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Cardiotoxicity is one of the most devastating complications of cancer treatment by methotrexate (MTX). The present study aimed to investigate the potential anti-cardiotoxic efficacy of taurine (Tau) and enzymatically modified isoquercitrin (EMIQ) alone or combined against MTX-induced cardiotoxicity in adult male rats. A total of 36 rats were randomly divided into six groups (six animals each): control, MTX (a single i.p. dose of 20 mg/kg), EMIQ + MTX (26 mg/kg of EMIQ, p.o. for 16 days), Tau + MTX (500 mg/kg of Tau, p.o. for 16 days), EMIQ + Tau + MTX at the same previous doses, and (EMIQ + Tau)½ + MTX. MTX reduced the percentage of body weight change, the expression of dihydrofolate reductase (DHFR) and folypolyglutamyl synthetase (FPGS), the cleaved tumor necrosis factor alpha (TNF-α) level in the cardiac tissue, and the elevated serum TNF-α level. MTX extensively deteriorated the electrocardiography (ECG), inducing tachycardia with shortening of the time intervals between successive heartbeats (R-R interval), associated with elongation of ventricular depolarization (QRS interval), and the corrected total time for ventricular de- and repolarization (QTc) duration. Treatment with MTX resulted in a significant reduction in atrial depolarization (P amplitude) and rapid repolarization (T amplitude) and a significant elevation in plateau phase (ST height). MTX treatment resulted in swelling of cardiomyocytes with extensive vacuolization of sarcoplasm with numerous variably sized vacuoles in addition to apoptotic cells. Tau and EMIQ protected against MTX-induced deteriorations in the conductivity and rhythmicity of the heart through antioxidative, anti-inflammatory, and antiapoptotic activities. Treatment with tau and EMIQ combined at high or low doses offered superior protection to the heart than using each agent alone.
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MOTIVATION: Imaging single molecules has emerged as a powerful characterization tool in the biological sciences. The detection of these under various noise conditions requires the use of algorithms that are dependent on the end-user inputting several parameters, the choice of which can be challenging and subjective. RESULTS: In this work, we propose DeepSinse, an easily trainable and useable deep neural network that can detect single molecules with little human input and across a wide range of signal-to-noise ratios. We validate the neural network on the detection of single bursts in simulated and experimental data and compare its performance with the best-in-class, domain-specific algorithms. AVAILABILITYAND IMPLEMENTATION: Ground truth ROI simulating code, neural network training, validation code, classification code, ROI picker, GUI for simulating, training and validating DeepSinse as well as pre-trained networks are all released under the MIT License on www.github.com/jdanial/DeepSinse. The dSTORM dataset processing code is released under the MIT License on www.github.com/jdanial/StormProcessor. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Disciplinas de las Ciencias Biológicas , Aprendizaje Profundo , Humanos , Redes Neurales de la Computación , Algoritmos , Relación Señal-RuidoRESUMEN
Schistosomiasis is one of the most important parasitic diseases in tropical and subtropical areas. Its prevalence is associated with the distribution of freshwater snails, which are their intermediate hosts. Thus, control of freshwater snails is the solution to reduce the transmission of this disease. This will be achieved by understanding the relationship between the snails and their habitats including natural enemies and associated aquatic plants as well as the factors affecting their distribution. In this study, Maximum Entropy model (MaxEnt) was used for mapping and predicting the possible geographic distribution of Bulinus truncatus snail (the intermediate host of Schistosoma haematobium), Odonata nymph (predatory aquatic insect), and Ceratophyllum demersum (the associated aquatic plant) in Egypt based on topographic and climatic factors. The models of the investigated species were evaluated using the area under receiver operating characteristic curve. The results showed that the potential risk areas were along the banks of the Nile River and its irrigation canals. In addition, the MaxEnt models revealed some similarities in the distribution pattern of the vector, the predator, and the aquatic plant. It is obvious that the predictive distribution range of B. truncatus was affected by altitude, precipitation seasonality, isothermality, and mean temperature of warmest quarter. The presence of B. truncatus decreases with the increase of altitude and precipitation seasonality values. It could be concluded that the MaxEnt model could help introducing a predictive risk map for Schistosoma haematobium prevalence and performing better management strategies for schistosomiasis.
