RESUMO
Delirium is a multifactorial medical condition of waxing and waning impairment across various domains of mental functioning over time. Importantly, delirium is also one of the greatest risk factors for prolonged hospitalization, morbidity, and mortality. Studying this important condition is challenging due to the difficulty in both objective diagnosis in patients and validation of laboratory models. As a result, there is a lack of protective treatments for delirium. Our recent studies report the efficacy of bispectral electroencephalography (BSEEG) in diagnosing delirium in patients and predicting patient outcomes, advancing the concept that this simple measure could represent an additional vital sign for patients. Here, we applied BSEEG to characterize and validate a novel lipopolysaccharide (LPS) mouse model of infection-related delirium. We then applied this model to evaluate the protective efficacy of three putative therapeutic agents: the conventional antipsychotic medication haloperidol, the neuroprotective compound P7C3-A20, and the antibiotic minocycline. Aged mice were more susceptible than young mice to LPS-induced aberration in BSEEG, reminiscent of the greater vulnerability of older adults to delirium. In both young and old mice, P7C3-A20 and minocycline administration prevented LPS-induced BSEEG abnormality. By contrast, haloperidol did not. P7C3-A20 and minocycline have been shown to limit different aspects of LPS toxicity, and our data offers proof of principle that these agents might help protect patients from developing infection-related delirium. Thus, utilization of BSEEG in a mouse model for infection-related delirium can identify putative therapeutic agents for applications in patient clinical trials.
Assuntos
Delírio , Modelos Animais de Doenças , Eletroencefalografia , Lipopolissacarídeos , Animais , Camundongos , Delírio/tratamento farmacológico , Masculino , Minociclina/farmacologia , Haloperidol/farmacologia , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Antipsicóticos/farmacologiaRESUMO
Minocycline (Min), as an antibiotic, possesses various beneficial properties such as anti-inflammatory, antioxidant, and anti-apoptotic effects. Despite these known qualities, the precise cardioprotective effect and mechanism of Min in protecting against sepsis-induced cardiotoxicity (SIC) remain unspecified. To address this, our study sought to assess the protective effects of Min on the heart. Lipopolysaccharide (LPS) was utilized to establish a cardiotoxicity model both in vivo and in vitro. Min was pretreated in the models. In the in vivo setting, evaluation of heart tissue histopathological injury was performed using hematoxylin and eosin (H&E) staining and TUNEL. Immunohistochemistry (IHC) was employed to evaluate the expression levels of NLRP3 and Caspase-1 in the heart tissue of mice. During in vitro experiments, the viability of H9c2 cells was gauged utilizing the CCK8 assay kit. Intracellular ROS levels in H9c2 cells were quantified using a ROS assay kit. Both in vitro and in vivo settings were subjected to measurement of oxidative stress indexes, encompassing glutathione (GSH), malondialdehyde (MDA), and superoxide dismutase (SOD) levels. Additionglly, myocardial injury markers like lactate dehydrogenase (LDH) and creatine kinase MB (CK-MB) activity were quantified using appropriate assay kits. Western blotting (WB) analysis was conducted to detect the expression levels of NOD-like receptor protein-3 (NLRP3), caspase-1, IL-18, and IL-1ß, alongside apoptosis-related proteins such as Bcl-2 and Bax, and antioxidant proteins including superoxide dismutase-1 (SOD-1) and antioxidant proteins including superoxide dismutase-1 (SOD-2), both in H9c2 cells and mouse heart tissues. In vivo, Min was effective in reducing LPS-induced inflammation in cardiac tissue, preventing cell damage and apoptosis in cardiomyocytes. The levels of LDH and CK-MB were significantly reduced with Min treatment. In vitro studies showed that Min improved the viability of H9C2 cells, reduced apoptosis, and decreased ROS levels in these cells. Further analysis indicated that Min decreased the protein levels of NLRP3, Caspase-1, IL-18, and IL-1ß, while increasing the levels of SOD-1 and SOD-2 both in vivo and in vitro. Min alleviates LPS-induced SIC by suppressing the NLRP3/Caspase-1 signalling pathway in vivo and in vitro.
