ABSTRACT
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.
Subject(s)
Chondroitin Sulfates , Drug Carriers , Gelatin , Hyaluronic Acid , Hydrogels , Minocycline , Polyelectrolytes , Hyaluronic Acid/chemistry , Gelatin/chemistry , Chondroitin Sulfates/chemistry , Hydrogels/chemistry , Hydrogels/pharmacology , Minocycline/chemistry , Minocycline/pharmacology , Minocycline/administration & dosage , Polyelectrolytes/chemistry , Humans , Drug Carriers/chemistry , Drug Liberation , Aldehydes/chemistry , Animals , Drug Delivery Systems/methods , Interleukin-6/metabolismABSTRACT
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.
Subject(s)
Nanoparticles , Oxidative Stress , Periodontitis , Oxidative Stress/drug effects , Periodontitis/drug therapy , Periodontitis/metabolism , Periodontitis/pathology , Nanoparticles/chemistry , Humans , Animals , Inflammation/drug therapy , Inflammation/metabolism , Inflammation/pathology , Minocycline/pharmacology , Minocycline/chemistry , Minocycline/therapeutic use , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Metal-Organic Frameworks/chemistry , Metal-Organic Frameworks/pharmacology , Mice , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Lipopolysaccharides/pharmacology , Antioxidants/pharmacology , Antioxidants/chemistry , Reactive Oxygen Species/metabolism , ImidazolesABSTRACT
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.
Subject(s)
Anti-Bacterial Agents , Doxycycline , Microbial Sensitivity Tests , Minocycline , Mycobacterium Infections, Nontuberculous , Mycobacterium abscessus , Tigecycline , Minocycline/pharmacology , Minocycline/analogs & derivatives , Tigecycline/pharmacology , Humans , Doxycycline/pharmacology , Doxycycline/therapeutic use , Mycobacterium abscessus/drug effects , Anti-Bacterial Agents/pharmacology , Mycobacterium Infections, Nontuberculous/drug therapy , Mycobacterium Infections, Nontuberculous/microbiology , Drug Resistance, BacterialABSTRACT
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.
Subject(s)
Encephalitis Viruses, Tick-Borne , Minocycline , Virus Replication , Animals , Encephalitis Viruses, Tick-Borne/drug effects , Encephalitis Viruses, Tick-Borne/physiology , Minocycline/pharmacology , Chlorocebus aethiops , Vero Cells , Virus Replication/drug effects , Humans , Antiviral Agents/pharmacology , Encephalitis, Tick-Borne/virology , Encephalitis, Tick-Borne/drug therapy , Cell Line , Signal Transduction/drug effectsABSTRACT
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.
Subject(s)
Homeostasis , Minocycline , Mitochondria , Reactive Oxygen Species , Retinitis Pigmentosa , Minocycline/pharmacology , Minocycline/therapeutic use , Animals , Retinitis Pigmentosa/drug therapy , Retinitis Pigmentosa/metabolism , Mitochondria/drug effects , Mitochondria/metabolism , Homeostasis/drug effects , Mice , Reactive Oxygen Species/metabolism , Retinal Degeneration/drug therapy , Retinal Degeneration/pathology , Retinal Degeneration/metabolism , Disease Models, Animal , Mice, Inbred C57BL , Photoreceptor Cells, Vertebrate/drug effects , Photoreceptor Cells, Vertebrate/pathology , Photoreceptor Cells, Vertebrate/metabolism , Membrane Potential, Mitochondrial/drug effects , Microglia/drug effects , Microglia/metabolism , Retina/drug effects , Retina/pathology , Retina/metabolism , Humans , Antioxidants/pharmacology , Antioxidants/therapeutic useABSTRACT
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.
Subject(s)
Anti-Bacterial Agents , Biofilms , Klebsiella pneumoniae , Microbial Sensitivity Tests , Biofilms/drug effects , Klebsiella pneumoniae/drug effects , Klebsiella pneumoniae/genetics , Anti-Bacterial Agents/pharmacology , Minocycline/pharmacology , Klebsiella Infections/microbiology , Klebsiella Infections/drug therapy , Gene Expression Regulation, Bacterial/drug effects , Animals , Tetracycline/pharmacology , Bacterial Adhesion/drug effects , Drug Resistance, Bacterial/drug effects , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Moths/drug effects , Moths/microbiology , Humans , Hydrophobic and Hydrophilic InteractionsABSTRACT
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.
