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Journal of Experimental Orthopaedics Jul 2024Establishing zonal tendon-to-bone attachment could accelerate the anterior cruciate ligament reconstruction (ACLR) rehabilitation schedule and facilitate an earlier...
PURPOSE
Establishing zonal tendon-to-bone attachment could accelerate the anterior cruciate ligament reconstruction (ACLR) rehabilitation schedule and facilitate an earlier return to sports. KI24RGDS is a self-assembling peptide hydrogel scaffold (SAPS) with the RGDS amino acid sequence. This study aimed to elucidate the therapeutic potential of KI24RGDS in facilitating zonal tendon-to-bone attachment after ACLR.
METHODS
Sixty-four C57BL/6 mice were divided into the ACLR + SAPS and ACLR groups. ACLR was performed using the tail tendon. To assess the maturation of tendon-to-bone attachment, we quantified the area of mineralized fibrocartilage (MFC) in the tendon graft with demeclocycline. Immunofluorescence staining of α-smooth muscle actin (α-SMA) was performed to evaluate progenitor cell proliferation. The strength of tendon-to-bone attachment was evaluated using a pull-out test.
RESULTS
The MFC and maximum failure load in the ACLR + SAPS group were remarkably higher than in the ACLR group on Day 14. However, no significant difference was observed between the two groups on Day 28. The number of α-SMA-positive cells in the tendon graft was highest on Day 7 after ACLR in both the groups and was significantly higher in the ACLR + SAPS group than in the ACLR group.
CONCLUSION
This study highlighted the latent healing potential of KI24RGDS in facilitating early-stage zonal attachment of tendon grafts and bone tunnels post-ACLR. These findings may expedite rehabilitation protocols and shorten the timeline for returning to sports.
LEVEL OF EVIDENCE
Not applicable.
PubMed: 38899049
DOI: 10.1002/jeo2.12061 -
International Immunopharmacology Jan 2024Eph receptor tyrosine kinase EphB1/2 contributes to the development of liver fibrosis, suggesting the rationale that EphB1/2 inhibitors may be effective in liver...
Eph receptor tyrosine kinase EphB1/2 contributes to the development of liver fibrosis, suggesting the rationale that EphB1/2 inhibitors may be effective in liver fibrosis therapy. Since tetracycline antibiotics were recently demonstrated as EphB kinase inhibitors, in present study we investigated their therapeutic potential against liver fibrosis. Our results showed that the tetracycline combination of demeclocycline (D), chlortetracycline (C), and minocycline (M) inhibited the activation of hepatic stellate cells (HSCs) in vitro and alleviated CCl-induced animal model of liver fibrosis in vivo. Mechanistically, DCM combination inhibited EphB1/2 phosphorylation and subsequent activation of the MAPK signaling. Moreover, we found that short-term and low-dose DCM combination treatment decreased tissue inflammation and improved liver fibrosis in mice. Thus, our study indicates that tetracyclines may be repurposed for the treatment of liver fibrosis.
Topics: Animals; Mice; Signal Transduction; Tetracyclines; Tetracycline; Liver Cirrhosis; Anti-Bacterial Agents; Hepatic Stellate Cells; Liver; Carbon Tetrachloride
PubMed: 37992441
DOI: 10.1016/j.intimp.2023.111261 -
Scientific Reports Aug 2023Tetracyclines exhibit anti-viral, anti-inflammatory, and immunomodulatory activities via various mechanisms. The present study investigated the efficacy and safety of... (Randomized Controlled Trial)
Randomized Controlled Trial
Tetracyclines exhibit anti-viral, anti-inflammatory, and immunomodulatory activities via various mechanisms. The present study investigated the efficacy and safety of demeclocycline in patients hospitalized with mild-to-moderate COVID-19 via an open-label, multicenter, parallel-group, randomized controlled phase 2 trial. Primary and secondary outcomes included changes from baseline (day 1, before the study treatment) in lymphocytes, cytokines, and SARS-CoV-2 RNA on day 8. Seven, seven, and six patients in the control, demeclocycline 150 mg daily, and demeclocycline 300 mg daily groups, respectively, were included in the modified intention-to-treat population that was followed until day 29. A significant change of 191.3/μL in the number of CD4 T cells from day 1 to day 8 was observed in the demeclocycline 150 mg group (95% CI 5.1/μL-377.6/μL) (p = 0.023), whereas that in the control group was 47.8/μL (95% CI - 151.2/μL to 246.8/μL), which was not significant (p = 0.271). The change rates of CD4 T cells negatively correlated with those of IL-6 in the demeclocycline-treated groups (R = - 0.807, p = 0.009). All treatment-emergent adverse events were of mild-to-moderate severity. The present results indicate that the treatment of mild-to-moderate COVID-19 patients with demeclocycline elicits immune responses conducive to recovery from COVID-19 with good tolerability.Trial registration: This study was registered with the Japan Registry of Clinical Trials (Trial registration number: jRCTs051200049; Date of the first registration: 26/08/2020).
