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Frontiers in Immunology 2023Tuberculosis (TB) is caused by the bacterial pathogen and is one of the principal reasons for mortality and morbidity worldwide. Currently, recommended... (Review)
Review
Tuberculosis (TB) is caused by the bacterial pathogen and is one of the principal reasons for mortality and morbidity worldwide. Currently, recommended anti-tuberculosis drugs include isoniazid, rifampicin, ethambutol, and pyrazinamide. TB treatment is lengthy and inflicted with severe side-effects, including reduced patient compliance with treatment and promotion of drug-resistant strains. TB is also prone to other concomitant diseases such as diabetes and HIV. These drug-resistant and complex co-morbid characteristics increase the complexity of treating MTB. Host-directed therapy (HDT), which effectively eliminates MTB and minimizes inflammatory tissue damage, primarily by targeting the immune system, is currently an attractive complementary approach. The drugs used for HDT are repositioned drugs in actual clinical practice with relative safety and efficacy assurance. HDT is a potentially effective therapeutic intervention for the treatment of MTB and diabetic MTB, and can compensate for the shortcomings of current TB therapies, including the reduction of drug resistance and modulation of immune response. Here, we summarize the state-of-the-art roles and mechanisms of HDT in immune modulation and treatment of MTB, with a special focus on the role of HDT in diabetic MTB, to emphasize the potential of HDT in controlling MTB infection.
Topics: Humans; Tuberculosis; Diabetes Mellitus; Antitubercular Agents; Ethambutol; Isoniazid
PubMed: 38259491
DOI: 10.3389/fimmu.2023.1305325 -
Cellular and Molecular Life Sciences :... Aug 2023Retinal ganglion cells (RGCs) are essential for vision perception. In glaucoma and other optic neuropathies, RGCs and their optic axons undergo degenerative change and...
Retinal ganglion cells (RGCs) are essential for vision perception. In glaucoma and other optic neuropathies, RGCs and their optic axons undergo degenerative change and cell death; this can result in irreversible vision loss. Here we developed a rapid protocol for directly inducing RGC differentiation from human induced pluripotent stem cells (hiPSCs) by the overexpression of ATOH7, BRN3B, and SOX4. The hiPSC-derived RGC-like cells (iRGCs) show robust expression of various RGC-specific markers by whole transcriptome profiling. A functional assessment was also carried out and this demonstrated that these iRGCs display stimulus-induced neuronal activity, as well as spontaneous neuronal activity. Ethambutol (EMB), an effective first-line anti-tuberculosis agent, is known to cause serious visual impairment and irreversible vision loss due to the RGC degeneration in a significant number of treated patients. Using our iRGCs, EMB was found to induce significant dose-dependent and time-dependent increases in cell death and neurite degeneration. Western blot analysis revealed that the expression levels of p62 and LC3-II were upregulated, and further investigations revealed that EMB caused a blockade of lysosome-autophagosome fusion; this indicates that impairment of autophagic flux is one of the adverse effects of that EMB has on iRGCs. In addition, EMB was found to elevate intracellular reactive oxygen species (ROS) levels increasing apoptotic cell death. This could be partially rescued by the co-treatment with the ROS scavenger NAC. Taken together, our findings suggest that this iRGC model, which achieves both high yield and high purity, is suitable for investigating optic neuropathies, as well as being useful when searching for potential drugs for therapeutic treatment and/or disease prevention.
Topics: Humans; Retinal Ganglion Cells; Reactive Oxygen Species; Induced Pluripotent Stem Cells; Optic Nerve Diseases; Apoptosis; Ethambutol; SOXC Transcription Factors
PubMed: 37540379
DOI: 10.1007/s00018-023-04890-w -
Journal of Agricultural and Food... Oct 2023Serious concerns about the negative impact of ethylenediaminetetraacetic acid (EDTA) on the environment resulted in severe restrictions imposed on this compound in many...
Serious concerns about the negative impact of ethylenediaminetetraacetic acid (EDTA) on the environment resulted in severe restrictions imposed on this compound in many countries. One of the main concerns is related to the use of EDTA in agriculture as a chelator in microelement fertilizers: being introduced directly into the sawing fields, it penetrates into groundwater, with no chance to be captured/recycled. Respectively, there is an active search for environmentally friendly, biodegradable alternatives for this chelator. In this study, we proposed a biodegradable chelating agent, 2-((1,2-dicarboxyethyl)amino)pentanedioic acid (IGSA). It was synthesized in accordance with the principles of "green chemistry" from readily available nonhazardous precursors using water as a solvent; in addition, the method yields literally no waste. The synthesized chelator in the form of the crude reaction mixture was further used for preparing a multicomponent micronutrient fertilizer (B, Zn, Fe, Cu, Mn, and Mo). The fertilizer was shown to be highly biodegradable (72% in 28 days), while the EDTA-based product degraded only by 13%. The plant growing efficiency was tested on lettuce in the greenhouse experiments. The results were compared against the known commercial fertilizers based on EDTA and iminodisuccinic acid (IDS). The newly developed IGSA-based fertilizer significantly outperformed the EDTA-based fertilizer in lettuce biomass (1.4 and 1.6 times for root and foliar application, respectively). The total mineral uptake was almost two times higher (1.9 and 1.8 times for root and foliar treatments, respectively) compared to the EDTA-based complex and even slightly higher (1.2 and 1.1 times, respectively) compared to the IDS-based complex. Our work opens the doors for the industrial scale production and application of this fully "green", inexpensive microelement fertilizer that has the potential to replace the EDTA-based products.
