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Brazilian Oral Research 2023The current study aims to assess the effectiveness of e-learning in compliance with the new biosafety recommendations in dentistry in the context of COVID-19 applied to...
The current study aims to assess the effectiveness of e-learning in compliance with the new biosafety recommendations in dentistry in the context of COVID-19 applied to the clinical staff of a dental school in Brazil. A quasi-experimental epidemiological study was carried out by means of a structured, pre-tested online questionnaire, applied before and after an educational intervention, using an e-learning format. After data collection, statistical tests were performed. A total of 549 members of the clinical staff participated in the study in the two collection phases, with a return rate of 26.9%. After the e-learning stage, a reduction was found in the reported use of disposable gloves, protective goggles, and surgical masks. The course had no impact on the staff's knowledge concerning the proper sequence for donning PPE and showed 100% effectiveness regarding proper PPE doffing sequence. Knowledge about avoiding procedures that generate aerosols in the clinical setting was improved. Despite the low rate of return, it can be concluded that online intervention alone was ineffective in significantly improving learning about the new clinical biosafety guidelines. Therefore, the use of hybrid teaching and repetitive training is highly recommended.
Topics: Humans; Computer-Assisted Instruction; COVID-19; Brazil; Diazooxonorleucine; Dentistry
PubMed: 37341233
DOI: 10.1590/1807-3107bor-2023.vol37.0060 -
Journal of Cellular Physiology Sep 2021Pre-eclampsia (PE) is a pregnancy-related disorder that occurs after 20 weeks of gestation. It seriously affects the health of maternity and the fetus. However, the...
Pre-eclampsia (PE) is a pregnancy-related disorder that occurs after 20 weeks of gestation. It seriously affects the health of maternity and the fetus. However, the pathogenesis of PE is still unknown. Decidualization deficiency is considered a contributing factor to the development of PE. CTP synthetase (CTPS) which is the rate-limiting enzyme in the CTP de novo biosynthesis, is essential for nucleic acid synthesis and cellular energy metabolism, and often appears as cytoophidium in many cell types. Here, we found that the expression of CTPS was significantly downregulated in decidual tissues of patients with severe PE compared with healthy pregnant women. During in vitro decidualization, changes in CTPS were accompanied by opposite fluctuation of the AMPK signaling pathway. Moreover, the downregulation of CTPS by glutamine analogs or CTPS small interfering RNA inhibited the decidualization process and the AMPK signaling pathway. Investigating the underlying mechanism of action by co-immunoprecipitation coupled with mass spectrometry showed that CTPS interacted with ATP synthase (ATPS) and maintained the content of ATP on Day 3 of decidualization. However, when combined with mitochondrial stress protein STRESS-70 instead of ATPS, the concentration of ATP on Day 6 of induction was reduced. Corresponding to this, CTPS was mainly distributes in the cytoplasm on Day 3 of induction, while it appeared both in the cytoplasm and the nucleus on Day 6 in decidualized cells, which was similar to that in cells before induction. In summary, we believe that CTPS plays an important role in decidualization by participating in energy metabolism. Abnormal expression of CTPS in decidualization would lead to abnormal decidualization and consequently result in the occurrence of PE.
Topics: Adenylate Kinase; Carbon-Nitrogen Ligases; Cell Line; Cell Proliferation; Decidua; Diazooxonorleucine; Down-Regulation; Endometrium; Energy Metabolism; Female; Gene Silencing; Human Embryonic Stem Cells; Humans; Mitochondrial Proton-Translocating ATPases; Pre-Eclampsia; Pregnancy; Protein Binding; Signal Transduction; Stromal Cells
PubMed: 33576499
DOI: 10.1002/jcp.30326 -
Molecular Cancer Therapeutics Oct 2022Glutamine is a conditionally essential amino acid consumed by rapidly proliferating cancer cells, which deprives the same fuel from immune cells and contributes to tumor...
