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Molecules (Basel, Switzerland) May 2023The abuse of tetracycline antibiotics (TCs) has caused serious environmental pollution and risks to public health. Degradation of TCs by cold atmospheric plasmas (CAPs)...
The abuse of tetracycline antibiotics (TCs) has caused serious environmental pollution and risks to public health. Degradation of TCs by cold atmospheric plasmas (CAPs) is a high efficiency, low energy consumption and environmentally friendly method. In this study, a reactive molecular dynamics (MD) simulation is applied to study the interactions of reactive oxygen species (ROS) produced in CAPs and TCs (including tetracycline (TC), oxytetracycline (OTC), chlortetracycline (CTC) and demeclocycline (DMC)). As revealed by the simulation data at the atomic level, the main reaction sites on TCs are the C2 acylamino, the C4 dimethylamine, the C6 methyl group, the C8 site on the benzene ring and the C12a tertiary alcohol. The interaction between ROS and TCs is usually initiated by H-abstraction, followed by the breaking and formation of the crucial chemical bonds, such as the breaking of C-C bonds, C-N bonds and C-O bonds and the formation of C=C bonds and C=O bonds. Due to the different structures of TCs, when the ROS impact OTC, CTC and DMC, some specific reactions are observed, including carbonylation at the C5 site, dechlorination at the C7 site and carbonylation at the C6 site, respectively. Some degradation products obtained from the simulation data have been observed in the experimental measurements. In addition, the dose effects of CAP on TCs by adjusting the number of ROS in the simulation box are also investigated and are consistent with experimental observation. This study explains in detail the interaction mechanisms of degradation of TCs treated by CAPs with the final products after degradation, provides theoretical support for the experimental observation, then suggests optimization to further improve the efficiency of degradation of TCs by CAPs in applications.
Topics: Molecular Dynamics Simulation; Reactive Oxygen Species; Anti-Bacterial Agents; Tetracycline; Oxytetracycline; Chlortetracycline
PubMed: 37175259
DOI: 10.3390/molecules28093850 -
Frontiers in Microbiology 2021Tetracycline has positively impacted human health as well as the farming and animal industries. Its extensive usage and versatility led to the spread of resistance...
Tetracycline has positively impacted human health as well as the farming and animal industries. Its extensive usage and versatility led to the spread of resistance mechanisms followed by the development of new variants of the antibiotic. Tetracyclines inhibit bacterial growth by impeding the binding of elongator tRNAs to the ribosome. However, a small number of reports indicated that Tetracyclines could also inhibit translation initiation, yet the molecular mechanism remained unknown. Here, we use biochemical and computational methods to study how Oxytetracycline (Otc), Demeclocycline (Dem), and Tigecycline (Tig) affect the translation initiation phase of protein synthesis. Our results show that all three Tetracyclines induce Initiation Factor IF3 to adopt a compact conformation on the 30S ribosomal subunit, similar to that induced by Initiation Factor IF1. This compaction was faster for Tig than Dem or Otc. Furthermore, all three tested tetracyclines affected IF1-bound 30S complexes. The dissociation rate constant of IF1 in early 30S complexes was 14-fold slower for Tig than Dem or Otc. Late 30S initiation complexes (30S pre-IC or IC) exhibited greater IF1 stabilization by Tig than for Dem and Otc. Tig and Otc delayed 50S joining to 30S initiation complexes (30S ICs). Remarkably, the presence of Tig considerably slowed the progression to translation elongation and retained IF1 in the resulting 70S initiation complex (70S IC). Molecular modeling of Tetracyclines bound to the 30S pre-IC and 30S IC indicated that the antibiotics binding site topography fluctuates along the initiation pathway. Mainly, 30S complexes show potential contacts between Dem or Tig with IF1, providing a structural rationale for the enhanced affinity of the antibiotics in the presence of the factor. Altogether, our data indicate that Tetracyclines inhibit translation initiation by allosterically perturbing the IF3 layout on the 30S, retaining IF1 during 70S IC formation, and slowing the transition toward translation elongation. Thus, this study describes a new complementary mechanism by which Tetracyclines may inhibit bacterial protein synthesis.
PubMed: 34262544
DOI: 10.3389/fmicb.2021.682682 -
Proceedings of the National Academy of... Mar 2021Previous studies have demonstrated that the synaptic EphB1 receptor tyrosine kinase is a major mediator of neuropathic pain, suggesting that targeting the activity of...
