Titanium dioxide (TiO
2) is used in several commercial products such as cosmetics, sunscreen, toothpaste and pharmaceuticals. However, some recent investigations have revealed that titanium particles ...generate potential harmful effects on the environment and humans. Because of its strong antioxidant activity, ascorbic acid (AA) is admitted to act as an anti-mutagenic agent. The present study was undertaken to investigate the protective effect of AA against TiO
2-induced genotoxicity. Sister chromatid exchange (SCE), micronucleus (MN) and the comet assays were used to assess TiO
2-induced genotoxicity and to establish the protective effects of AA. There were significant increases (
P<0.05) in both SCE and MN frequencies of cultures treated with TiO
2 as compared to controls. However, co-application of AA (4.87 and 9.73
μM) and TiO
2 resulted in decreases of SCE and MN rates as compared to the group treated with titanium alone. Besides, significant reductions of primary DNA damage (comet assay) were determined when the AA was added to the cell culture medium simultaneously with TiO
2. In conclusion, the preventive role of AA in alleviating TiO
2-induced DNA damage was indicated for the first time in the present study.
Myocardial infarction (MI) promotes a range of systemic effects, many of which are unknown. Here, we investigated the alterations associated with MI progression in heart and other metabolically ...active tissues (liver, skeletal muscle, and adipose) in a mouse model of MI (induced by ligating the left ascending coronary artery) and sham-operated mice. We performed a genome-wide transcriptomic analysis on tissue samples obtained 6- and 24-hours post MI or sham operation. By generating tissue-specific biological networks, we observed: (1) dysregulation in multiple biological processes (including immune system, mitochondrial dysfunction, fatty-acid beta-oxidation, and RNA and protein processing) across multiple tissues post MI; and (2) tissue-specific dysregulation in biological processes in liver and heart post MI. Finally, we validated our findings in two independent MI cohorts. Overall, our integrative analysis highlighted both common and specific biological responses to MI across a range of metabolically active tissues.
Despite numerous clinical trials and decades of endeavour, there is still no effective cure for Alzheimer's disease. Computational drug repositioning approaches may be employed for the development of ...new treatment strategies for Alzheimer's patients since an extensive amount of omics data has been generated during pre-clinical and clinical studies. However, targeting the most critical pathophysiological mechanisms and determining drugs with proper pharmacodynamics and good efficacy are equally crucial in drug repurposing and often imbalanced in Alzheimer's studies.
Here, we investigated central co-expressed genes upregulated in Alzheimer's disease to determine a proper therapeutic target. We backed our reasoning by checking the target gene's estimated non-essentiality for survival in multiple human tissues. We screened transcriptome profiles of various human cell lines perturbed by drug induction (for 6798 compounds) and gene knockout using data available in the Connectivity Map database. Then, we applied a profile-based drug repositioning approach to discover drugs targeting the target gene based on the correlations between these transcriptome profiles. We evaluated the bioavailability, functional enrichment profiles and drug-protein interactions of these repurposed agents and evidenced their cellular viability and efficacy in glial cell culture by experimental assays and Western blotting. Finally, we evaluated their pharmacokinetics to anticipate to which degree their efficacy can be improved.
We identified glutaminase as a promising drug target. Glutaminase overexpression may fuel the glutamate excitotoxicity in neurons, leading to mitochondrial dysfunction and other neurodegeneration hallmark processes. The computational drug repurposing revealed eight drugs: mitoxantrone, bortezomib, parbendazole, crizotinib, withaferin-a, SA-25547 and two unstudied compounds. We demonstrated that the proposed drugs could effectively suppress glutaminase and reduce glutamate production in the diseased brain through multiple neurodegeneration-associated mechanisms, including cytoskeleton and proteostasis. We also estimated the human blood-brain barrier permeability of parbendazole and SA-25547 using the SwissADME tool.
This study method effectively identified an Alzheimer's disease marker and compounds targeting the marker and interconnected biological processes by use of multiple computational approaches. Our results highlight the importance of synaptic glutamate signalling in Alzheimer's disease progression. We suggest repurposable drugs (like parbendazole) with well-evidenced activities that we linked to glutamate synthesis hereby and novel molecules (SA-25547) with estimated mechanisms for the treatment of Alzheimer's patients.
