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Autophagy Jan 2023Aminoglycosides exhibit ototoxicity by damaging mitochondria, which in turn generate reactive oxygen species that induce hair cell death and subsequent hearing loss. It...
Aminoglycosides exhibit ototoxicity by damaging mitochondria, which in turn generate reactive oxygen species that induce hair cell death and subsequent hearing loss. It is well known that damaged mitochondria are degraded by mitophagy, an important mitochondrial quality control system that maintains mitochondrial homeostasis and ensures cell survival. However, it is unclear whether dysregulation of mitophagy contributes to aminoglycoside-induced hair cell injury. In the current study, we found that PINK1-PRKN-mediated mitophagy was impaired in neomycin-treated hair cells. Our data suggested that mitochondrial recruitment of PRKN and phagophore recognition of damaged mitochondria during mitophagy were blocked following neomycin treatment. In addition, the degradation of damaged mitochondria by lysosomes was significantly decreased as indicated by the mitophagic flux reporter mt-mKeima. Moreover, we demonstrated that neomycin disrupted mitophagy through transcriptional inhibition of expression, the key initiator of mitophagy. Moreover, we found that neomycin impaired mitophagy by inducing ATF3 expression. Importantly, treatment with a mitophagy activator could rescue neomycin-treated hair cells by increasing mitophagy, indicating that genetic modulation or drug intervention in mitophagy may have therapeutic potential for aminoglycoside-induced hearing loss. AAV: adeno-associated virus; ABR: auditory brainstem response; ATF3: activating transcription factor 3; ATOH1/MATH1: atonal bHLH transcription factor 1; BafA1: bafilomycin A; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; COX4I1/COXIV: cytochrome c oxidase subunit 4I1; CTBP2/RIBEYE: C-terminal binding protein 2; DFP: deferiprone; EGFP: enhanced green fluorescent protein; FOXO3: forkhead box O3; GRIA2/GLUR2: glutamate receptor, ionotropic, AMPA2 (alpha 2); HC: hair cell; HSPD1/HSP60: heat shock protein 1 (chaperonin); IHC: inner hair cell; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MYO7A: myosin VIIA; OPTN: optineurin; OMM: outer mitochondrial membrane; PRKN: parkin RBR E3 ubiquitin protein ligase; PINK1: PTEN induced putative kinase 1; RT-qPCR: real-time quantitative polymerase chain reaction; TOMM20/TOM20: translocase of outer mitochondrial membrane 20; TUNEL: Terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling; USP30: ubiquitin specific peptidase 30; XBP1: X-box binding protein 1.
Topics: Mitophagy; Autophagy; Aminoglycosides; Protein Kinases; Ubiquitin-Protein Ligases; Anti-Bacterial Agents; Neomycin; Hair Cells, Auditory
PubMed: 35471096
DOI: 10.1080/15548627.2022.2062872 -
Microbiology Spectrum Apr 2022Oral antibiotics remain the therapy of choice for severe bacterial infections; however, antibiotic use disrupts the intestinal microbiota, increasing the risk of...
Oral antibiotics remain the therapy of choice for severe bacterial infections; however, antibiotic use disrupts the intestinal microbiota, increasing the risk of colonization by intestinal pathogens. Currently, our understanding of antibiotic-mediated disturbances of the microbiota remains at the level of bacterial families or specific species, and little is known about the effect of antibiotics on potentially beneficial and pathogenic bacteria under the conditions of gut microbiota dysbiosis. Additionally, the question of whether the effects of antibiotics on the gut microbiota are temporary or permanent is controversial. In this study, we used 16S rRNA gene sequencing to evaluate the short- and long-term effects of ampicillin, vancomycin, metronidazole, and neomycin on the murine intestinal microbiota. We found that the changes in the intestinal microbiota reflected the antibiotics' mechanisms of action and that dysbiosis of the intestinal microbiota led to competition between different bacterial communities. In particular, an increase in , which accompanies a decrease in probiotics-related genera such as , is commonly seen across antibiotic treatments. In addition, we found that these oral antibiotics had long-term negative effects on the intestinal microbiota and promoted the development of antibiotic-resistant bacterial strains. These results indicate that ampicillin, vancomycin, metronidazole, and neomycin have long-term negative effects and can cause irreversible changes in the diversity of the intestinal microbiota, thereby increasing the risk of host disease. The intestinal microbiota is a dynamic community of hundreds of millions of microorganisms that play important roles in human health. However, treatment with antibiotics can disrupt the delicate balance of this community, leading to deleterious effects on the host such as inflammation and enhanced susceptibility to infection. To date, most studies of the effects of antibiotic treatment on the microbiota have focused on specific intestinal pathogens and bacterial families. However, few studies have investigated the effects of antibiotic treatment on the relative abundance of probiotic bacteria, pathogenic bacteria, and opportunistic bacterial pathogens in the gut.