Previous studies have demonstrated that the synaptic EphB1 receptor tyrosine kinase is a major mediator of neuropathic pain, suggesting that targeting the activity of this receptor might be a viable therapeutic option. Therefore, we set out to determine if any FDA-approved drugs can act as inhibitors of the EphB1 intracellular catalytic domain. An in silico screen was first used to identify a number of tetracycline antibiotics which demonstrated potential docking to the ATP-binding catalytic domain of EphB1. Kinase assays showed that demeclocycline, chlortetracycline, and minocycline inhibit EphB1 kinase activity at low micromolar concentrations. In addition, we cocrystallized chlortetracycline and EphB1 receptor, which confirmed its binding to the ATP-binding domain. Finally, in vivo administration of the three-tetracycline combination inhibited the phosphorylation of EphB1 in the brain, spinal cord, and dorsal root ganglion (DRG) and effectively blocked neuropathic pain in mice. These results indicate that demeclocycline, chlortetracycline, and minocycline can be repurposed for treatment of neuropathic pain and potentially for other indications that would benefit from inhibition of EphB1 receptor kinase activity.
Topics: Animals; Central Nervous System; Chlortetracycline; Crystallography, X-Ray; Humans; Male; Mice; Neuralgia; Protein Domains; Protein Kinase Inhibitors; Receptor, EphB1
PubMed: 33627480
DOI: 10.1073/pnas.2016265118 -
Endocrinology, Diabetes & Metabolism... 2015The syndrome of inappropriate antidiuretic hormone secretion (SIADH) can occur following traumatic brain injury (TBI), but is usually transient. There are very few case...
UNLABELLED
The syndrome of inappropriate antidiuretic hormone secretion (SIADH) can occur following traumatic brain injury (TBI), but is usually transient. There are very few case reports describing chronic SIADH and all resolved within 12 months, except for one case complicated by meningo-encephalitis. Persistent symptomatic hyponatremia due to chronic SIADH was present for 4 years following a TBI in a previously well 32-year-old man. Hyponatremia consistent with SIADH initially occurred in the immediate period following a high-speed motorbike accident in 2010. There were associated complications of post-traumatic amnesia and mild cognitive deficits. Normalization of serum sodium was achieved initially with fluid restriction. However, this was not sustained and he subsequently required a permanent 1.2 l restriction to maintain near normal sodium levels. Multiple episodes of acute symptomatic hyponatremia requiring hospitalization occurred over the following years when he repeatedly stopped the fluid restriction. Given the ongoing nature of his hyponatremia and difficulties complying with strict fluid restriction, demeclocycline was commenced in 2014. Normal sodium levels without fluid restriction have been maintained for 6 months since starting demeclocycline. This case illustrates an important long-term effect of TBI, the challenges of complying with permanent fluid restrictions and the potential role of demeclocycline in patients with chronic hyponatremia due to SIADH.
LEARNING POINTS
Hyponatraemia due to SIADH commonly occurs after TBI, but is usually mild and transient.Chronic hyponatraemia due to SIADH following TBI is a rare but important complication.It likely results from damage to the pituitary stalk or posterior pituitary causing inappropriate non-osmotic hypersecretion of ADH.First line management of SIADH is generally fluid restriction, but hypertonic saline may be required in severe cases. Adherence to long-term fluid restriction is challenging. Other options include oral urea, vasopressin receptor antagonists and demeclocycline.While effective, oral urea is poorly tolerated and vasopressin receptor antagonists are currently not licensed for use in Australia or the USA beyond 30 days due to insufficient long-term safety data and specific concerns of hepatotoxicity.Demeclocycline is an effective, well-tolerated and safe option for management of chronic hyponatraemia due to SIADH.
PubMed: 26527077
DOI: 10.1530/EDM-15-0070 -
Mikrochimica Acta May 2023The fabrication of iron oxide quantum dots (IO-QDs) modified with glutamic acid (Glu) under controllable conditions is reported. The IO-QDs have been characterized by...
The fabrication of iron oxide quantum dots (IO-QDs) modified with glutamic acid (Glu) under controllable conditions is reported. The IO-QDs have been characterized by transmission electron microscopy, spectrofluorometry, powder X-ray diffraction, vibrating sample magnetometry, UV-Vis spectroscopy, X-ray photoelectron spectroscopy, and Fourier-transform infrared spectroscopy. The IO-QDs exhibited good stability towards irradiation, temperature elevations, and ionic strength, and the quantum yield (QY) of IO-QDs was calculated to be 11.91 ± 0.09%. The IO-QDs were furtherly measured at an excitation wavelength of 330 nm with emission maxima at 402 nm, which were employed to detect tetracycline (TCy) antibiotics, including tetracycline (TCy), chlortetracycline (CTCy), demeclocycline (DmCy), and oxytetracycline (OTCy) in biological samples. The results indicated that TCy, CTCy, DmCy, and OTCy in urine samples show a dynamic working range between 0.01 and 80.0 μM; 0.01 and 1.0 μM; 0.01 and 10 μM; and 0.04 and 1.0 μM, respectively, with detection limits of 7.69 nM, 120.23 nM, 18.20 nM, and 67.74 nM, respectively. The detection was not interfered with by the auto-fluorescence from the matrices. In addition, the obtained recovery in real urine samples suggested that the developed method could be used in practical applications. Therefore, the current study has prospect to develop an easy, fast, eco-friendly, and efficient new sensing method for detecting tetracycline antibiotics in biological samples.
