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Biological & Pharmaceutical Bulletin 2022Cancer immunotherapies are powerful therapeutic options for cancer patients. To enhance the therapeutic effects of cancer immunotherapies, we plan to develop novel...
Cancer immunotherapies are powerful therapeutic options for cancer patients. To enhance the therapeutic effects of cancer immunotherapies, we plan to develop novel immunostimulatory drugs for use in combination with cancer immunotherapy. In the present study, we focused on tetracyclines, the effects of which are controversial for immunotherapy. We examined the effects of tetracyclines on human T cells in the peripheral blood of healthy donors and the tumor tissues of non-small cell lung cancer (NSCLC) patients. By using bispecific T-cell engager technology to assess the cytotoxicity of peripheral T cells against tumor cells, we showed that tetracyclines (minocycline, tetracycline, doxycycline, meclocycline, chlortetracycline, and demeclocycline) enhanced T-cell cytotoxicity through granzyme B expression and CD4+ and CD8+ T-cell proliferation. In analyses of the peripheral blood mononuclear cells (PBMCs) and lung tumor-infiltrated cells of NSCLC patients, we found that demeclocycline enhanced T-cell cytotoxicity not only in PBMCs, but also in lung tumor tissues. These results support the further application of tetracyclines to combination cancer immunotherapy.
Topics: Carcinoma, Non-Small-Cell Lung; Humans; Leukocytes, Mononuclear; Lung Neoplasms; Minocycline; T-Lymphocytes
PubMed: 35370267
DOI: 10.1248/bpb.b21-00806 -
Biosensors Dec 2022As an antibody-free sensing membrane for the detection of the antibiotic tetracycline (TC), a liquid PVC membrane doped with the ion-pair tetracycline/θ-shaped anion...
As an antibody-free sensing membrane for the detection of the antibiotic tetracycline (TC), a liquid PVC membrane doped with the ion-pair tetracycline/θ-shaped anion [3,3'-Co(1,2-CBH)] ([-COSAN]) was formulated and deposited on a SWCNT modified gold microelectrode. The chosen transduction technique was electrochemical impedance spectroscopy (EIS). The PVC membrane was composed of: the tetracycline/[-COSAN] ion-pair, a plasticizer. A detection limit of 0.3 pg/L was obtained with this membrane, using bis(2-ethylhexyl) sebacate as a plasticizer. The sensitivity of detection of tetracycline was five times higher than that of oxytetracycline and of terramycin, and 22 times higher than that of demeclocycline. A shelf-life of the prepared sensor was more than six months and was used for detection in spiked honey samples. These results open the way to having continuous monitoring sensors with a high detection capacity, are easy to clean, avoid the use of antibodies, and produce a direct measurement.
Topics: Plasticizers; Tetracycline; Anti-Bacterial Agents; Microelectrodes; Antibodies; Oxytetracycline
PubMed: 36671906
DOI: 10.3390/bios13010071 -
Cells Sep 2022The antibiotic tetracycline demeclocycline (DMC) was recently reported to rescue α-synuclein (α-Syn) fibril-induced pathology. However, the antimicrobial activity of...
The antibiotic tetracycline demeclocycline (DMC) was recently reported to rescue α-synuclein (α-Syn) fibril-induced pathology. However, the antimicrobial activity of DMC precludes its potential use in long-term neuroprotective treatments. Here, we synthesized a doubly reduced DMC (DDMC) derivative with residual antibiotic activity and improved neuroprotective effects. The molecule was obtained by removal the dimethylamino substituent at position 4 and the reduction of the hydroxyl group at position 12a on ring A of DMC. The modifications strongly diminished its antibiotic activity against Gram-positive and Gram-negative bacteria. Moreover, this compound preserved the low toxicity of DMC in dopaminergic cell lines while improving its ability to interfere with α-Syn amyloid-like aggregation, showing the highest effectiveness of all tetracyclines tested. Likewise, DDMC demonstrated the ability to reduce seeding induced by the exogenous addition of α-Syn preformed fibrils (α-Syn) in biophysical assays and in a SH-SY5Y-α-Syn-tRFP cell model. In addition, DDMC rendered α-Syn less inflammogenic. Our results suggest that DDMC may be a promising drug candidate for hit-to-lead development and preclinical studies in Parkinson's disease and other synucleinopathies.
