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Sci Rep ; 9(1): 19095, 2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31836811


Sorafenib (SO) is a multi-kinase inhibitor that targets upstream signals in the MAPK pathway. Drug resistance and transient survival benefits are the main obstacles associated with SO treatment in Hepatocellular carcinoma (HCC) patients. Mebendazole (MBZ), an anthelmintic agent, has demonstrated activity against various cancer types. Therefore, we aimed to investigate the possible mechanisms of MBZ other than its anti-tubulin activity. MBZ (100 mg/kg/day, P.O.) was administered to N-nitrosodiethylamine-induced HCC mice as a monotherapeutic agent or in combination with SO. Our results revealed that MBZ decreased AFP levels, improved liver function and histology and increased survival in HCC mice, particularly when administered in combination with SO. MBZ also reduced hepatic inflammation and fibrogenesis as evidenced by reductions in TNF-α and TGF-ß1 levels, respectively. Increased hepatic caspases-3 and -9 and decreased BCL-2 levels suggest induced-cell death. In addition, MBZ demonstrated anti-angiogenic, anti-metastatic, and anti-proliferative effects, as indicated by reduced VEGF levels, MMP-2:TIMP-1 ratios, and reduced cyclin D1 levels and Ki67 immunostaining, respectively. Our main finding was that MBZ targeted downstream signal of the MAPK pathway by inhibiting ERK1/2 phosphorylation. Targeting downstream MAPK signalling by MBZ and upstream signalling by SO is a novel approach to minimizing resistance and prolonging survival.

Pharmacology ; : 1-9, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31747659


INTRODUCTION: The clinical use of doxorubicin (DOX) is challenged by its incremental dose-related cardiotoxicity. OBJECTIVE: The aim of the hereby study was to investigate sandalwood essential oil (SEO) against DOX-induced cardiac toxicity. METHODS: Male Sprague-Dawley rats were allocated into 4 groups. Groups 1 signified the control, whereas group 2 administered 100 mg/kg/day SEO, both act as control. In group 3, DOX was given intraperitoneal in a dose of 3 mg/kg/ every other day for 2 weeks to induced cardiotoxicity. While group 4 received a combination of SEO and DOX for 2 weeks. DOX prompted variations were assessed by measuring cardiac injury biomarkers, including creatine phosphokinase, cardiac troponin T, and lactate dehydrogenase (LDH), electrocardiogram (ECG) fluctuations, heart rate (HR), and blood pressure (BP) indices. The effect of both DOX and SEO on various antioxidants such as glutathione, superoxide dismutase, and catalase and inflammatory mediators including interleukin-1ß, tumor necrosis factor-alpha, and NF-κB was quantified. RESULTS: DOX augmented cardiac injury biomarkers, altered ECG, deceased HR and antioxidants, and finally increased BP indices. Treatment with SEO significantly (p < 0.05) decreased cardiac biomarkers and reversing ECG changes and BP. Moreover, treatment with SEO enhanced HR anomalies and antioxidant activity reduction and precluded the intensive inflammatory response induced by DOX. CONCLUSION: SEO may have the potential of mitigating cardiac rhythm and BP indices changes induced with DOX. SEO modifications may be due to antioxidant capacity improvement and inflammatory response prohibition of the heart muscle.