Topics: Ampicillin; Animals; Anti-Bacterial Agents; Bacteria; Dysbiosis; Gastrointestinal Microbiome; Humans; Metronidazole; Mice; Neomycin; RNA, Ribosomal, 16S; Vancomycin
PubMed: 35311555
DOI: 10.1128/spectrum.01904-21 -
Polimery W Medycynie 2021Neomycin is a natural aminoglycoside antibiotic produced by actinomycete Streptomyces fradiae. It exerts bacteriostatic and bactericidal activity against Gram-negative...
BACKGROUND
Neomycin is a natural aminoglycoside antibiotic produced by actinomycete Streptomyces fradiae. It exerts bacteriostatic and bactericidal activity against Gram-negative bacteria, certain Gram-positive bacteria and Mycobacterium tuberculosis. Neomycin inhibits the biosynthesis of bacterial proteins by impairing their life functions, leading to death of cells.
OBJECTIVES
To examine the effect of molecular weight of polylactide (PLA), the applied stabilizer as well as mixing speed used in the encapsulation process on the size of obtained spheres. Examination of the kinetics of neomycin release from the obtained PLA spheres and determination of the antimicrobial activity of the neomycin-containing spheres against selected strains of bacteria, yeast and fungi have also been necessary.
MATERIAL AND METHODS
Polylactide (Mn 3000-40,000 g/mol) was obtained in-house. Other materials used in the study were as follows: L-lactic acid (PLLA; Mn 66,500 g/mol and 86,000 g/mol), polyvinyl alcohol (PVA) as a stabilizer of emulsion (Mw 30,000 g/mol, 130,000 g/mol; degree of hydrolysis 88%) as well as dichloromethane, p.a. and dimethyl sulfoxide (DMSO), p.a. as solvents. Distilled water was obtained in-house. Neomycin sulfate was used for encapsulation; phosphate (pH 7.2) and acetate (pH 4.5) buffers were used for the examination of the active pharmaceutical ingredient (API) dissolution profile. Antimicrobial activity was tested using commercial cell lines and the following media: Mueller-Hinton agar (MHA), Mueller-Hinton broth (MHB), yeast extract peptone dextrose (YPD), and potato dextrose agar (PDA).
RESULTS
Neomycin-containing PLA spheres were obtained using an emulsion method. The average molecular weight of PLA, the average molecular weight of PVA and mixing speed on the size of obtained spheres were investigated. Furthermore, the profile of API dissolution from the spheres and antimicrobial activity of neomycin-containing spheres against certain strains of bacteria, yeast and fungi were determined.
CONCLUSIONS
We demonstrated that efficient encapsulation of neomycin requires spheres of a <200 mm diameter.
Topics: Anti-Bacterial Agents; Kinetics; Neomycin; Polyesters; Streptomyces
PubMed: 34327877
DOI: 10.17219/pim/139586 -
BMC Biotechnology Oct 2022In the search for methods to biodegrade recalcitrant compounds, the use of saprotrophic fungi and white rot fungi, in particular belonging to the phylum Basidiomycota,...
BACKGROUND
In the search for methods to biodegrade recalcitrant compounds, the use of saprotrophic fungi and white rot fungi, in particular belonging to the phylum Basidiomycota, has gained interest. This group of fungi possesses a battery of unspecific extracellular enzymes that can be utilized in the biodegradation of preferably phenolic compounds. In this work, it was investigated under which conditions the white rot fungus Trametes versicolor and the ericoid mycorrhizal fungus Rhizoscyphus ericae (belonging to the phylum Ascomycota) could be used to biodegrade the antibiotic aminoglycoside neomycin at co-metabolic conditions in which external nutrients were supplied. Furthermore, it was also investigated whether a biodegradation could be accomplished using neomycin as the sole nutrient.
