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1.
Int J Mol Sci ; 22(23)2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34884494

RESUMO

Abnormality in glucose homeostasis due to hyperglycemia or insulin resistance is the hallmark of type 2 diabetes mellitus (T2DM). These metabolic abnormalities in T2DM lead to cellular dysfunction and the development of diabetic cardiomyopathy leading to heart failure. New antihyperglycemic agents including glucagon-like peptide-1 receptor agonists and the sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been shown to attenuate endothelial dysfunction at the cellular level. In addition, they improved cardiovascular safety by exhibiting cardioprotective effects. The mechanism by which these drugs exert their cardioprotective effects is unknown, although recent studies have shown that cardiovascular homeostasis occurs through the interplay of the sodium-hydrogen exchangers (NHE), specifically NHE1 and NHE3, with SGLT2i. Another theoretical explanation for the cardioprotective effects of SGLT2i is through natriuresis by the kidney. This theory highlights the possible involvement of renal NHE transporters in the management of heart failure. This review outlines the possible mechanisms responsible for causing diabetic cardiomyopathy and discusses the interaction between NHE and SGLT2i in cardiovascular diseases.

2.
Chem Biol Interact ; 351: 109738, 2021 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-34740598

RESUMO

The rapid spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19), has had a dramatic negative impact on public health and economies worldwide. Recent studies on COVID-19 complications and mortality rates suggest that there is a higher prevalence in cardiovascular diseases (CVD) patients. Past investigations on the associations between pre-existing CVDs and susceptibility to coronavirus infections including SARS-CoV and the Middle East Respiratory Syndrome coronavirus (MERS-CoV), have demonstrated similar results. However, the underlying mechanisms are poorly understood. This has impeded adequate risk stratification and treatment strategies for CVD patients with SARS-CoV-2 infections. Generally, dysregulation of the expression of angiotensin-converting enzyme (ACE) and the counter regulator, angiotensin-converting enzyme 2 (ACE2) is a hallmark of cardiovascular risk and CVD. ACE2 is the main host receptor for SARS-CoV-2. Although further studies are required, dysfunction of ACE2 after virus binding and dysregulation of the renin-angiotensin-aldosterone system (RAAS) signaling may worsen the outcomes of people affected by COVID-19 and with preexisting CVD. Here, we review the current knowledge and outline the gaps related to the relationship between CVD and COVID-19 with a focus on the RAAS. Improved understanding of the mechanisms regulating viral entry and the role of RAAS may direct future research with the potential to improve the prevention and management of COVID-19.

3.
Pharm Dev Technol ; 26(4): 490-500, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33416013

RESUMO

Breast cancer is one of the leading causes of brain metastasis. Metastasis to the brain occurs if cancer cells manage to traverse the 'blood-brain barrier' (BBB), which is a barrier with a very tight junction (TJ) of endothelial cells between blood circulation and brain tissue. It is highly important to develop novel in vitro BBB models to investigate breast cancer metastasis to the brain to facilitate the screening of chemotherapeutic agents against it. We herein report the development of gelatin methacryloyl (GelMA) modified transwell insert based BBB model composed of endothelial and astrocyte cell layers for testing the efficacy of anti-metastatic agents against breast cancer metastasis to the brain. We characterized the developed model for the morphology and in vitro breast cancer cell migration. Furthermore, we investigated the effect of cisplatin, a widely used chemotherapeutic agent, on the migration of metastatic breast cancer cells using the model. Our results showed that breast cancer cells migrate across the developed BBB model. Cisplatin treatment inhibited the migration of cancer cells across the model. Findings of this study suggest that our BBB model can be used as a suitable tool to investigate breast cancer-associated brain metastasis and to identify suitable therapeutic agents against this.


