetin, unlike pomegranate that insignificantly affected CYP activities. CONCLUSION: All combinations enhanced the anticoagulant activity of warfarin as the results of in vivo and in vitro studies were consistent. The current investigation confirmed serious drug herb interactions between warfarin and pomegranate peel or guava leaf extracts. Such results might conclude a high risk of bleeding from the co-administration of the investigated herbal drugs with warfarin therapy. In addition, the results raise attention to the blood-thinning effects of pomegranate peel and guava leaves when used alone.


Assuntos
Anticoagulantes/farmacocinética , Interações Ervas-Drogas , Lythraceae/química , Extratos Vegetais/farmacocinética , Psidium/química , Varfarina/farmacocinética , Animais , Anticoagulantes/sangue , Anticoagulantes/farmacologia , Testes de Coagulação Sanguínea , Células Cultivadas , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/metabolismo , Ácido Elágico , Hepatócitos/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Quercetina , Ratos , Ratos Sprague-Dawley , Varfarina/sangue , Varfarina/farmacologia
11.
Medicina (Kaunas) ; 55(5)2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31117289

RESUMO

Background and objectives: Ascorbic acid, alpha lipoic acid (ALA) and silymarin are well-known antioxidants that have hepatoprotective effects. This study aims to investigate the effects of these three compounds combined with attenuating drug-induced oxidative stress and cellular damage, taking acetaminophen (APAP)-induced toxicity in rats as a model both in vivo and in vitro. Materials and Methods: Freshly cultured primary rat hepatocytes were treated with ascorbic acid, ALA, silymarin and their combination, both with and without the addition of APAP to evaluate their in vitro impact on cell proliferation and mitochondrial activity. In vivo study was performed on rats supplemented with the test compounds or their combination for one week followed by two toxic doses of APAP. Results: Selected liver function tests and oxidative stress markers including superoxide dismutase (SOD), malondialdehyde (MDA) and oxidized glutathione (GSSG) were detected. The in vivo results showed that all three pretreatment compounds and their combination prevented elevation of SOD and GSSG serum levels indicating a diminished burden of oxidative stress. Moreover, ascorbic acid, ALA and silymarin in combination reduced serum levels of liver enzymes; however, silymarin markedly maintained levels of all parameters to normal ranges. Silymarin either alone or combined with ascorbic acid and ALA protected cultured rat hepatocytes and increased cellular metabolic activity. The subjected agents were capable of significantly inhibiting the presence of oxidative stress induced by APAP toxicity and the best result for protection was seen with the use of silymarin. Conclusions: The measured liver function tests may suggest an augmented hepatoprotection of the combination preparation than when compared individually.


Assuntos
Acetaminofen/efeitos adversos , Ácido Ascórbico/farmacocinética , Fatores de Proteção , Silimarina/farmacocinética , Ácido Tióctico/farmacocinética , Acetaminofen/intoxicação , Animais , Ácido Ascórbico/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/complicações , Modelos Animais de Doenças , Masculino , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Silimarina/uso terapêutico , Ácido Tióctico/uso terapêutico
12.
Mar Drugs ; 16(1)2018 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-29337857

RESUMO

Oral insulin delivery that better mimics physiological pathways is a necessity as it ensures patient comfort and compliance. A system which is based on a vehicle of nano order where positively charged chitosan interacts with negatively charged insulin and forms a polyelectrolyte complex (PEC) solubilizate, which is then solubilized into an oily phase of oleic acid, labrasol, and plurol oleaque-protects insulin against enzymatic gastrointestinal reduction. The use of an anionic fatty acid in the oily phase, such as oleic acid, is thought to allow an interaction with cationic chitosan, hence reducing particle size. Formulations were assessed based on their hypoglycaemic capacities in diabetic rats as compared to conventional subcutaneous dosage forms. 50 IU/kg oral insulin strength could only induce blood glucose reduction equivalent to that of 5 IU/kg (1 International unit = 0.0347 mg of human insulin). Parameters that influence the pharmacological availability were evaluated. A preliminary investigation of the mechanism of absorption suggests the involvement of the lymphatic route.