Assuntos
Cardiotoxicidade , Caspase 1 , Lipopolissacarídeos , Minociclina , Proteína 3 que Contém Domínio de Pirina da Família NLR , Transdução de Sinais , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Transdução de Sinais/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Caspase 1/metabolismo , Cardiotoxicidade/metabolismo , Cardiotoxicidade/tratamento farmacológico , Camundongos , Minociclina/farmacologia , Masculino , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Linhagem Celular , Apoptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Camundongos Endogâmicos C57BL , RatosRESUMO
OBJECTIVE: Ischemic stroke is a leading cause of death and disability in individuals worldwide. Cerebral ischemia-reperfusion injury (CIRI) typically results in severe secondary injury and complications following reperfusion therapy. Microglia play critical roles in the inflammatory reaction of CIRI. However, less attention has been given to microglial death in this process. Our study aims to explore microglial death in CIRI and the effects and mechanism of minocycline treatment on microglia. METHODS: A middle cerebral artery occlusion (MCAO) model was applied to induce CIRI in rats. At 0 h, 24 h and 48 h post-operation, rats were intraperitoneally injected with 45 mg/kg minocycline. Neurological deficit scoring, 2,3,5-triphenyltetrazolium chloride (TTC) staining, assessment of activated microglia and examination of mitochondrial structure were conducted and checked at 72 h after reperfusion. Additionally, an in vitro model of oxygen-glucose deprivation/reperfusion (OGD/R) model was established. BV-2 cells were treated with various pharmacological inhibitors of cell death or minocycline. Cell viability, lipid peroxidation, mitochondrial structure and function, and labile Fe2+ and ferroptosis-associated gene/protein levels were measured. Hemin was used for further validation after transcriptome analysis. RESULTS: In the MCAO and OGD/R models, ferroptosis was identified as a major form of microglial death. Minocycline inhibited microglia ferroptosis by reducing HO-1 expression. In addition, minocycline improved mitochondrial membrane potential, mitochondrial structures and microglial survival in vivo. Minocycline also decreased labile Fe2+ levels, lipid peroxidation, and expression of ferritin heavy chain (FTH) and it improved mitochondrial structure and function in vitro. Upregulation of HO-1 counteracted the protective effect of minocycline. CONCLUSION: Ferroptosis is a major form of microglial death in CIRI. The protective mechanism of minocycline in CIRI partially hinges on its ability to effectively ameliorate microglia ferroptosis by downregulating HO-1 expression. Consequently, targeting microglia ferroptosis is a promising treatment for CIRI.
Assuntos
Ferroptose , Infarto da Artéria Cerebral Média , Microglia , Minociclina , Ratos Sprague-Dawley , Traumatismo por Reperfusão , Minociclina/farmacologia , Minociclina/uso terapêutico , Animais , Microglia/efeitos dos fármacos , Microglia/metabolismo , Ferroptose/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Masculino , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia , Camundongos , Ratos , Linhagem Celular , Heme Oxigenase-1/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Isquemia Encefálica/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Heme Oxigenase (Desciclizante)RESUMO
INTRODUCTION: This study aimed to investigate whether the maternal administration of minocycline, a tetracycline antibiotic known to have anti-inflammatory and neuroprotective properties in models of neural injury, reduces inflammation and neural cell death in a fetal rat model of myelomeningocele (MMC). METHODS: E10 pregnant rats were gavaged with olive oil or olive oil + retinoic acid to induce fetal MMC. At E12, the dams were exposed to regular drinking water or water containing minocycline (range, 40-140 mg/kg/day). At E21, fetal lumbosacral spinal cords were isolated for immunohistochemistry and quantitative gene expression studies focused on microglia activity, inflammation, and apoptosis (P < 0.05). RESULTS: There was a trend toward decreased activated Iba1+ microglial cells within the dorsal spinal cord of MMC pups following minocycline exposure when compared to water (H2O) alone (P = 0.052). Prenatal minocycline exposure was correlated with significantly reduced expression of the proinflammatory cytokine, IL-6 (minocycline: 1.75 versus H2O: 3.52, P = 0.04) and apoptosis gene, Bax (minocycline: 0.71 versus H2O: 1.04, P < 0.001) among MMC pups. CONCLUSIONS: This study found evidence that the maternal administration of minocycline reduces selected markers of inflammation and apoptosis within the exposed dorsal spinal cords of fetal MMC rats. Further study of minocycline as a novel prenatal treatment strategy to mitigate spinal cord damage in MMC is warranted.
Assuntos
Modelos Animais de Doenças , Meningomielocele , Minociclina , Ratos Sprague-Dawley , Medula Espinal , Animais , Feminino , Minociclina/farmacologia , Minociclina/administração & dosagem , Gravidez , Meningomielocele/patologia , Ratos , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Medula Espinal/patologia , Apoptose/efeitos dos fármacos , Terapias Fetais/métodos , Antibacterianos , Microglia/efeitos dos fármacos , Microglia/patologia , Microglia/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/administração & dosagemRESUMO
Chronic stress increases activity of the brain's innate immune system and impairs function of the medial prefrontal cortex (mPFC). However, whether acute stress triggers similar neuroimmune mechanisms is poorly understood. Across four studies, we used a Syrian hamster model to investigate whether acute stress drives changes in mPFC microglia in a time-, subregion-, and social status-dependent manner. We found that acute social defeat increased expression of ionized calcium binding adapter molecule 1 (Iba1) in the infralimbic (IL) and prelimbic (PL) and altered the morphology Iba1+ cells 1, 2, and 7 days after social defeat. We also investigated whether acute defeat induced tissue degeneration and reductions of synaptic plasticity 2 days post-defeat. We found that while social defeat increased deposition of cellular debris and reduced synaptophysin immunoreactivity in the PL and IL, treatment with minocycline protected against these cellular changes. Finally, we tested whether a reduced conditioned defeat response in dominant compared to subordinate hamsters was associated with changes in microglia reactivity in the IL and PL. We found that while subordinate hamsters and those without an established dominance relationships showed defeat-induced changes in morphology of Iba1+ cells and cellular degeneration, dominant hamsters showed resistance to these effects of social defeat. Taken together, these findings indicate that acute social defeat alters microglial morphology, increases markers of tissue degradation, and impairs structural integrity in the IL and PL, and that experience winning competitive interactions can specifically protect the IL and reduce stress vulnerability.