Subject(s)
Anti-Bacterial Agents , Bacterial Proteins , Gene Expression Regulation, Bacterial , Klebsiella Infections , Klebsiella pneumoniae , Microbial Sensitivity Tests , Tigecycline , Klebsiella pneumoniae/genetics , Klebsiella pneumoniae/drug effects , Klebsiella pneumoniae/metabolism , Tigecycline/pharmacology , Anti-Bacterial Agents/pharmacology , Klebsiella Infections/microbiology , Humans , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Membrane Transport Proteins/genetics , Membrane Transport Proteins/metabolism , Drug Resistance, Bacterial/genetics , RNA, Bacterial/genetics , Drug Resistance, Multiple, Bacterial/genetics , Minocycline/pharmacology , Minocycline/analogs & derivativesABSTRACT
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.
Subject(s)
Astrocytes , Memory Disorders , Methamphetamine , Microglia , Minocycline , Spatial Memory , Animals , Methamphetamine/toxicity , Microglia/drug effects , Microglia/metabolism , Mice , Memory Disorders/chemically induced , Astrocytes/metabolism , Astrocytes/drug effects , Astrocytes/pathology , Spatial Memory/physiology , Spatial Memory/drug effects , Male , Minocycline/pharmacology , Mice, Inbred C57BL , Substance Withdrawal Syndrome/metabolism , Substance Withdrawal Syndrome/pathology , Central Nervous System Stimulants/toxicityABSTRACT
INTRODUCTION: Tigecycline has a broad spectrum of activity, including activity against drug-resistant Gram-positive and -negative microorganisms. Its side effects are significant, but hypoglycemia is a rare finding during treatment. We aim to present an event of severe hypoglycemia in a patient with type 2 diabetes mellitus with replacement renal therapy, and hemodialysis after initiating tigecycline. CASE PRESENTATION: A 54-year-old female diagnosed with type 2 diabetes mellitus was under treatment with basal-bolus insulin therapy and oral antihypertensive drugs. She started hemodialysis 24 months ago. She complained of recurrent fever for the last seven months and was treated with several antibiotics. In two separate blood cultures, she tested positive for methicillin-resistant Staphylococcus epidermidis (MRSE). Based on the antibiogram, we started treatment with tigecycline 100 mg/day. After 6-8 hours from the first dose, the patient is complicated with events of hypoglycemia and then continues with severe hypoglycemia (40-47 mg/dL). The patient continued to have hypoglycemia for about 16-18 hours after the last dose. We didn't find any reasons to explain the cause of episodes of hypoglycemia. She did not have high blood insulin levels (insulin 4.11 mIU/L [range 2.6-24.9]). We followed her for six months and the patient did not experience episodes of hypoglycemia. CONCLUSIONS: The association of severe hypoglycemia with tigecycline treatment is a very rare event and published papers on this topic are limited. Clinicians should be aware of this rare event when administering tigecycline and should routinely check blood glucose level during the treatment.
Subject(s)
Anti-Bacterial Agents , Diabetes Mellitus, Type 2 , Hypoglycemia , Minocycline , Renal Dialysis , Staphylococcus epidermidis , Tigecycline , Humans , Tigecycline/adverse effects , Tigecycline/therapeutic use , Female , Middle Aged , Hypoglycemia/chemically induced , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/complications , Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/therapeutic use , Minocycline/analogs & derivatives , Minocycline/adverse effects , Minocycline/therapeutic use , Staphylococcal Infections/drug therapyABSTRACT
Aim: Bullous pemphigoid induced by secukinumab in treatment of psoriasis is rare.Methods: We report a 49-year-old man with psoriasis who developed bullous pemphigoid during treatment with secukinumab.Results: Scattered tense vesicles with itching appeared all over the body after the fourth treatment. Bullous pemphigoid was confirmed by pathological examination and direct immunofluorescence. The patient was treated with topical corticosteroids, oral nicotinamide and minocycline hydrochloride. The lesions of bullous pemphigoid improved significantly after 7 days of treatment.Conclusions: Bullous pemphigoid is a rare adverse event following administration of secukinumab.
Subject(s)
Antibodies, Monoclonal, Humanized , Pemphigoid, Bullous , Psoriasis , Humans , Pemphigoid, Bullous/chemically induced , Pemphigoid, Bullous/drug therapy , Pemphigoid, Bullous/pathology , Pemphigoid, Bullous/diagnosis , Male , Middle Aged , Antibodies, Monoclonal, Humanized/adverse effects , Psoriasis/drug therapy , Psoriasis/chemically induced , Minocycline/adverse effects , Niacinamide/analogs & derivatives , Niacinamide/adverse effects , Niacinamide/therapeutic use , Dermatologic Agents/adverse effects , Treatment OutcomeABSTRACT
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.
