BPA Decreases PDCD4 in Bovine Granulosa Cells Independently of miR-21 Inhibition

microRNAs (miRNAs) are susceptible to environmental factors that might affect cellular function and impose negative effects on female reproduction. miR-21 is the most abundant miRNA in bovine granulosa cells and is widely reported as affected by Bisphenol A (BPA) exposure, yet the cause and consequences are not entirely elucidated. BPA is a synthetic endocrine disruptor associated with poor fertility. miR-21 function in bovine granulosa cells is investigated utilizing locked nucleic acid (LNA) oligonucleotides to suppress miR-21. Before measuring apoptosis and quantifying miR-21 apoptotic targets PDCD4 and PTEN, transfection was optimized and validated. BPA was introduced to see how it affects miR-21 regulation and which BPA-mediated effects are influenced by miR-21. miR-21 knockdown and specificity against additional miRNAs were confirmed. miR-21 was found to have antiapoptotic effects, which could be explained by its effect on the proapoptotic target PDCD4, but not PTEN. Previous findings of miR-21 overexpression were validated using BPA treatments, and the temporal influence of BPA on miR-21 levels was addressed. Finally, BPA effects on upstream regulators, such as VMP1 and STAT3, explain the BPA-dependent upregulation of miR-21 expression. Overall, this research enhances our understanding of miR-21 function in granulosa cells and the mechanisms of BPA-induced reproductive impairment.     

Post-Stroke Timing of ECM Hydrogel Implantation Affects Biodegradation and Tissue Restoration

Extracellular matrix (ECM) hydrogel promotes tissue regeneration in lesion cavities after stroke. However, a bioscaffold’s regenerative potential needs to be considered in the context of the evolving pathological environment caused by a stroke. To evaluate this key issue in rats, ECM hydrogel was delivered to the lesion core/cavity at 7-, 14-, 28-, and 90-days post-stroke. Due to a lack of tissue cavitation 7-days post-stroke, implantation of ECM hydrogel did not achieve a sufficient volume and distribution to warrant comparison with the other time points. Biodegradation of ECM hydrogel implanted 14- and 28-days post-stroke were efficiently (80%) degraded by 14-days post-bioscaffold implantation, whereas implantation 90-days post-stroke revealed only a 60% decrease. Macrophage invasion was robust at 14- and 28-days post-stroke but reduced in the 90-days post-stroke condition. The pro-inflammation (M1) and pro-repair (M2) phenotype ratios were equivalent at all time points, suggesting that the pathological environment determines macrophage invasion, whereas ECM hydrogel defines their polarization. Neural cells (neural progenitors, neurons, astrocytes, oligodendrocytes) were found at all time points, but a 90-days post-stroke implantation resulted in reduced densities of mature phenotypes. Brain tissue restoration is therefore dependent on an efficient delivery of a bioscaffold to a tissue cavity, with 28-days post-stroke producing the most efficient biodegradation and tissue regeneration, whereas by 90-days post-stroke, these effects are significantly reduced. Improving our understanding of how the pathological environment influences biodegradation and the tissue restoration process is hence essential to devise engineering strategies that could extend the therapeutic window for bioscaffolds to repair the damaged brain.     

Can Cisplatin Therapy Be Improved? Pathways That Can Be Targeted

Cisplatin (cis-diamminedichloroplatinum (II)) is the oldest known chemotherapeutic agent. Since the identification of its anti-tumour activity, it earned a remarkable place as a treatment of choice for several cancer types. It remains effective against testicular, bladder, lung, head and neck, ovarian, and other cancers. Cisplatin treatment triggers different cellular responses. However, it exerts its cytotoxic effects by generating inter-strand and intra-strand crosslinks in DNA. Tumour cells often develop tolerance mechanisms by effectively repairing cisplatin-induced DNA lesions or tolerate the damage by adopting translesion DNA synthesis. Cisplatin-associated nephrotoxicity is also a huge challenge for effective therapy. Several preclinical and clinical studies attempted to understand the major limitations associated with cisplatin therapy, and so far, there is no definitive solution. As such, a more comprehensive molecular and genetic profiling of patients is needed to identify those individuals that can benefit from platinum therapy. Additionally, the treatment regimen can be improved by combining cisplatin with certain molecular targeted therapies to achieve a balance between tumour toxicity and tolerance mechanisms. In this review, we discuss the importance of various biological processes that contribute to the resistance of cisplatin and its derivatives. We aim to highlight the processes that can be modulated to suppress cisplatin resistance and provide an insight into the role of uptake transporters in enhancing drug efficacy.     