Assuntos
Glicemia/efeitos dos fármacos , Quitosana/química , Glucose/metabolismo , Glicerídeos/química , Insulina/administração & dosagem , Insulina/química , Administração Oral , Animais , Portadores de Fármacos/química , Excipientes/química , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Masculino , Peso Molecular , Nanopartículas/química , Ácido Oleico/química , Tamanho da Partícula , Ratos , Ratos Wistar
13.
Inhal Toxicol ; 29(2): 46-52, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28330430

RESUMO

OBJECTIVE: There has been an increase in the popularity of waterpipe tobacco smoking (WTS) worldwide, especially in the younger population, including asthma patients. In this study, we investigated the effects of waterpipe smoking on airway inflammation, cytokine levels and oxidative stress markers in an antigen-driven murine model of asthma. MATERIALS AND METHODS: Balb/c mice were divided into four groups; (1) control (received fresh air, ovalbumin sensitization and saline challenge), (2) WTS (received WTS, ovalbumin sensitization and saline challenge), (3) Ova S/C (received fresh air, ovalbumin sensitization and ovalbumin challenge) and (4) simultaneous WTS and Ova S/C (received WTS, ovalbumin sensitization and ovalbumin challenge). Airway inflammatory cells were evaluated in the broncho-alveolar lavage fluid. Cytokines [interleukin (IL)-13, 10 and 18] and oxidative stress markers [superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx)] were evaluated in the lung homogenates. RESULTS: Chronic exposure to WTS significantly increased the number of airway inflammatory cells in mice, specifically: eosinophils, neutrophils, macrophages and lymphocytes. The level of IL-13 in the lungs was increased and the level of IL-10 was reduced (p < 0.05) by WTS. Chronic WTS potentiated the increase in inflammatory cells induced by Ova S/C (p < 0.05). The level of IL-13 in the lungs was increased by simultaneous WTS and Ova S/C (p < 0.05) while, levels of IL-10, IL-18, SOD, catalase and GPx in the lungs were not affected. CONCLUSIONS: Chronic WTS exposure induced airway inflammation in control mice and enhanced airway inflammation in murine model of asthma.


Assuntos
Asma/imunologia , Fumar Cachimbo de Água/efeitos adversos , Alérgenos , Animais , Asma/metabolismo , Líquido da Lavagem Broncoalveolar , Catalase/metabolismo , Citocinas/imunologia , Modelos Animais de Doenças , Glutationa Peroxidase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina , Superóxido Dismutase/metabolismo
14.
Molecules ; 21(6)2016 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-27271577

RESUMO

Eriobotrya japonica (Thunb.) Lindl. (Loquat) (EJ) has been used as a medicinal plant to treat chronic bronchitis, coughs, phlegm, high fever and gastro-enteric disorders. Since the traditional use of EJ is related to modulating inflammation processes, our earlier studies on EJ leaves were performed on the water extract to investigate specific cytokines' modulation. These earlier studies, however, have shown that EJ leaf water extract (WE) and the water phase (WP) induce cytokines' production in in vitro and in vivo models. Therefore, the aim of this study was to specify the group(s) of compounds in EJ leaves that have this immunomodulatory activity and their mechanism of action. WE was obtained from boiling the leaves followed by butanol extraction, yielding a butanol-water phase (WP). WP was then subjected to methanol:acetone fractionation, yielding upper (MAU) and lower (MAL) phases. For further fractionation, MAU was subjected to column chromatography followed by elution with ethanol:water (EW), methanol:ethanol (ME) and, lastly, acetone:water (AW), respectively, to reveal three sub-fractions; MAU-EW, MAU-ME and MAU-AW. MAU-AW significantly increased IFN-γ production from unstimulated and stimulated mouse spleen cells, as well as CD3+ T cells and natural killer cells. Furthermore, the fold increase of IFN-γ production by MAU-AW was concentration dependent, higher than the parent extract or any of the other sub-fractions, and such an IFN-γ increase was reversed by two JAK-STAT inhibitors. In addition, MALDI-TOF-MS analysis of the extracts and sub-fractions showed compounds with molecular weights of >500 Daltons. The MAU-AW sub-fraction contained more polar compounds, such as flavonol and caffeic glycosides. In conclusion, these polar compounds in the EJ extract are responsible for inducing IFN-γ production. Further chemical elucidation is warranted to lead to a specific IFN-γ inducer and an immunomodulator in polarizing immune cells and balancing immune responses in certain diseases.