The rapid and global spread of a new human coronavirus (SARS-CoV-2) has produced an immediate urgency to discover promising targets for the treatment of COVID-19. Drug repositioning is an attractive ...approach that can facilitate the drug discovery process by repurposing existing pharmaceuticals to treat illnesses other than their primary indications. Here, we review current information concerning the global health issue of COVID-19 including promising approved drugs and ongoing clinical trials for prospective treatment options. In addition, we describe computational approaches to be used in drug repurposing and highlight examples of in silico studies of drug development efforts against SARS-CoV-2.
Health Sciences; Medicine
The search for an innovative and effective drug delivery system that can carry and release targeted drugs with enhanced activity to treat Alzheimer’s disease has received much attention in the last ...decade. In this study, we first designed a boron-based drug delivery system for effective treatment of AD by integrating the folic acid (FA) functional group into hexagonal boron nitride (hBN) nanoparticles (NPs) through an esterification reaction. The hBN-FA drug carrier system was assembled with a new drug candidate and a novel boron-based hybrid containing an antioxidant as BLA, to constitute a self-assembled AD nano transport system. We performed molecular characterization analyses by using UV-vis spectroscopy, Fourier transform infrared spectrophotometer (FTIR), scanning electron microscope (SEM), Energy-dispersive X-ray spectroscopy (EDS) and Zeta potential investigations. Second, we tested the anti-Alzheimer properties of the carrier system on a differentiated neuroblastoma (SHSY5-Y) cell line, which was exposed to beta-amyloid (1–42) peptides to stimulate an experimental in vitro AD model. Next, we performed cytotoxicity analyses of synthesized molecules on the human dermal fibroblast cell line (HDFa) and the experimental AD model. Cytotoxicity analyses showed that even higher concentrations of the carrier system did not enhance the toxicological outcome in HDFa cells. Drug loading analyses reported that uncoated hBN nano conjugate could not load the BLA, whereas the memantine loading capacity of hBN was 84.3%. On the other hand, memantine and the BLA loading capacity of the hBN-FA construct was found to be 95% and 97.5%, respectively. Finally, we investigated the neuroprotective properties of the nano carrier systems in the experimental AD model. According to the results, 25 µg/mL concentrations of hBN-FA+memantine (94% cell viability) and hBN-FA+BLA (99% cell viability) showed ameliorative properties against beta-amyloid (1–42) peptide toxicity (50% cell viability). These results were generated through the use of flow cytometry, acetylcholinesterase (AChE) and antioxidant assays. In conclusion, the developed drug carrier system for AD treatment showed promising potential for further investigations and enlightened neuroprotective capabilities of boron molecules to treat AD and other neurodegenerative diseases. On the other hand, enzyme activity, systematic toxicity analyses, and animal studies should be performed to understand neuroprotective properties of the designed carrier system comprehensively.
COVID-19 is a global threat with an increasing number of infections. Research on IgG seroprevalence among health care workers (HCWs) is needed to re-evaluate health policies. This study was performed ...in three pandemic hospitals in Istanbul and Kocaeli. Different clusters of HCWs were screened for SARS-CoV-2 infection. Seropositivity rate among participants was evaluated by chemiluminescent microparticle immunoassay. We recruited 813 non-infected and 119 PCR-confirmed infected HCWs. Of the previously undiagnosed HCWs, 22 (2.7%) were seropositive. Seropositivity rates were highest for cleaning staff (6%), physicians (4%), nurses (2.2%) and radiology technicians (1%). Non-pandemic clinic (6.4%) and ICU (4.3%) had the highest prevalence. HCWs in "high risk" group had similar seropositivity rate with "no risk" group (2.9 vs 3.5 p = 0.7). These findings might lead to the re-evaluation of infection control and transmission dynamics in hospitals.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Lung adenocarcinoma (LUAD) is the one of the most common subtypes in lung cancer. Although various targeted therapies have been used in the clinical practice, the 5-year overall survival rate of ...patients is still low. Thus, it is urgent to identify new therapeutic targets and develop new drugs for the treatment of the LUAD patients.
Survival analysis was used to identify the prognostic genes. Gene co-expression network analysis was used to identify the hub genes driving the tumor development. A profile-based drug repositioning approach was used to repurpose the potentially useful drugs for targeting the hub genes. MTT and LDH assay were used to measure the cell viability and drug cytotoxicity, respectively. Western blot was used to detect the expression of the proteins.
