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EMBO Molecular Medicine Jan 2024Japanese encephalitis virus (JEV) pathogenesis is driven by a combination of neuronal death and neuroinflammation. We tested 42 FDA-approved drugs that were shown to...
Japanese encephalitis virus (JEV) pathogenesis is driven by a combination of neuronal death and neuroinflammation. We tested 42 FDA-approved drugs that were shown to induce autophagy for antiviral effects. Four drugs were tested in the JE mouse model based on in vitro protective effects on neuronal cell death, inhibition of viral replication, and anti-inflammatory effects. The antipsychotic phenothiazines Methotrimeprazine (MTP) & Trifluoperazine showed a significant survival benefit with reduced virus titers in the brain, prevention of BBB breach, and inhibition of neuroinflammation. Both drugs were potent mTOR-independent autophagy flux inducers. MTP inhibited SERCA channel functioning, and induced an adaptive ER stress response in diverse cell types. Pharmacological rescue of ER stress blocked autophagy and antiviral effect. MTP did not alter translation of viral RNA, but exerted autophagy-dependent antiviral effect by inhibiting JEV replication complexes. Drug-induced autophagy resulted in reduced NLRP3 protein levels, and attenuation of inflammatory cytokine/chemokine release from infected microglial cells. Our study suggests that MTP exerts a combined antiviral and anti-inflammatory effect in JEV infection, and has therapeutic potential for JE treatment.
Topics: Animals; Mice; Encephalitis Virus, Japanese; Methotrimeprazine; Neuroinflammatory Diseases; Encephalitis, Japanese; Antiviral Agents; Autophagy; Anti-Inflammatory Agents
PubMed: 38177535
DOI: 10.1038/s44321-023-00014-w -
Journal of Environmental Management Nov 2023In the adsorption process, the surface area, pore and particle size distribution and the chemical structure of the solid and the type of adsorbent are of vital...
Production of demineralised high quality hierarchical activated carbon from lignite and determination of adsorption performance using methylene blue and p-nitrophenol: The role of surface functionality, accessible pore size and surface area.
In the adsorption process, the surface area, pore and particle size distribution and the chemical structure of the solid and the type of adsorbent are of vital importance. Activated carbon (AC) is a very good adsorbent material and its cost is highly dependent on the starting material and production method. The pore size and functional structure of the surface depend on the amount of activation chemical used. Hierarchical ACs were produced from lignite by loading two different amounts of KOH. The impregnation ratio (KOH/lignite) was chosen as 1/1 and 3/1 and the produced ACs were labelled as AC1 and AC3. The surface areas of AC1 and AC3 were determined as 1321.3 and 2421.3 m/g, and the total pore volumes were 1.079 and 1.425 cm/g. Methylene blue (MB) and p-nitrophenol (p-NP) were used to determine the adsorption performance of the produced ACs. The adsorption data were evaluated in terms of the Langmuir and Freundlich models. The amounts of MB and p-NP adsorbed on the surface were calculated in mg/g, total and accessible surface area in mg/m. It was determined that the MB and p-NP adsorbed to the AC1 sample were higher than the AC3 sample per m of population. Molecular orientation is possible depending on the solid surface functionality and chemical structure of the molecule to be adsorbed. It was concluded that in addition to the large surface area, the pore width that can be entered and the functional structure of the surface are very significant factors in the adsorption processes.
Topics: Adsorption; Charcoal; Methylene Blue; Coal; Kinetics; Water Pollutants, Chemical
PubMed: 37586173
DOI: 10.1016/j.jenvman.2023.118812 -
Molecular Pharmaceutics Dec 2023Mucus mechanically protects the intestinal epithelium and impacts the absorption of drugs, with a largely unknown role for bile. We explored the impacts of bile on...
