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Microorganisms Jun 2024serovar Gallinarum biovar Gallinarum (SG) causes fowl typhoid, a notifiable infectious disease in poultry. However, the pathogenic mechanism of SG-induced systemic...
serovar Gallinarum biovar Gallinarum (SG) causes fowl typhoid, a notifiable infectious disease in poultry. However, the pathogenic mechanism of SG-induced systemic infection in chickens remains unclear. Thioredoxin reductase (TrxB) is a redox protein crucial for regulating various enzyme activities in serovar, but the role in SG-induced chicken systemic infection has yet to be determined. Here, we constructed a mutant SG strain lacking the gene (::Cm) and used chicken embryo inoculation and chicken oral infection to investigate the role of gene in the pathogenicity of SG. Our results showed that ::Cm exhibited no apparent differences in colony morphology and growth conditions but exhibited reduced tolerance to HO and increased resistance to bile acids. In the chicken embryo inoculation model, there was no significant difference in the pathogenicity of ::Cm and wild-type (WT) strains. In the chicken oral infection, the WT-infected group exhibited typical clinical symptoms of fowl typhoid, with complete mortality between days 6 and 9 post infection. In contrast, the ::Cm group showed a 100% survival rate, with no apparent clinical symptoms or pathological changes observed. The viable bacterial counts in the liver and spleen of the ::Cm-infected group were significantly reduced, accompanied by decreased expression of cytokines and chemokines (IL-1β, IL-6, IL-12, CXCLi1, TNF-α, and IFN-γ), which were significantly lower than those in the WT group. These results show that the pathogenicity of the -deficient strain was significantly attenuated, indicating that the gene is a crucial virulence factor in SG-induced systemic infection in chickens, suggesting that may become a potentially effective target for controlling and preventing SG infection in chickens.
PubMed: 38930562
DOI: 10.3390/microorganisms12061180 -
Antioxidants (Basel, Switzerland) May 2024Fluconazole (FLC) is extensively employed for the prophylaxis and treatment of invasive fungal infections (IFIs). However, the fungistatic nature of FLC renders...
Fluconazole (FLC) is extensively employed for the prophylaxis and treatment of invasive fungal infections (IFIs). However, the fungistatic nature of FLC renders pathogenic fungi capable of developing tolerance towards it. Consequently, converting FLC into a fungicidal agent using adjuvants assumes significance to circumvent FLC resistance and the perpetuation of fungal infections. This drug repurposing study has successfully identified pitavastatin calcium (PIT) as a promising adjuvant for enhancing the fungicidal activity of FLC from a comprehensive library of 2372 FDA-approved drugs. PIT could render FLC fungicidal even at concentrations as low as 1 μM. The median lethal dose (LD) of PIT was determined to be 103.6 mg/kg. We have discovered that PIT achieves its synergistic effect by inhibiting the activity of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, thereby impeding ubiquinone biosynthesis, inducing reactive oxygen species (ROS) generation, triggering apoptosis, and disrupting Golgi function. We employed a strain that demonstrated a notable tolerance to FLC to infect mice and found that PIT effectively augmented the antifungal efficacy of FLC against IFIs. This study is an illustrative example of how FDA-approved drugs can effectively eliminate fungal tolerance to FLC.
PubMed: 38929106
DOI: 10.3390/antiox13060667 -
International Journal of Molecular... Jun 2024Salt stress seriously affects crop growth, leading to a decline in crop quality and yield. Application of exogenous substances to improve the salt tolerance of crops and...