We identified 341 consistent prognostic genes from two independent LUAD cohorts, whose high expression was associated with poor survival outcomes of patients. Among them, eight genes were identified as hub genes due to their high centrality in the key functional modules in the gene-co-expression network analysis and these genes were associated with the various hallmarks of cancer (e.g., DNA replication and cell cycle). We performed drug repositioning analysis for three of the eight genes (CDCA8, MCM6, and TTK) based on our drug repositioning approach. Finally, we repurposed five drugs for inhibiting the protein expression level of each target gene and validated the drug efficacy by performing in vitro experiments.
We found the consensus targetable genes for the treatment of LUAD patients with different races and geographic characteristics. We also proved the feasibility of our drug repositioning approach for the development of new drugs for disease treatment.
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•Nine hub genes are essential for the LUAD tumor cell growth and play central roles during the tumor development.•Mitoxantrone and two pre-clinical drugs GCP-60474 and wortmannin are promising for the treatment of LUAD patients.•The drug efficacy has been validated in in vitro cell line model.
Abstract
Cell lines are valuable resources as model for human biology and translational medicine. It is thus important to explore the concordance between the expression in various cell lines ...vis-à-vis human native and disease tissues. In this study, we investigate the expression of all human protein-coding genes in more than 1,000 human cell lines representing 27 cancer types by a genome-wide transcriptomics analysis. The cell line gene expression is compared with the corresponding profiles in various tissues, organs, single-cell types and cancers. Here, we present the expression for each cell line and give guidance for the most appropriate cell line for a given experimental study. In addition, we explore the cancer-related pathway and cytokine activity of the cell lines to aid human biology studies and drug development projects. All data are presented in an open access cell line section of the Human Protein Atlas to facilitate the exploration of all human protein-coding genes across these cell lines.
: Favipiravir (FPV) is an antiviral medication and has an inhibitory effect on Cytochrome P450 (CYP2C8) protein, which is mainly involved in drug metabolism in the liver, and the expression of this ...gene is known to be enhanced in neuronal cells. The metabolization of Paclitaxel (PTX), a chemotherapeutic drug used in cancer patients, was analyzed for the first time in the human SH-SY5Y neuroblastoma cell line for monitoring possible synergistic effects when administered with FPV.
: Further, in vitro cytotoxic and genotoxic evaluations of FPV and PTX were also performed using wide concentration ranges in a human fibroblast cell culture (HDFa). Nuclear abnormalities were examined under a fluorescent microscope using the Hoechst 33258 fluorescent staining technique. In addition, the synergistic effects of these two drugs on cultured SH-SY5Y cells were determined by MTT cell viability assay. In addition, the death mechanisms that can occur in SHSY-5Y were revealed by using the flow cytometry technique.
: Cell viability analyses on the HDFa healthy cell culture showed that both FPV and PTX have inhibitory effects at higher concentrations. On the other hand, there were no significant differences in nuclear abnormality numbers when both of the compounds were applied together. Cell viability analyses showed that FPV and PTX applications have higher cytotoxicity, which indicated synergistic toxicity against the SHSY-5Y cell line. Also, PTX exhibited higher anticancer properties against the neuroblastoma cell line when applied with FPV, as shown in both cytotoxicity and flow cytometry analyses.
: In light of our findings, the anticancer properties of PTX can be enhanced when the drug application is coupled with FPV exposure. Moreover, these results put forth that the anticancer drug dosage should be evaluated carefully in cancer patients who take COVID-19 treatment with FPV.
Glioblastoma multiforme (GBM) is one of the most malignant central nervous system tumors, showing a poor prognosis and low survival rate. Therefore, deciphering the underlying molecular mechanisms ...involved in the progression of the GBM and identifying the key driver genes responsible for the disease progression is crucial for discovering potential diagnostic markers and therapeutic targets. In this context, access to various biological data, development of new methodologies, and generation of biological networks for the integration of multi-omics data are necessary for gaining insights into the appearance and progression of GBM. Systems biology approaches have become indispensable in analyzing heterogeneous high-throughput omics data, extracting essential information, and generating new hypotheses from biomedical data. This review provides current knowledge regarding GBM and discusses the multi-omics data and recent systems analysis in GBM to identify key biological functions and genes. This knowledge can be used to develop efficient diagnostic and treatment strategies and can also be used to achieve personalized medicine for GBM.
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