Drug Target InsightsPub Date : 2023-05-29eCollection Date: 2023-01-01DOI: 10.33393/dti.2023.2595
Feny J Ruparel, Siddhi K Shah, Jhanvi H Patel, Nidhi R Thakkar, Gemini N Gajera, Vijay O Kothari
{"title":"Network analysis for identifying potential anti-virulence targets from whole transcriptome of <i>Pseudomonas aeruginosa</i> and <i>Staphylococcus aureus</i> exposed to certain anti-pathogenic polyherbal formulations.","authors":"Feny J Ruparel, Siddhi K Shah, Jhanvi H Patel, Nidhi R Thakkar, Gemini N Gajera, Vijay O Kothari","doi":"10.33393/dti.2023.2595","DOIUrl":"10.33393/dti.2023.2595","url":null,"abstract":"<p><strong>Introduction: </strong>Antimicrobial resistance (AMR) is a serious global threat. Identification of novel antibacterial targets is urgently warranted to help antimicrobial drug discovery programs. This study attempted identification of potential targets in two important pathogens <i>Pseudomonas aeruginosa</i> and <i>Staphylococcus aureus.</i></p><p><strong>Methods: </strong>Transcriptomes of <i>P. aeruginosa</i> and <i>S. aureus</i> exposed to two different quorum-modulatory polyherbal formulations were subjected to network analysis to identify the most highly networked differentially expressed genes (hubs) as potential anti-virulence targets.</p><p><strong>Results: </strong>Genes associated with denitrification and sulfur metabolism emerged as the most important targets in <i>P. aeruginosa</i>. Increased buildup of nitrite (NO<sub>2</sub>) in <i>P. aeruginosa</i> culture exposed to the polyherbal formulation <i>Panchvalkal</i> was confirmed through <i>in vitro</i> assay too. Generation of nitrosative stress and inducing sulfur starvation seemed to be effective anti-pathogenic strategies against this notorious gram-negative pathogen. Important targets identified in <i>S. aureus</i> were the transcriptional regulator <i>sarA</i>, immunoglobulin-binding protein Sbi, serine protease <i>SplA</i>, the <i>saeR/S</i> response regulator system, and gamma-hemolysin components <i>hlgB</i> and <i>hlgC</i>.</p><p><strong>Conclusion: </strong>Further validation of the potential targets identified in this study is warranted through appropriate <i>in </i><i>vitro</i> and <i>in vivo</i> assays in model hosts. Such validated targets can prove vital to many antibacterial drug discovery programs globally.</p>","PeriodicalId":11326,"journal":{"name":"Drug Target Insights","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2023-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/d8/69/dti-17-58.PMC10238913.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9584080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Feny J. Ruparel, Siddhi K. Shah, Jhanvi H. Patel, Nidhi R. Thakkar, Gemini N. Gajera, Vijay O. Kothari
{"title":"Network analysis for identifying potential anti-virulence targets from whole transcriptome of Pseudomonas aeruginosa and Staphylococcus aureus exposed to certain anti-pathogenic polyherbal formulations","authors":"Feny J. Ruparel, Siddhi K. Shah, Jhanvi H. Patel, Nidhi R. Thakkar, Gemini N. Gajera, Vijay O. Kothari","doi":"10.33393/dti.2023.2595","DOIUrl":"https://doi.org/10.33393/dti.2023.2595","url":null,"abstract":"Introduction: Antimicrobial resistance (AMR) is a serious global threat. Identification of novel antibacterial targets is urgently warranted to help antimicrobial drug discovery programs. This study attempted identification of potential targets in two important pathogens Pseudomonas aeruginosa and Staphylococcus aureus. Methods: Transcriptomes of P. aeruginosa and S. aureus exposed to two different quorum-modulatory polyherbal formulations were subjected to network analysis to identify the most highly networked differentially expressed genes (hubs) as potential anti-virulence targets. Results: Genes associated with denitrification and sulfur metabolism emerged as the most important targets in P. aeruginosa. Increased buildup of nitrite (NO2) in P. aeruginosa culture exposed to the polyherbal formulation Panchvalkal was confirmed through in vitro assay too. Generation of nitrosative stress and inducing sulfur starvation seemed to be effective anti-pathogenic strategies against this notorious gram-negative pathogen. Important targets identified in S. aureus were the transcriptional regulator sarA, immunoglobulin-binding protein Sbi, serine protease SplA, the saeR/S response regulator system, and gamma-hemolysin components hlgB and hlgC. Conclusion: Further validation of the potential targets identified in this study is warranted through appropriate in vitro and in vivo assays in model hosts. Such validated targets can prove vital to many antibacterial drug discovery programs globally.","PeriodicalId":11326,"journal":{"name":"Drug Target Insights","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135693233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Drug Target InsightsPub Date : 2023-04-13eCollection Date: 2023-01-01DOI: 10.33393/dti.2023.2574