Assuntos
Eriobotrya/química , Fatores Imunológicos/administração & dosagem , Células Matadoras Naturais/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Animais , Cromatografia , Flavonoides/administração & dosagem , Flavonoides/química , Flavonoides/isolamento & purificação , Glicosídeos/administração & dosagem , Glicosídeos/química , Glicosídeos/isolamento & purificação , Fatores Imunológicos/química , Interferon gama/biossíntese , Janus Quinases/biossíntese , Células Matadoras Naturais/imunologia , Camundongos , Extratos Vegetais/química , Folhas de Planta/química , Fatores de Transcrição STAT/biossíntese , Transdução de Sinais/efeitos dos fármacos , Baço/efeitos dos fármacos , Baço/imunologia , Água/química
15.
Mar Drugs ; 13(4): 1710-25, 2015 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-25826718

RESUMO

The objective of the present study was to prepare and characterize low molecular weight chitosan (LMWC) with different molecular weight and degrees of deacetylation (DDA) and to optimize their use in oral insulin nano delivery systems. Water in oil nanosized systems containing LMWC-insulin polyelectrolyte complexes were constructed and their ability to reduce blood glucose was assessed in vivo on diabetic rats. Upon acid depolymerization and testing by viscosity method, three molecular weights of LMWC namely, 1.3, 13 and 18 kDa were obtained. As for the DDA, three LMWCs of 55%, 80% and 100% DDA were prepared and characterized by spectroscopic methods for each molecular weight. The obtained LMWCs showed different morphological and in silico patterns. Following complexation of LMWCs with insulin, different aggregation sizes were obtained. Moreover, the in vivo tested formulations showed different activities of blood glucose reduction. The highest glucose reduction was achieved with 1.3 kDa LMWC of 55% DDA. The current study emphasizes the importance of optimizing the molecular weight along with the DDA of the incorporated LMWC in oral insulin delivery preparations in order to ensure the highest performance of such delivery systems.


Assuntos
Quitosana/química , Diabetes Mellitus Experimental/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Hipoglicemiantes/administração & dosagem , Insulina Regular Humana/administração & dosagem , Nanopartículas/química , Acetilação , Administração Oral , Animais , Glicemia/análise , Diabetes Mellitus Experimental/sangue , Composição de Medicamentos , Eletrólitos/química , Humanos , Hiperglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Insulina Regular Humana/uso terapêutico , Masculino , Peso Molecular , Nanopartículas/ultraestrutura , Tamanho da Partícula , Distribuição Aleatória , Ratos Sprague-Dawley , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Propriedades de Superfície , Viscosidade
16.
J Adv Pharm Technol Res ; 15(1): 1-7, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38389974