Assuntos
Mesocricetus , Microglia , Córtex Pré-Frontal , Predomínio Social , Estresse Psicológico , Animais , Microglia/metabolismo , Microglia/patologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Masculino , Estresse Psicológico/metabolismo , Cricetinae , Plasticidade Neuronal/fisiologia , Derrota Social , Minociclina/farmacologiaRESUMO
Influenza A virus (IAV) poses a global threat worldwide causing pandemics, epidemics, and seasonal outbreaks. Annual modification of vaccines is costly due to continual shifts in circulating genotypes, leading to inadequate coverage in low- and middle-income countries like India. Additionally, IAVs are evolving resistance to approved antivirals, necessitating a search for alternative treatments. In this study, the antiviral role of the FDA-approved antibiotic minocycline against IAV strains was evaluated in vitro and in vivo by quantifying viral gene expression by qRT-PCR, viral protein levels by Western blotting, and viral titers. Our findings demonstrate that minocycline at a non-toxic dose effectively inhibits IAV replication, regardless of viral strain or cell line. Its antiviral mechanism operates independently of interferon signaling by targeting the MEK/ERK signaling pathway, which is crucial for the export of viral ribonucleoproteins (vRNPs). Minocycline prevents the assembly and release of infectious viral particles by causing the accumulation of vRNPs within the nucleus. Moreover, minocycline also inhibits IAV-induced late-stage apoptosis, further suppressing viral propagation. The antiviral activity of minocycline against IAVs could offer a promising solution amidst the challenges posed by influenza and the limitations of current treatments.
Assuntos
Transporte Ativo do Núcleo Celular , Antivirais , Vírus da Influenza A , Minociclina , Replicação Viral , Minociclina/farmacologia , Antivirais/farmacologia , Humanos , Replicação Viral/efeitos dos fármacos , Animais , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/fisiologia , Infecções por Orthomyxoviridae/tratamento farmacológico , Infecções por Orthomyxoviridae/virologia , Camundongos , Ribonucleoproteínas/metabolismo , Ribonucleoproteínas/genética , Cães , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , Proteínas Virais/metabolismo , Proteínas Virais/genética , Núcleo Celular/metabolismo , Células A549 , Células Madin Darby de Rim Canino , Linhagem CelularRESUMO
Polysaccharides like hyaluronan (HA) and chondroitin sulfate (CS) are native of the brain's extracellular matrix crucial for myelination and brain maturation. Despite extensive research on HA and CS as drug delivery systems (DDS), their high water solubility limits their application as drug carriers. This study introduces an injectable DDS using aldehyde-modified hyaluronic acid (HAOX) hydrogel containing polyelectrolyte complexes (PEC) formed with calcium, gelatin, and either CS or aldehyde-modified CS (CSOX) to deliver minocycline for Multiple Sclerosis therapy. PECs with CSOX enable covalent crosslinking to HAOX, creating immobilized PECs (HAOX_PECOX), while those with CS remain unbound (HAOX_PECS). The in situ forming DDS can be administered via a 20 G needle, with rapid gelation preventing premature leakage. The system integrates into an implanted device for minocycline release through either Fickian or anomalous diffusion, depending on PEC immobilization. HAOX_PECOX reduced burst release by 88 %, with a duration of 127 h for 50 % release. The DDS exhibited an elastic modulus of 3800 Pa and a low swelling ratio (0-1 %), enabling precise control of minocycline release kinetics. Released minocycline reduced IL-6 secretion in the Whole Blood Monocytes Activation Test, suggesting that DDS formation may not alter the biological activity of the loaded drug.
Assuntos
Sulfatos de Condroitina , Portadores de Fármacos , Gelatina , Ácido Hialurônico , Hidrogéis , Minociclina , Polieletrólitos , Ácido Hialurônico/química , Gelatina/química , Sulfatos de Condroitina/química , Hidrogéis/química , Hidrogéis/farmacologia , Minociclina/química , Minociclina/farmacologia , Minociclina/administração & dosagem , Polieletrólitos/química , Humanos , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Aldeídos/química , Animais , Sistemas de Liberação de Medicamentos/métodos , Interleucina-6/metabolismoRESUMO
Tigecycline and the newly Food and Drug Administration-approved tetracyclines, including eravacycline and omadacycline, are regarded as last-resort treatments for multidrug-resistant Enterobacterales. However, tigecycline resistance in Klebsiella pneumoniae has increased, especially the underlying mechanism of heteroresistance is unclear. This study aimed to elucidate the mechanisms underlying tigecycline resistance and heteroresistance in clinical K. pneumoniae isolates. A total of 153 clinical K. pneumoniae isolates were collected, and identified 15 tigecycline-resistant and three tigecycline-heteroresistant isolates using broth microdilution and population analysis profile methods, respectively. Total RNAs from K. pneumoniae ATCC13883 and the laboratory-induced tigecycline-resistant strain were extracted and sequenced on an Illumina platform. Differentially expressed genes and regulatory small RNAs (sRNAs) were analyzed and validated in clinical isolates of K. pneumoniae using quantitative real-time PCR. RNA sequencing results showed that mdtABC efflux pump genes were significantly upregulated in the tigecycline-resistant strains. Overexpression of mdtABC was observed in a clinical K. pneumoniae isolate, which increased tigecycline minimum inhibitory concentrations (MICs) and was involved in tigecycline heteroresistance. Sequencing analysis of sRNA demonstrated that candidate sRNA-120 directly interacted with the mdtABC operon and was downregulated in tigecycline-resistant strains. We generated an sRNA-120 deletion mutation strain and a complemented strain of K. pneumoniae. The sRNA-120 deletion strain displayed increased mRNA levels of mdtA, mdtB, and mdtC and an increase in MICs of tigecycline. The complemented strain of sRNA-120 restored the mRNA levels of these genes and the susceptibility to tigecycline. RNA antisense purification and parallel reaction monitoring mass spectrometry were performed to verify the interactions between sRNA-120 and mdtABC. Collectively, our study highlights that the post-transcriptional repression of mdtABC through sRNA-120 may provide an additional layer of efflux pump gene expression control, which is important for resistance and heteroresistance in clinical K. pneumoniae isolates.