Salt stress seriously affects crop growth, leading to a decline in crop quality and yield. Application of exogenous substances to improve the salt tolerance of crops and promote their growth under salt stress has become a widespread and effective means. Eugenol is a small molecule of plant origin with medicinal properties such as antibacterial, antiviral, and antioxidant properties. In this study, tobacco seedlings were placed in Hoagland's solution containing NaCl in the presence or absence of eugenol, and physiological indices related to stress tolerance were measured along with transcriptome sequencing. The results showed that eugenol improved the growth of tobacco seedlings under salt stress. It promoted carbon and nitrogen metabolism, increased the activities of nitrate reductase (NR), sucrose synthase (SS), and glutamine synthetase (GS) by 31.03, 5.80, and 51.06%. It also activated the enzymatic and non-enzymatic antioxidant systems, reduced the accumulation of reactive oxygen species in the tobacco seedlings, and increased the activities of superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), and ascorbate peroxidase (APX) by 24.38%, 18.22%, 21.60%, and 28.8%, respectively. The content of glutathione (GSH) was increased by 29.49%, and the content of superoxide anion (O) and malondialdehyde (MDA) were reduced by 29.83 and 33.86%, respectively. Promoted osmoregulation, the content of Na decreased by 34.34, K increased by 41.25%, and starch and soluble sugar increased by 7.72% and 25.42%, respectively. It coordinated hormone signaling in seedlings; the content of abscisic acid (ABA) and gibberellic acid 3 (GA) increased by 51.93% and 266.28%, respectively. The transcriptome data indicated that the differentially expressed genes were mainly enriched in phenylpropanoid biosynthesis, the MAPK signaling pathway, and phytohormone signal transduction pathways. The results of this study revealed the novel role of eugenol in regulating plant resistance and provided a reference for the use of exogenous substances to alleviate salt stress.
Topics: Nicotiana; Seedlings; Antioxidants; Signal Transduction; Eugenol; Gene Expression Regulation, Plant; Salt Stress; Plant Growth Regulators; Salt Tolerance; Reactive Oxygen Species
PubMed: 38928476
DOI: 10.3390/ijms25126771 -
International Journal of Molecular... Jun 2024The objective of this study was to assess the impact of acute and chronic treatment with oxcarbazepine on its anticonvulsant activity, neurological adverse effects, and...
The objective of this study was to assess the impact of acute and chronic treatment with oxcarbazepine on its anticonvulsant activity, neurological adverse effects, and protective index in mice. Oxcarbazepine was administered in four protocols: once or twice daily for one week (7 × 1 or 7 × 2) and once or twice daily for two weeks (14 × 1 or 14 × 2). A single dose of the drug was employed as a control. The anticonvulsant effect was evaluated in the maximal electroshock test in mice. Motor and long-term memory impairment were assessed using the chimney test and the passive avoidance task, respectively. The concentrations of oxcarbazepine in the brain and plasma were determined via high-performance liquid chromatography. Two weeks of oxcarbazepine treatment resulted in a significant reduction in the anticonvulsant (in the 14 × 1; 14 × 2 protocols) and neurotoxic (in the 14 × 2 schedule) effects of this drug. In contrast, the protective index for oxcarbazepine in the 14 × 2 protocol was found to be lower than that calculated for the control. No significant deficits in memory or motor coordination were observed following repeated administration of oxcarbazepine. The plasma and brain concentrations of this anticonvulsant were found to be significantly higher in the one-week protocols. Chronic treatment with oxcarbazepine may result in the development of tolerance to its anticonvulsant and neurotoxic effects, which appears to be dependent on pharmacodynamic mechanisms.
Topics: Animals; Oxcarbazepine; Mice; Anticonvulsants; Electroshock; Male; Disease Models, Animal; Seizures; Brain; Memory, Long-Term; Carbamazepine; Avoidance Learning
PubMed: 38928457
DOI: 10.3390/ijms25126751 -
International Journal of Molecular... Jun 2024Stylo ( spp.) is an important pasture legume with strong aluminum (Al) resistance. However, the molecular mechanisms underlying its Al tolerance remain fragmentary. Due...