Subject(s)
Brain , Depression , Indoleamine-Pyrrole 2,3,-Dioxygenase , Lycopene , Receptors, Serotonin, 5-HT3 , Animals , Lycopene/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Mice , Depression/drug therapy , Depression/metabolism , Male , Brain/drug effects , Brain/metabolism , Receptors, Serotonin, 5-HT3/metabolism , Phenotype , Molecular Docking Simulation , Serotonin/metabolism , BCG Vaccine/pharmacology , Ondansetron/pharmacology , Behavior, Animal/drug effects , Serotonin 5-HT3 Receptor Antagonists/pharmacology , Antidepressive Agents/pharmacology , Minocycline/pharmacologyABSTRACT
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.
Subject(s)
Anti-Bacterial Agents , Carbon , Hyaluronic Acid , Infrared Rays , Minocycline , Peri-Implantitis , Hyaluronic Acid/chemistry , Hyaluronic Acid/pharmacology , Peri-Implantitis/drug therapy , Peri-Implantitis/therapy , Minocycline/chemistry , Minocycline/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Carbon/chemistry , Animals , Humans , Mice , Nanostructures/chemistry , Nanostructures/therapeutic use , Drug Delivery Systems , Drug LiberationABSTRACT
Chronic neuropathic pain precipitates a complex range of affective and behavioural disturbances that differ markedly between individuals. While the reasons for differences in pain-related disability are not well understood, supraspinal neuroimmune interactions are implicated. Minocycline has antidepressant effects in humans and attenuates affective disturbances in rodent models of pain, and acts by reducing neuroinflammation in both the spinal cord and brain. Previous studies, however, tend not to investigate how minocycline modulates individual affective responses to nerve injury, or rely on non-naturalistic behavioural paradigms that fail to capture the complexity of rodent behaviour. We investigated the development and resolution of pain-related affective disturbances in nerve-injured male rats by measuring multiple spontaneous ethological endpoints on a longitudinal naturalistic foraging paradigm, and the effect of chronic oral minocycline administration on these changes. Disrupted foraging behaviours appeared in 22% of nerve-injured rats - termed 'affected' rats - and were present at day 14 but partially resolved by day 21 post-injury. Minocycline completely prevented the emergence of an affected subgroup while only partly attenuating mechanical allodynia, dissociating the relationship between pain and affect. This was associated with a lasting downregulation of ΔFosB expression in ventral hippocampal neurons at day 21 post-injury. Markers of microglia-mediated neuroinflammation were not present by day 21, however proinflammatory microglial polarisation was apparent in the medial prefrontal cortex of affected rats and not in CCI minocycline rats. Individual differences in affective disturbances following nerve injury are therefore temporally related to altered microglial morphology and hippocampal neuronal activation, and are abrogated by minocycline.
Subject(s)
Minocycline , Neuroinflammatory Diseases , Animals , Minocycline/pharmacology , Male , Rats , Neuroinflammatory Diseases/drug therapy , Rats, Sprague-Dawley , Neuralgia/drug therapy , Neuralgia/metabolism , Neuralgia/prevention & control , Hyperalgesia/drug therapy , Hyperalgesia/prevention & control , Individuality , Mood Disorders/drug therapy , Mood Disorders/etiology , Peripheral Nerve Injuries/complicationsABSTRACT
Background: Tigecycline, a glycylcycline antibiotic is a promising option for the treatment of single or multidrug resistant pathogens. The aim of the study was to evaluate the in-vitro Tigecycline susceptibility of various pathogens from clinical samples received at the tertiary care hospitals in South India. Methods: The analysis of specimens from patients admitted were carried out in this prospective cross sectional study. The identification and antimicrobial susceptibility testing was performed by semi-automated Vitek 2 systems and Kirby Bauer method. Pattern of data analysis was done by descriptive statistics. Results: Among 2574 isolates, 812 isolates were Gram positive pathogens and 1762 isolates were Gram negative pathogens. Resistance to Tigecycline was more common among Gram negative pathogens (18.62%) in comparison to the Gram positive pathogens (0.49%). Among 740 Extended Spectrum Beta Lactamases (ESBL) producers such as Klebsiella species & E coli, 629 isolates were susceptible, and 93 isolates were resistant to the tigecycline. All the methicillin resistant Staphylococcus aureus (MRSA) isolates were susceptible to tigecycline. Conclusion: Multidrug resistant (MDR) pathogens like Acinetobacter species, and Klebsiella species were found to be highly effective in vitro to tigecycline for elimination of infections caused by both Gram positive and Gram negative pathogens. The use of combination therapy becomes crucial to prevent the development of Pan Drug resistance.