Mucus mechanically protects the intestinal epithelium and impacts the absorption of drugs, with a largely unknown role for bile. We explored the impacts of bile on mucosal biomechanics and drug transport within mucus. Bile diffused with square-root-of-time kinetics and interplayed with mucus, leading to transient stiffening captured in Brillouin images and a concentration-dependent change from subdiffusive to Brownian-like diffusion kinetics within the mucus demonstrated by differential dynamic microscopy. Bile-interacting drugs, Fluphenazine and Perphenazine, diffused faster through mucus in the presence of bile, while Metoprolol, a drug with no bile interaction, displayed consistent diffusion. Our findings were corroborated by rat studies, where co-dosing of a bile acid sequestrant substantially reduced the bioavailability of Perphenazine but not Metoprolol. We clustered over 50 drugs based on their interactions with bile and mucin. Drugs that interacted with bile also interacted with mucin but not vice versa. This study detailed the dynamics of mucus biomechanics under bile exposure and linked the ability of a drug to interact with bile to its abbility to interact with mucus.
Topics: Rats; Animals; Bile; Elevators and Escalators; Perphenazine; Mucus; Mucins
PubMed: 37906224
DOI: 10.1021/acs.molpharmaceut.3c00550 -
PeerJ 2023In this study, a natural compound quercetin (Qu) was investigated for its various antitumor effects. However, due to its poor water solubility and low bioavailability,...
BACKGROUND
In this study, a natural compound quercetin (Qu) was investigated for its various antitumor effects. However, due to its poor water solubility and low bioavailability, its clinical application is limited. To overcome this constraint, a modification was to Qu, which resulted in the creation of novel flavonoid self-assembling nanoparticles (HCQ NPs).
METHODS
HCQ NPs were synthesized by a self-assembly method and characterized using transmission electron microscopy, the Malvern Zetasizer instrument, X-ray photoelectron spectroscopy (XPS), the ultraviolet-visible spectrophotometric method (UV-vis), Fourier transform infrared (FITR) and inductively coupled plasma mass spectrometry. Extracellular, methylene blue spectrophotometric analysis was used to determine the ability of HCQ NPs to react with different concentrations of HO to form hydroxyl radicals (OH). Intracellular, DCFH-DA staining was used to detect the ability of HCQ NPs to react with HO to generate reactive oxygen species. Flow cytometry was used to detect the uptake of HCQ NPs by MDA-MB-231 cells at different time points. The biocompatibility of HCQ NPs was evaluated using the Cell Counting Kit-8 (CCK-8) assay. Calcein AM/PI double staining and the CCK-8 assay were used to evaluate the synergistic antitumor effect of HCQ NPs and HO.
RESULTS
HCQ NPs showed uniformly sized analogous spherical shapes with a hydrodynamic diameter of 55.36 ± 0.27 nm. XPS revealed that Cu was mainly present as Cu in the HCQ NPs. UV-vis absorption spectrum of the characteristic peak of HCQ NPs was located at 296 nm. Similarly, FTIR spectroscopy revealed a complex formation of Qu and Cu that substantially changed the wavenumber of the 4-position C = O characteristic absorption peak. Based on the proportion of Qu and Cu (1:2), the total drug loading of Qu and Cu in the HCQ NPs for therapeutic purposes was calculated to be 9%. Methylene blue spectrophotometric analysis of OH indicated that Cu can lead to the generation of OH by triggering Fenton-like reactions. HCQ NPs rapidly accumulated in MDA-MB-231 cells with the extension of time, and the maximum accumulation concentration was reached at about 0.5 h. Calcein AM/PI double staining and CCK-8 revealed synergistic antitumor effects of HCQ NPs including the chemotherapeutic effect of Qu and chemodynamic therapy by Cu in a simulated tumor microenvironment. HCQ NPs demonstrated very low toxicity in LO2 cells in the biocompatibility experiment.
CONCLUSION
This study show cases a new method of creating self-assembled flavonoid HCQ NPs that show great for fighting cancer.
Topics: Humans; Quercetin; Flavonoids; Hyaluronic Acid; Hydrogen Peroxide; Methylene Blue; Neoplasms; Tumor Microenvironment
PubMed: 37663303
DOI: 10.7717/peerj.15942 -
Environmental Research Oct 2023Textile and pharmaceutical effluents contain significant amounts of dyes and antibiotics, which pose a serious threat to the ecosystem when discharged directly....
Simultaneous adsorption of methylene blue and amoxicillin by starch-impregnated MgAl layered double hydroxide: Parametric optimization, isothermal studies and thermo-kinetic analysis.