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Bulinus , Odonata , Animales , Ecosistema , Insectos , Ninfa , Schistosoma haematobiumRESUMEN
Two novel chemotherapeutic chalcones were synthesized and their structures were confirmed by different spectral tools. Theoretical studies such as molecular modeling were done to detect the mechanism of action of these compounds. In vitro cytotoxicity showed a strong effect against all tested cell lines (MCF7, A459, HepG2, and HCT116), and low toxic effect against normal human melanocytes (HFB4). The lung carcinoma cell line was chosen for further molecular studies. Real-time PCR demonstrated that the two compounds upregulated gene expression of (BAX, p53, casp-3, casp-8, casp-9) genes and decreased the expression of anti-apoptotic genes bcl2, CDK4, and MMP1. Flow-cytometry indicated that cell cycle arrest of A459 was induced at the G2/M phase and the apoptotic percentage increased significantly compared to the control sample. Cytochrome c oxidase and VEGF enzyme activity were detected by ELISA assay. SEM tool was used to follow the morphological changes that occurred on the cell surface, cell granulation, and average roughness of the cell surface. The change in the number and morphology of mitochondria, cell shrinkage, increase in the number of cytoplasmic organelles, membrane blebbing, chromatin condensation, and apoptotic bodies were observed using TEM. The obtained data suggested that new chalcones exerted their pathways on lung carcinoma through induction of two pathways of apoptosis. Graphical abstract Novel chalcones were prepared and confirmed by different spectral tools. Docking simulations were done to detect the mechanism of action. In vitro cytotoxicity indicated a strong effect against different cancer cell lines and low toxic effects against normal human melanocytes (HFB4). The lung carcinoma cell line was chosen for further molecular studies that include Real-time PCR, Flow-cytometry, Cytochrome c oxidase, and ELISA assay. SEM and TEM tool were used to follow the morphological changes occurred on the cell surface.
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Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Chalconas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Caspasas/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Chalconas/química , Expresión Génica/efectos de los fármacos , Humanos , Simulación del Acoplamiento Molecular , Proteína p53 Supresora de Tumor/efectos de los fármacos , Proteína X Asociada a bcl-2/efectos de los fármacosRESUMEN
RATIONALE: Blood flow-induced shear stress controls endothelial cell (EC) physiology during atherosclerosis via transcriptional mechanisms that are incompletely understood. The mechanosensitive transcription factor TWIST is expressed during embryogenesis, but its role in EC responses to shear stress and focal atherosclerosis is unknown. OBJECTIVE: To investigate whether TWIST regulates endothelial responses to shear stress during vascular dysfunction and atherosclerosis and compare TWIST function in vascular development and disease. METHODS AND RESULTS: The expression and function of TWIST1 was studied in EC in both developing vasculature and during the initiation of atherosclerosis. In zebrafish, twist was expressed in early embryonic vasculature where it promoted angiogenesis by inducing EC proliferation and migration. In adult porcine and murine arteries, TWIST1 was expressed preferentially at low shear stress regions as evidenced by quantitative polymerase chain reaction and en face staining. Moreover, studies of experimental murine carotid arteries and cultured EC revealed that TWIST1 was induced by low shear stress via a GATA4-dependent transcriptional mechanism. Gene silencing in cultured EC and EC-specific genetic deletion in mice demonstrated that TWIST1 promoted atherosclerosis by inducing inflammation and enhancing EC proliferation associated with vascular leakiness. CONCLUSIONS: TWIST expression promotes developmental angiogenesis by inducing EC proliferation and migration. In addition to its role in development, TWIST is expressed preferentially at low shear stress regions of adult arteries where it promotes atherosclerosis by inducing EC proliferation and inflammation. Thus, pleiotropic functions of TWIST control vascular disease and development.
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Aterosclerosis/metabolismo , Velocidad del Flujo Sanguíneo/fisiología , Endotelio Vascular/metabolismo , Proteínas Nucleares/biosíntesis , Proteína 1 Relacionada con Twist/biosíntesis , Animales , Aterosclerosis/patología , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Células Cultivadas , Células Endoteliales/metabolismo , Células Endoteliales/patología , Endotelio Vascular/patología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Porcinos , Pez CebraRESUMEN
The discovery of microRNAs (miRNAs) 20 years ago has advocated a new era of "small molecular genetics." About 2000 miRNAs are present that regulate one third of the genome. MiRNA dysregulated expression arising as a response to our environment insult or stress or changes may contribute to several diseases, namely non-communicable diseases, including tumor growth. Their presence in body fluids, reflecting level alteration in various cancers, merit circulating miRNAs as the "next-generation biomarkers" for early-stage tumor diagnosis and/or prognosis. Herein, we performed a comprehensive literature search focusing on the origin, biosynthesis, and role of miRNAs and summarized the foremost studies centering on miR value as non-invasive biomarkers in different environment-related non-communicable diseases, including various cancer types. Moreover, during chemotherapy, many miRNAs were linked to multidrug resistance, via modulating numerous, environment triggered or not, biological processes and/or pathways that will be highlighted as well.
