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No other cases of similar fatal renovascular injuries due to stab wounds have been published in the current forensic literature.Malaria is a life-threatening infectious disease with an estimated 229 million cases in the year 2019 worldwide. Plasmodium falciparum 1-deoxy-d-xylulose-5-phosphate reductoisomerase (PfDXR) is one of the key enzymes in the biosynthetic pathway of isoprenoid, (required for parasite growth and survival) and considered as an attractive target for designing anti-malarial drugs. Fosmidomycin is an effective DXR inhibitor and has been proven effective and safe against P. falciparum in clinical trials. However, due to low bioavailability and inappropriate drug attributes, it is not a preferred option. The present study was performed to identify PfDXR inhibitors with improved pharmacology/safety. For this purpose, an integrated computational framework, comprising of pharmacophore modeling, virtual screening, molecular docking, molecular dynamics (MD) simulation and MM/PBSA, was used. The binding free energy analysis was performed using a focused library of phytochemicals established from medicinal plants. The study identified four bioactive compounds namely, Myricetin 3-rhamnoside, 7-O-Galloyltricetiflavan, (25S)-5-beta-spirostan-3-beta-ol 3-O-beta-d-glucopyranosyl-(1->2)-beta-d-glucopyranoside, and Oleanolic acid 28-O-beta-d-glucopyranoside as potential inhibitors of PfDXR. The selection of these four compounds was based on pharmacophore mapping, docking score, binding stability, molecular interactions with the residues of PfDXR active site, binding stability and free energy estimation. In conclusion, medicinal plant-based scaffolds were predicted with enhanced efficacy and adequate physiochemical/pharmacokinetic profile that might be helpful in controlling malaria.Previous studies have shown that secreted protein acidic and rich in cysteine (SPARC) proteins can inhibit the development of cancer cells in various ways, such as by inhibiting angiogenesis and inhibiting cell proliferation. In fact, SPARC proteins may have an effect on the chemoresistance of gastric cancer cells to 5-Fluorouracil (5-FU), which needs further research in the future. Therefore, the purpose of this study was to explore the relationship between SPARC proteins and the chemosensitivity of gastric cancer cells to 5-FU. In vitro, after SPARC protein levels were regulated by plasmid, siRNA and human recombinant SPARC protein transfection in MGC-803, SGC-7901 and BGC-823 cells, we detected epithelial-mesenchymal transition (EMT), apoptosis markers and cell viability after 5-FU treatment. In vivo, we implanted BGC-823 cells with stable SPARC overexpression into nude mice. Tumour size was measured to assess the effect of SPARC protein on tumour formation and 5-FU chemosensitivity. In SGC-7901 and BGC-823 cells, both endogenous and exogenous upregulation of SPARC protein levels decreased cell viability, destroyed cytoskeletal F-actin, inhibited cell migration, and downregulated a series of transcription factors to inhibit cell EMT; it also upregulated cell apoptosis-related proteins to promote cell apoptosis. However, we obtained opposite results in SPARC knockdown MGC-803 cells. In vivo, compared with the control group, the group engrafted with BGC-823 cells stably overexpressing SPARC had a significant smaller tumour size. After 5-FU treatment, the new tumour gradually decreased in size. Our results show that the SPARC protein could enhance 5-FU chemosensitivity in gastric cancer cell lines by inhibiting EMT and promoting cell apoptosis.Human concentrative nucleoside transporters (CNTs) are responsible for cellular uptake of ribonucleosides; however, although it is important to better characterize CNT-subtype specificity to understand the systemic disposition of deoxyribonucleosides (dNs) and their analogs, the involvement of CNTs in transporting dNs is not fully understood. In this study, using COS-7 cells that transiently expressed CNT1, CNT2, or CNT3, we investigated if CNTs could transport not only ribonucleosides but also dNs, i.e., 2'-deoxyadenosine (dAdo), 2'-deoxyguanosine (dGuo), and 2'-deoxycytidine (dCyd). The cellular uptake study demonstrated that dAdo and dGuo were taken up by CNT2 but not by CNT1. Although dCyd was taken up by CNT1, no significant uptake was detected in COS-7 cells expressing CNT2. Similarly, these dNs were transported by CNT3. The apparent Km values of their uptake were as follows CNT1, Km = 141 μM for dCyd; CNT2, Km = 62.4 μM and 54.9 μM for dAdo and dGuo, respectively; CNT3, Km = 14.7 μM and 34.4 μM for dGuo and dCyd, respectively. These results demonstrate that CNTs contribute not only to ribonucleoside transport but also to the transport of dNs. Moreover, our data indicated that CNT1 and CNT2 selectively transported pyrimidine and purine dNs, respectively, and CNT3 was shown to transport both pyrimidine and purine dNs.The extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway involves a three-step cascade of kinases that transduce signals and promote processes such as cell growth, development, and apoptosis. An aberrant response of this pathway is related to the proliferation of cell diseases and tumors. By using simulation modeling, we document that the protein arginine methyltransferase 5 (PRMT5) modulates the MAPK pathway and thus avoids an aberrant behavior. PRMT5 methylates the Raf kinase, reducing its catalytic activity and thereby, reducing the activation of ERK in time and amplitude. https://www.selleckchem.com/products/Temsirolimus.html Two minimal computational models of the epidermal growth factor (EGF)-Ras-ERK MAPK pathway influenced by PRMT5 were proposed a first model in which PRMT5 is activated by EGF and a second one in which PRMT5 is stimulated by the cascade response. The reported results show that PRMT5 reduces the time duration and the expression of the activated ERK in both cases, but only in the first model PRMT5 limits the EGF range that generates an ERK activation. Based on our data, we propose the protein PRMT5 as a regulatory factor to develop strategies to fight against an excessive activity of the MAPK pathway, which could be of use in chronic diseases and cancer.
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