Topics: Quantum Dots; Glutamic Acid; Tetracycline; Anti-Bacterial Agents
PubMed: 37198413
DOI: 10.1007/s00604-023-05801-3 -
BMJ Case Reports Aug 2021Hyponatraemia is the most common electrolyte disturbance observed in hospital inpatients. We report a 90-year-old woman admitted generally unwell following a fall with...
Hyponatraemia is the most common electrolyte disturbance observed in hospital inpatients. We report a 90-year-old woman admitted generally unwell following a fall with marked confusion. Examination revealed a tender suprapubic region, and investigations observed elevated inflammatory markers and bacteriuria. Admission investigations demonstrated a serum sodium of 110 mmol/L with associated serum osmolality 236 mmol/kg and urine osmolality 346 mmol/kg. She was treated for hyponatraemia secondary to syndrome of inappropriate antidiuretic hormone (SIADH) and urosepsis. However, her serum sodium failed to normalise despite fluid restriction, necessitating treatment with demeclocycline and hypertonic saline. Despite slow reversal of hyponatraemia over 1 month, the patient developed generalised seizures with pontine and thalamic changes on MRI consistent with osmotic demyelination syndrome (ODS). This case highlights the risk of ODS, a rare but devastating consequence of hyponatraemia treatment, despite cautious sodium correction.
Topics: Aged, 80 and over; Demyelinating Diseases; Female; Humans; Hyponatremia; Inappropriate ADH Syndrome; Saline Solution, Hypertonic; Sodium
PubMed: 34373247
DOI: 10.1136/bcr-2020-241407 -
Journal of Biomedical Optics Sep 2014Contrast agents have shown to be useful in the detection of cancers. The goal of this study was to compare enhancement of brain cancer contrast using reflectance and... (Comparative Study)
Comparative Study
Contrast agents have shown to be useful in the detection of cancers. The goal of this study was to compare enhancement of brain cancer contrast using reflectance and fluorescence confocal imaging of two fluorophores, methylene blue (MB) and demeclocycline (DMN). MB absorbs light in the red spectral range and fluoresces in the near-infrared. It is safe for in vivo staining of human skin and breast tissue. However, its safety for staining human brain is questionable. Thus, DMN, which absorbs light in the violet spectral range and fluoresces between 470 and 570 nm, could provide a safer alternative to MB. Fresh human gliomas, obtained from surgeries, were cut in half and stained with aqueous solutions of MB and DMN, respectively. Stained tissues were imaged using multimodal confocal microscopy. Resulting reflectance and fluorescence optical images were compared with hematoxylin and eosin histopathology, processed from each imaged tissue. Results indicate that images of tissues stained with either stain exhibit comparable contrast and resolution of morphological detail. Further studies are required to establish the safety and efficacy of these contrast agents for use in human brain.
Topics: Brain; Brain Chemistry; Brain Neoplasms; Contrast Media; Demeclocycline; Glioma; Humans; Image Processing, Computer-Assisted; Methylene Blue; Optical Imaging
PubMed: 25239672
DOI: 10.1117/1.JBO.19.9.090504 -
PloS One 2022Polycystic ovary syndrome (PCOS) is a common endocrine disorder with high incidence. Recently it has been implicated as a significant risk factor for endometrial cancer...
OBJECTIVE
Polycystic ovary syndrome (PCOS) is a common endocrine disorder with high incidence. Recently it has been implicated as a significant risk factor for endometrial cancer (EC). Our study aims to detect shared gene signatures and biological mechanism between PCOS and EC by bioinformatics analysis.
METHODS
Bioinformatics analysis based on GEO database consisted of data integration, network construction and functional enrichment analysis was applied. In addition, the pharmacological methodology and molecular docking was also performed.
RESULTS
Totally 10 hub common genes, MRPL16, MRPL22, MRPS11, RPL26L1, ESR1, JUN, UBE2I, MRPL17, RPL37A, GTF2H3, were considered as shared gene signatures for EC and PCOS. The GO and KEGG pathway analysis of these hub genes showed that "mitochondrial translational elongation", "ribosomal subunit", "structural constituent of ribosome" and "ribosome" were highly correlated. Besides, associated transcription factors (TFs) and miRNAs network were constructed. We identified candidate drug molecules including fenofibrate, cinnarizine, propanil, fenthion, clindamycin, chloramphenicol, demeclocycline, hydrochloride, azacitidine, chrysene and artenimol according to these hub genes. Molecular docking analysis verified a good binding interaction of fenofibrate against available targets (JUN, ESR1, UBE2I).