Rapid synthesis of cesium-doped hydroxyapatite nanorods: characterisation and microbial activity

Rapid synthesis of cesium-doped hydroxyapatite (Ca₁₀(PO₄)₆(OH)₂, (HAp)) by rapid microwave synthesis technique is reported. The crystal, chemical, and dielectric properties, along with the phase composition and morphology were investigated. SEM study proved successful synthesis of HAp nanorods. The dielectric properties were affected by the doping amount of Cs-ions in HAp. The values of crystallinity degree at different concentrations of Cs-ions were decreased on increasing the Cs content. The antimicrobial activities of Cs-doped HAp showed high effects of growth inhibition on Staphylococcus aureus, S. saprophyticus, Escherichia coli, Haemophilus influenza, Candida albicans, and C. tropicalis. The concentration of 0.32 Cs-doped HAp has the high inhibition effect against S. aureus with the percentage of inhibition to 88.89%. The microbial inhibition growth reflected on the MICs and MBCs and MFCs. This newly designed Cs-doped HAp can be applicable in wide scales biomedical applications such as bone cement engineering and antimicrobial agents.     

A new facile synthesis of ultra fine magnesium oxide nanowires and optical properties

One-dimensional metal oxides nanowires like magnesium oxide (MgO) play an important role in several nanotechnological applications. MgO nanowires were synthesized for the first time via hydrothermal route using magnesium acetate and urea at 180?°C for 2?h. The synthesized MgO nanowires were characterized by means of X-ray diffraction (XRD), Fourier transformer Infrared spectroscopy (FTIR), field emission scanning electron microscopy (FESEM), energy dispersive X-ray spectroscopy (EDS), transmission scanning electron microscopy (TEM) and thermal gravimetric analysis (TGA). The obtained results indicated that the MgO nanowires show a predominant well- crystalline cubic face-centered with an average diameter of 10?nm and an average length of 40???m. The optical band gap energy of the sample was found to be 3.45?eV. The sample indicates a broadband PL emission in UV region and exhibits a good photoluminescence behavior for photonic devices applications. It is evaluated that this novel synthetic method is very useful and serves as a facile, direct preparation mild chemical method giving mass production of one dimensional MgO nanowires.     

Nourin-Associated miRNAs: Novel Inflammatory Monitoring Markers for Cyclocreatine Phosphate Therapy in Heart Failure