Topics: Humans; COVID-19; Demeclocycline; RNA, Viral; SARS-CoV-2
PubMed: 37612352
DOI: 10.1038/s41598-023-41051-2 -
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 -
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 -
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 -
Antioxidants (Basel, Switzerland) Feb 2023Several studies have reported that the tetracycline (TC) class antibiotic doxycycline () is effective against Parkinson's disease (PD) pathomechanisms. The aim of the...
Several studies have reported that the tetracycline (TC) class antibiotic doxycycline () is effective against Parkinson's disease (PD) pathomechanisms. The aim of the present work was three-fold: (i) Establish a model system to better characterize neuroprotection by ; (ii) Compare the rescue effect of to that of other TC antibiotics; (iii) Discover novel neuroprotective TCs having reduced antibiotic activity. For that, we used cultures of mouse midbrain dopamine (DA) neurons and experimental conditions that model iron-mediated oxidative damage, a key mechanism in PD pathobiology. We found that and the other TC antibiotic, demeclocycline (), provided sustained protection to DA neurons enduring iron-mediated insults, whereas chlortetracycline and non-TC class antibiotics did not. Most interestingly, non-antibiotic derivatives of and , i.e., and , respectively, were also robustly protective for DA neurons. Interestingly, , , and remained protective for DA neurons until advanced stages of neurodegeneration, and the rescue effects of TCs were observable regardless of the degree of maturity of midbrain cultures. Live imaging studies with the fluorogenic probes DHR-123 and TMRM revealed that protective TCs operated by preventing intracellular oxidative stress and mitochondrial membrane depolarization, i.e., cellular perturbations occurring in this model system as the ultimate consequence of ferroptosis-mediated lipid peroxidation. If oxidative/mitochondrial insults were generated acutely, , and were no longer neuroprotective, suggesting that these compounds are mostly effective when neuronal damage is chronic and of low-intensity. Overall, our data suggest that TC derivatives, particularly those lacking antibiotic activity, might be of potential therapeutic utility to combat low-level oxidative insults that develop chronically in the course of PD neurodegeneration.
PubMed: 36978822
DOI: 10.3390/antiox12030575 -
Tuberculosis (Edinburgh, Scotland) May 2023Multidrug-resistant tuberculosis (MDR-TB) has become a big threaten to global health. The current strategy for treatment of MDR-TB and extensive drug resistant...
BACKGROUND
Multidrug-resistant tuberculosis (MDR-TB) has become a big threaten to global health. The current strategy for treatment of MDR-TB and extensive drug resistant tuberculosis (XDR-TB) is with low efficacy and high side effect. While new drug is fundamental for cure MDR-TB, repurposing the Food and Drug Administration (FDA)-approved drugs represents an alternative soluation with less cost.
METHODS
The activity of 8 tetracycline-class antibiotics against mycobacterium tuberculosis (M.tb) were determined by Minimum Inhibitory Concentration (MIC) in vitro. A transposon M.smeg libraries was generated by using the Harm phage and then used to isolate the conditional growth mutants in doxycycline containing plate. Eleven mutants were isolated and genomic DNAs were extracted using the cetyltrimethyl ammonium bromide (CTAB) method and analyzed by whole genome sequencing.
RESULTS
We found that three of eight drugs efficiently inhibited mycobacteria growth under the peak plasma concentration in the human body. Further tests showed these three tetracycline analogs (demeclocycline, doxycycline and methacycline) had antimicrobial activity against seven clinical isolates, including MDR and XDR strains. Among them, Doxycycline had the lowest MICs in all mycobacteria strains tested in this study. By using a transposon library, we identify the insertion of transposon in two genes, porin and MshA, associatewith the resistant to doxycycline.