Topics: Chelating Agents; Edetic Acid; Fertilizers; Micronutrients; Trace Elements; Fertilization; Soil
PubMed: 37791964
DOI: 10.1021/acs.jafc.3c03500 -
European Journal of Medicinal Chemistry Oct 2023Tuberculosis remains a major public health problem and one of the top ten causes of death worldwide. The alarming increase in multidrug-resistant and extensively...
Tuberculosis remains a major public health problem and one of the top ten causes of death worldwide. The alarming increase in multidrug-resistant and extensively resistant variants (MDR, pre-XDR, and XDR) makes the disease more difficult to treat and control. New drugs that act against MDR/XDR strains are needed for programs to contain this major epidemic. The present study aimed to evaluate new compounds related to dihydro-sphingosine and ethambutol against sensitive and pre-XDR Mycobacterium strains, as well as to characterize the pharmacological activity through in vitro and in silico approaches in mmpL3 protein. Of the 48 compounds analyzed, 11 demonstrated good to moderate activity on sensitive and MDR Mycobacterium tuberculosis (Mtb), with a Minimum Inhibitory Concentration (MIC) ranging from 1.5 to 8 μM. They presented 2 to 14 times greater potency of activity when compared to ethambutol in pre-XDR strain, and demonstrated a selectivity index varying between 2.21 and 82.17. The substance 12b when combined with rifampicin, showed a synergistic effect (FICI = 0.5) on sensitive and MDR Mtb. It has also been shown to have a concentration-dependent intracellular bactericidal effect, and a time-dependent bactericidal effect in M. smegmatis and pre-XDR M. tuberculosis. The binding mode of the compounds in its cavity was identified through molecular docking and using a predicted structural model of mmpL3. Finally, we observed by transmission electron microscopy the induction of damage to the cell wall integrity of M. tuberculosis treated with the substance 12b. With these findings, we demonstrate the potential of a 2-aminoalkanol derivative to be a prototype substance and candidate for further optimization of molecular structure and anti-tubercular activity in preclinical studies.
Topics: Humans; Mycobacterium tuberculosis; Ethambutol; Antitubercular Agents; Sphingosine; Molecular Docking Simulation; Tuberculosis, Multidrug-Resistant; Tuberculosis; Microbial Sensitivity Tests; Drug Resistance, Multiple, Bacterial
PubMed: 37399709
DOI: 10.1016/j.ejmech.2023.115579 -
Journal of Visualized Experiments : JoVE Mar 2024The interaction of iron and oxygen is an integral part of the development of life on Earth. Nonetheless, this unique chemistry continues to fascinate and puzzle, leading...
The interaction of iron and oxygen is an integral part of the development of life on Earth. Nonetheless, this unique chemistry continues to fascinate and puzzle, leading to new biological ventures. In 2012, a Columbia University group recognized this interaction as a central event leading to a new type of regulated cell death named "ferroptosis." The major feature of ferroptosis is the accumulation of lipid hydroperoxides due to (1) dysfunctional antioxidant defense and/or (2) overwhelming oxidative stress, which most frequently coincides with increased content of free labile iron in the cell. This is normally prevented by the canonical anti-ferroptotic axis comprising the cystine transporter xCT, glutathione (GSH), and GSH peroxidase 4 (GPx4). Since ferroptosis is not a programmed type of cell death, it does not involve signaling pathways characteristic of apoptosis. The most common way to prove this type of cell death is by using lipophilic antioxidants (vitamin E, ferrostatin-1, etc.) to prevent it. These molecules can approach and detoxify oxidative damage in the plasma membrane. Another important aspect in revealing the ferroptotic phenotype is detecting the preceding accumulation of lipid hydroperoxides, for which the specific dye BODIPY C11 is used. The present manuscript will show how ferroptosis can be induced in wild-type medulloblastoma cells by using different inducers: erastin, RSL3, and iron-donor. Similarly, the xCT-KO cells that grow in the presence of NAC, and which undergo ferroptosis once NAC is removed, will be used. The characteristic "bubbling" phenotype is visible under the light microscope within 12-16 h from the moment of ferroptosis triggering. Furthermore, BODIPY C11 staining followed by FACS analysis to show the accumulation of lipid hydroperoxides and consequent cell death using the PI staining method will be used. To prove the ferroptotic nature of cell death, ferrostatin-1 will be used as a specific ferroptosis-preventing agent.