RESUMO

Type 2 diabetes is common globally. Pioglitazone (PGZ) is an oral TZD antidiabetic, whereas chromium-picolinate (Cr-PL) and Cr-glucose tolerance factor (Cr-GTF) are useful type 2 diabetes mellitus (T2DM) supplements. Cr-PL/GTF antioxidants cure T2DM. They may fail in diabetes with or without insulin-sensitizing medications. It examined how Cr-PL, Cr-GTF, PGZ, and their combination affected glucose, glycosylated hemoglobin, insulin, and HOMA-IR. Sixty-three adult Sprague-Dawley rats (220-300 g) were selected, and nine rats were randomly assigned to a normal nondiabetic group. In contrast, 54 rats were randomly split into 9 rats per each of the 6 major groups and injected intraperitoneally with 40 mg/kg STZ to induce T2DM. Rats were administered PGZ = 0.65 mg/kg (rat weight)/day, Cr-PL = 1 mg/kg, Cr-GTF = 1 mg/kg, and their combinations (PGZ + Cr-PL and Cr-GTF) daily for 6 weeks per intervention. The PGZ + Cr-PL and PGZ + Cr-GTF groups had substantially lower insulin levels than the PGZ group (13.38 ± 0.06, 12.98 ± 0.19 vs. 14.11 ± 0.02, respectively), with the PGZ + Cr-GTF group having the lowest insulin levels (12.98 ± 0.19 vs. 14.11 ± 0.02, 13.38±0.06, respectively). Intervention substantially reduced HOMA-IR in the PZ + Cr-PL and PZ + Cr-GTF groups compared to PGZ (7.49 ± 0.04, 6.69 ± 0.11 vs. 8.37 ± 0.04, respectively). This research found that combining PGZ with Cr-GTF resulted in considerably lower HOMA-IR levels than the PGZ and Cr-PL groups (6.69 ± 0.11 vs. 8.37 ± 0.04, 7.49 ± 0.04, respectively). Both Cr-PL and Cr-GTF may control T2DM. Both Cr complexes improved T2DM biomarkers more than the control diabetic group without medication. PGZ alone and PGZ + Cr-PL had less pharmacological synergy than Cr-GTF and PGZ in altering insulin and HOMA-IR blood levels. These encouraging discoveries need more study.

17.
J Pharm Biomed Anal ; 232: 115423, 2023 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-37146497

RESUMO

Tivozanib is a recently approved tyrosine kinase inhibitor for the treatment of renal cell carcinoma. In this work, two new HPLC methods coupled with fluorescence (FLD), or photodiode array detectors (PDA) were developed and used for the first time for tivozanib quantification in rat plasma and liver microsomes. The described methods were efficient with a 4-min runtime employing a Gemini-NX C18 column (50 × 2.1 mm, 3 µm) and a mobile phase of acetonitrile and ammonium acetate buffer (pH 4.7, 10 mM) (40:60, v/v) delivered at a flow rate of 0.4 mL/min. The use of HPLC-FLD allowed the quantification of 50 ng/ mL tivozanib using only 100 µL rat plasma. The HPLC-FLD method was validated according to the US food and drug administration (FDA) bioanalytical guidelines and was applied successfully in a rat pharmacokinetic study (n = 7) following oral administration of 1 mg/ kg tivozanib. Furthermore, HPLC-PDA was used for monitoring the depletion of 1 µM (454.9 ng/mL) tivozanib in rat liver microsomes and was applied to study the effect of dexamethasone induction on tivozanib metabolism in vitro. Results showed that dexamethasone enhanced the intrinsic clearance of tivozanib by 60 % suggesting a potential drug-drug interaction at the metabolism level. Dexamethasone is commonly used in the management of cancer disease and thus coadministration with tivozanib therapy may cause treatment failure in patients. The simplicity, speed and cost-effectiveness of the reported methods are ideal for supporting in vivo and in vitro tivozanib studies, including drug-drug interaction studies, particularly in bioanalytical labs lacking LC-MS/MS capabilities.


Assuntos
Dexametasona , Espectrometria de Massas em Tandem , Ratos , Animais , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Reprodutibilidade dos Testes
18.
BMC Complement Med Ther ; 23(1): 132, 2023 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-37098530