Assuntos
Antibacterianos , Proteínas de Bactérias , Regulação Bacteriana da Expressão Gênica , Infecções por Klebsiella , Klebsiella pneumoniae , Testes de Sensibilidade Microbiana , Tigeciclina , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/metabolismo , Tigeciclina/farmacologia , Antibacterianos/farmacologia , Infecções por Klebsiella/microbiologia , Humanos , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Farmacorresistência Bacteriana/genética , RNA Bacteriano/genética , Farmacorresistência Bacteriana Múltipla/genética , Minociclina/farmacologia , Minociclina/análogos & derivadosRESUMO
Biofilm formation of Klebsiella pneumoniae can protect bacteria from antibiotics and is difficult to eradicate. Thus, the influence of subinhibitory concentrations of antibiotics on bacteria is becoming increasingly important. Our study showed that subminimum inhibitory concentrations (sub-MICs) of tetracycline antibiotics can increase biofilm formation in minocycline-resistant Klebsiella pneumoniae clinical strains. However, in the bacterial adhesion and invasion experiments, the adhesion and invasion ability decreased and the survival rate of Galleria mellonella increased. Under sub-MICs of tetracycline antibiotics treatment, abnormal stretching of bacteria was observed by scanning electron microscopy. Treatment with sub-MICs of tetracyclines leads to increased surface hydrophobicity and eDNA content and decreased outer membrane permeability. The expression levels of the fimA, luxS, qseB, and qseC genes decreased, the expression level of mrkA increased, and the expression level of acrA was inconsistent under different tetracycline antibiotics treatments. Together, our results suggested that the increase in Klebsiella pneumoniae biofilm formation caused by sub-MICs of tetracycline antibiotics may occur by affecting bacterial physical and chemical properties and associated genes expression.
Assuntos
Antibacterianos , Biofilmes , Klebsiella pneumoniae , Testes de Sensibilidade Microbiana , Biofilmes/efeitos dos fármacos , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/genética , Antibacterianos/farmacologia , Minociclina/farmacologia , Infecções por Klebsiella/microbiologia , Infecções por Klebsiella/tratamento farmacológico , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Animais , Tetraciclina/farmacologia , Aderência Bacteriana/efeitos dos fármacos , Farmacorresistência Bacteriana/efeitos dos fármacos , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Mariposas/efeitos dos fármacos , Mariposas/microbiologia , Humanos , Interações Hidrofóbicas e HidrofílicasRESUMO
Minocycline, a broad-spectrum tetracycline antibiotic, has been shown to possess anti-inflammatory and antioxidative effects in various neurodegenerative diseases. However, its specific effects on retinitis pigmentosa (RP) have not been thoroughly investigated. Therefore, the objective of this study was to explore the potential role of minocycline in treating RP. In this investigation, we used rd1 to explore the antioxidant effect of minocycline in RP. Minocycline therapy effectively restored retinal function and structure in rd1 mice at 14 days postnatal. Additionally, minocycline inhibited the activation of microglia. Moreover, RNA sequencing analysis revealed a significant downregulation in the expression of mitochondrial genes within the retina of rd1 mice. Further KEGG and GO pathway analysis indicated impaired oxidative phosphorylation and electron transport chain processes. TEM confirmed the presence of damaged mitochondria in photoreceptors, while JC-1 staining demonstrated a decrease in mitochondrial membrane potential, accompanied by an increase in mitochondrial reactive oxygen species (ROS) levels. However, treatment with minocycline successfully reversed the abnormal expression of mitochondrial genes and reduced the levels of mitochondrial ROS, thereby providing protection against photoreceptor degeneration. Collectively, minocycline demonstrated the ability to rescue photoreceptor cells in RP by effectively modulating mitochondrial homeostasis and subsequently inflammation. These findings hold significant implications for the development of potential therapeutic strategies for RP.