Textile and pharmaceutical effluents contain significant amounts of dyes and antibiotics, which pose a serious threat to the ecosystem when discharged directly. Therefore, they should be treated by facile treatment techniques using low-cost materials. Layered double hydroxide (LDH) and its hybrids have emerged as robust and economic adsorbents for water treatment. Herein, magnesium/aluminum LDH and its starch-based composite were synthesized by a co-precipitation technique. The physicochemical features of the developed adsorbents were thoroughly characterized using various analytical tools. The developed materials were tested for the eradication of methylene blue (MB) and amoxicillin (AMX) in batch mode adsorption by varying operating conditions. Adsorption performance depends on the solution's pH. Under optimum adsorption conditions of pH 11, adsorbent dosage of 50 mg/L, and treatment time of 120 min, starch-impregnated MgAl-LDH exhibited maximum MB and AMX adsorption capacities of 114.94 and 48.08 mg/g, respectively. The adsorption mechanism states that hydrogen bonds and weak van der Waals forces are responsible for the removal of pollutants by the developed materials. Moreover, equilibrium and kinetic studies revealed that the removal of dye and antibiotic followed the Freundlich and Langmuir models with the pseudo-second-order reaction kinetics, respectively. The spent adsorbents were regenerated using 0.1 M HCl (for MB) and methanol (for AMX) eluent, and reusability studies ensured that the developed adsorbents retained their performance for up to four consecutive adsorption/desorption cycles. MgAl-LDH and its starch-based hybrid could thus be used to effectively remove organic contaminants from wastewater streams on a commercial scale.
Topics: Kinetics; Methylene Blue; Adsorption; Amoxicillin; Ecosystem; Water Pollutants, Chemical; Hydroxides; Coloring Agents; Anti-Bacterial Agents; Hydrogen-Ion Concentration
PubMed: 37437872
DOI: 10.1016/j.envres.2023.116610 -
PeerJ 2023Amultigenerational study on was carried out by exposing three subsequent generations to pharmaceuticals chlorpromazine (CPZ) and diclofenac (DCF), and two lanthanide...
Amultigenerational study on was carried out by exposing three subsequent generations to pharmaceuticals chlorpromazine (CPZ) and diclofenac (DCF), and two lanthanide chlorides, gadolinium as GdCl and europium as EuCl. As the treatments, environmentally relevant concentrations were chosen (0.001, 0.01 and 0.1 mg/L for CPZ; 0.1, 1 and 10 mg/L for DCF; 0.425, 4.25 and 42.5 µg/L for Gd and 0.41, 4.1 and 41 µg/L for Eu). Survival, population growth and reproduction success were evaluated at 21 and 30 days of exposure, and the whole observation period lasted 40 days. The least sensitive to all selected substances was the first daphnid generation (F1). Within 21-day exposure, no significant effects of the psychotropic drug CPZ on survival were observed in generations F1-F3. The anti-inflammatory drug DCF did not affect survival in the F1 generation; however, it significantly reduced survival in the F3 generation at 1-10 mg/L. Both lanthanides did not affect survival in the F1 and F2 generations of but considerably decreased survival in the F3 at 4-42 µg/L. Both pharmaceuticals stimulated the reproduction of in the F1 generation, while inhibition occurred at the highest tested concentrations in generations F2 and F3. The inhibitory effect on the reproductive success of lanthanides in the F2 generation resembled that for CPZ but not for DCF. The dynamics of adverse effects during the 21-30-day period revealed that despite increased mortality in the controls (up to 30%), concentrations used in the study minified, in most instances, the survival and aggravated population growth and reproduction success of . Our data suggest that as a test organism can be used for 21 days in multigenerational investigations, especially when testing close to environmental concentrations. In this respect, the standard chronic toxicity assay seems limited since prolonged observations and several generations of daphnids are required to obtain reliable information for the risk assessment of potentially aggressive chemicals.
Topics: Animals; Chlorpromazine; Cladocera; Diclofenac; Lanthanoid Series Elements
PubMed: 38025671
DOI: 10.7717/peerj.16472 -
Translational Vision Science &... Oct 2023This study aimed to establish a mouse model of chlorpromazine-induced corneal trigeminal denervation (CCTD).
PURPOSE
This study aimed to establish a mouse model of chlorpromazine-induced corneal trigeminal denervation (CCTD).