Vanessa Zambelli, Emma J Murphy, Paolo Delvecchio, Laura Rizzi, Roberto Fumagalli, Emanuele Rezoagli, Giacomo Bellani
{"title":"Treatment with levosimendan in an experimental model of early ventilator-induced diaphragmatic dysfunction.","authors":"Vanessa Zambelli, Emma J Murphy, Paolo Delvecchio, Laura Rizzi, Roberto Fumagalli, Emanuele Rezoagli, Giacomo Bellani","doi":"10.33393/dti.2023.2574","DOIUrl":"10.33393/dti.2023.2574","url":null,"abstract":"<p><strong>Introduction: </strong>Mechanical ventilation (MV) is a life-saving approach in critically ill patients. However, it may affect the diaphragmatic structure and function, beyond the lungs. Levosimendan is a calcium sensitizer widely used in clinics to improve cardiac contractility in acute heart failure patients. In vitro studies have demonstrated that levosimendan increased force-generating capacity of the diaphragm in chronic obstructive pulmonary disease patients. Thus the aim of this study was to evaluate the effects of levosimendan administration in an animal model of ventilator-induced diaphragmatic dysfunction (VIDD) on muscle contraction and diaphragm muscle cell viability.</p><p><strong>Methods: </strong>Sprague-Dawley rats underwent prolonged MV (5 hours). VIDD+Levo group received a starting bolus of levosimendan immediately after intratracheal intubation and then an intravenous infusion of levosimendan throughout the study. Diaphragms were collected for ex vivo contractility measurement (with electric stimulation), histological analysis and Western blot analysis. Healthy rats were used as the control.</p><p><strong>Results: </strong>Levosimendan treatment maintained an adequate mean arterial pressure during the entire experimental protocol, preserved levels of autophagy-related proteins (LC3BI and LC3BII) and the muscular cell diameter demonstrated by histological analysis. Levosimendan did not affect the diaphragmatic contraction or the levels of proteins involved in the protein degradation (atrogin).</p><p><strong>Conclusions: </strong>Our data suggest that levosimendan preserves muscular cell structure (cross-sectional area) and muscle autophagy after 5 hours of MV in a rat model of VIDD. However, levosimendan did not improve diaphragm contractile efficiency.</p>","PeriodicalId":11326,"journal":{"name":"Drug Target Insights","volume":null,"pages":null},"PeriodicalIF":2.0,"publicationDate":"2023-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/fb/41/dti-17-39.PMC10105369.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9324491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Are calcium channel blockers related to lung cancer?","authors":"Ratchanon Rattanathanoo, Jarin Chindaprasirt, Watchara Boonsawat, Panita Limpawattana, Sittichai Khamsai, Kittisak Sawanyawisuth","doi":"10.33393/dti.2023.2573","DOIUrl":"https://doi.org/10.33393/dti.2023.2573","url":null,"abstract":"Abstract Background: Calcium channel blocker (CCB) is a common antihypertensive agent for the treatment of hypertension. There are inconsistent data of an association of CCB and lung cancer in the literature. This study aimed to evaluate this association by a case-control design. Methods: The inclusion criteria were adult patients 18 years or over, diagnosed with hypertension, lung cancer or pulmonary tuberculosis, and presenting with one of the suggestive symptoms of lung cancer. Those who were pregnant or had a diagnosis of lung cancer or pulmonary tuberculosis prior to the diagnosis of hypertension were excluded. Diagnosis of lung cancer was made pathologically, while tuberculosis was made by positive acid-fast bacilli on sputum examination, sputum culture positive for Mycobacterium tuberculosis, or polymerase chain reaction positive