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MicroARNs , Enfermedades no Transmisibles , Biomarcadores de Tumor , Resistencia a Múltiples Medicamentos , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/genéticaRESUMEN
Breast cancer (BC) is the leading cause of female cancer-related mortalities. Evidence has illustrated the role of long non-coding RNAs (lncRNA) and microRNAs (miRNA) as promising pool of protein non-coding regulators, for tuning the aggressiveness of several malignancies. This research aims to unravel the expression pattern and the emphases of the diagnostic value of the long intergenic ncRNA00511 (LINC00511) and its downstream microRNA (miR-185-3p) and the pathogenic significance of the onco-miR-301a-3p in naïve BC patients. LINC00511 was chosen and validated, and its molecular binding was confirmed using bioinformatics. LINC00511 was measured in 25 controls and 70 patients using qPCR. The association between the investigated ncRNA's expression and the BC patients' clinicopathological features was assessed. Receiver operating characteristic (ROC) curve was blotted to weigh out their diagnostic efficacy over the classical tumor markers (TMs). Bioinformatics and Spearman correlation were used to predict the interaction between LINC00511, miR-185-3p, and miR-301a-3p altogether to patients' features. LINC00511 and miR-301a-3p, in BC patients' blood, were overexpressed, and their median levels increased significantly, while miR-185-3p was, in contrast, downregulated, being decreased fourfold. LINC00511 was elevated in BC early stages, when compared to late stages (p < 0.0003). LINC00511, miR-185-3p, and miR-301a-3p showed AUC superior to classical TMs, allowing us to conclude that the investigated ncRNAs, in BC patients' liquid biopsy, are novel diagnostic molecular biomarker signatures. Lymph node metastasis (LNM) and advanced tumor grade were directly correlated with LINC00511 significantly. Additionally, both LINC00511 and miR-301a-3p were positively correlated with the aggressiveness of BC, as manifested in patients with larger tumors (>2 cm) at (p < 0.001). Therefore, these findings aid our understanding of BC pathogenesis, in the clinical setting, being related in part to the LINC00511/miR axis, which could be a future potential therapeutic target.
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This study aimed to clarify the role of glypican-1 and PECAM-1 in shear-induced nitric oxide production in endothelial cells. Atomic force microscopy pulling was used to apply force to glypican-1 and PECAM-1 on the surface of human umbilical vein endothelial cells and nitric oxide was measured using a fluorescent reporter dye. Glypican-1 pulling for 30 min stimulated nitric oxide production while PECAM-1 pulling did not. However, PECAM-1 downstream activation was necessary for the glypican-1 force-induced response. Glypican-1 knockout mice exhibited impaired flow-induced phosphorylation of eNOS without changes to PECAM-1 expression. A cooperation mechanism for the mechanotransduction of fluid shear stress to nitric oxide production was elucidated in which glypican-1 senses flow and phosphorylates PECAM-1 leading to endothelial nitric oxide synthase phosphorylation and nitric oxide production.
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Endotelio Vascular/metabolismo , Glipicanos/metabolismo , Óxido Nítrico/biosíntesis , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Animales , Endotelio Vascular/citología , Glipicanos/genética , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ratones , Ratones Noqueados , Microscopía de Fuerza Atómica , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fosforilación , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/genética , Unión Proteica , ARN Interferente Pequeño/genéticaRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Blood flow influences atherosclerosis by generating wall shear stress, which alters endothelial cell (EC) physiology. Low shear stress induces dedifferentiation of EC through a process termed endothelial-to-mesenchymal transition (EndMT). The mechanisms underlying shear stress-regulation of EndMT are uncertain. Here we investigated the role of the transcription factor Snail in low shear stress-induced EndMT. Studies of cultured EC exposed to flow revealed that low shear stress induced Snail expression. Using gene silencing it was demonstrated that Snail positively regulated the expression of EndMT markers (Slug, N-cadherin, α-SMA) in EC exposed to low shear stress. Gene silencing also revealed that Snail enhanced the permeability of endothelial monolayers to macromolecules by promoting EC proliferation and migration. En face staining of the murine aorta or carotid arteries modified with flow-altering cuffs demonstrated that Snail was expressed preferentially at low shear stress sites that are predisposed to atherosclerosis. Snail was also expressed in EC overlying atherosclerotic plaques in coronary arteries from patients with ischemic heart disease implying a role in human arterial disease. We conclude that Snail is an essential driver of EndMT under low shear stress conditions and may promote early atherogenesis by enhancing vascular permeability.