Stylo ( spp.) is an important pasture legume with strong aluminum (Al) resistance. However, the molecular mechanisms underlying its Al tolerance remain fragmentary. Due to the incomplete genome sequence information of stylo, we first conducted full-length transcriptome sequencing for stylo root tips treated with and without Al and identified three genes, namely, , , and . Through quantitative RT-PCR, we found that only was significantly upregulated by Al treatments in stylo root tips. Histochemical localization assays further verified the Al-enhanced expression of in stylo root tips. Subcellular localization in both tobacco and onion epidermis cells showed that SgSnakin1 localized to the cell wall. Overexpression of conferred Al tolerance in transgenic Arabidopsis, as reflected by higher relative root growth and cell vitality, as well as lower Al concentration in the roots of transgenic plants. Additionally, overexpression of increased the activities of SOD and POD and decreased the levels of O and HO in transgenic Arabidopsis in response to Al stress. These findings indicate that may function in Al resistance by enhancing the scavenging of reactive oxygen species through the regulation of antioxidant enzyme activities.
Topics: Aluminum; Reactive Oxygen Species; Gene Expression Regulation, Plant; Plant Proteins; Arabidopsis; Plants, Genetically Modified; Fabaceae; Plant Roots; Hydrogen Peroxide; Nicotiana
PubMed: 38928379
DOI: 10.3390/ijms25126672 -
International Journal of Molecular... Jun 2024bacteremia continues to be associated with significant morbidity and mortality, despite improvements in diagnostics and management. Persistent infections pose a major... (Review)
Review
bacteremia continues to be associated with significant morbidity and mortality, despite improvements in diagnostics and management. Persistent infections pose a major challenge to clinicians and have been consistently shown to increase the risk of mortality and other infectious complications. , while typically not considered an intracellular pathogen, has been proven to utilize an intracellular niche, through several phenotypes including small colony variants, as a means for survival that has been linked to chronic, persistent, and recurrent infections. This intracellular persistence allows for protection from the host immune system and leads to reduced antibiotic efficacy through a variety of mechanisms. These include antimicrobial resistance, tolerance, and/or persistence in that contribute to persistent bacteremia. This review will discuss the challenges associated with treating these complicated infections and the various methods that uses to persist within the intracellular space.
Topics: Bacteremia; Humans; Staphylococcus aureus; Staphylococcal Infections; Anti-Bacterial Agents; Animals; Drug Resistance, Bacterial
PubMed: 38928191
DOI: 10.3390/ijms25126486 -
International Journal of Molecular... Jun 2024Alcohol use disorder (AUD) is a chronic neurobehavioral condition characterized by a cycle of tolerance development, increased consumption, and reinstated craving and...
Alcohol use disorder (AUD) is a chronic neurobehavioral condition characterized by a cycle of tolerance development, increased consumption, and reinstated craving and seeking behaviors during withdrawal. Understanding the intricate mechanisms of AUD necessitates reliable animal models reflecting its key features. (), with its conserved nervous system and genetic tractability, has emerged as a valuable model organism to study AUD. Here, we employ an ethanol vapor exposure model in , recapitulating AUD features while maintaining high-throughput scalability. We demonstrate that ethanol vapor exposure induces intoxication-like behaviors, acute tolerance, and ethanol preference, akin to mammalian AUD traits. Leveraging this model, we elucidate the conserved role of c-jun N-terminal kinase (JNK) signaling in mediating acute ethanol tolerance. Mutants lacking JNK signaling components exhibit impaired tolerance development, highlighting JNK's positive regulation. Furthermore, we detect ethanol-induced JNK activation in . Our findings underscore the utility of with ethanol vapor exposure for studying AUD and offer novel insights into the molecular mechanisms underlying acute ethanol tolerance through JNK signaling.
Topics: Animals; Caenorhabditis elegans; Ethanol; Drug Tolerance; Caenorhabditis elegans Proteins; MAP Kinase Signaling System; JNK Mitogen-Activated Protein Kinases; Alcoholism; Disease Models, Animal
PubMed: 38928105
DOI: 10.3390/ijms25126398 -
Biomedicines Jun 2024Pain is a multifaceted, multisystem disorder that adversely affects neuro-psychological processes. This study compares the effectiveness of central stimulation...