Glutamine is a conditionally essential amino acid consumed by rapidly proliferating cancer cells, which deprives the same fuel from immune cells and contributes to tumor immune evasion. As such, the broad antagonism of glutamine in tumors and the tumor microenvironment may lead to direct antitumor activity and stimulation of antitumoral immune responses. DRP-104 (sirpiglenastat) was designed as a novel prodrug of the broad-acting glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON). DRP-104 is an inactive form that is preferentially converted to DON within tumors. Metabolomic profiling of tumors treated with DRP-104 revealed widespread changes indicative of the disruption of tumor anabolism and canonical cancer metabolism pathways; including altered glutamine metabolism while several immunosuppressive metabolites were decreased. Gene expression profiling revealed broad immunological modulation, confirmed by flow cytometry indicating that DRP-104 treatment resulted in substantial and broad changes in various immune cell infiltrates, such as increased TIL, T, NK, and NK T cells. Functionally, T cells became more proliferative and less exhausted; tumor-associated macrophages were polarized to the M1 phenotype; MDSCs and protumorigenic proteins were decreased in TME. Finally, DRP-104 demonstrated significant antitumor activity as a monotherapy, which was further enhanced in combination with checkpoint blockade therapies, leading to improved survival and long-term durable cures. In summary, DRP-104 broadly remodels the tumor microenvironment by inducing extensive tumor metabolism effects and enhancing the infiltration and function of multiple immune cells distinct from those obtained by checkpoint inhibitor therapy. This unique mechanism of action supports the ongoing clinical development of DRP-104 alone and in combination with checkpoint inhibitors.
Topics: Amino Acids, Essential; Cell Line, Tumor; Diazooxonorleucine; Glutamine; Humans; Immune System; Neoplasms; Prodrugs; Tumor Microenvironment
PubMed: 35930753
DOI: 10.1158/1535-7163.MCT-22-0282 -
Drug Discoveries & Therapeutics Nov 2023This work describes a novel artificial intelligence-based training and monitoring system (AITMS) that was used to control and prevent nosocomial infections (NIs) by...
This work describes a novel artificial intelligence-based training and monitoring system (AITMS) that was used to control and prevent nosocomial infections (NIs) by improving the skills of donning/removing personal protective equipment (PPE). The AITMS has two working modes, namely an AI-based protective equipment surveillance mode and an AI-based training mode, that were used for routine surveillance and training, respectively. Data revealed that the accuracy rate of donning/removing PPE improved as a result of the AITMS. Interestingly, the frequency of NIs decreased with the use of the AITMS. This study suggested the key role of using PPE in controlling and preventing NIs. Data preliminarily proved that appropriate donning/removing PPE may help to reduce the risk of NIs. In addition, the newest computerized technologies, such as AI, have proven to be useful in controlling and preventing NIs. These findings should helpful to formulate a better strategy against NIs in the future.
Topics: Humans; Artificial Intelligence; Pilot Projects; Cross Infection; Diazooxonorleucine; Hospitals
PubMed: 37673650
DOI: 10.5582/ddt.2023.01068 -
International Journal of Molecular... May 2021Excessive proliferation and migration of vascular smooth muscle cells (VSMCs) contribute to the development of atherosclerosis and restenosis. Glycolysis and...
Excessive proliferation and migration of vascular smooth muscle cells (VSMCs) contribute to the development of atherosclerosis and restenosis. Glycolysis and glutaminolysis are increased in rapidly proliferating VSMCs to support their increased energy requirements and biomass production. Thus, it is essential to develop new pharmacological tools that regulate metabolic reprogramming in VSMCs for treatment of atherosclerosis. The effects of 6-diazo-5-oxo-L-norleucine (DON), a glutamine antagonist, have been broadly investigated in highly proliferative cells; however, it is unclear whether DON inhibits proliferation of VSMCs and neointima formation. Here, we investigated the effects of DON on neointima formation in vivo as well as proliferation and migration of VSMCs in vitro. DON simultaneously inhibited FBS- or PDGF-stimulated glycolysis and glutaminolysis as well as mammalian target of rapamycin complex I activity in growth factor-stimulated VSMCs, and thereby suppressed their proliferation and migration. Furthermore, a DON-derived prodrug, named JHU-083, significantly attenuated carotid artery ligation-induced neointima formation in mice. Our results suggest that treatment with a glutamine antagonist is a promising approach to prevent progression of atherosclerosis and restenosis.