Assuntos
Homeostase , Minociclina , Mitocôndrias , Espécies Reativas de Oxigênio , Retinose Pigmentar , Minociclina/farmacologia , Minociclina/uso terapêutico , Animais , Retinose Pigmentar/tratamento farmacológico , Retinose Pigmentar/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Homeostase/efeitos dos fármacos , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Degeneração Retiniana/tratamento farmacológico , Degeneração Retiniana/patologia , Degeneração Retiniana/metabolismo , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Células Fotorreceptoras de Vertebrados/efeitos dos fármacos , Células Fotorreceptoras de Vertebrados/patologia , Células Fotorreceptoras de Vertebrados/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Retina/efeitos dos fármacos , Retina/patologia , Retina/metabolismo , Humanos , Antioxidantes/farmacologia , Antioxidantes/uso terapêuticoRESUMO
BACKGROUND: 0.05% Chlorhexidine gluconate (CHG; Irrisept [IrriMax]) is a commercial wound irrigation solution approved by the Food and Drug Administration that has seen recent adoption in the field of prosthetic urology; however, no study has evaluated whether 0.05% CHG is compatible with the minocycline-rifampin-impregnated surface (InhibiZone) of the AMS 700 penile prosthesis (Boston Scientific). AIM: To evaluate whether 0.05% CHG alters the antibiotic efficacy of the minocycline-rifampin-impregnated penile prosthesis surface. METHODS: Discs (8 mm) were taken by a punch biopsy (Sklar) from sterile penile prosthesis reservoirs whose surfaces had been impregnated with rifampin and minocycline. Discs (n = 10) were suspended in 0.05% CHG, vancomycin and gentamicin, or normal saline for 2 minutes to simulate intraoperative irrigation. Discs were then rinsed in normal saline to remove any unbound solution and incubated with methicillin-sensitive Staphylococcus aureus for 48 hours. Adherent surface bacteria were suspended by shaking in a 0.3% Tween 20 solution, serially diluted, plated onto 3M PetriFilms, and counted. Kirby-Bauer disc diffusion assays were conducted to generalize findings across various organisms. OUTCOMES: Outcomes included (1) bacterial adherence to the implant surface measured as bacterial counts (in colony-forming units per milliliter) and (2) bacterial growth reduction measured as zones of inhibitions (in millimeters). RESULTS: Incubation of implant surfaces in 0.05% CHG did not alter recovered bacterial counts as compared with normal saline and vancomycin/gentamycin. Similarly, within a single bacterial species, 0.05% CHG and vancomycin/gentamycin did not alter zone-of-inhibition measurements in Kirby-Bauer disc diffusion studies. CLINICAL TRANSLATION: This study demonstrates in vitro that 0.05% CHG may be used directly on the minocycline-rifampin-impregnated surface without altering the antibiotic efficacy of the coating. STRENGTHS AND LIMITATIONS: Strengths include that this is the first study to evaluate if 0.05% CHG affected the minocycline-rifampin-impregnated surface. Limitations include the use of in vitro studies, which serve as a proxy for in vivo practices and may not be entirely accurate or translatable in a clinical setting. CONCLUSION: 0.05% CHG does not alter the antimicrobial activity of the minocycline-rifampin-impregnated surface as compared with vancomycin/gentamycin and normal saline in vitro; however, its efficacy in clinical practice remains to be evaluated.
Assuntos
Antibacterianos , Clorexidina , Minociclina , Prótese de Pênis , Rifampina , Clorexidina/análogos & derivados , Clorexidina/farmacologia , Clorexidina/administração & dosagem , Humanos , Minociclina/farmacologia , Minociclina/administração & dosagem , Antibacterianos/farmacologia , Antibacterianos/administração & dosagem , Masculino , Rifampina/farmacologia , Rifampina/administração & dosagem , Irrigação Terapêutica/métodos , Gentamicinas/farmacologia , Gentamicinas/administração & dosagem , Vancomicina/farmacologia , Vancomicina/administração & dosagem , Staphylococcus aureus/efeitos dos fármacos , Anti-Infecciosos Locais/farmacologia , Anti-Infecciosos Locais/administração & dosagemRESUMO
PURPOSE: Mycobacterium abscessus complex (MABC) infections are increasing worldwide. Furthermore, these infections have a low treatment success rate due to their resistance to many current antibiotics. This study aimed to determine the overall in vitro activity of the tetracyclines doxycycline (DOX), minocycline (MIN), and tigecycline (TGC) against MABC clinical isolates. PATIENTS AND METHODS: A systematic review of PubMed/MEDLINE, Web of Science, and Embase was conducted up to August 28, 2023. Studies applying the drug susceptibility testing standards of the Clinical and Laboratory Standards Institute were considered. A random effects model was used to assess the total in vitro resistance rates of the MABC clinical isolates to DOX, MIN, and TGC. The I2 and Cochran's Q statistics were employed to evaluate the origins of heterogeneity. All analyses were conducted using CMA V.3 software. RESULTS: Twenty-six publications (22, 12, and 11 studies on DOX, MIN, and TGC, respectively) were included. The pooled in vitro resistance rates of the MABC clinical isolates to DOX and MIN at the breakpoint of 8 µg/mL were 93.0 % (95 % CI, 89.2 %-95.5 %) and 87.2 % (95 % CI, 76.5 %-93.4 %), respectively. In the case of TGC, the breakpoints of 2, 4, and 8 µg/mL were associated with pooled resistance rates of 2.5 % (95 % CI, 0.5 %-11.6 %), 7.2 % (95 % CI, 4.0 %-12.5 %), and 16.8 % (95 % CI, 4.7 %-45.0 %), respectively. CONCLUSION: Among the three examined tetracyclines, MABC exhibited extremely high resistance rates to DOX and MIN, thereby limiting their use in treating MABC infections. Conversely, MABC showed an increased susceptibility rate to TGC, highlighting TGC administration as a viable treatment option for patients with MABC infections.