for M. tuberculosis with a chest x-ray compatible with tuberculosis. Cases were those diagnosed with lung cancer, while controls were those diagnosed with tuberculosis. Factors associated with lung cancer were calculated by logistic regression analysis. Results: There were 178 patients who met the study criteria. Of those, 69 patients (38.8%) were in the case group. The lung cancer group had EGFR gene mutation in 21 patients (52.5%) and adenocarcinoma was the most common cell type of lung cancer (55 patients; 79.7%). There were two factors independently associated with lung cancer including dyslipidemia and family history of lung cancer. Conclusions: CCB was not associated with lung cancer in patients with hypertension but dyslipidemia and family history of lung cancer were independently associated with lung cancer in this setting.","PeriodicalId":11326,"journal":{"name":"Drug Target Insights","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e4/b6/dti-17-54.PMC10203876.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9526478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Activity of sotorasib against brain metastases from NSCLC harboring <i>KRAS</i> p.G12C mutation: a case report.","authors":"Alessandro Inno, Fabiana Marchetti, Matteo Valerio, Niccolò Giaj Levra, Filippo Alongi, Giovanni Foti, Stefania Gori","doi":"10.33393/dti.2023.2593","DOIUrl":"https://doi.org/10.33393/dti.2023.2593","url":null,"abstract":"<p><p>In the CodeBreaK 100 phase 2 study, sotorasib was active for patients with metastatic non-small cell lung cancer (NSCLC) harboring Kirsten rat sarcoma viral oncogene homologue (KRAS) p.G12C mutation. However, patients with untreated and/or active brain metastases were excluded from the trial, and the activity of sotorasib in the setting of brain metastases should be further investigated. Here we report the case of a KRAS p.G12C mutant NSCLC patient with three brain metastases, of whom one was untreated and the other two had progressed after radiotherapy with symptoms requiring steroids, that responded to sotorasib. Our report suggests that sotorasib may be active against untreated or progressive brain metastases, supporting further evaluation of sotorasib in this setting.</p>","PeriodicalId":11326,"journal":{"name":"Drug Target Insights","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/d9/0c/dti-17-90.PMC10318585.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10180423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gurvinder Singh Bumbrah, Sarika Jain, Zeeshan Fatima, Saif Hameed
{"title":"Efficacy of LAMP assay for Mycobacterial spp. detection to prevent treatment delays and onset of drug resistance: a systematic review and meta-analysis.","authors":"Gurvinder Singh Bumbrah, Sarika Jain, Zeeshan Fatima, Saif Hameed","doi":"10.33393/dti.2023.2596","DOIUrl":"https://doi.org/10.33393/dti.2023.2596","url":null,"abstract":"<p><strong>Background: </strong>Tuberculosis (TB) <i>re</i>mains a deadly disease affecting one-third population globally. Long turnaround time and poor sensitivity of the conventional diagnostics are the major impediments for faster diagnosis of <i>Mycobacterial spp</i> to prevent drug resistance. To overcome these issues, molecular diagnostics have been developed. They offer enhanced sensitivity but require sophisticated infrastructure, skilled manpower and remain expensive.</p><p><strong>Methods: </strong>In that context, loop-mediated isothermal amplification (LAMP) assay, recommended by the WHO in 2016 for TB diagnosis, sounds as a promising alternative that facilitates visual read outs. Therefore, the aim of the present study is to conduct a meta-analysis to assess the diagnostic efficiency of LAMP for the detection of a panel of <i>Mycobacterium spp</i>. following PRISMA guidelines using scientific databases. From 1600 studies reported on the diagnosis of <i>Mycobacterium spp</i>., a selection of 30 articles were identified as eligible to meet the criteria of LAMP based diagnosis.</p><p><strong>Results: </strong>It was found that most of the studies were conducted in high disease burden nations such as India, Thailand, and Japan with sputum as the most common specimen to be used for LAMP assay. Furthermore, <i>IS6110</i> gene and fluorescence-based detections ranked as the most used target and method respectively. The accuracy and precision rates mostly varied between 79.2% to 99.3% and 73.9% to 100%, respectively. Lastly, a quality assessment based on QUADAS-2 of bias and applicability was conducted.