Topics: Animals; Antimetabolites, Antineoplastic; Cell Cycle; Cell Movement; Cell Proliferation; Cells, Cultured; Diazooxonorleucine; Glutamine; Glycolysis; Immunohistochemistry; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred C57BL; Mitochondria; Muscle, Smooth, Vascular; Neointima; Oxidative Phosphorylation; Platelet-Derived Growth Factor; Rats; Rats, Sprague-Dawley; Serum Albumin, Bovine
PubMed: 34070527
DOI: 10.3390/ijms22115602 -
Bioorganic & Medicinal Chemistry Letters Oct 2021Two distinct diazo precursors, imidazotetrazine and nitrous amide, were explored as promoieties in designing prodrugs of 6-diazo-5-oxo-l-norleucine (DON), a glutamine...
Two distinct diazo precursors, imidazotetrazine and nitrous amide, were explored as promoieties in designing prodrugs of 6-diazo-5-oxo-l-norleucine (DON), a glutamine antagonist. As a model for an imidazotetrazine-based prodrug, we synthesized (S)-2-acetamido-6-(8-carbamoyl-4-oxoimidazo[5,1-d][1,2,3,5]tetrazin-3(4H)-yl)-5-oxohexanoic acid (4) containing the entire scaffold of temozolomide, a precursor of the DNA-methylating agent clinically approved for the treatment of glioblastoma multiforme. For a nitrous amide-based prodrug, we synthesized 2-acetamido-6-(((benzyloxy)carbonyl)(nitroso)amino)-5-oxohexanoic acid (5) containing a N-nitrosocarbamate group, which can be converted to a diazo moiety via a mechanism similar to that of streptozotocin, a clinically approved diazomethane-releasing drug containing an N-nitrosourea group. Preliminary characterization confirmed formation of N-acetyl DON (6), also known as duazomycin A, from compound 4 in a pH-dependent manner while compound 5 did not exhibit sufficient stability to allow further characterization. Taken together, our model studies suggest that further improvements are needed to translate this prodrug approach into glutamine antagonist-based therapy.
Topics: Diazooxonorleucine; Drug Design; Drug Stability; Glutamine; Molecular Structure; Prodrugs
PubMed: 34400301
DOI: 10.1016/j.bmcl.2021.128321 -
Molecules (Basel, Switzerland) Aug 2022Cancer cells change their glucose and glutamine (GLU) metabolism to obtain the energy required to continue growing. Glutaminase (GLS) plays a crucial role in promoting...
Cancer cells change their glucose and glutamine (GLU) metabolism to obtain the energy required to continue growing. Glutaminase (GLS) plays a crucial role in promoting cell metabolism for cancer cell growth; targeting GLU metabolism by inhibiting GLS has attracted interest as a potential cancer management strategy. Herein, we employed a sequential screening of traditional Chinese medicine (TCM) database followed by drug-likeness and molecular dynamics simulations against the active site of GLS. We report 12 potent compounds after screening the TCM database against GLS, followed by a drug-likeness filter with Lipinski and Veber rule criteria. Among them, ZINC03978829 and ZINC32296657 were found to have higher binding energy (BE) values than the control compound 6-Diazo-5-Oxo-L-Norleucine, with BEs of -9.3 and -9.7 kcal/mol, respectively, compared to the BE of 6-Diazo-5-Oxo-L-Norleucine (-4.7 kcal/mol) with GLS. Molecular dynamics simulations were used to evaluate the results further, and a 100 ns MD simulation revealed that the hits form stable complexes with GLS and formed 2-5 hydrogen bond interactions. This study indicates that these hits might be employed as GLS inhibitors in the battle against cancer. However, more laboratory tests are a prerequisite to optimize them as GLS inhibitors.
Topics: Diazooxonorleucine; Early Detection of Cancer; Glutaminase; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Neoplasms; Neoplastic Processes
PubMed: 35956989
DOI: 10.3390/molecules27155042 -
Frontiers in Public Health 2023The global impact of Coronavirus Disease 2019 (COVID-19) has been profound, affecting public health, the global economy, and overall human life. Past experiences with...
BACKGROUND
The global impact of Coronavirus Disease 2019 (COVID-19) has been profound, affecting public health, the global economy, and overall human life. Past experiences with global pandemics underscored the significance of understanding the perception of HCWs and hospital staff in developing and implementing preventive measures. The World Health Organization (WHO) provided protocols to manage the spread of COVID-19 and assist healthcare workers and health systems globally in maintaining high-quality health services.
OBJECTIVE
This study aims to assess nurses' perception, awareness, and compliance regarding the implementation of COVID-19 protocols and explore factors influencing their perception.