Assuntos
Antibacterianos , Doxiciclina , Testes de Sensibilidade Microbiana , Minociclina , Infecções por Mycobacterium não Tuberculosas , Mycobacterium abscessus , Tigeciclina , Minociclina/farmacologia , Minociclina/análogos & derivados , Tigeciclina/farmacologia , Humanos , Doxiciclina/farmacologia , Doxiciclina/uso terapêutico , Mycobacterium abscessus/efeitos dos fármacos , Antibacterianos/farmacologia , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/microbiologia , Farmacorresistência BacterianaRESUMO
Periodontitis, an inflammatory bone resorption disease associated with dental plaque, poses significant challenges for effective treatment. In this study, we developed Mino@ZIF-8 nanoparticles inspired by the periodontal microenvironment and the unique properties of zeolitic imidazolate framework 8, aiming to address the complex pathogenesis of periodontitis. Transcriptome analysis revealed the active engagement of Mino@ZIF-8 nanoparticles in innate and adaptive inflammatory host defense and cellular metabolic remodeling. Through sustained release of the anti-inflammatory and antibacterial agent minocycline hydrochloride (Mino) and the generation of Zn2+ with pro-antioxidant effects during degradation, Mino@ZIF-8 nanoparticles synergistically alleviate inflammation and oxidative damage. Notably, our study focuses on the pivotal role of zinc ions in mitochondrial oxidation protection. Under lipopolysaccharide (LPS) stimulation, periodontal ligament cells undergo a metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis, leading to reduced ATP production and increased reactive oxygen species levels. However, Zn2+ effectively rebalances the glycolysis-OXPHOS imbalance, restoring cellular bioenergetics, mitigating oxidative damage, rescuing impaired mitochondria, and suppressing inflammatory cytokine production through modulation of the AKT/GSK3ß/NRF2 pathway. This research not only presents a promising approach for periodontitis treatment but also offers novel therapeutic opportunities for zinc-containing materials, providing valuable insights into the design of biomaterials targeting cellular energy metabolism regulation.
Assuntos
Nanopartículas , Estresse Oxidativo , Periodontite , Estresse Oxidativo/efeitos dos fármacos , Periodontite/tratamento farmacológico , Periodontite/metabolismo , Periodontite/patologia , Nanopartículas/química , Humanos , Animais , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Minociclina/farmacologia , Minociclina/química , Minociclina/uso terapêutico , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Camundongos , Antibacterianos/química , Antibacterianos/farmacologia , Lipopolissacarídeos/farmacologia , Antioxidantes/farmacologia , Antioxidantes/química , Espécies Reativas de Oxigênio/metabolismo , ImidazóisRESUMO
Tick-borne Encephalitis (TBE) is a zoonotic disease caused by the Tick-borne Encephalitis virus (TBEV), which affects the central nervous system of both humans and animals. Currently, there is no specific therapy for patients with TBE, with symptomatic treatment being the primary approach. In this study, the effects of minocycline (MIN), which is a kind of tetracycline antibiotic, on TBEV propagation and cellular protection in TBEV-infected cell lines were evaluated. Indirect immunofluorescence, virus titers, and RT-qPCR results showed that 48 h post-treatment with MIN, TBEV replication was significantly inhibited in a dose-dependent manner. In addition, the inhibitory effect of MIN on different TBEV multiplicities of infection (MOIs) in Vero cells was studied. Furthermore, the transcriptomic analysis and RT-qPCR results indicate that after incubation with MIN, the levels of TBEV and CALML4 were decreased, whereas the levels of calcium channel receptors, such as RYR2 and SNAP25, were significantly increased. MIN also regulated MAPK-ERK-related factors, including FGF2, PDGFRA, PLCB2, and p-ERK, and inhibited inflammatory responses. These data indicate that administering MIN to TBEV-infected cells can reduce the TBEV level, regulate calcium signaling pathway-associated proteins, and inhibit the MAPK-ERK signaling pathway and inflammatory responses. This research offers innovative strategies for the advancement of anti-TBEV therapy.
Assuntos
Vírus da Encefalite Transmitidos por Carrapatos , Minociclina , Replicação Viral , Animais , Vírus da Encefalite Transmitidos por Carrapatos/efeitos dos fármacos , Vírus da Encefalite Transmitidos por Carrapatos/fisiologia , Minociclina/farmacologia , Chlorocebus aethiops , Células Vero , Replicação Viral/efeitos dos fármacos , Humanos , Antivirais/farmacologia , Encefalite Transmitida por Carrapatos/virologia , Encefalite Transmitida por Carrapatos/tratamento farmacológico , Linhagem Celular , Transdução de Sinais/efeitos dos fármacosRESUMO
Previously, we found that dCA1 A1-like polarization of astrocytes contributes a lot to the spatial memory deficit in methamphetamine abstinence mice. However, the underlying mechanism remains unclear, resulting in a lack of promising therapeutic targets. Here, we found that methamphetamine abstinence mice exhibited an increased M1-like microglia and A1-like astrocytes, together with elevated levels of interleukin 1α and tumor necrosis factor α in dCA1. In vitro, the M1-like BV2 microglia cell medium, containing high levels of Interleukin 1α and tumor necrosis factor α, elevated A1-like polarization of astrocytes, which weakened their capacity for glutamate clearance. Locally suppressing dCA1 M1-like microglia activation with minocycline administration attenuated A1-like polarization of astrocytes, ameliorated dCA1 neurotoxicity, and, most importantly, rescued spatial memory in methamphetamine abstinence mice. The effective time window of minocycline treatment on spatial memory is the methamphetamine exposure period, rather than the long-term methamphetamine abstinence.