RESULTS
The results show that both species can biodegrade neomycin 70% under co-metabolic conditions during a one-week time course and that Rhizoscyphus ericae is able to use neomycin as sole nutrient and to approximatively biodegrade it 60% under chosen non co-metabolic conditions. At selected conditions, the biodegradation of neomycin using Rhizoscyphus ericae was monitored by oxidation products of D-ribose which is a hydrolysis product of neomycin.
CONCLUSION
The results are of general interest in the search for fungal species that can biodegrade recalcitrant compounds without the need of external nutrients. The key future application area that will be investigated is purification of waste from recombinant protein production in which neomycin, nutrients and E. coli with neomycin resistance genes are present.
Topics: Anti-Bacterial Agents; Ascomycota; Biodegradation, Environmental; Escherichia coli; Mycorrhizae; Neomycin; Recombinant Proteins; Ribose; Trametes
PubMed: 36221128
DOI: 10.1186/s12896-022-00759-1 -
Neurobiology of Disease Jul 2023Aminoglycoside antibiotics (AGAs) are widely used in life-threatening infections, but they accumulate in cochlear hair cells (HCs) and result in hearing loss. Increases...
Aminoglycoside antibiotics (AGAs) are widely used in life-threatening infections, but they accumulate in cochlear hair cells (HCs) and result in hearing loss. Increases in adenosine triphosphate (ATP) concentrations and P2X7 receptor expression were observed after neomycin treatment. Here, we demonstrated that P2X7 receptor, which is a non-selective cation channel that is activated by high ATP concentrations, may participate in the process through which AGAs enter hair cells. Using transgenic knockout mice, we found that P2X7 receptor deficiency protects HCs against neomycin-induced injury in vitro and in vivo. Subsequently, we used fluorescent gentamicin-Fluor 594 to study the uptake of AGAs and found fluorescence labeling in wild-type mice but not in P2rx7-/- mice in vitro. In addition, knocking-out P2rx7 did not significantly alter the HC count and auditory signal transduction, but it did inhibit mitochondria-dependent oxidative stress and apoptosis in the cochlea after neomycin exposure. We thus conclude that the P2X7 receptor may be linked to the entry of AGAs into HCs and is likely to be a therapeutic target for auditory HC protection.
Topics: Animals; Mice; Aminoglycosides; Receptors, Purinergic P2X7; Ototoxicity; Anti-Bacterial Agents; Neomycin; Hair Cells, Auditory; Cochlea; Adenosine Triphosphate
PubMed: 37263384
DOI: 10.1016/j.nbd.2023.106176 -
Revista Espanola de Enfermedades... Nov 2015Tight-junction (TJ) proteins regulate paracellular permeability. Gut permeability can be modulated by commensal microbiota. Manipulation of the gut microbiota with...
BACKGROUND
Tight-junction (TJ) proteins regulate paracellular permeability. Gut permeability can be modulated by commensal microbiota. Manipulation of the gut microbiota with antibiotics like bacitracin and neomycin turned out to be useful for the treatment of diarrhoea induced by Clostridium difficile or chemotherapy drugs.
AIM
To evaluate the effects of the microbiota depletion evoked by the oral administration of neomycin and bacitracin on the intestinal permeability and expression of TJ proteins in mice.
METHODS
Mice received neomycin and bacitracin orally for 7 days. Intestinal permeability was measured by the fluorescein-isothiocyanate-dextran (FITC-dextran) method. The gene expression of TJ proteins in the intestine was determined by real time-PCR.
RESULTS
FITC-dextran levels in serum were reduced by half in antibiotic-treated mice, indicating a reduction of intestinal permeability. Antibiotics increased the expression of zonula occludens 1 (ZO-1), junctional adhesion molecule A (JAM-A, and occludin in the ileum and ZO-1, claudin-3, and claudin-4 in the colon.
CONCLUSION
The combination of neomycin and bacitracin reduce intestinal permeability and increase the gene expression of ZO-1, junctional adhesion molecule A (JAM-A), and occludin in the ileum and ZO-1, claudin-3, and claudin-4 in the colon.