Assuntos
Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias da Mama/patologia , Gelatina/química , Metacrilatos/química , Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Cisplatino/farmacologia , Feminino , Humanos , Hidrogéis , Técnicas In Vitro
4.
ACS Biomater Sci Eng ; 6(12): 6460-6477, 2020 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-33320615

RESUMO

In recent years, an increasing rate of mortality due to myocardial infarction (MI) has led to the development of nanobased platforms, especially gold nanoparticles (AuNPs), as promising nanomaterials for diagnosis and treatment of MI. These promising NPs have been used to develop different nanobiosensors, mainly optical sensors for early detection of biomarkers as well as biomimetic/bioinspired platforms for cardiac tissue engineering (CTE). Therefore, in this Review, we presented an overview on the potential application of AuNPs as optical (surface plasmon resonance, colorimetric, fluorescence, and chemiluminescence) nanobiosensors for early diagnosis and prognosis of MI. On the other hand, we discussed the potential application of AuNPs either alone or with other NPs/polymers as promising three-dimensional (3D) scaffolds to regulate the microenvironment and mimic the morphological and electrical features of cardiac cells for potential application in CTE. Furthermore, we presented the challenges and ongoing efforts associated with the application of AuNPs in the diagnosis and treatment of MI. In conclusion, this Review may provide outstanding information regarding the development of AuNP-based technology as a promising platform for current MI treatment approaches.


Assuntos
Nanopartículas Metálicas , Infarto do Miocárdio , Colorimetria , Ouro , Humanos , Infarto do Miocárdio/diagnóstico , Ressonância de Plasmônio de Superfície
5.
Eur J Pharmacol ; 888: 173420, 2020 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-32781168

RESUMO

Previous studies have established the role of Na+/H+ exchanger isoform-1 (NHE1) and cathepsin B (Cat B) in the development of cardiomyocyte hypertrophy (CH). Both NHE1 and Cat B are activated under acidic conditions suggesting that their activities might be interrelated. The inhibition of NHE1 has been demonstrated to reduce cardiac hypertrophy but the mechanism that contributes to the anti-hypertrophic effect of NHE1 inhibition still remains unclear. H9c2 cardiomyoblasts were stimulated with Angiotensin (Ang) II in the presence and absence of N-[2-methyl-4,5-bis(methylsulphonyl)-benzoyl]-guanidine, hydrochloride (EMD, EMD 87580), an NHE1 inhibitor or CA-074Me, a Cat B inhibitor, and various cardiac hypertrophic parameters, namely cell surface area, protein content and atrial natriuretic peptide (ANP) mRNA were analyzed. EMD significantly suppressed markers of cardiomyocyte hypertrophy and inhibited Ang II stimulated Cat B protein and gene expression. Cat B is located within the acidic environment of lysosomes. Cat B proteases are released into the cytoplasm upon disintegration of the lysosomes. EMD or CA-074Me prevented the dispersal of the lysosomes induced by Ang II and reduced the ratio of LC3-II to LC3-I, a marker of autophagy. Moreover, Cat B protein expression and MMP-9 activity in the extracellular space were significantly attenuated in the presence of EMD or CA-074Me. Our study demonstrates a novel mechanism for attenuation of the hypertrophic phenotype by NHE1 inhibition that is mediated by a regression in Cat B. The inhibition of Cat B via EMD or CA-074Me attenuates the autosomal-lysosomal pathway and MMP-9 activation.


Assuntos
Catepsina B/antagonistas & inibidores , Catepsina B/metabolismo , Guanidinas/farmacologia , Miócitos Cardíacos/metabolismo , Trocador 1 de Sódio-Hidrogênio/antagonistas & inibidores , Trocador 1 de Sódio-Hidrogênio/metabolismo , Sulfonas/farmacologia , Animais , Cardiomegalia/tratamento farmacológico , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Linhagem Celular , Dipeptídeos/farmacologia , Dipeptídeos/uso terapêutico , Guanidinas/uso terapêutico , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Ratos , Sulfonas/uso terapêutico
6.
J Pharm Pharmacol ; 72(11): 1536-1545, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32667058