Topics: Humans; Medulloblastoma; Lipid Peroxidation; Antioxidants; Iron; Glutathione; Lipid Peroxides; Cerebellar Neoplasms; Phenotype; Boron Compounds; Cyclohexylamines; Phenylenediamines
PubMed: 38557602
DOI: 10.3791/66645 -
Environmental Science & Technology Oct 2023-(1,3-Dimethylbutyl)-'-phenyl--phenylenediamine (6-PPD) is a widely used antioxidant in tire rubber known to enter the aquatic environment via road runoff. The...
-(1,3-Dimethylbutyl)-'-phenyl--phenylenediamine (6-PPD) is a widely used antioxidant in tire rubber known to enter the aquatic environment via road runoff. The associated transformation product (TP) 6-PPD quinone (6-PPDQ) causes extreme acute toxicity in some fish species (e.g., coho salmon). To interpret the species-specific toxicity, information about biotransformation products of 6-PPDQ would be relevant. This study investigated toxicokinetics of 6-PPD and 6-PPDQ in the zebrafish embryo (ZFE) model. Over 96 h of exposure, 6-PPD and 6-PPDQ accumulated in the ZFE with concentration factors ranging from 140 to 2500 for 6-PPD and 70 to 220 for 6-PPDQ. A total of 22 TPs of 6-PPD and 12 TPs of 6-PPDQ were tentatively identified using liquid chromatography coupled to high-resolution mass spectrometry. After 96 h of exposure to 6-PPD, the TPs of 6-PPD comprised 47% of the total peak area (TPA), with 4-hydroxydiphenylamine being the most prominent in the ZFE. Upon 6-PPDQ exposure, >95% of 6-PPDQ taken up in the ZFE was biotransformed, with 6-PPDQ + O + glucuronide dominating (>80% of the TPA). Among other TPs of 6-PPD, a reactive -phenyl--benzoquinone imine was found. The knowledge of TPs of 6-PPD and 6-PPDQ from this study may support biotransformation studies in other organisms.
Topics: Animals; Biotransformation; Chromatography, Liquid; Rubber; Zebrafish; Embryo, Nonmammalian; Toxicokinetics; Phenylenediamines; Benzoquinones
PubMed: 37782849
DOI: 10.1021/acs.est.3c02819 -
International Endodontic Journal Oct 2023Sodium hypochlorite (NaOCl) and ethylenediaminetetraacetic acid (EDTA) and/or calcium hydroxide (Ca(OH) ) are commonly used during root canal treatment. Evaluation of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Sodium hypochlorite (NaOCl) and ethylenediaminetetraacetic acid (EDTA) and/or calcium hydroxide (Ca(OH) ) are commonly used during root canal treatment. Evaluation of their effectiveness regarding clinical and patient-related outcomes requires further understanding.
OBJECTIVES
To assess the effectiveness of root canal irrigation and dressing for the treatment of teeth with apical periodontitis (AP).
METHODS
A search was conducted in the PubMed-MEDLINE, Scopus, EMBASE, Google scholar databases and available repositories, followed by hand searches, until July 2021. Eligibility criteria followed the a priori formulated Population, Intervention, Comparator, Outcomes, Timing, and Study design (PICOTS) framework. Clinical studies restricted to English language were included. The revised Cochrane risk-of-bias tool for randomised trials (RoB 2) was used to assess the quality of included studies. Meta-analyses were performed using the fixed-effect model to obtain Risk Ratio (RR) and 95% Confidence Interval (CI), with sensitivity analysis. Overall quality of evidence of meta-analyses was assessed through the Grading of Recommendations Assessment, Development, and Evaluation tool.
RESULTS
The search identified 1357 records of which six fulfilled the inclusion criteria, providing data for 'irrigation' from 212 teeth and for 'dressings' from 438 teeth. Two studies reported no significant difference regarding the outcome 'pain at 7 days' using 2% chlorhexidine vs. 5.25% NaOCl and EDTA or after using different concentrations of NaOCl (1% vs. 5%). No significant difference was detected between different NaOCl concentrations regarding the reduction of AP. A meta-analysis was possible for the comparison of single-visit (SV) versus multiple-visits including the use of Ca(OH) demonstrating a significant effect in favour of SV (RR: 1.10; 95% CI: 1.03-1.19; p = .007; I = 0). RoB of included studies was moderate to low.
DISCUSSION
The use of Ca(OH) for the treatment of AP may not be beneficial. There is scarce or no evidence fulfilling the proposed PICOTS regarding irrigants and dressings.