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Arterias Carótidas/patología , Endotelio Vascular/patología , Transición Epitelial-Mesenquimal , Regulación de la Expresión Génica , Placa Aterosclerótica/patología , Factores de Transcripción de la Familia Snail/metabolismo , Estrés Mecánico , Animales , Aorta/metabolismo , Aorta/patología , Arterias Carótidas/metabolismo , Proliferación Celular , Células Cultivadas , Endotelio Vascular/metabolismo , Humanos , Ratones , Ratones Noqueados , Proteínas Nucleares/fisiología , Placa Aterosclerótica/metabolismo , Receptor TIE-1/fisiología , Factores de Transcripción de la Familia Snail/genética , Porcinos , Proteína 1 Relacionada con Twist/fisiologíaRESUMEN
The anticancer drug; doxorubicin (DOX), causes testicular toxicity as an adverse effect. P-glycoprotein (P-gp) is a multidrug resistance efflux transporter expressed in blood-testis barrier, which extrudes DOX from the testis. We investigated whether DOX-induced gonadal injury could be prevented by the use of antioxidant; coenzyme-Q10 (CoQ10). The involvement of P-gp expression, as a possible protective mechanism, was also investigated. CoQ10 was administered orally for 8 days, and DOX toxicity was induced via a single i.p. dose of 15 mg/kg at day 4. Concomitant administration of CoQ10 with DOX significantly restored testicular oxidative stress parameters and the distorted histopathological picture, reduced the up-regulation of caspase 3 caused by DOX, and increased P-gp expression. We show for the first time that CoQ10 up-regulates P-gp as a novel mechanism for gonadal protection. In conclusion, CoQ10 protects against DOX-induced testicular toxicity in rats via ameliorating oxidative stress, reducing apoptosis and up-regulating testicular P-gp.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Antibióticos Antineoplásicos/toxicidad , Doxorrubicina/toxicidad , Sustancias Protectoras/farmacología , Testículo/efectos de los fármacos , Ubiquinona/análogos & derivados , Animales , Apoptosis/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Catalasa/metabolismo , Glutatión/metabolismo , Masculino , Malondialdehído/metabolismo , Nitratos/metabolismo , Nitritos/metabolismo , Tamaño de los Órganos/efectos de los fármacos , Ratas Wistar , Testículo/metabolismo , Testículo/patología , Ubiquinona/farmacología , Regulación hacia ArribaRESUMEN
Nephrotoxicity is one of the limiting factors for using doxorubicin (Dox) as an anticancer chemotherapeutic. Here, we investigated possible protective effect of coenzyme-Q10 (CoQ10) on Dox-induced nephrotoxicity and the mechanisms involved. Two doses (10 and 100 mg/kg) of CoQ10 were administered orally to rats for 8 days, in the presence or absence of nephrotoxicity induced by a single intraperitoneal injection of Dox (15 mg/kg) at day 4 of the experiment. Our results showed that the low dose of CoQ10 succeeded in reversing Dox-induced nephrotoxicity to control levels (e.g., levels of blood urea nitrogen and serum creatinine, concentrations of renal reduced glutathione (GSH) and malondialdehyde, catalase activity and caspase 3 expression, and renal histopathology). Alternatively, the high dose of CoQ10 showed no superior nephroprotection over the low dose, as there were no significant improvements in renal histopathology, catalase activity, or caspase 3 expression compared to the Dox-treated group. Interestingly, the high dose of CoQ10 alone significantly decreased renal GSH level as well as catalase activity and caused a mild induction of caspase 3 expression compared to control, probably due to a prooxidant effect at this dose of CoQ10. We conclude that CoQ10 protects from Dox-induced nephrotoxicity with a precaution to dosage adjustment.