RESUMO

OBJECTIVE: Cisplatin is a standard treatment approach against lung adenocarcinoma. Resistance to cisplatin and the toxic side effects of cisplatin continue to remain a challenge. Combining drugs with different mechanisms is being investigated as a means to overcome these challenges. In ovarian cancer cells, the knockdown of RSK2 increased the sensitivity of cisplatin. RSK is a downstream mediator of the MAPK pathway that is responsible for cell survival, proliferation and migration. METHODS: Our study examined the effect of cisplatin, BI-D1870 (RSK inhibitor) or their combination on cell migration, apoptosis, autophagy and cell cycle in A549 human lung adenocarcinoma cells. KEY FINDINGS: The combination of cisplatin and BI-D1870 potentiated the antimigration rate, the activation of caspases-3 and was associated with a significant decrease in RSK1 and ERK expression when compared to cisplatin alone. The combination of cisplatin and BI-D1870 also resulted in the inhibition of LC3 II to LC3 I expression when compared to BI-D1870. The combination of cisplatin and BI-D1870 increased the number of cells in the G2/M-phase when compared to cisplatin alone. CONCLUSIONS: These findings suggest that combining cisplatin with agents that target the RSK mediated cell survival pathway, may potentiate the cisplatin effect in lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cisplatino/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pteridinas/farmacologia , Proteínas Quinases S6 Ribossômicas 90-kDa/antagonistas & inibidores , Células A549 , Adenocarcinoma de Pulmão/enzimologia , Adenocarcinoma de Pulmão/patologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Caspase 3/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Proteínas Associadas aos Microtúbulos/metabolismo , Terapia de Alvo Molecular , Invasividade Neoplásica , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Transdução de Sinais
7.
Mar Drugs ; 18(4)2020 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-32276401

RESUMO

Lung cancer is one of the major causes of death worldwide. Natural molecules with anti-lung cancer potential are of a great interest and considered as very promising alternative to substitute or enhance the efficiency of the conventional drugs. Recently, algae as source of high value-added compounds are considered as very promising source of these bioactive molecules. These are secondary metabolites that consist mainly of derivatives of peptides, carbohydrates, and lipids with various structures. Accordingly, various mechanisms by which different algae molecules demonstrate attenuation of tumor angiogenesis were stated and discussed. The mode of action of the algae bioactives is closely related to their nature and chemical structure. Furthermore, this literature review considers the synergistic effect between microalgae bioactives and conventional drugs and discuss the economic feasibility of producing microalgae bioactives at large scale to conclude with some future perspectives related to algae-based drug discovery.


Assuntos
Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Compostos Fitoquímicos/farmacologia , Carboidratos/farmacologia , Descoberta de Drogas , Humanos , Lipídeos/farmacologia , Microalgas/química , Peptídeos/farmacologia , Compostos Fitoquímicos/química , Alga Marinha/química
8.
Pharmacogenomics J ; 20(2): 277-284, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31653973

RESUMO

The objective of this study is to estimate the prevalence of VKORC1, CYP2C9, and CYP4F2 genetic variants and their contribution to warfarin dose variability in Qataris. One hundred and fifty warfarin-treated Qatari patients on a stable dose and with a therapeutic INR for at least three consecutive clinic visits were recruited. Saliva samples were collected using Oragene DNA self-collection kit, followed by DNA purification and genotyping via TaqMan Real-Time-PCR assay. The population was stratified into derivation and validation cohorts for the dosing model. The minor allele frequency (MAF) of VKORC1 (-1639G>A) was A (0.47), while the MAF's for the CYP2C9*2 and *3 and CYP4F2*3 were T (0.12), C (0.04) and T (0.43), respectively. Carriers of at least one CYP2C9 decreased function allele (*2 or *3) required lower median (IQR) warfarin doses compared to noncarriers [24.5 (14.5) mg/week vs. 35 (21) mg/week, p < 0.001]. Similarly, carriers of each additional copy of (A) variant in VKORC1 (-1639G>A) led to reduction in warfarin dose requirement compared to noncarriers [21(7.5) vs. 31.5(18.7) vs. 43.7(15), p < 0.0001]. CYP4F2*3 polymorphism on the other hand was not associated with warfarin dose. Multivariate analysis on the derivation cohort (n = 104) showed that a dosing model consisting of hypertension (HTN), heart failure (HF), VKORC1 (-1639G>A), CYP2C9*2 & *3, and smoking could explain 39.2% of warfarin dose variability in Qataris (P < 0.001). In the validation cohort (n = 45), correlation between predicted and actual warfarin doses was moderate (Spearman's rho correlation coefficient = 0.711, p < 0.001). This study concluded that VKORC1 (-1639G>A), CYP2C9*2 & *3 are the most significant predictors of warfarin dose along with HTN, HF and smoking.