METHODOLOGY
A quantitative cross-sectional survey-based study was conducted, distributing a constructed survey among nurses in the Eastern Province of Saudi Arabia.
RESULTS
Out of 141 participants, most adhered to protocols such as hand sanitization, social distancing, and proper personal protective equipment (PPE) usage. The predominant age group among respondents was 31 to 40 years ( = 71, 50%). A significant portion of participants reported holding a bachelor's degree ( = 86, 61%), with only 14% possessing advanced degrees ( = 19). Nearly a third of the nurses in the study had accumulated 6 to 10 years of professional experience ( = 49, 34.8%). A noteworthy percentage of nurses were engaged in daily shifts exceeding 8 h ( = 98, 70%). Gender differences were observed, with females exhibiting a higher tendency to avoid shaking hands and social gatherings. Saudi nationals were more inclined to shake hands and engage in gatherings. Non-Saudi nurses and those aged between <25 to 40 years demonstrated proper donning/doffing practices. Nurses with over 6 years of experience avoided social gatherings, while those working >8 h adhered better to PPE usage, proper donning/doffing, and disposal of PPE in designated bins.
CONCLUSION
Understanding COVID-19 protocols is crucial for tailoring interventions and ensuring effective compliance with COVID-19 preventive measures among nurses. More efforts should be made toward preparing the healthcare nursing to deal with the outbreak. Preparing healthcare nursing with the right knowledge, attitude, and precautionary practices during the COVID-19 outbreak is very essential to patient and public safety.
Topics: Female; Humans; Adult; Saudi Arabia; Cross-Sectional Studies; COVID-19; Diazooxonorleucine; Perception; Nurses
PubMed: 38249370
DOI: 10.3389/fpubh.2023.1291261 -
Angewandte Chemie (International Ed. in... Apr 2021DON (6-diazo-5-oxo-l-norleucine), a diazo-containing amino acid, has been studied for more than 60 years as a potent antitumor agent, but its biosynthesis has not been...
DON (6-diazo-5-oxo-l-norleucine), a diazo-containing amino acid, has been studied for more than 60 years as a potent antitumor agent, but its biosynthesis has not been elucidated. Here we reveal the complete biosynthetic pathway of alazopeptin, the tripeptide Ala-DON-DON, which has antitumor activity, by gene inactivation and in vitro analysis of recombinant enzymes. We also established heterologous production of N-acetyl-DON in Streptomyces albus. DON is synthesized from lysine by three enzymes and converted to alazopeptin by five enzymes and one carrier protein. Most interestingly, transmembrane protein AzpL was indicated to catalyze diazotization using 5-oxolysine and nitrous acid as substrates. Site-directed mutagenesis of AzpL indicated that the hydroxy group of Tyr-93 is important for the diazotization. These findings expand our knowledge of the enzymology of N-N bond formation.
Topics: Alanine; Diazooxonorleucine; Dipeptides; Molecular Structure; Streptomyces
PubMed: 33624374
DOI: 10.1002/anie.202100462 -
Methods in Molecular Biology (Clifton,... 2021Colon cancer is a highly anabolic entity with upregulation of glycolysis, glutaminolysis, and de novo synthesis of fatty acids, which also induces a hypercatabolic state...
Colon cancer is a highly anabolic entity with upregulation of glycolysis, glutaminolysis, and de novo synthesis of fatty acids, which also induces a hypercatabolic state in the patient. The blockade of either cancer anabolism or host catabolism has been previously proven to be a successful anticancer experimental treatment. However, it is still unclear whether the simultaneous blockade of both metabolic counterparts can limit malignant survival and the energetic consequences of such an approach. In this chapter, by using the CT26.WT murine colon adenocarcinoma cell line as a model of study, we provide a method to simultaneously perform a pharmacological blockade of tumor anabolism and host catabolism, as a feasible therapeutic approach to treat cancer, and to limit its energetic supply.
Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Colonic Neoplasms; Diazooxonorleucine; Drug Screening Assays, Antitumor; Fatty Acid Synthase, Type I; Fatty Acids; Female; Glutaminase; Glutamine; Glycolysis; Hexokinase; Indazoles; Mice; Mice, Inbred BALB C; Molecular Targeted Therapy; Orlistat; Smegmamorpha
PubMed: 32813244
DOI: 10.1007/978-1-0716-0759-6_5