Assuntos
Astrócitos , Transtornos da Memória , Metanfetamina , Microglia , Minociclina , Memória Espacial , Animais , Metanfetamina/toxicidade , Microglia/efeitos dos fármacos , Microglia/metabolismo , Camundongos , Transtornos da Memória/induzido quimicamente , Astrócitos/metabolismo , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Memória Espacial/fisiologia , Memória Espacial/efeitos dos fármacos , Masculino , Minociclina/farmacologia , Camundongos Endogâmicos C57BL , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/patologia , Estimulantes do Sistema Nervoso Central/toxicidadeRESUMO
OBJECTIVE: The aim of the present study is to explore the impact of the tet(A) type I variant (tetA-v1) on its fitness effect in Klebsiella pneumoniae. METHODS: Clinical K. pneumoniae strains were utilized as parental strains to generate strains carrying only the plasmid vector (pBBR1MCS-5) or the tetA-v1 recombinant plasmid (ptetA-v1). Antimicrobial susceptibility testing was conducted to estimate the contribution of tetA-v1 to drug resistance. Plasmid stability was evaluated by serial passage over 10 consecutive days in the absence of tigecycline. Biological fitness was examined through growth curve analysis, in vitro competition assays and a neutropenic mouse thigh infection model. RESULTS: A 2-4-fold increase in tigecycline MIC was observed following the acquisition of tetA-v1. Without tigecycline treatment, the stability of ptetA-v1 plasmids has been decreasing since day 1. The ptetA-v1 plasmid in Kp89, Kp91, and Kp93 exhibited a decrease of about 20% compared to the pBBR1MCS-5 plasmid. The acquisition of the tetA-v1 gene could inhibit the growth ability of K. pneumoniae strains both in vitro and in vivo. tetA-v1 gene imposed a fitness cost in K. pneumoniae, particularly in the CRKP strain Kp51, with a W value of approximately 0.56. CONCLUSION: The presence of tetA-v1 is associated with a significant fitness cost in K. pneumoniae in the absence of tigecycline, both in vitro and in vivo.
Assuntos
Antibacterianos , Infecções por Klebsiella , Klebsiella pneumoniae , Testes de Sensibilidade Microbiana , Plasmídeos , Tigeciclina , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/genética , Tigeciclina/farmacologia , Animais , Antibacterianos/farmacologia , Infecções por Klebsiella/microbiologia , Infecções por Klebsiella/tratamento farmacológico , Plasmídeos/genética , Camundongos , Proteínas de Bactérias/genética , Minociclina/análogos & derivados , Minociclina/farmacologia , Humanos , Modelos Animais de Doenças , Farmacorresistência Bacteriana/genética , Aptidão Genética , AntiportersRESUMO
Dental implant therapy is a reliable treatment for replacing missing teeth. However, as dental implants become more widely used, peri-implantitis increasingly has become a severe complication, making successful treatment more difficult. As a result, the development of effective drug delivery systems (DDSs) and treatments for peri-implantitis are urgently needed. Carbon nanohorns (CNHs) are carbon nanomaterials that have shown promise for use in DDSs and have photothermal effects. The present study exploited the unique properties of CNHs to develop a phototherapy employing a near-infrared (NIR) photoresponsive composite of minocycline, hyaluronan, and CNH (MC/HA/CNH) for peri-implantitis treatments. MC/HA/CNH demonstrated antibacterial effects that were potentiated by NIR-light irradiation, a property that was mediated by photothermal-mediated drug release from HA/CNH. These antibacterial effects persisted even following 48 h of dialysis, a promising indication for the clinical use of this material. We propose that the treatment of peri-implantitis using NIR and MC/HA/CNH, in combination with surgical procedures, might be employed to target relatively deep affected areas in a timely and efficacious manner. We envision that this innovative approach will pave the way for future developments in implant therapy.
Assuntos
Antibacterianos , Carbono , Ácido Hialurônico , Raios Infravermelhos , Minociclina , Peri-Implantite , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Peri-Implantite/tratamento farmacológico , Peri-Implantite/terapia , Minociclina/química , Minociclina/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Carbono/química , Animais , Humanos , Camundongos , Nanoestruturas/química , Nanoestruturas/uso terapêutico , Sistemas de Liberação de Medicamentos , Liberação Controlada de FármacosRESUMO
Depression triggered by harmful stress during adolescence is a common problem that can affect mental health. To date, the mechanisms underlying this type of depression remain unclear. One mechanism for the promotion of depression by chronic stress in adulthood is the loss of hippocampal microglia. Since deleterious stress in adolescence also activates microglia, we investigated the dynamic changes of microglia in the hippocampus in mice exposed to chronic unpredictable stress (CUS) in adolescence. Our results showed that 12 days of CUS stimulation in adolescence induced typical depression-like behaviors in adult mice, which were accompanied by a significant decrease and dystrophy of microglia in the dentate gyrus of the hippocampus. Further analysis showed that this decrease in microglia was mediated by the initial response of microglia to unpredictable stress in the dentate gyrus of the hippocampus and their subsequent apoptosis. Blocking the initial response of microglia to unpredictable stress by pretreatment with minocycline was able to prevent apoptosis and microglial decline as well as the development of depression-like behaviors in adult mice induced by adolescent CUS. Moreover, administration of lipopolysaccharide (LPS) or macrophage-colony stimulatory factor (M-CSF), two drugs that reversed microglia decline in the dentate gyrus, ameliorated the depression-like behaviors induced by CUS stimulation in adolescence. These findings reveal a novel mechanism for the development of depression-like behaviors in animals triggered by deleterious stress in adolescence and suggest that reversing microglial decline in the hippocampus may be a hopeful strategy for the treatment of depression triggered by deleterious stress in adolescence.