METHODS
Retrobulbar chlorpromazine injections were administered to 6- to 8-week-old C57BL/6j mice to induce corneal denervation. Additionally, apoptosis was assessed in isolated primary trigeminal ganglion cells after culturing in a conditioned medium containing chlorpromazine. Finally, the success rate of model generation, mortality and complication rates, and model-preparation learning curves were compared between the CCTD model and the electrocoagulation and axotomy models.
RESULTS
Chlorpromazine retrobulbar injections resulted in trigeminal denervation, leading to a reduced blink reflex, corneal nerve density, and corneal epithelium thickness. Furthermore, 90% (9/10) of the mice developed epithelial defects, accompanied by increased apoptosis and inhibited proliferation of corneal epithelial cells. In vitro, trigeminal ganglion cell apoptosis increased after culturing in a conditioned medium containing chlorpromazine. Moreover, the CCTD model exhibited a higher success rate, longer survival rate, and lower complication rate compared to the electrocoagulation and axotomy models. Crucially, the learning curve demonstrated that the method used to generate the CCTD model was easy to learn.
CONCLUSIONS
The CCTD model is a user-friendly mouse model for studying corneal trigeminal denervation that offers a less invasive alternative to existing models.
TRANSLATIONAL RELEVANCE
The CCTD model serves as a valuable tool for investigating the functional mechanisms of corneal trigeminal nerves and their interactions with corneal cells.
Topics: Animals; Mice; Mice, Inbred C57BL; Chlorpromazine; Culture Media, Conditioned; Cornea; Disease Models, Animal; Denervation
PubMed: 37906054
DOI: 10.1167/tvst.12.10.21 -
Photodiagnosis and Photodynamic Therapy Sep 2023Ethylenediamine-N,N,N',N'-tetrakis(methylenephosphonic acid (EDTMP), nitrilotri(methylphosphonic acid (ATMP) and zoledronic acid were studied to enhance the methylene...
Ethylenediamine-N,N,N',N'-tetrakis(methylenephosphonic acid (EDTMP), nitrilotri(methylphosphonic acid (ATMP) and zoledronic acid were studied to enhance the methylene blue-mediated photodynamic inactivation of Acinetobacter baumannii. Laser light (wavelength 638 nm; standard light output 40 mW) was used in all experiment. Planktonic cultures were irradiated for 10, 20 and 30 min which corresponded to the light dose of 63 Jcm, 126 Jcm and 189 Jcm. Biocidal effect depended on the exposure time and it was shown that MB alone caused the highest reduction in the number of viable cells by 3.10 ± 0.2 log units after 30 min of irradiation. A significantly more effective killing effect was achieved when the bacteria were pre-treated with zoledronate, ATMP, or EDTMP (prior to photosensitisation) as the number of viable bacteria was reduced by 4.04±0.2 log, 3.95±0.2 log and 4.01 ± 0.2 log, respectively. The photo-killing effect caused by MB against biofilm pre-incubated with zoledronate, ATMP, or EDTMP and the number of viable bacteria was reduced by 0.80±0.1 log, 1.25±0.05 log and 0.65±0.05 log, respectively. Polyphosphonic chelating agents increased the efficiency of photo-destruction of A. baumannii by increasing the amount of bound photosensitizer by planktonic cells and biofilm, and increasing the detachment of live planktonic cells from the biofilm. The presence of glucose in the photosensitizing system significantly affected the bacterial photo-elimination. Pre-incubation of planktonic bacteria with the studied polyphosphonic chelating agents in the presence of glucose, and then exposure to light (with MB) for 30 min caused the lethal effect. This photo-eradication protocol (in the case of biofilms) reduced the number of viable bacteria by 2.05±0.2 log, 3.2±0.2 log and 2.02±0.2 log for zoledronic acid, ATMP and EDTMP, respectively.
Topics: Photosensitizing Agents; Photochemotherapy; Acinetobacter baumannii; Zoledronic Acid; Light; Biofilms; Methylene Blue; Anti-Bacterial Agents
PubMed: 37364665
DOI: 10.1016/j.pdpdt.2023.103672 -
BMC Surgery Sep 2023This study aimed to assess the effects of surgical timing and approach on operative duration, postoperative suture removal time, and postoperative recurrence rate in the...