Background: Cyclocreatine phosphate (CCrP) is a potent bioenergetic cardioprotective compound known to preserve high levels of cellular adenosine triphosphate during ischemia. Using the standard Isoproterenol (ISO) rat model of heart failure (HF), we recently demonstrated that the administration of CCrP prevented the development of HF by markedly reducing cardiac remodeling (fibrosis and collagen deposition) and maintaining normal ejection fraction and heart weight, as well as physical activity. The novel inflammatory mediator, Nourin is a 3-KDa formyl peptide rapidly released by ischemic myocardium and is associated with post-ischemic cardiac inflammation. We reported that the Nourin-associated miR-137 (marker of cell damage) and miR-106b-5p (marker of inflammation) are significantly upregulated in unstable angina patients and patients with acute myocardial infarction, but not in healthy subjects. Objectives: To test the hypothesis that Nourin-associated miR-137 and miR-106b-5p are upregulated in ISO-induced “HF rats” and that the administration of CCrP prevents myocardial injury (MI) and reduces Nourin gene expression in “non-HF rats”. Methods: 25 male Wistar rats (180–220 g) were used: ISO/saline (n = 6), ISO/CCrP (0.8 g/kg/day) (n = 5), control/saline (n = 5), and control/CCrP (0.8 g/kg/day) (n = 4). In a limited study, CCrP at a lower dose of 0.4 g/kg/day (n = 3) and a higher dose of 1.2 g/kg/day (n = 2) were also tested. The Rats were injected SC with ISO for two consecutive days at doses of 85 and 170 mg/kg/day, respectively, then allowed to survive for an additional two weeks. CCrP and saline were injected IP (1 mL) 24 h and 1 h before first ISO administration, then daily for two weeks. Serum CK-MB (U/L) was measured 24 h after the second ISO injection to confirm myocardial injury. After 14 days, gene expression levels of miR-137 and miR-106b-5p were measured in serum samples using quantitative real-time PCR (qPCR). Results: While high levels of CK-MB were detected after 24 h in the ISO/saline rats indicative of MI, the ISO/CCrP rats showed normal CK-MB levels, supporting prevention of MI by CCrP. After 14 days, gene expression profiles showed significant upregulation of miR-137 and miR-106b-5p by 8.6-fold and 8.7-fold increase, respectively, in the ISO/saline rats, “HF rats,” compared to the control/saline group. On the contrary, CCrP treatment at 0.8 g/kg/day markedly reduced gene expression of miR-137 by 75% and of miR-106b-5p by 44% in the ISO/CCrP rats, “non-HF rats,” compared to the ISO/Saline rats, “HF rats.” Additionally, healthy rats treated with CCrP for 14 days showed no toxicity in heart, liver, and renal function. Conclusions: Results suggest a role of Nourin-associated miR-137 and miR-106b-5p in the pathogenesis of HF and that CCrP treatment prevented ischemic injury in “non-HF rats” and significantly reduced Nourin gene expression levels in a dose–response manner. The Nourin gene-based mRNAs may, therefore, potentially be used as monitoring markers of drug therapy response in HF, and CCrP—as a novel preventive therapy of HF due to ischemia.     

Synthesis and Enantioselective Pharmacokinetic/Pharmacodynamic Analysis of New CNS-Active Sulfamoylphenyl Carbamate Derivatives

We recently reported a new class of carbamate derivatives as anticonvulsants. Among these, 3-methylpentyl(4-sulfamoylphenyl)carbamate (MSPC) stood out as the most potent compound with ED₅₀ values of 13 mg/kg (i.p.) and 28 mg/kg (p.o.) in the rat maximal electroshock test (MES). 3-Methylpropyl(4-sulfamoylphenyl)carbamate (MBPC), reported and characterized here, is an MSPC analogous compound with two less aliphatic carbon atoms in its structure. As both MSPC and MBPC are chiral compounds, here, we studied the carbonic anhydrase inhibitory and anticonvulsant action of both MBPC enantiomers in comparison to those of MSPC as well as their pharmacokinetic properties. Racemic-MBPC and its enantiomers showed anticonvulsant activity in the rat maximal electroshock (MES) test with ED₅₀ values in the range of 19–39 mg/kg. (R)-MBPC had a 65% higher clearance than its enantiomer and, consequently, a lower plasma exposure (AUC) than (S)-MSBC and racemic-MSBC. Nevertheless, (S)-MBPC had a slightly better brain permeability than (R)-MBPC with a brain-to-plasma (AUC) ratio of 1.32 (S-enantiomer), 1.49 (racemate), and 1.27 (R-enantiomer). This may contribute to its better anticonvulsant-ED₅₀ value. The clearance of MBPC enantiomers was more enantioselective than the brain permeability and MES-ED₅₀ values, suggesting that their anticonvulsant activity might be due to multiple mechanisms of action.     