Topics: Anti-Bacterial Agents; Demeclocycline; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Lead; Neuroblastoma; Neuroprotective Agents; Synucleinopathies
PubMed: 36078167
DOI: 10.3390/cells11172759 -
Synthetic and Systems Biotechnology Sep 2020Demecycline (DMTC) and demeclocycline (DMCTC) are C6-demethylated derivatives of tetracycline (TC) and chlortetracycline (CTC), respectively. They are precursors of...
Demecycline (DMTC) and demeclocycline (DMCTC) are C6-demethylated derivatives of tetracycline (TC) and chlortetracycline (CTC), respectively. They are precursors of minocycline and tigecycline, which showed remarkable bioactivity against TC-resistant bacteria and have been used clinically for decades. In order to biosynthesize drug precursors DMTC and DMCTC, the function of a possible C-methyltransferase encoding gene was studied systematically in the CTC high-yielding industrial strain F3. The mutant accumulated two new products, which were turned out to be DMTC and DMCTC. Meanwhile, time-course analysis of the fermentation products detected the epimers of DMTC and DMCTC transformed spontaneously. Finally, an engineering strain with higher productivity of DMCTC was constructed by deleting and overexpressing of three extra copies simultaneously. Construction of these two engineering strains not only served as a successful example of synthesizing required products through metabolic engineering, but also provided original strains for following elaborate engineering to synthesize more effective tetracycline derivatives.
PubMed: 32637665
DOI: 10.1016/j.synbio.2020.06.001 -
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 -
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 -
The Journal of Clinical Endocrinology... Oct 2021In patients with cancer, hyponatremia is associated with increased morbidity and mortality and can delay systemic therapy.
CONTEXT
In patients with cancer, hyponatremia is associated with increased morbidity and mortality and can delay systemic therapy.
OBJECTIVE
To assess the safety and efficacy of low-dose tolvaptan (7.5 mg) for hospitalized, adult patients with hyponatremia due to syndrome of inappropriate antidiuresis (SIAD), and coexisting malignancy.
METHODS
Retrospective evaluation in a tertiary cancer center.
RESULTS
Fifty-five patients with mean baseline serum sodium (sNa) 117.9 ± 4.6 mmol/L were included. In total, 90.9% had severe hyponatremia (sNa < 125 mmol/L). Mean age was 65.1 ± 9.3 years. Following an initial dose of tolvaptan 7.5 mg, median (range) increase in sNa observed at 24 hours was 9 (1-19) mmol/L. Within 1 week, 39 patients (70.9%) reached sNa ≥ 130 mmol/L and 48 (87.3%) had sNa rise of ≥5 mmol/L within 48 hours. No severe adverse events were reported. Thirty-three (60%) and 17 (30.9%) patients experienced sNa rise of ≥8 and ≥12 mmol/L/24 hours, respectively. The rate of sNa correction in the first 24 hours was significantly higher among participants that continued fluid restriction after tolvaptan administration (median [quantiles]: 14 [9-16] versus 8 [5-11] mmol/L, P = .036). Moreover, in the over-rapid correction cohort (≥12 mmol/L/24 hours) demeclocycline was appropriately discontinued only in 60% compared with 91.7% of the remaining participants (P = .047). Lower creatinine was predictive of higher sNa correction rate within 24 hours (P = .01).
CONCLUSION
In the largest series to date, although low-dose tolvaptan was demonstrated to be effective in correcting hyponatremia due to SIAD in cancer patients, a significant proportion experienced over-rapid correction. Concurrent administration of demeclocycline and/or fluid restriction must be avoided due to the increased risk of over-rapid correction.
Topics: Aged; Antidiuretic Hormone Receptor Antagonists; Female; Follow-Up Studies; Humans; Hyponatremia; Male; Neoplasms; Prognosis; Retrospective Studies; Tolvaptan
PubMed: 33693944
DOI: 10.1210/clinem/dgab131