Drug Target Insights https://journals.aboutscience.eu/index.php/dti <p><strong>Drug Target Insights (DTI)</strong><em>&nbsp;</em>is an international, peer-reviewed, open access journal, covering current developments in all areas of the field of clinical therapeutics and focusing on molecular drug targets which include disease-specific proteins, receptors, enzymes, and genes. The journal seeks to elucidate the impact of new therapeutic agents on patient acceptability, preference, satisfaction and quality of life. The journal welcomes unsolicited article proposals. All articles are listed on PubMed and are freely available via PubMed Central.</p> <p>&nbsp;</p> en-US <p>Authors contributing to <strong>Drug Target Insights</strong> agree to publish their articles under&nbsp;the&nbsp;<a href="https://creativecommons.org/licenses/by-nc/4.0/" target="_blank" rel="noopener">Creative Common Attribution Non Commercial 4.0&nbsp;(CC-BY-NC 4.0)</a> license, which allows third parties&nbsp;to re-use the work without permission as long as the work is properly referenced and the use is non-commercial.</p> lucia.steele@aboutscience.eu (Lucia Steele) silvia.minora@aboutscience.eu (Silvia Minora) Mon, 28 Dec 2020 00:00:00 +0000 OJS http://blogs.law.harvard.edu/tech/rss 60 Prevalence of multidrug-resistant and extended-spectrum beta-lactamase (ESBL)-producing gram-negative bacilli: A meta-analysis report in Ethiopia https://journals.aboutscience.eu/index.php/dti/article/view/2170 <p class="abstract">Multidrug-resistant (MDR) extended-spectrum beta-lactamase (ESBL)-producing bacterial isolates have emerged as a global threat to human health. Little is known about the overall prevalence of multidrug resistance profile and ESBL-producing gram-negative bacilli (GNB) in Ethiopia. Therefore, this meta-analysis was performed to produce proportional estimates of multidrug resistance and ESBL-producing GNB in Ethiopia.</p> <p class="abstract_indent">A web-based search was conducted in PubMed, Google Scholar, Research Gate, Scopus and other databases. Articles published till 2019 on the prevalence and antimicrobial resistance profiles of ESBL-producing GNB in Ethiopia were included in the study. Relevant data were extracted and statistical analysis was performed using comprehensive meta-analysis version 3.3.0 software. Publication bias was analyzed and presented with funnel plots.</p> <p class="abstract_indent">In this meta-analysis, the overall proportional estimate of ESBL-producing GNB was 48.9% (95% confidence interval [CI]: 0.402, 0.577). The pooled proportional estimates of ESBL-producing <em>Klebsiella pneumoniae, Escherichia coli</em> and other GNB were 61.8%, 41.2% and 42.9%, respectively. Regarding antimicrobial resistance profiles against selected drugs, the pooled proportional estimates of resistance against amoxicillin-clavulanic acid, trimethoprim-sulfamethoxazole, cefotaxime, ceftazidime, tetracycline, gentamicin and ciprofloxacin was 79.0%, 78.4%, 78.0%, 72.4%, 72.7%, 58.9% and 43.8%, respectively. The pooled proportional estimates of MDR isolates were found to be 82.7% (95% CI: 0.726, 0.896), which are relatively high as compared to other countries. This highlights a need for active surveillance systems which can help understand the actual epidemiology of ESBL, aid in formulating national guidelines for proper screening of ESBL and support developing standardized approaches for managing patients colonized with ESBL</p> Mengistu Abayneh, Teshale Worku ##submission.copyrightStatement## http://creativecommons.org/licenses/by-nc/4.0 https://journals.aboutscience.eu/index.php/dti/article/view/2170 Mon, 05 Oct 2020 00:00:00 +0000 Interaction of drugs with lipid raft membrane domains as a possible target https://journals.aboutscience.eu/index.php/dti/article/view/2185 <p class="abstract"><strong>Introduction:</strong> Plasma membranes are not the homogeneous bilayers of uniformly distributed lipids but the lipid complex with laterally separated lipid raft membrane domains, which provide receptor, ion channel and enzyme proteins with a platform. The aim of this article is to review the mechanistic interaction of drugs with membrane lipid rafts and address the question whether drugs induce physicochemical changes in raft-constituting and raft-surrounding membranes.</p> <p class="abstract"><strong>Methods:</strong> Literature searches of PubMed/MEDLINE and Google Scholar databases from 2000 to 2020 were conducted to include articles published in English in internationally recognized journals. Collected articles were independently reviewed by title, abstract and text for relevance.