Subject(s)
Drug Resistance, Multiple, Bacterial , Microbial Sensitivity Tests , Tertiary Care Centers , Tigecycline , Tigecycline/pharmacology , Humans , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Cross-Sectional Studies , Minocycline/analogs & derivatives , Minocycline/pharmacology , Minocycline/therapeutic use , Gram-Negative Bacteria/drug effects , Prospective Studies , India , Gram-Positive Bacteria/drug effectsABSTRACT
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.
Subject(s)
Hypernatremia , Microglia , Minocycline , Nitric Oxide Synthase Type II , Nitric Oxide , Microglia/metabolism , Microglia/drug effects , Animals , Nitric Oxide/metabolism , Hypernatremia/metabolism , Hypernatremia/pathology , Hypernatremia/genetics , Minocycline/pharmacology , Mice , Nitric Oxide Synthase Type II/metabolism , Nitric Oxide Synthase Type II/genetics , Sodium/metabolism , Cell Line , Calcium/metabolism , Sodium-Calcium Exchanger/metabolism , Sodium-Calcium Exchanger/genetics , NFATC Transcription Factors/metabolism , NFATC Transcription Factors/geneticsABSTRACT
A 43-year-old man was admitted to our department due to fever and headache. The cerebrospinal fluid analysis confirmed bacterial meningitis. Campylobacter species were isolated from blood cultures on the third day of admission. The patient was treated with meropenem (MEPM) and discharged on the 17th day. However, he experienced a recurrence of meningitis and was readmitted on the 68th day, initiating MEPM therapy. Campylobacter fetus was isolated from cerebrospinal fluid cultures on the 74th day. MEPM was continued until the 81st day, followed by one month of minocycline (MINO) therapy. The patient had an uneventful recovery without further recurrence. This case highlights the potential for recurrence of Campylobacter fetus meningitis approximately two months after the resolution of the initial infection. In addition to carbapenem therapy for at least two weeks, the adjunctive administration of MINO may be beneficial.
Subject(s)
Anti-Bacterial Agents , Campylobacter Infections , Campylobacter fetus , Meningitis, Bacterial , Meropenem , Minocycline , Recurrence , Humans , Male , Adult , Campylobacter fetus/isolation & purification , Campylobacter Infections/drug therapy , Campylobacter Infections/complications , Campylobacter Infections/diagnosis , Campylobacter Infections/microbiology , Meropenem/administration & dosage , Meningitis, Bacterial/drug therapy , Meningitis, Bacterial/microbiology , Meningitis, Bacterial/diagnosis , Anti-Bacterial Agents/administration & dosage , Time Factors , Minocycline/administration & dosage , Treatment Outcome , Thienamycins/administration & dosage , Drug Therapy, CombinationABSTRACT
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.
Subject(s)
Apoptosis , Behavior, Animal , Depression , Hippocampus , Microglia , Stress, Psychological , Animals , Microglia/drug effects , Microglia/pathology , Stress, Psychological/complications , Stress, Psychological/psychology , Apoptosis/drug effects , Mice , Male , Hippocampus/drug effects , Hippocampus/pathology , Behavior, Animal/drug effects , Minocycline/pharmacology , Mice, Inbred C57BL , Dentate Gyrus/drug effects , Dentate Gyrus/pathology , Disease Models, Animal , Age Factors , Lipopolysaccharides/pharmacologyABSTRACT
Tigecycline is a parenteral glycycline antibiotic that is used to treat severe infections caused by susceptible organisms, butitis also associated with hepatotoxicity. We present 2 similar patients with hepatic steatosis possibly associated with early tigecycline after transplant. In the first case, a 61-year-old woman underwent liver transplant for acute severe hepatitis; 6 days posttransplant, because of nonroutine resistant fever, the patient received tigecycline combined with daptomycin. Retransplant was applied to the patient on day 12 posttransplant because of acute liver failure secondary to hepatic vein thrombosis. After retransplant, biochemical levels gradually increased, exceeding the upper limit of normal. In liver biopsy, the patient had macrovesicular steatosis in 70% to 80% ofthe parenchyma. In the second case, a 53-yearold woman underwent liver transplant for liver cirrhosis. Tigecycline was added to the treatment because of recurrent fever on day 6 after transplant, with treatment also comprising piperacillin-tazobactam and meropenem. On day 15 of the patient's tigecycline treatment, her liver function tests were elevated. In liver biopsy, the patient had 30% to 40% macrovesicular steatosis and canalicular cholestasis in the parenchyma, especially in zone 3. Reports of hepatic steatosis associated with early tigecycline after transplant are quite new to the literature.