Assuntos
Apoptose , Comportamento Animal , Depressão , Hipocampo , Microglia , Estresse Psicológico , Animais , Microglia/efeitos dos fármacos , Microglia/patologia , Estresse Psicológico/complicações , Estresse Psicológico/psicologia , Apoptose/efeitos dos fármacos , Camundongos , Masculino , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Comportamento Animal/efeitos dos fármacos , Minociclina/farmacologia , Camundongos Endogâmicos C57BL , Giro Denteado/efeitos dos fármacos , Giro Denteado/patologia , Modelos Animais de Doenças , Fatores Etários , Lipopolissacarídeos/farmacologiaRESUMO
The 5-HT3 receptor and indoleamine 2,3-dioxygenase 1 (IDO1) enzyme play a crucial role in the pathogenesis of depression as their activation reduces serotonin contents in the brain. Since molecular docking analysis revealed lycopene as a potent 5-HT3 receptor antagonist and IDO1 inhibitor, we hypothesized that lycopene might disrupt the interplay between the 5-HT3 receptor and IDO1 to mitigate depression. In mice, the depression-like phenotypes were induced by inoculating Bacillus Calmette-Guerin (BCG). Lycopene (intraperitoneal; i.p.) was administered alone or in combination with 5-HT3 receptor antagonist ondansetron (i.p.) or IDO1 inhibitor minocycline (i.p.), and the behavioral screening was performed by the sucrose preference test, open field test, tail suspension test, and splash test which are based on the different principles. Further, the brains were subjected to the biochemical analysis of serotonin and its precursor tryptophan by the HPLC. The results showed depression-like behavior in BCG-inoculated mice, which was reversed by lycopene administration. Moreover, prior treatment with ondansetron or minocycline potentiated the antidepressant action of lycopene. Minocycline pretreatment also enhanced the antidepressant effect of ondansetron indicating the regulation of IDO1 activity by 5-HT3 receptor-triggered signaling. Biochemical analysis of brain samples revealed a drastic reduction in the levels of tryptophan and serotonin in depressed animals, which were restored following treatment with lycopene and its combination with ondansetron or minocycline. Taken together, the data from molecular docking, behavioral experiments, and biochemical estimation suggest that lycopene might block the 5-HT3 receptor and consequently inhibit the activity of IDO1 to ameliorate BCG-induced depression in mice.
Assuntos
Encéfalo , Depressão , Indolamina-Pirrol 2,3,-Dioxigenase , Licopeno , Receptores 5-HT3 de Serotonina , Animais , Licopeno/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Camundongos , Depressão/tratamento farmacológico , Depressão/metabolismo , Masculino , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Receptores 5-HT3 de Serotonina/metabolismo , Fenótipo , Simulação de Acoplamento Molecular , Serotonina/metabolismo , Vacina BCG/farmacologia , Ondansetron/farmacologia , Comportamento Animal/efeitos dos fármacos , Antagonistas do Receptor 5-HT3 de Serotonina/farmacologia , Antidepressivos/farmacologia , Minociclina/farmacologiaRESUMO
Signs and symptoms of hypernatremia largely indicate central nervous system dysfunction. Acute hypernatremia can cause demyelinating lesions similar to that observed in osmotic demyelination syndrome (ODS). We have previously demonstrated that microglia accumulate in ODS lesions and minocycline protects against ODS by inhibiting microglial activation. However, the direct effect of rapid rise in the sodium concentrations on microglia is largely unknown. In addition, the effect of chronic hypernatremia on microglia also remains elusive. Here, we investigated the effects of acute (6 or 24â¯h) and chronic (the extracellular sodium concentration was increased gradually for at least 7 days) high sodium concentrations on microglia using the microglial cell line, BV-2. We found that both acute and chronic high sodium concentrations increase NOS2 expression and nitric oxide (NO) production. We also demonstrated that the expression of nuclear factor of activated T-cells-5 (NFAT5) is increased by high sodium concentrations. Furthermore, NFAT5 knockdown suppressed NOS2 expression and NO production. We also demonstrated that high sodium concentrations decreased intracellular Ca2+ concentration and an inhibitor of Na+/Ca2+ exchanger, NCX, suppressed a decrease in intracellular Ca2+ concentrations and NOS2 expression and NO production induced by high sodium concentrations. Furthermore, minocycline inhibited NOS2 expression and NO production induced by high sodium concentrations. These in vitro data suggest that microglial activity in response to high sodium concentrations is regulated by NFAT5 and Ca2+ efflux through NCX and is suppressed by minocycline.