CONCLUSION
Gene signatures and regulatory biological pathways were identified through bioinformatics analysis. Moreover, the molecular mechanisms of these signatures were explored and potential drug molecules associated with PCOS and EC were screened out.
Topics: Computational Biology; Endometrial Neoplasms; Female; Fenofibrate; Gene Regulatory Networks; Humans; Molecular Docking Simulation; Polycystic Ovary Syndrome
PubMed: 35830453
DOI: 10.1371/journal.pone.0271380 -
Pharmaceuticals (Basel, Switzerland) Apr 2023Type 2 diabetes mellitus is a chronic health problem that can be controlled by slowing one's carbohydrate metabolism by inhibiting α-glucosidase, an enzyme responsible...
Type 2 diabetes mellitus is a chronic health problem that can be controlled by slowing one's carbohydrate metabolism by inhibiting α-glucosidase, an enzyme responsible for carbohydrate degradation. Currently, drugs for type 2 diabetes have limitations in terms of safety, efficiency, and potency, while cases are rapidly increasing. For this reason, the study planned and moved towards drug repurposing by utilizing food and drug administration (FDA)-approved drugs against α-glucosidase, and investigated the molecular mechanisms. The target protein was refined and optimized by introducing missing residues, and minimized to remove clashes to find the potential inhibitor against α-glucosidase. The most active compounds were selected after the docking study to generate a pharmacophore query for the virtual screening of FDA-approved drug molecules based on shape similarity. The analysis was performed using (ADV)-based on binding affinities (-8.8 kcal/mol and -8.6 kcal/mol) and root-mean-square-deviation (RMSD) values (0.4 Å and 0.6 Å). Two of the most potent lead compounds were selected for a molecular dynamics (MD) simulation to determine the stability and specific interactions between receptor and ligand. The docking score, RMSD values, pharmacophore studies, and MD simulations revealed that two compounds, namely Trabectedin (ZINC000150338708) and Demeclocycline (ZINC000100036924), are potential inhibitors for α-glucosidase compared to standard inhibitors. These predictions showed that the FDA-approved molecules Trabectedin and Demeclocycline are potential suitable candidates for repurposing against type 2 diabetes. The in vitro studies showed that trabectedin was significantly effective with an IC of 1.263 ± 0.7 μM. Further investigation in the laboratory is needed to justify the safety of the drug to be used in vivo.
PubMed: 37111312
DOI: 10.3390/ph16040555 -
Australian Dental Journal Jun 2018Many studies have investigated the effectiveness of root canal irrigants and medicaments against Enterococcus faecalis. The aim of this study was to compare the efficacy... (Comparative Study)
Comparative Study
BACKGROUND
Many studies have investigated the effectiveness of root canal irrigants and medicaments against Enterococcus faecalis. The aim of this study was to compare the efficacy of commonly used medicaments against E. faecalis cultured as a biofilm on dentine substrate.
METHODS
An E. faecalis biofilm was established on human dentine slices using a continuous flow cell. Each test medicament (Ledermix, Ca(OH) , Odontopaste, 0.2% chlorhexidine and 50:50 combinations of Ledermix/Ca(OH) and Odontopaste/Ca(OH) ) was introduced into the flow cell and biofilms were harvested and quantitated by determining cellular protein. Cellular viability was determined using serial plating and the number of colony-forming units was normalized against cellular protein to allow treatment protocols to be compared. Qualitative scanning electron microscopy analyses of the biofilm were performed after a 48-h exposure to each test agent.
RESULTS
Sodium hypochlorite achieved total bacterial elimination. Ledermix and Odontopaste had no significant effect on the E. faecalis biofilm. Ca(OH) and 50:50 combinations of Ca(OH) /Ledermix or Ca(OH) /Odontopaste reduced the viability by more than 99% while 0.2% chlorhexidine reduced bacterial numbers by 97%.
CONCLUSIONS
Sodium hypochlorite remains the gold standard for bacterial elimination in root canal therapy. However, Ca(OH) in isolation and combined with Ledermix, and Odontopaste was highly effective in reducing bacterial viability.
Topics: Biofilms; Calcium Hydroxide; Chlorhexidine; Demeclocycline; Dental Pulp Cavity; Dentin; Drug Combinations; Enterococcus faecalis; Humans; Microbial Viability; Microscopy, Electron, Scanning; Root Canal Irrigants; Sodium Hypochlorite; Triamcinolone Acetonide
PubMed: 29181844
DOI: 10.1111/adj.12580