Assuntos
Anticoagulantes/administração & dosagem , Citocromo P-450 CYP2C9/genética , Vigilância da População , Vitamina K Epóxido Redutases/genética , Varfarina/administração & dosagem , Idoso , Estudos de Coortes , Estudos Transversais , Relação Dose-Resposta a Droga , Feminino , Cardiopatias/tratamento farmacológico , Cardiopatias/epidemiologia , Cardiopatias/genética , Humanos , Masculino , Pessoa de Meia-Idade , Catar/epidemiologia , Fumar/epidemiologia , Fumar/genética
9.
Cells ; 8(12)2019 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-31816901

RESUMO

Osteopontin (OPN) is recognized for its significant roles in both physiological and pathological processes. Initially, OPN was recognized as a cytokine with pro-inflammatory actions. More recently, OPN has emerged as a matricellular protein of the extracellular matrix (ECM). OPN is also known to be a substrate for proteolytic cleavage by several proteases that form an integral part of the ECM. In the adult heart under physiological conditions, basal levels of OPN are expressed. Increased expression of OPN has been correlated with the progression of cardiac remodeling and fibrosis to heart failure and the severity of the condition. The intricate process by which OPN mediates its effects include the coordination of intracellular signals necessary for the differentiation of fibroblasts into myofibroblasts, promoting angiogenesis, wound healing, and tissue regeneration. In this review, we discuss the role of OPN in contributing to the development of cardiac fibrosis and its suitability as a therapeutic target.


Assuntos
Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Osteopontina/genética , Osteopontina/metabolismo , Biomarcadores , Cardiomiopatias/patologia , Suscetibilidade a Doenças , Fibrose , Regulação da Expressão Gênica , Cardiopatias/etiologia , Cardiopatias/metabolismo , Cardiopatias/patologia , Humanos , Transdução de Sinais
10.
PLoS One ; 14(8): e0221318, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31465475

RESUMO

Syzygium cumini (S. cumini) is an evergreen tropical plant that is well recognized for its therapeutic potential of common diseases. In this study, the therapeutic potential and biomedical application of S. cumini are assessed in vitro and in vivo to find its effectiveness for different complications. The methanolic crude extract of S. cumini leaves were screened for total phenolic and flavonoid content. In vitro, the DPPH scavenging assay, XTT assay, prothrombin and activated partial thromboplastin time were used to assess antioxidant, cytoprotective and thrombolytic activity of the S. cumini extract, respectively. The anti-inflammatory potential and the analgesic activity of the S. cumini extract were analyzed in rabbits by the Carrageenan induced paw edema method and the writhing method, respectively. Phytochemical analysis showed the presence of considerable amounts of total phenolic (369.75 ± 17.9 mg GAE/g) and flavonoid (75.8 ± 5.3 mgRE/g) content in the S. cumini extract. The DPPH assay demonstrated a higher antioxidant potential (IC-50 value of 133 µg/ml), which was comparable to the IC-50 of ascorbic acid (122.4 µg/ml). Moreover, the S. cumini extract showed a dose dependent cytoprotective effect against H2O2 treated bone marrow mesenchymal stem cells (BM-MSCs). S. cumini also possesses significant anticoagulant activity with a prothrombin time of 28.3 ± 1.8 seconds vs 15.8 ± 0.2 seconds of control, p<0.05. The leaf extract also demonstrated an analgesic effect in rabbits as indicated by the decrease in writhing (12.2 ± 1.7 control vs. 3.7 ± 0.6 treated) and anti-inflammatory activity in rabbits paw with a protection against inflammation of 64.1 ± 2.4%. Our findings suggest that the methanolic extract of S. cumini leaves has antioxidant, cytoprotective, anticoagulant, analgesic and anti-inflammatory properties, and therefore, can be applied for treating cardiovascular diseases and cancers.