RESUMO

BACKGROUND: Apitherapy is an emerging field in cancer research, particularly in developing communities. The potency of Melittin (MEL), a major constituent in bee venom is accounted for the cytotoxic capacity against cancer cells. It is postulated that the genotype of bees and the time of venom collection influences its specific activity against certain types of cancer. METHOD: Hereby, Jordanian crude bee venom (JCBV) was collected during different seasons of the year, specifically spring, summer and autumn and investigated for in vitro antitumour effects. Venom collected during springtime comprised the highest quantity of MEL in comparison to venom collected some other time. Springtime-collected JCBV extract and MEL were tested on an immortal myelogenous leukaemia cell line, namely K562 leukemic cells. Treated cells were examined for cell modality via flow cytometry analysis and cell death mediating gene expressions. RESULTS: Springtime-collected JCBV extract and MEL showed an IC50 of 3.7 ± 0.37 µg/ml and 1.84 ± 0.75 µg/ml, respectively. In comparison to JCBV and positive control, MEL-treated cells exhibited late apoptotic death with a moderate cellular arrest at G0/G1 and an increase of cell number at G2/M phase. Expression of NF-κB/MAPK14 axis was inhibited in MEL and JCBV-treated cells, as well as expression of c-MYC and CDK4. Moreover, marked upregulation in ABL1, JUN and TNF was observed. In conclusion, springtime-collected JCBV showed the highest content of MEL while both JCBV and pure MEL showed apoptotic, necrotic, and cell cycle arrest efficiency against K562 leukemic cells. CONCLUSION: Integration of bee venom in chemotherapy needs more investigation and should be carefully translated into clinical use. During such translation, the correlation of bee genotype, collection time and concentration of MEL in CBV should be profiled.


Assuntos
Venenos de Abelha , Leucemia , Humanos , Abelhas , Animais , Meliteno/farmacologia , Meliteno/química , Meliteno/genética , Venenos de Abelha/farmacologia , Células K562 , Peptídeos , Leucemia/tratamento farmacológico
19.
Pharmaceuticals (Basel) ; 15(7)2022 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-35890161

RESUMO

Irisin, encoded by the FNDC5 (fibronectin type III domain containing 5) gene, is a novel myokine that has been implicated as an essential mediator of exercise benefits. Effects of irisin on heart physiology is still ambiguous. This study aimed to evaluate the impact of exogenous administration of irisin on heart physiology and the pharmacokinetic profile of pump-administered irisin. To do so, Sprague Dawley rats were implanted with an irisin-loaded osmotic pump (5 µg/kg/day) for 42 days, and other animals were administered with single bolus subcutaneous injections of irisin (5 µg/kg). Body weights and blood samples were collected weekly for 42 days for serum irisin quantification and histopathology. Clinical biochemistry analyses were performed. Heart mRNA expression was assessed in 26 selected genes. Chronic interventional exogenous irisin significantly reduced body weight without affecting the heart myocyte size and significantly reduced creatine kinase enzyme level. Blood CBC, serum biochemistry, and heart morphology were normal. Gene expression of FNCD5, Raf1, CPT1, IGF-1, and CALCIN, encoding for heart physiology, increased while PGC1, Nox4, and Mfn1 significantly decreased. Nevertheless, irisin increased the expression of cardioprotective genes and inhibited some genes that harm heart physiology. Administration of irisin promotes myocardial functions and could be translated into clinical settings after preclinical profiling.

20.
Toxicol Rep ; 9: 1674-1680, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36518403

RESUMO

Regulations often are imposing long postmortem times before autopsy leading to certain toxicity-unrelated changes in biomarkers, which in turn may affect the reliability of toxicity evaluation during forensic investigations. Since methomyl pesticide shows significant toxicity and is frequently encountered in poisoning cases, the current study evaluated different parameters in methomyl intoxicated rats at three different postmortem intervals (Hour 0, Hour 3 and Hour 6). Eighteen adult Sprague Dawley rats were poisoned with methomyl to simulate actual methomyl poisoning cases. The time of death was assigned as Hour 0. The animals were divided into 3 groups (n = 6) to collect blood and tissue samples at the selected time points. Body weight, relative organ weight, protein concentration, methomyl concentration and acetylcholinesterase activity (AChE) were assessed in blood and different tissues (liver, spleen, kidney, brain, eye, and bone marrow) to evaluate the effect of postmortem sampling time. Outcomes revealed significant decreases in methomyl concentration in blood and bone marrow with advanced sampling time (P < 0.001). Similarly, there were significant reductions in AChE activity in the kidney (P < 0.01), while the enzyme activity significantly increased in brain samples (P < 0.05). Findings illustrated the importance of sampling time in toxicity studies because it could alter experimental results and impact consequent interpretations, as well as it may alter postmortem biomarkers in related forensic cases.

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