</p> <p class="abstract"><strong>Results:</strong> The literature search indicated that pharmacologically diverse drugs interact with raft model membranes and cellular membrane lipid rafts. They could physicochemically modify functional protein-localizing membrane lipid rafts and the membranes surrounding such domains, affecting the raft organizational integrity with the resultant exhibition of pharmacological activity. Raft-acting drugs were characterized as ones to decrease membrane fluidity, induce liquid-ordered phase or order plasma membranes, leading to lipid raft formation; and ones to increase membrane fluidity, induce liquid-disordered phase or reduce phase transition temperature, leading to lipid raft disruption.</p> <p class="abstract"><strong>Conclusion:</strong> Targeting lipid raft membrane domains would open a new way for drug design and development. Since angiotensin-converting enzyme 2 receptors which are a cell-specific target of and responsible for the cellular entry of novel coronavirus are localized in lipid rafts, agents that specifically disrupt the relevant rafts may be a drug against coronavirus disease 2019.</p> Hironori Tsuchiya, Maki Mizogami ##submission.copyrightStatement## http://creativecommons.org/licenses/by-nc/4.0 https://journals.aboutscience.eu/index.php/dti/article/view/2185 Tue, 22 Dec 2020 00:00:00 +0000 Identification of the possible therapeutic targets in the insulin-like growth factor 1 receptor pathway in a cohort of Egyptian hepatocellular carcinoma complicating chronic hepatitis C type 4 https://journals.aboutscience.eu/index.php/dti/article/view/1548 <p class="abstract"><strong>Background:</strong> Molecular targeted drugs are the first line of treatment of advanced hepatocellular carcinoma (HCC) due to its chemo- and radioresistant nature. HCC has several well-documented etiologic factors that drive hepatocarcinogenesis through different molecular pathways. Currently, hepatitis C virus (HCV) is a leading cause of HCC. Therefore, we included a unified cohort of HCV genotype 4-related HCCs to study the expression levels of genes involved in the insulin-like growth factor 1 receptor (IGF1R) pathway, which is known to be involved in all aspects of cancer growth and progression.</p> <p class="abstract"><strong>Aim:</strong> Determine the gene expression patterns of IGF1R pathway genes in a cohort of Egyptian HCV-related HCCs. Correlate them with different patient/tumor characteristics. Determine the activity status of involved pathways.</p> <p class="abstract"><strong>Methods:</strong> Total ribonucleic acid (RNA) was extracted from 32 formalin-fixed paraffin-embedded tissues of human HCV-related HCCs and 6 healthy liver donors as controls. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) using RT<sup>2</sup> Profiler PCR Array for Human Insulin Signaling Pathway was done to determine significantly up- and downregulated genes with identification of most frequently coregulated genes, followed by correlation of gene expression with different patient/tumor characteristics. Finally, canonical pathway analysis was performed using the Ingenuity Pathway Analysis software.</p> <p class="abstract"><strong>Results:</strong> Six genes – AEBP1, AKT2, C-FOS, PIK3R1, PRKCI, SHC1 – were significantly overexpressed. Thirteen genes&nbsp;– ADRB3, CEBPA, DUSP14, ERCC1, FRS3, IGF2, INS, IRS1, JUN, MTOR, PIK3R2, PPP1CA, RPS6KA1&nbsp;– were significantly underexpressed. Several differentially expressed genes were related to different tumor/patient characteristics. Nitric oxide and reactive oxygen species production pathway was significantly activated in the present cohort, while the growth hormone signaling pathway was inactive.</p> <p class="abstract"><strong>Conclusions:</strong> The gene expression patterns identified in this study may serve as possible therapeutic targets in HCV-related HCCs. The most frequently coregulated genes may serve to guide combined molecular targeted therapies. The IGF1R pathway showed evidence of inactivity in the present cohort of HCV-related HCCs, so targeting this pathway in therapy may not be effective.