Mar Drugs ; 17(7)2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31288394


Cyanothece sp., a coccoid, unicellular, nitrogen-fixing and hydrogen-producing cyanobacterium, has been used in this study to biosynthesize customized gold nanoparticles under certain chemical conditions. The produced gold nanoparticles had a characteristic absorption band at 525-535 nm. Two types of gold nanoparticle, the purple and blue, were formed according to the chemical environment in which the cyanobacterium was grown. Dynamic light scattering was implemented to estimate the size of the purple and blue nanoparticles, which ranged from 80 ± 30 nm and 129 ± 40 nm in diameter, respectively. The highest scattering of laser light was recorded for the blue gold nanoparticles, which was possibly due to their larger size and higher concentration. The appearance of anodic and cathodic peaks in cyclic voltammetric scans of the blue gold nanoparticles reflected the oxidation into gold oxide, followed by the subsequent reduction into the nano metal state. The two produced forms of gold nanoparticles were used to treat isoproterenol-induced myocardial infarction in experimental rats. Both forms of nanoparticles ameliorated myocardial infarction injury, with a slight difference in their curative activity with the purple being more effective. Mechanisms that might explain the curative effect of these nanoparticles on the myocardial infarction were proposed. The morphological, physiological, and biochemical attributes of the Cyanothece sp. cyanobacterium were fundamental for the successful production of "tailored" nanoparticles, and complemented the chemical conditions for the differential biosynthesis process. The present research represents a novel approach to manipulate cyanobacterial cells towards the production of different-sized gold nanoparticles whose curative impacts vary accordingly. This is the first report on that type of manipulated gold nanoparticles biosynthesis which will hopefully open doors for further investigations and biotechnological applications.

Cianobactérias/química , Cyanothece/química , Ouro/química , Ouro/farmacologia , Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/química , Infarto do Miocárdio/tratamento farmacológico , Animais , Isoproterenol/química , Luz , Masculino , Miocárdio/química , Nitrogênio/química , Fixação de Nitrogênio/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
Molecules ; 24(10)2019 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-31109132


Myocardial infarction (MI) remains one of the major causes of mortality around the world. A possible mechanism involved in myocardial infarction is the engagement of Toll-like receptors (TLRs). This study was intended to discover the prospective cardioprotective actions of ß-caryophyllene, a natural sesquiterpene, to ameliorate isoproterenol (ISO)-induced myocardial infarction through HSP-60/TLR/MyD88/NFκB pathway. ß-Caryophyllene (100 or 200 mg/kg/day orally) was administered for 21 days then MI was induced via ISO (85 mg/kg, subcutaneous) on 20th and 21st days. The results indicated that ISO induced a significant infarcted area associated with several alterations in the electrocardiogram (ECG) and blood pressure (BP) indices and caused an increase in numerous cardiac indicators such as creatine phosphokinase (CPK), creatine kinase-myocardial bound (CK-MB), lactate dehydrogenase (LDH), and cardiac tropinine T (cTnT). In addition, ISO significantly amplified heat shock protein 60 (HSP-60) and other inflammatory markers, such as TNF-α, IL-Iß, and NFκB, and affected TLR2 and TLR4 expression and their adaptor proteins; Myeloid differentiation primary response 88 (MYD88), and TIR-domain-containing adapter-inducing interferon-ß (TRIF). On the other hand, consumption of ß-caryophyllene significantly reversed the infarcted size, ECG and BP alterations, ameliorated the ISO elevation in cardiac indicators; it also notably diminished HSP-60, and subsequently TLR2, TLR4, MYD88, and TRIF expression, with a substantial reduction in inflammatory mediator levels. This study revealed the cardioprotective effect of ß-caryophyllene against MI through inhibiting HSP-60/TLR/MyD88/NFκB signaling pathways.

Produtos Biológicos/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Substâncias Protetoras/farmacologia , Sesquiterpenos/farmacologia , Receptores Toll-Like/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Pressão Sanguínea/efeitos dos fármacos , Creatina Quinase/metabolismo , Eletrocardiografia/efeitos dos fármacos , Isoproterenol/metabolismo , L-Lactato Desidrogenase/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Ratos Sprague-Dawley
Ther Innov Regul Sci ; 53(5): 618-622, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30380941