</p><p><strong>Conclusion: </strong>LAMP technology could be considered as a feasible alternative to current diagnostics considering high burden for rapid testing in low resource regions.</p>","PeriodicalId":11326,"journal":{"name":"Drug Target Insights","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/d4/e1/dti-17-78.PMC10249090.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9619511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Lipid profiles of people with human immunodeficiency virus with dyslipidemia after switching from efavirenz to dolutegravir.","authors":"Supphachoke Khemla, Atibordee Meesing, Wantin Sribenjalux, Ploenchan Chetchotisakd","doi":"10.33393/dti.2023.2529","DOIUrl":"https://doi.org/10.33393/dti.2023.2529","url":null,"abstract":"ABSTRACT Introduction: Human immunodeficiency virus (HIV) infection and the long-term use of antiretroviral therapy, especially efavirenz (EFV)-based regimens, impact lipid profiles due to insulin resistance and lead to a higher risk of metabolic diseases. Dolutegravir (DTG) is an integrase inhibitor with better lipid profiles than EFV. However, data on treatment experience in Thailand are limited. The primary outcome was lipid profile changes at 24 weeks after switching therapy. Methods: We conducted a prospective, open-label, cohort study in people with HIV aged ≥18 years who had undergone at least 6 months of EFV-based therapy, had HIV-1 ribonucleic acid levels <50 copies/mL for ≥6 months before switching, and were diagnosed with dyslipidemia or had risk factors for atherosclerosis cardiovascular disease based on modified National Cholesterol Education Program Adult Treatment Panel III guidelines. Results: Sixty-four patients were enrolled. The mean age (standard deviation [SD]) was 48.20 ± 10.46 years, and 67.19% were male. At week 24, there were decreases from baseline in mean total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides. However, mean body weight and waist circumference had increased. Conclusions: DTG resulted in better lipid profiles after switching from EFV-based therapy, suggesting that this switch could benefit patients with a high risk of cardiovascular disease. However, it is essential to note that weight gain and increased waist circumference were also observed.","PeriodicalId":11326,"journal":{"name":"Drug Target Insights","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/85/b8/dti-17-45.PMC10158613.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9433065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bhavya Shetty, Ibrahim Fazal, Safiya Fatima Khan, Manjusha Nambiar, Khadijathul Irfana D, Rohit Prasad, Akshata Raj
{"title":"Association between cardiovascular diseases and periodontal disease: more than what meets the eye.","authors":"Bhavya Shetty, Ibrahim Fazal, Safiya Fatima Khan, Manjusha Nambiar, Khadijathul Irfana D, Rohit Prasad, Akshata Raj","doi":"10.33393/dti.2023.2510","DOIUrl":"https://doi.org/10.33393/dti.2023.2510","url":null,"abstract":"ABSTRACT Cardiovascular diseases (CVDs) are inflammatory diseases of coronary arteries accompanying atheroma formation that can spawn impairment and, in severe cases, death. CVDs are the leading cause of death in the world. In recent decades, investigators have focused their impact on CVD by periodontal disease (PD). PD is a risk factor that can trigger the formation, maturation, and instability of atheroma in the arteries. Two mechanisms have been proposed to explain this relationship: periodontopathic pathogens explicitly invade the circulation or indirectly increase systemic levels of inflammatory mediators. It has been suggested that improvement in disease state has a positive effect on others. This review summarizes evidence from epidemiological studies as well as researches focusing on potential causation channels to deliver a comprehensive representation of the relationship between PD and CVD.","PeriodicalId":11326,"journal":{"name":"Drug Target Insights","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/98/61/dti-17-31.PMC9906023.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10688633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}