Assuntos
Analgésicos , Anti-Inflamatórios , Antioxidantes , Edema/tratamento farmacológico , Fenóis , Extratos Vegetais , Folhas de Planta/química , Syzygium/química , Analgésicos/química , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Carragenina/toxicidade , Edema/induzido quimicamente , Edema/metabolismo , Edema/patologia , Flavonoides/química , Flavonoides/farmacologia , Humanos , Fenóis/química , Fenóis/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ratos , Ratos Sprague-Dawley
11.
Curr Pharm Teach Learn ; 11(1): 76-80, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30527879

RESUMO

BACKGROUND AND PURPOSE: Engagement of students in the didactic classroom setting restricts students' time spent towards active learning, which in turn, adversely affects the retention of concepts taught through traditional teaching methods. Thus, interactive learning is used as an alternative to engage students in the classroom and to enrich their learning experience. Integrating interactive learning activities has been shown to facilitate student learning and improve the learning outcomes. The objectives of this study are to assess the perceptions of students on the benefits and appropriateness of using online tools (e.g., Socrative and Yammer) to promote interaction of students with the instructor and other students in the classroom setting. EDUCATIONAL ACTIVITY AND SETTING: Students enrolled in the second and third professional years of the bachelor of pharmacy program at Qatar University were introduced to various interactive learning tools in two Pharmaceutical Sciences courses. Students were then surveyed to assess their perceptions about the benefits and appropriateness of the respective interactive learning tools introduced in the courses. FINDINGS: Our survey results indicate that the students are in favor of using online educational tools and believe that the use of interactive learning tools enhances their learning experience. SUMMARY: Pharmacy students at Qatar University perceive that the incorporation of online technology in Pharmaceutical Sciences courses enhances interactive learning in the classroom setting.


Assuntos
Educação à Distância/normas , Educação em Farmácia/normas , Treinamento por Simulação/normas , Adulto , Currículo/normas , Educação à Distância/métodos , Educação em Farmácia/métodos , Feminino , Humanos , Internet , Masculino , Catar , Treinamento por Simulação/métodos , Inquéritos e Questionários
12.
Leuk Lymphoma ; 60(3): 782-794, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30187808

RESUMO

Sanguinarine (Sang), a plant-derived compound isolated from the roots of Sanguinaria canadensis was evaluated for its potential pro-apoptotic effects in precursor B acute lymphoblastic leukemia (Pre-ALL) cell lines. Treatment of 697, REH, RS4;11, and SupB15 cell lines with Sang exhibited significant inhibition of cell viability via induction of apoptotic cell death. Sang-mediated apoptosis was found to be associated with the increased expression of proapoptotic bax with concomitant decrease of Bcl-2 expression leading to depolarization of mitochondria membrane resulting in loss of mitochondrial membrane potential (MMP). The reduced MMP caused the leakage in mitochondrial membrane and release of cytochrome c into the cytosol. The cytochrome c then mediates the activation of caspase-cascade and subsequently PARP cleavage. Furthermore, pretreatment with z-VAD-FMK, a pan-caspase inhibitor, abrogated Sang-induced inhibition of cell viability, induction of apoptosis. Sang treatment also reduced the phosphorylation of AKT and suppressed the expression of a number of anti-apoptotic genes such as cIAP1, cIAP2, and XIAP. Sang mediates its anti-cancer activity by generation of reactive oxygen species (ROS) due to depletion of glutathione level in leukemic cell lines. Pretreatment of these cells with N-acetyl cysteine (NAC) prevented Sang-induced depletion of glutathione level and mitochondrial-caspase-induced apoptosis. Finally, Sang treatment of Pre-ALL cell suppressed colony formation ability of these cells suggesting Sang has an anti-leukemic potential. Altogether, our data suggest that Sang is an efficient inducer of intrinsic apoptotic cell death via generation of ROS and exhibition of anti-leukemic effect in Pre-ALL cells raises the possibility to develop Sang as a therapeutic modality for the treatment and management of Pre-ALL.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Benzofenantridinas/farmacologia , Isoquinolinas/farmacologia , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
13.
Biomed Res Int ; 2018: 1642684, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30363733