OBJECTIVE
This study aimed to assess the effects of surgical timing and approach on operative duration, postoperative suture removal time, and postoperative recurrence rate in the management of preauricular fistula. A 12-year single-center clinical observation was conducted to analyze the potential effects of different surgical strategies on these critical outcomes.
METHODS
The clinical data from 576 (782 ears) patients who underwent surgical resection for preauricular fistulas were examined in this retrospective study. The patients were classified into various groups based on differences in operative duration, surgical techniques and the use of intraoperative magnifying equipment. Furthermore, the specific data on operative duration, postoperative suture removal time, and postoperative recurrence rate were also recorded.
RESULTS
The average operative duration for 782 ears and the average time required for postoperative suture removal were determined to be (34.57 ± 4.25) min and (3.62 ± 0.76) days, respectively. Among the cases examined, recurrence occurred in 13 ears, but all of them were cured after a second surgery, resulting in a recurrence rate of 1.67% (13/782). Interestingly, the operative and postoperative suture removal time was prolonged during the infection period (P < 0.05). The postoperative recurrence rate was significantly higher in the absence of magnifying equipment, as compared to those with the use of a microscope with 2.5× magnification (P < 0.05). No statistically significant differences were noted in the recurrence rate when comparing different anesthesia methods and types of surgical incisions, as well as the intraoperative use of methylene blue, and partial removal of cartilage of the pedicle (P > 0.05).
CONCLUSION
The use of methylene blue, partial removal of the cartilage of the pedicle, and surgical incision during preauricular fistula resection did not affect the operative duration, postoperative suture removal time, and postoperative recurrence rate. Therefore, surgeons can select their preferred approaches based on their individual practices and patient-specific situations. However, the use of magnifying equipment during surgery is associated with a reduced risk of recurrence.
Topics: Humans; Retrospective Studies; Treatment Outcome; Methylene Blue; Ear, External; Recurrence; Fistula
PubMed: 37775750
DOI: 10.1186/s12893-023-02198-x -
Techniques in Coloproctology Oct 2023To evaluate how effective methylene blue injection was at treating intractable idiopathic pruritus ani. (Meta-Analysis)
Meta-Analysis Review
PURPOSE
To evaluate how effective methylene blue injection was at treating intractable idiopathic pruritus ani.
METHODS
A comprehensive literature search of the PubMed, Embase, Cochrane library, and Web of Science databases was conducted. All clinical studies (prospective and retrospective) that evaluated the efficacy of methylene blue in treating intractable idiopathic pruritus ani were included. Studies that reported the resolution rate, after a single injection and after a second injection, the recurrence rate, symptom scores, and transient complications of methylene blue injections in treating intractable idiopathic pruritus ani were included.
RESULTS
The seven selected studies included 225 patients with idiopathic pruritus ani. The resolution rates after a single injection and after a second injection was 0.761 (0.649-0.873, P < 0.01, I = 69.06%) and 0.854 (0.752-0.955, P < 0.01, I = 77.391%), respectively, the remission rates at 1, 3, and 5 years were 0.753 (0.612-0.893, P < 0.001), 0.773 (0.675-0.871, P < 0.001) and 0.240 (0.033-0.447, P < 0.001), respectively, the effect value of the merger was 0.569 (0.367-0.772, P < 0.001, I = 79.199%), and the recurrence rates at 1, 2, 3, and < 1 year were 0.202 (0.083-0.322, P < 0.001), 0.533 (0.285-0.781, P < 0.001), 0.437 (-0.044, 0.917, P < 0.001) and 0.067 (0.023-0.111, P < 0.001), respectively. The effect value of the merger was 0.223 (0.126-0.319, P < 0.001, I = 75.840).
CONCLUSION
Using methylene blue injections to treat intractable idiopathic pruritus ani is relatively efficacious, resulting in a relatively low recurrence rate and no severe complications. However, the available literature was of poor quality. Therefore, higher quality studies are necessary to confirm that methylene blue injection is efficacious for pruritus ani, such as a randomized prospective multicenter studies.
Topics: Humans; Pruritus Ani; Methylene Blue; Retrospective Studies; Prospective Studies; Injections, Intradermal
PubMed: 37306793
DOI: 10.1007/s10151-023-02825-y