CONCLUSIONS
Our findings show that tetracycline analogs such as doxycycline, has bactericidal activity against not only drug sensitive M.tb, but also clinical MDR and XDR strains, provided proof of concept to repurpose doxycycline to fight MDR-TB and XDR-TB. Further investigations are warranted to clarify the underlying mechanism and optimize the strategy in combination with other anti-TB drugs.
Topics: Humans; Mycobacterium tuberculosis; Antitubercular Agents; Extensively Drug-Resistant Tuberculosis; Doxycycline; Tuberculosis, Multidrug-Resistant; Tetracycline; Drug Resistance; Microbial Sensitivity Tests; Drug Resistance, Multiple, Bacterial
PubMed: 36963294
DOI: 10.1016/j.tube.2023.102336 -
ACS Chemical Neuroscience Feb 2023H,N-Heteronuclear Single Quantum Coherence (HSQC) NMR is a powerful technique that has been employed to characterize small-molecule interactions with intrinsically...
H,N-Heteronuclear Single Quantum Coherence (HSQC) NMR is a powerful technique that has been employed to characterize small-molecule interactions with intrinsically disordered monomeric α-Synuclein (aSyn). We report how solution pH can impact the interpretation of aSyn HSQC NMR spectra and demonstrate that small-molecule formulations (e.g., complexation with acidic salts) can lower sample pH and confound interpretation of drug binding and concomitant protein structural changes. Through stringent pH control, we confirm that several previously identified compounds (EGCG, Baicalin, and Dopamine (DOPA)) as well as a series of potent small-molecule inhibitors of aSyn pathology (Demeclocycline, Ro90-7501, and (±)-Bay K 8644) are capable of direct target engagement of aSyn. Previously, DOPA-aSyn interactions have been shown to elicit a dramatic chemical shift perturbation (CSP) localized to aSyn's H50 at low DOPA concentrations then expanding to aSyn's acidic C-terminal residues at increasing DOPA levels. Interestingly, this CSP profile mirrors our pH titration, where a small reduction in pH affects H50 CSP, and large pH changes induce robust C-terminal CSP. In contrast, under tightly controlled pH 5.0, DOPA induces significant CSPs observed at both ionizable and nonionizable residues. These results suggest that previous interpretations of DOPA-aSyn interactions were conflated with pH-induced CSP, highlighting the need for stringent pH control to minimize potential false-positive interpretations of ligand interactions in HSQC NMR experiments. Furthermore, DOPA's preferential interaction with aSyn under acidic pH represents a novel understanding of DOPA-aSyn interactions that may provide insight into the potential gain of toxic function of aSyn misfolding in α-synucleinopathies.
Topics: alpha-Synuclein; Dihydroxyphenylalanine; Hydrogen-Ion Concentration; Nuclear Magnetic Resonance, Biomolecular; Small Molecule Libraries
PubMed: 36749138
DOI: 10.1021/acschemneuro.2c00782 -
Advances in Experimental Medicine and... 2023One of the most prevalent indications of water-electrolyte imbalance is edema. Aquaporins (AQPs) are a protein family that can function as water channels. Osmoregulation...
One of the most prevalent indications of water-electrolyte imbalance is edema. Aquaporins (AQPs) are a protein family that can function as water channels. Osmoregulation and body water homeostasis are dependent on the regulation of AQPs. Human kidneys contain nine AQPs, five of which have been demonstrated to have a role in body water balance: AQP1, AQP2, AQP3, AQP4, and AQP7. Water imbalance is connected with AQP dysfunction. Hyponatremia with elevated AQP levels can accompany edema, which can be caused by disorders with low effective circulating blood volume and systemic vasodilation, such as congestive heart failure (CHF), hepatic cirrhosis, or the syndrome of incorrect antidiuretic hormone secretion (SIADH). In CHF, upregulation of AQP2 expression and targeting is critical for water retention. AQP2 is also involved in aberrant water retention and the formation of ascites in cirrhosis of the liver. Furthermore, water retention and hyponatremia in SIADH are caused by increased expression of AQP2 in the collecting duct. Fluid restriction, demeclocycline, and vasopressin type-2 receptor antagonists are widely utilized to treat edema. The relationship between AQPs and edema is discussed in this chapter.
Topics: Humans; Aquaporin 2; Inappropriate ADH Syndrome; Hyponatremia; Aquaporins; Edema; Heart Failure; Water
PubMed: 36717501
DOI: 10.1007/978-981-19-7415-1_19