Topics: Animals; Anti-Bacterial Agents; Bacitracin; Gene Expression; Intestinal Absorption; Intestinal Mucosa; Intestines; Mice; Neomycin; Permeability; Tight Junction Proteins
PubMed: 26541656
DOI: 10.17235/reed.2015.3868/2015 -
Neural Plasticity 2022Ototoxic hearing loss results from hair cell death via reactive oxygen species (ROS) overproduction and consequent apoptosis. We investigated the effects of vitamin C...
Ototoxic hearing loss results from hair cell death via reactive oxygen species (ROS) overproduction and consequent apoptosis. We investigated the effects of vitamin C (VC) on neomycin-induced HEI-OC1 cell damage, as well as the mechanism of inhibition. HEI-OC1 cells were treated with neomycin or with vitamin C (VC). The results indicated that VC had a protective effect on neomycin-induced HEI-OC1 cell death. Mechanistically, VC decreased neomycin-induced ROS generation, suppressed cell death, and increased cell viability. VC inhibited neomycin-induced apoptosis, ameliorated neomycin reduced antiapoptotic Bcl-2 expression, and suppressed neomycin increased expression of proapoptotic Bax, caspase-3 cleavage and caspase-8. TUNEL labeling demonstrated that VC blocked neomycin-induced apoptosis. Further study revealed that the effect of VC on neomycin-induced hair cell death was through interference with JNK activation and p38 phosphorylation. These results indicate that VC via suppressed ROS generation, which inhibited cell death by counteracting apoptotic signaling induced by neomycin in cells. Hence, VC is a potential candidate for protection agent against neomycin-induced HEI-OC1 cell ototoxicity.
Topics: Apoptosis; Ascorbic Acid; Cell Survival; Hair Cells, Auditory; Neomycin; Reactive Oxygen Species
PubMed: 35601667
DOI: 10.1155/2022/1298692 -
British Medical Journal Jun 1977
Topics: Administration, Topical; Anti-Bacterial Agents; Drug Resistance; Gentamicins; Humans; Neomycin; Skin Diseases
PubMed: 871630
DOI: No ID Found -
British Medical Journal May 1977
Topics: Administration, Topical; Adrenal Cortex Hormones; Drug Combinations; Eczema; Humans; Neomycin; Staphylococcal Infections
PubMed: 861588
DOI: No ID Found -
Anais Brasileiros de Dermatologia 2023Neomycin is used in several over-the-counter pharmaceutical formulations in Brazil. In Europe and Canada, where it is not freely available, its sensitization frequency...
BACKGROUND
Neomycin is used in several over-the-counter pharmaceutical formulations in Brazil. In Europe and Canada, where it is not freely available, its sensitization frequency is lower than in the United States, where this does not occur.
OBJECTIVE
To present the frequency of sensitization to neomycin observed in a tertiary hospital and the pharmaceutical formulations sold in Brazil containing neomycin.
METHOD
Retrospective analysis of positive results to neomycin, obtained through patch tests performed in a tertiary hospital, from 2009 to 2018 and investigation of topical drugs and vaccines containing neomycin in Brazilian databases available on the internet.
RESULTS
Among 1,162 patients, 71 (6%) had positive reactions to neomycin, 65% female and 35% male individuals, 46% were over 50 years old, and 24% had a personal history of atopy. The dermatitis lasted from four months to 20 years. Lesions were located in 69% of the patients on the upper limbs, in 55% they were on the lower limbs, and in 42% they were disseminated in more than 4 sites. Polysensitization was detected in 55% of cases. Of these, 28% were linked to sensitization to rubber allergens and 27% to potassium bichromate. A total of 158 topical presentations of neomycin were found: 79 ointments, 58 creams, 10 ophthalmic solutions, seven otological solutions, one oral solution, two nasal solutions, and one antiseptic powder, in addition to 11 types of vaccines.
STUDY LIMITATIONS
Retrospective study.
CONCLUSION
Sensitization to neomycin occurred in 6% of the studied population, affecting more females aged over 50 years, with skin lesions located mainly on the upper and lower limbs, in the context of chronic contact dermatitis. Neomycin was found in 135 formulations, most of them available over the counter, as well as in 11 miscellaneous vaccines.
Topics: Humans; Male; Female; Middle Aged; Neomycin; Dermatitis, Allergic Contact; Retrospective Studies; Allergens; Patch Tests; Pharmaceutical Preparations
PubMed: 37003899
DOI: 10.1016/j.abd.2022.07.008