RESUMO

Over the last decade, the zebrafish (Danio rerio) has emerged as a model organism for cardiovascular research. Zebrafish have several advantages over mammalian models. For instance, the experimental cost of using zebrafish is comparatively low; the embryos are transparent, develop externally, and have high fecundity making them suitable for large-scale genetic screening. More recently, zebrafish embryos have been used for the screening of a variety of toxic agents, particularly for cardiotoxicity testing. Zebrafish has been shown to exhibit physiological responses that are similar to mammals after exposure to medicinal drugs including xenobiotics, hormones, cancer drugs, and also environmental pollutants, including pesticides and heavy metals. In this review, we provided a summary for recent studies that have used zebrafish to investigate the molecular mechanisms of drug-induced cardiotoxicity. More specifically, we focused on the techniques that were exploited by us and others for cardiovascular toxicity assessment and described several microscopic imaging and analysis protocols that are being used for the estimation of a variety of cardiac hemodynamic parameters.


Assuntos
Cardiotoxicidade/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Preparações Farmacêuticas/administração & dosagem , Peixe-Zebra/fisiologia , Animais , Hemodinâmica/fisiologia , Humanos
14.
Front Oncol ; 8: 399, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30333956

RESUMO

S-phase kinase-associated protein2 (Skp2), a proto-oncoprotein, plays an important role in development and progression of human malignancies. Skp2 is frequently overexpressed in many human malignancies. It targets cell cycle progression through ubiquitin mediated degradation of G1-checkpoint CDK inhibitors-p21 (CDKN1A) and p27 (CDKN1B). We investigated the role of Skp2 and its ubiquitin-proteasome pathway in head and neck squamous cell carcinoma (HNSCC) using a panel of cell lines with and without human papillomavirus (HPV+, HPV-). Treatment of HNSCC cell lines with curcumin, a natural compound isolated from rhizomes of the plant Curcuma longa, or transfection of small interfering RNA of Skp2, causes down-regulation of Skp2 with concomitant accumulation of p21 and p27 in HPV+, HPV- cells. Furthermore curcumin inhibits cell viability and induces apoptosis in a dose-dependent manner. Treatment of HPV+ and HPV- cells with curcumin induced apoptosis via mitochondrial pathway and activation of caspases. In addition, treatment of HPV+ and HPV- cell lines with curcumin down-regulated the expression of XIAP, cIAP1, and cIAP2. Interestingly, co-treatment of HNSCC cells with curcumin and cisplatin potentiated inhibition of cell viability and apoptotic effects. Altogether, these data suggest an important function for curcumin, acting as a suppressor of oncoprotein Skp2 in squamous cell carcinoma cells in both HPV+ and HPV- cells; raise the possibility that this agent may have a future therapeutic role in squamous cell carcinoma.

15.
Life Sci ; 209: 197-201, 2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-30089233

RESUMO

Cardiac remodeling, characterized by excessive extracellular matrix (ECM) remodeling, predisposes the heart to failure if left unresolved. Understanding the signaling mechanisms involved in excessive extracellular matrix (ECM) remodeling is necessary to identify the means to regress the development of cardiac remodeling and heart failure. Recently, hyaluronan (HA), a ubiquitously expressed glycosaminoglycan in the ECM, was shown to participate in tissue fibrosis and myofibroblast proliferation through interacting with its ubiquitously expressed cell-surface receptor, CD44. CD44 is a multifunctional transmembrane glycoprotein that serves as a cell-surface receptor for a number of ECM proteins. The mechanism by which the interaction between CD44-HA contributes to ECM and cardiac remodeling remains unknown. A previous study performed on a non-cardiac model showed that CD44-HA enhances Na+/H+ exchanger isoform-1 (NHE1) activity, causing ECM remodeling, HA metabolism and tumor invasion. Interestingly, NHE1 has been demonstrated to be involved in cardiac remodeling and myocardial fibrosis. In addition, it has previously been demonstrated that CD44 is upregulated in transgenic mouse hearts expressing active NHE-1. The role of CD44, HA and NHE1 and the cellular interplay of these factors in the ECM and cardiac remodeling is the focus of this review.