CONCLUSIONS
There is moderate certainty that SV treatment is associated with better radiographic evidence of normal periodontal ligament space (strict criteria) compared with the use of Ca(OH) Reduction of AP is comparable after irrigation with 1% and 5% NaOCl, whereas postoperative pain at 7 days for the irrigants assessed is similar.
REGISTRATION
PROSPERO database CRD42021260271.
Topics: Humans; Dental Pulp Cavity; Edetic Acid; Root Canal Therapy; Periapical Periodontitis; Bandages; Root Canal Irrigants
PubMed: 35579074
DOI: 10.1111/iej.13777 -
Science Advances Mar 2024Much is known about molecular mechanisms by which animals detect pathogenic microbes, but how animals sense beneficial microbes remains poorly understood. The roundworm...
Much is known about molecular mechanisms by which animals detect pathogenic microbes, but how animals sense beneficial microbes remains poorly understood. The roundworm is a microbivore that must distinguish nutritive microbes from pathogens. We characterized a neural circuit used by to rapidly discriminate between nutritive bacteria and pathogens. Distinct sensory neuron populations responded to chemical cues from nutritive and pathogenic , and these neural signals are decoded by downstream AIB interneurons. The polyamine metabolites cadaverine, putrescine, and spermidine produced by activate this neural circuit and elicit positive chemotaxis. Our study shows how polyamine odorants can be sensed by animals as proxies for microbe identity and suggests that, hence, polyamines might have widespread roles brokering host-microbe interactions.
Topics: Animals; Polyamines; Caenorhabditis elegans; Escherichia coli; Spermidine; Putrescine
PubMed: 38517971
DOI: 10.1126/sciadv.adj4387 -
International Immunopharmacology Mar 2024The pathological mechanism of sepsis-associated acute kidney injury (SA-AKI) is complex and involves tubular epithelial cell (TEC) death and immune cell activation....
The pathological mechanism of sepsis-associated acute kidney injury (SA-AKI) is complex and involves tubular epithelial cell (TEC) death and immune cell activation. However, the interaction between tubular cell death and macrophage-mediated inflammation remains unclear. In this study, we uncovered that TEC ferroptosis was activated in SA-AKI. Increased levels of ferroptotic markers, including ferroptosis-related proteins, lipid peroxidation, malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), reactive oxygen species (ROS), and mitochondrial damage, were observed in the kidney tissue of cecum ligation and puncture (CLP) and Lipopolysaccharide (LPS)-induced SA-AKI mouse models, which were subsequently suppressed by Ferrostatin-1 (Fer-1). In vitro experiments showed that Fer-1 inhibits LPS-induced mitochondrial damage, Fe accumulation, and cytosolic ROS production. Moreover, it was found that TEC ferroptosis induced by promoted macrophage-inducible C-type lectin (Mincle) and its downstream expression and M1 polarization, which was mediated by the release of spliceosome-associated protein 130 (SAP130), an endogenous ligand of Mincle, from TEC. It was confirmed in vitro that the supernatant from LPS-stimulated TECs promoted Mincle expression and M1 polarization in macrophages. Further experiments revealed that M1 macrophages aggravated TEC ferroptosis, which was offset by neutralizing SAP130 or inhibiting Mincle expression. In addition, neutralizing the circulatory SAP130 blunted kidney ferroptosis and Mincle expression, as well as macrophage infiltration in the kidney of SA-AKI mice. In conclusion, the release of SAP130 from ferroptotic TECs promoted M1 macrophage polarization by triggering Mincle/syk/NF-κB signaling, and M1 macrophages, in turn, aggravated TEC ferroptosis.
Topics: Animals; Mice; Acute Kidney Injury; Cyclohexylamines; Epithelial Cells; Ferroptosis; Lipopolysaccharides; Phenylenediamines; Reactive Oxygen Species; Sepsis
PubMed: 38320352
DOI: 10.1016/j.intimp.2024.111564 -
Praxis Feb 2024BCG instillations are considered to be the standard of care therapy for superficial urothelial bladder carcinoma. Although serious adverse events are uncommon, the...
BCG instillations are considered to be the standard of care therapy for superficial urothelial bladder carcinoma. Although serious adverse events are uncommon, the presence of high fever for at least two days in conjunction with systemic and/or local organ manifestations (except for urogenital symptoms), with the exclusion of other causes, suffice for the diagnosis of a disseminated BCG infection. Microbiologic detection of the pathogen is not necessary for diagnosis, as the detection of granuloma is more often successful and sufficient. Therapy for this infection includes oral Isoniazid, Rifampicin and Ethambutol for six months.
Topics: Humans; BCG Vaccine; Carcinoma, Transitional Cell; Ethambutol; Isoniazid; Rifampin
PubMed: 38536193
DOI: No ID Found