BACKGROUND: Acne vulgaris, a chronic inflammatory disease, is among the most common dermatologic conditions worldwide. In Saudi Arabia, Isotretinoin is commonly used to treat mild acne even without prescription. OBJECTIVE: To explore the practice and knowledge of community in Saudi Arabia regarding dispensing, counseling practices, and safety of isotretinoin-containing products. METHODS: A cross-sectional survey, using a self-administered questionnaire, was conducted in 3 sections: demographics, self-medication attitude (in the form of self Isotretinoin use), and identifying the side effects associated with the use of isotretinoin. RESULTS: A total of 1069 participated in the study. Around half of the participants (44.2%) used isotretinoin with only mild acne as their first choice, which is contrary to the recommended guidelines. Virtually one-fifth of the participants did not examine the lipid profile, liver enzymes, and blood glucose level before isotretinoin use. Not many participants identified lipid (58.7%) and liver (44.1%) depression (53.3%), inflammatory bowel disease (75.9%), osteoporosis (60.3%), and sunburns (36.3%) as risks allied with isotretinoin use. Most participants (88.9%) appropriately recognized teratogenicity as the greatest hazard concomitant with the use of isotretinoin. Nevertheless, 20% of the women did not know that they must cease the drug at least 6 months before pregnancy. CONCLUSION: This study shows that community residents are not satisfactorily aware of the proper use and jeopardies of isotretinoin. Therefore, greater consideration ought to be dedicated to augment the safe use of isotretinoin. We recommend the implementation of tools to enhance the safe use of isotretinoin and the imposition of more effective regulations to limit nonprescribed isotretinoin dispensing in Saudi Arabia.

Mar Drugs ; 16(6)2018 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-29925786


To the best of our knowledge, cyanobacterial strains from the Arabian Gulf have never been investigated with respect to their potential for nanoparticle production. Lyngbya majuscula was isolated from the AlOqair area, Al-Ahsa Government, Eastern Province, Kingdom of Saudi Arabia. The cyanobacterium was initially incubated with 1500 mg/mL of HAuCl4 for two days. The blue-green strain turned purple, which indicated the intracellular formation of gold nanoparticles. Prolonged incubation for over two months triggered the extracellular production of nanogold particles. UV-visible spectroscopy measurements indicated the presence of a resonance plasmon band at ~535 nm, whereas electron microscopy scanning indicated the presence of gold nanoparticles with an average diameter of 41.7 ± 0.2 nm. The antioxidant and anti-myocardial infarction activities of the cyanobacterial extract, the gold nanoparticle solution, and a combination of both were investigated in animal models. Isoproterenol (100 mg/kg, SC (sub cutaneous)) was injected into experimental rats for three days to induce a state of myocardial infarction; then the animals were given cyanobacterial extract (200 mg/kg/day, IP (intra peritoneal)), gold nanoparticles (200 mg/kg/day, IP), ora mixture of both for 14 days. Cardiac biomarkers, electrocardiogram (ECG), blood pressure, and antioxidant enzymes were determined as indicators of myocardial infarction. The results showed that isoproterenol elevates ST and QT segments and increases heart rate and serum activities of creatine phosphokinase (CPK), creatine kinase-myocardial bound (CP-MB), and cardiac troponin T (cTnT). It also reduces heart tissue content of glutathione peroxidase (GRx) and superoxide dismutase (SOD), and the arterial pressure indices of systolic arterial pressure (SAP), diastolic arterial pressure (DAP), and mean arterial pressure (MAP). Gold nanoparticles alone or in combination with cyanobacterial extract produced an inhibitory effect on isoproterenol-induced changes in serum cardiac injury markers, ECG, arterial pressure indices, and antioxidant capabilities of the heart.

Antioxidantes/farmacologia , Organismos Aquáticos/metabolismo , Cardiotônicos/farmacologia , Cianobactérias/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Animais , Antioxidantes/química , Antioxidantes/uso terapêutico , Biomarcadores/sangue , Biotecnologia/métodos , Pressão Sanguínea/efeitos dos fármacos , Cardiotônicos/química , Cardiotônicos/uso terapêutico , Modelos Animais de Doenças , Ouro/química , Ouro/uso terapêutico , Coração/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Humanos , Isoproterenol/toxicidade , Masculino , Nanopartículas Metálicas/química , Nanopartículas Metálicas/uso terapêutico , Infarto do Miocárdio/sangue , Infarto do Miocárdio/induzido quimicamente , Miocárdio/metabolismo , Ratos , Ratos Sprague-Dawley , Arábia Saudita , Água do Mar/microbiologia