Assuntos
Remodelamento Atrial , Insuficiência Cardíaca/fisiopatologia , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/metabolismo , Miócitos Cardíacos/fisiologia , Trocador 1 de Sódio-Hidrogênio/metabolismo , Remodelação Ventricular , Humanos , Miócitos Cardíacos/citologia , Transdução de Sinais
16.
Curr Pharm Teach Learn ; 10(4): 423-426, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29793702

RESUMO

PROBLEM DESCRIPTION: Written assessments are essential components of higher education practices. However, faculty members encounter common pitfalls when designing questions intended to evaluate student-learning outcomes. The objective of this project was to determine the impact of a mandatory examination peer review process on question accuracy, alignment with learning objectives, use of best practices in question design, and language/grammar. QUALITY IMPROVEMENT METHODS: A mandatory peer review process was implemented for all midterm (before phase) and final (after phase) examinations. Peer review occurred by two reviewers and followed a pre-defined guidance document. Non-punitive feedback given to faculty members served as the intervention. Frequencies of flagged questions according to guidance categories were compared between phases. RESULTS OF CQI INQUIRY: A total of 21 midterm and 21 final exam reviews were included in the analysis. A total of 637 questions were reviewed across all midterms and 1003 questions were reviewed across all finals. Few questions were flagged for accuracy and alignment with learning outcomes. The median total proportion of questions flagged for best practices was significantly lower for final exams versus midterm exams (15.8 vs. 6.45%, p = 0.014). The intervention did not influence language and grammar errors (9.68 vs. 10.0% of questions flagged before and after, respectively, p = 0.305). CONCLUSIONS: A non-punitive peer review process for written examinations can overcome pitfalls in exam creation and improve best practices in question writing. The peer-review process had a substantial effect at flagging language/grammar errors but error rate did not differ between midterm and final exams.


Assuntos
Educação em Farmácia , Avaliação Educacional/métodos , Docentes de Farmácia , Revisão por Pares , Estudantes de Farmácia , Redação , Desempenho Acadêmico , Avaliação Educacional/normas , Humanos , Aprendizagem , Programas Obrigatórios , Avaliação de Programas e Projetos de Saúde , Catar , Universidades
17.
J Transl Med ; 16(1): 96, 2018 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-29642900

RESUMO

Cisplatin is a widely used chemotherapeutic agent for treatment of various cancers. However, treatment with cisplatin is associated with drug resistance and several adverse side effects such as nephrotoxicity, reduced immunity towards infections and hearing loss. A Combination of cisplatin with other drugs is an approach to overcome drug resistance and reduce toxicity. The combination therapy also results in increased sensitivity of cisplatin towards cancer cells. The mitogen activated protein kinase (MAPK) pathway in the cell, consisting of extracellular signal regulated kinase, c-Jun N-terminal kinase, p38 kinases, and downstream mediator p90 ribosomal s6 kinase (RSK); is responsible for the regulation of various cellular events including cell survival, cell proliferation, cell cycle progression, cell migration and protein translation. This review article demonstrates the role of MAPK pathway in cisplatin based therapy, illustrates different combination therapy involving cisplatin and also shows the importance of targeting MAPK family, particularly RSK, to achieve increased anticancer effect and overcome drug resistance when combined with cisplatin.