IWD-Miner: A Novel Metaheuristic Algorithm for Medical Data Classification

Medical data classification (MDC) refers to the application of classification methods on medical datasets. This work focuses on applying a classification task to medical datasets related to specific diseases in order to predict the associated diagnosis or prognosis. To gain experts’ trust, the prediction and the reasoning behind it are equally important. Accordingly, we confine our research to learn rule-based models because they are transparent and comprehensible. One approach to MDC involves the use of metaheuristic (MH) algorithms. Here we report on the development and testing of a novel MH algorithm: IWD-Miner. This algorithm can be viewed as a fusion of Intelligent Water Drops (IWDs) and AntMiner+. It was subjected to a four-stage sensitivity analysis to optimize its performance. For this purpose, 21 publicly available medical datasets were used from the Machine Learning Repository at the University of California Irvine. Interestingly, there were only limited differences in performance between IWD-Miner variants which is suggestive of its robustness. Finally, using the same 21 datasets, we compared the performance of the optimized IWD-Miner against two extant algorithms, AntMiner+ and J48. The experiments showed that both rival algorithms are considered comparable in the effectiveness to IWD-Miner, as confirmed by the Wilcoxon nonparametric statistical test. Results suggest that IWD-Miner is more efficient than AntMiner+ as measured by the average number of fitness evaluations to a solution (1,386,621.30 vs. 2,827,283.88 fitness evaluations, respectively). J48 exhibited higher accuracy on average than IWD-Miner (79.58 vs. 73.65, respectively) but produced larger models (32.82 leaves vs. 8.38 terms, respectively).     

Mitochondrial Dysfunction and Induction of Apoptosis in Hepatocellular Carcinoma and Cholangiocarcinoma Cell Lines by Thymoquinone

Thymoquinone (TQ), a plant-based bioactive constituent derived from the volatile oil of Nigella sativa, has been shown to possess some anti-neoplastic activities. The present study aimed to investigate the mitochondria and apoptosis observed when TQ is applied against hepatocellular carcinoma (HepG2) and cholangiocarcinoma (HuCCT1) cells, two of the most common primary tumors of the liver. All cell lines were treated with increasing concentrations of TQ for varying durations. The anti-proliferative effect of TQ was measured using the methoxyphenyl-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and resulted in dose- and time-dependent growth inhibition in both cell lines. Cell cycle, apoptosis, and assessment of mitochondria viability by morphology assessment and evaluation of the mitochondrial membrane potential were investigated. The present study confirms that TQ caused cell cycle arrest at different phases and induced apoptosis in both cell lines. A systematic review of rodent animal models was also carried out. Overall, our data seem to represent the most robust results, suggesting that TQ possesses promising therapeutic potential as an anti-tumor agent for the treatment of hepatocellular carcinoma and cholangiocarcinoma.     

An Improved Deep Structure for Accurately Brain Tumor Recognition

Brain neoplasms are recognized with a biopsy, which is not commonly done before decisive brain surgery. By using Convolutional Neural Networks (CNNs) and textural features, the process of diagnosing brain tumors by radiologists would be a noninvasive procedure. This paper proposes a features fusion model that can distinguish between no tumor and brain tumor types via a novel deep learning structure. The proposed model extracts Gray Level Co-occurrence Matrix (GLCM) textural features from MRI brain tumor images. Moreover, a deep neural network (DNN) model has been proposed to select the most salient features from the GLCM. Moreover, it manipulates the extraction of the additional high levels of salient features from a proposed CNN model. Finally, a fusion process has been utilized between these two types of features to form the input layer of additional proposed DNN model which is responsible for the recognition process. Two common datasets have been applied and tested, Br35H and FigShare datasets. The first dataset contains binary labels, while the second one splits the brain tumor into four classes; glioma, meningioma, pituitary, and no cancer. Moreover, several performance metrics have been evaluated from both datasets, including, accuracy, sensitivity, specificity, F-score, and training time. Experimental results show that the proposed methodology has achieved superior performance compared with the current state of art studies. The proposed system has achieved about 98.22% accuracy value in the case of the Br35H dataset however, an accuracy of 98.01% has been achieved in the case of the FigShare dataset.