Novel 5-oxo-hexahydroquinoline derivatives: design, synthesis, in vitro P-glycoprotein-mediated multidrug resistance reversal profile and molecular dynamics simulation study

Overexpression of the efflux pump P-glycoprotein (P-gp) is one of the important mechanisms of multidrug resistance (MDR) in many tumor cells. In this study, 26 novel 5-oxo-hexahydroquinoline derivatives containing different nitrophenyl moieties at C-4 and various carboxamide substituents at C-3 were designed, synthesized and evaluated for their ability to inhibit P-gp by measuring the amount of rhodamine 123 (Rh123) accumulation in uterine sarcoma cells that overexpress P-gp (MES-SA/Dx5) using flow cytometry. The effect of compounds with highest MDR reversal activities was further evaluated by measuring the alterations of MES-SA/Dx5 cells' sensitivity to doxorubicin (DXR) using MTT assay. The results of both biological assays indicated that compounds bearing 2-nitrophenyl at C-4 position and compounds with 4-chlorophenyl carboxamide at C-3 demonstrated the highest activities in resistant cells, while they were devoid of any effect in parental nonresistant MES-SA cells. One of the active derivatives, 5c, significantly increased intracellular Rh123 at 100 mu M, and it also significantly reduced the IC50 of DXR by 70.1% and 88.7% at 10 and 25 mu M, respectively, in MES-SA/Dx5 cells. The toxicity of synthesized compounds against HEK293 as a noncancer cell line was also investigated. All tested derivatives except for 2c compound showed no cytotoxicity. A molecular dynamics simulation study was also performed to investigate the possible binding site of 5c in complex with human P-gp, which showed that this compound formed 11 average H-bonds with Ser909, Thr911, Arg547, Arg543 and Ser474 residues of P-gp. A good agreement was found between the results of the computational and experimental studies. The findings of this study show that some 5-oxo-hexahydroquinoline derivatives could serve as promising candidates for the discovery of new agents for P-gp-mediated MDR reversal

Asi1 is an inner nuclear membrane protein that restricts promoter access of two latent transcription factors

Stp1 and Stp2 are homologous transcription factors in yeast that are synthesized as latent cytoplasmic precursors with NH2-terminal regulatory domains. In response to extracellular amino acids, the plasma membrane–localized Ssy1–Ptr3–Ssy5 (SPS) sensor endoproteolytically processes Stp1 and Stp2, an event that releases the regulatory domains. The processed forms of Stp1 and Stp2 efficiently target to the nucleus and bind promoters of amino acid permease genes. In this study, we report that Asi1 is an integral component of the inner nuclear membrane that maintains the latent characteristics of unprocessed Stp1 and Stp2. In cells lacking Asi1, full-length forms of Stp1 and Stp2 constitutively induce SPS sensor–regulated genes. The regulatory domains of Stp1 and Stp2 contain a conserved motif that confers Asi1-mediated control when fused to an unrelated DNA-binding protein. Our results indicate that latent precursor forms of Stp1 and Stp2 inefficiently enter the nucleus; however, once there, Asi1 restricts them from binding SPS sensor–regulated promoters. These findings reveal an unanticipated role of inner nuclear membrane proteins in controlling gene expression

Evaluacija svojstava vezanja sluzi sjemenki biljke Plantago psyllium

Mucilage extracted from Plantago psyllium seeds was evaluated for inertness and safety parameters. The suitability of psyllium mucilage for a pharmaceutical binder was assessed in paracetamol tablets. Properties of the granules prepared using different concentrations of psyllium mucilage was compared with PVP and tragacanth. Psyllium mucilage at 5 % (m⁄m) level was found to be comparable with 3 % (m⁄m) of PVP. Investigated paracetamol tablets indicated that psyllium mucilage can retard the drug release.U radu je ispitivana neškodljivost i sigurnost uporabe sluzi ekstrahirane iz sjemenki biljke Plantago psyllium. Primjenjivost te sluzi kao veziva u farmaceutskim pripravcima ispitana je na tabletama paracetamola. Granule pripravljene s različitim koncentracijama sluzi uspoređene su s granulama s PVP-om i tragakantom. Sluz s udjelom 5 % (m/m) usporediva je s otopinom PVP-a masenog udjela 3 %. Pripravljene tablete paracetamola ukazuju na to da ispitivana sluz može usporiti oslobađanje lijeka

Effects of COVID-19 prevention procedures on other common infections: a systematic review

Introduction: Since the outbreak of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) began, necessary measures to prevent virus transmission and reduce mortality have been implemented, including mandatory public use of masks, regular hand-sanitizing and hand-washing, social distancing, avoidance of crowds, remote work, and cancellation of public events. During and after the introduction of COVID-19 lockout, we performed a systematic review of available published literature to investigate the incidence of seasonal influenza and other respiratory viral infections. Methods: PubMed, Embase, Web of Science, Scopus, Science Direct, Google Scholar, Research Gate, and the World Health Organization databases and websites were systematically searched for original studies concerning the impact of COVID-19 prevention means and measures on other common respiratory infectious diseases during the pandemic published by March 2021. Results: The findings showed that the adherence to health protocols to prevent COVID-19 could help to reduce the incidence of other infectious diseases such as influenza, pneumonia, and Mycobacterium tuberculosis. Conclusion: The implemented prevention measures and protocols might have reduced the incidence of influenza and some other common respiratory infections. However, controversies exist on this matter and future large population-based studies might provide further information to address these controversies. © 2021, The Author(s)

Content-aware tweet location inference using quadtree spatial partitioning and jaccard-cosine word embedding

Inferring locations from user texts on social media platforms is a non-trivial and challenging problem relating to public safety. We propose a novel non-uniform grid-based approach for location inference from Twitter messages using Quadtree spatial partitions. The proposed algorithm uses natural language processing (NLP) for semantic understanding and incorporates Cosine similarity and Jaccard similarity measures for feature vector extraction and dimensionality reduction. We chose Twitter as our experimental social media platform due to its popularity and effectiveness for the dissemination of news and stories about recent events happening around the world. Our approach is the first of its kind to make location inference from tweets using Quadtree spatial partitions and NLP, in hybrid word-vector representations. The proposed algorithm achieved significant classification accuracy and outperformed state-of-the-art grid-based content-only location inference methods by up to 24% in correctly predicting tweet locations within a 161km radius and by 300km in median error distance on benchmark datasets

"MULTIPLE GRANULAR CELL TUMOR IN A TEENAGER: REPORT OF A CASE AND REVIEW OF THE LITERATURE"

Granular cell tumors are rare neoplasms of uncertain histogenesis but with a typical histologic appearance composed of cells with characteristic granular cytoplasm. These tumors occur most often in adults as an asymptomatic solitary papule or nodule. Multiple granular cell tumors are rare, especially in children and teenagers. We represent a case of multiple granular cell tumors in a 19-year-old girl presented with multiple cutaneous and mucosal nodular lesions. The diagnosis was documented by histopathology and immunohistochemistry