Assuntos
Cisplatino/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Terapia de Alvo Molecular
18.
Physiol Genomics ; 50(5): 332-342, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29473817

RESUMO

Cardiovascular diseases are the leading cause of death worldwide. One in three cases of heart failure is due to dilated cardiomyopathy. The Na+/H+ exchanger isoform 1 (NHE1), a multifunctional protein and the key pH regulator in the heart, has been demonstrated to be increased in this condition. We have previously demonstrated that elevated NHE1 activity induced cardiac hypertrophy in vivo. Furthermore, the overexpression of active NHE1 elicited modulation of gene expression in cardiomyocytes including an upregulation of myocardial osteopontin (OPN) expression. To determine the role of OPN in inducing NHE1-mediated cardiomyocyte hypertrophy, double transgenic mice expressing active NHE1 and OPN knockout were generated and assessed by echocardiography and the cardiac phenotype. Our studies showed that hearts expressing active NHE1 exhibited cardiac remodeling indicated by increased systolic and diastolic left ventricular internal diameter and increased ventricular volume. Moreover, these hearts demonstrated impaired function with decreased fractional shortening and ejection fraction. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) mRNA was upregulated, and there was an increase in heart cell cross-sectional area confirming the cardiac hypertrophic effect. Moreover, NHE1 transgenic mice also showed increased collagen deposition, upregulation of CD44 and phosphorylation of p90 ribosomal s6 kinase (RSK), effects that were regressed in OPN knockout mice. In conclusion, we developed an interesting comparative model of active NHE1 transgenic mouse lines which express a dilated hypertrophic phenotype expressing CD44 and phosphorylated RSK, effects which were regressed in absence of OPN.


Assuntos
Cardiomegalia/metabolismo , Osteopontina/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Trocador 1 de Sódio-Hidrogênio/metabolismo , Animais , Cardiomegalia/genética , Regulação da Expressão Gênica , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Camundongos Knockout , Camundongos Transgênicos , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Osteopontina/genética , Fosforilação , Trocador 1 de Sódio-Hidrogênio/genética
19.
Future Med Chem ; 9(9): 933-950, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28636454

RESUMO

Sanguinarine (Sang) - a benzophenanthridine alkaloid extracted from Sanguinaria canadensis - exhibits antioxidant, anti-inflammatory, proapoptotic and growth inhibitory activities on tumor cells of various cancer types as established by in vivo and in vitro studies. Although the underlying mechanism of Sang antitumor activity is yet to be fully elucidated, Sang has displayed multiple biological effects, which remain to suggest its possible use in plant-derived treatments of human malignancies. This review covers the anticancer abilities of Sang including inhibition of aberrantly activated signal transduction pathways, induction of cell death and inhibition of cancer cell proliferation. It also highlights Sang-mediated inhibition of angiogenesis, inducing the expression of tumor suppressors, sensitization of cancer cells to standard chemotherapeutics to enhance their cytotoxic effects, while addressing the present need for further pharmacokinetic-based studies.


Assuntos
Antineoplásicos/farmacologia , Benzofenantridinas/farmacologia , Isoquinolinas/farmacologia , Antineoplásicos/química , Benzofenantridinas/química , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Isoquinolinas/química , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade
20.
J Cell Physiol ; 232(12): 3244-3250, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28255990

RESUMO

Cardiac hypertrophy (CH), characterized by the enlargement of cardiomyocytes, fibrosis and apoptosis, is one of the leading causes of death worldwide. Despite the advances in cardiovascular research, there remains a need to further investigate the signaling pathways that mediate CH in order to identify novel therapeutic targets. One of the hallmarks of CH is the remodeling of the extracellular matrix (ECM). Multiple studies have shown an important role of cysteine proteases and matrix metalloproteinases (MMPs) in the remodeled heart. This review focuses on the role of cysteine cathepins and MMPs in cardiac remodeling.


Assuntos
Miocárdio/enzimologia , Peptídeo Hidrolases/metabolismo , Animais , Matriz Extracelular/metabolismo , Humanos , Hipertensão/metabolismo , Metaloproteinases da Matriz/metabolismo , Remodelação Ventricular
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