</p> Nada M.K. Mabrouk, Dalal M. Elkaffash, Mona Abdel-Hadi, Salah-ElDin Abdelmoneim, Sameh Saad ElDeen, Gihan Gewaifel, Khaled A. Elella, Maher Osman, Nahed Baddour ##submission.copyrightStatement## http://creativecommons.org/licenses/by-nc/4.0 https://journals.aboutscience.eu/index.php/dti/article/view/1548 Wed, 08 Apr 2020 00:00:00 +0000 Targeting Streptococcus pneumoniae UDP-glucose pyrophosphorylase (UGPase): in vitro validation of a putative inhibitor https://journals.aboutscience.eu/index.php/dti/article/view/2103 <p><strong>Background:</strong> Genome plasticity of&nbsp;<em>Streptococcus pneumoniae</em>&nbsp;is responsible for the reduced efficacy of various antibiotics and capsular polysaccharide based vaccines. Therefore targets independent of capsular types are sought to control the pneumococcal pathogenicity. UcrDP-glucose pyrophosphorylase (UGPase) is one such desired candidate being responsible for the synthesis of UDP-glucose, a sugar-precursor in capsular biosynthesis and metabolic Leloir pathway. Being crucial to pneumococcal&nbsp;pathobiology,&nbsp;the effect of UGPase inhibition on virulence was evaluated&nbsp;<em>in vitro</em>.</p> <p><strong>Methods:</strong> A putative inhibitor (UDP) was evaluated for effective inhibitory concentration in S. pneumoniae and A549 cells, its efficacy and toxicity. Effect of UDP on adherence and phagocytosis was measured in human respiratory epithelial (A549 and HEp-2) and macrophage (THP1 and J774.A.1) cell lines respectively.</p> <p><strong>Results:</strong> A differential effective inhibitory concentration of UDP for UGPase inhibition was observed in&nbsp;<em>S. pneumoniae</em>&nbsp;and A549 cells i.e. 5 µM and 100 µM respectively. UDP treatments lowered percent cytotoxicity in pneumococcal infected monolayers and didn't exert adverse&nbsp;effects on viabilities.&nbsp;<em>S. pneumoniae</em>&nbsp;adherence to host cells was decreased significantly&nbsp;with UDP treatments. UDP&nbsp;induced the secretion of IL-1β, TNF-α, IL-6, and IL-8 and increased pneumococcal phagocytosis.</p> <p><strong>Conclusion:</strong> Our&nbsp;study shows&nbsp;UDP mediated decrease in the virulence of&nbsp;<em>S. pneumoniae</em>&nbsp;and demonstrates&nbsp;UDP as an effective inhibitor of pneumococcal UGPase.</p> Monica Sharma, Swati Sharma, Pallab Ray, Anuradha Chakraborti ##submission.copyrightStatement## http://creativecommons.org/licenses/by-nc/4.0 https://journals.aboutscience.eu/index.php/dti/article/view/2103 Wed, 07 Oct 2020 00:00:00 +0000 Paradoxical bronchoconstriction caused by β2-adrenoceptor agonists https://journals.aboutscience.eu/index.php/dti/article/view/2188 <p class="abstract"><strong>Introduction</strong>: Salbutamol and terbutaline are short-acting β<sub>2</sub> adrenergic agonists that produce bronchial smooth muscle relaxation and are widely used in obstructive pulmonary diseases. Nevertheless, their use has been the cause of a paradoxical bronchoconstriction, which is a rare and potentially serious adverse reaction. The aim of this study is to report a case of paradoxical bronchoconstriction caused by β<sub>2</sub> adrenergic agonists.</p> <p class="abstract"><strong>Methods</strong>: This case is about a 50-year-old asthmatic patient who describes a history of repeated acute asthma attacks after salbutamol inhalation or terbutaline nebulization. A double-blind crossover study was performed over 3 days, in order to compare the effects of each bronchodilator. Forced expiratory volume in 1 second (FEV<sub>1</sub>), forced vital capacity (FVC), and maximal expiratory flow 25-75 (MEF25-75) were measured.</p> <p class="abstract"><strong>Results</strong>: On the first day, a bronchoconstriction caused by deep and repeated inhalations was eliminated. On the second day, an airway obstruction was confirmed by a decrease in FEV<sub>1</sub> at 40% from baseline values after nebulization of a standard dose of terbutaline. On the third day, a spirometry was performed before and after nebulization of a standard dose of ipratropium bromide, and there were no significant changes in the spirometric parameters. Finally the patient was discharged with a written warning mentioning the danger of salbutamol and terbutaline use.</p> <p class="abstract"><strong>Conclusion</strong>: Salbutamol and terbutaline are generally well-tolerated β<sub>2</sub> adrenergic agonists. Nevertheless, in rare cases, these substances can cause a paradoxical bronchoconstriction. Doctors must therefore remain vigilant about its side effect and possibly investigate each case.</p> Khadija Ayed, Islam Latifa Hadi Khalifa, Salma Mokaddem, Saloua Ben Khamsa Jameleddine ##submission.copyrightStatement## http://creativecommons.org/licenses/by-nc/4.0 https://journals.aboutscience.eu/index.php/dti/article/view/2188 Mon, 05 Oct 2020 00:00:00 +0000