Pain is a multifaceted, multisystem disorder that adversely affects neuro-psychological processes. This study compares the effectiveness of central stimulation (transcranial direct current stimulation-tDCS over F3/F4) and peripheral stimulation (transcutaneous electrical nerve stimulation-TENS over the median nerve) in pain inhibition during a cognitive task in healthy volunteers and to observe potential neuro-cognitive improvements. Eighty healthy participants underwent a comprehensive experimental protocol, including cognitive assessments, the Cold Pressor Test (CPT) for pain induction, and tDCS/TENS administration. EEG recordings were conducted pre- and post-intervention across all conditions. The protocol for this study was categorized into four groups: G1 (control), G2 (TENS), G3 (anodal-tDCS), and G4 (cathodal-tDCS). Paired -tests ( < 0.05) were conducted to compare Pre-Stage, Post-Stage, and neuromodulation conditions, with t-values providing insights into effect magnitudes. The result showed a reduction in pain intensity with TENS ( = 0.002, t-value = -5.34) and cathodal-tDCS ( = 0.023, t-value = -5.08) and increased pain tolerance with TENS ( = 0.009, t-value = 4.98) and cathodal-tDCS ( = 0.001, t-value = 5.78). Anodal-tDCS ( = 0.041, t-value = 4.86) improved cognitive performance. The EEG analysis revealed distinct neural oscillatory patterns across the groups. Specifically, G2 and G4 showed delta-power reductions, while G3 observed an increase. Moreover, G2 exhibited increased theta-power in the occipital region during CPT and Post-Stages. In the alpha-band, G2, G3, and G4 had reductions Post-Stage, while G1 and G3 increased. Additionally, beta-power increased in the frontal region for G2 and G3, contrasting with a reduction in G4. Furthermore, gamma-power globally increased during CPT1, with G1, G2, and G3 showing reductions Post-Stage, while G4 displayed a global decrease. The findings confirm the efficacy of TENS and tDCS as possible non-drug therapeutic alternatives for cognition with alleviation from pain.
PubMed: 38927476
DOI: 10.3390/biomedicines12061269 -
Antibiotics (Basel, Switzerland) Jun 2024In this study, we assessed the impact of commercially available polymyxin B against VRP-034 (novel formulation of polymyxin B) using a validated in vitro human renal...
In this study, we assessed the impact of commercially available polymyxin B against VRP-034 (novel formulation of polymyxin B) using a validated in vitro human renal model, aProximate. Freshly isolated primary proximal tubule cells (PTCs) were cultured in Transwell plates and treated with various concentrations of the formulations for up to 48 h. The functional expression of megalin-cubilin receptors in PTC monolayers was validated using FITC-conjugated albumin uptake assays. Polymyxin B and VRP-034 were evaluated at six concentrations (0.3, 1, 3, 10, 30, and 60 µM), and nephrotoxicity was assessed through measurements of transepithelial electrical resistance (TEER), intracellular adenosine triphosphate (ATP) levels, lactate dehydrogenase (LDH) release, and novel injury biomarkers [kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and clusterin]. Additionally, histological analysis using annexin V apoptosis staining was performed. Our results indicated a significant decrease in TEER with polymyxin B at concentrations ≥10 μM compared to VRP-034. Toxic effects were observed from ATP and LDH release only at concentrations ≥30 μM for both formulations. Furthermore, injury biomarker release was higher with polymyxin B compared to VRP-034, particularly at concentrations ≥10 µM. Histologically, polymyxin B-treated PTCs showed increased apoptosis compared to VRP-034-treated cells. Overall, VRP-034 demonstrated improved tolerance in the aProximate model compared to polymyxin B, suggesting its potential as a safer alternative for renal protection.
PubMed: 38927196
DOI: 10.3390/antibiotics13060530 -
Antibiotics (Basel, Switzerland) Jun 2024, as a notorious fungal pathogen, is associated with high morbidity and mortality worldwide due to its ability to form biofilms and persisters that can withstand...
, as a notorious fungal pathogen, is associated with high morbidity and mortality worldwide due to its ability to form biofilms and persisters that can withstand currently available antifungals. Direct current (DC) has demonstrated a promising antimicrobial effect and synergistic effect with antimicrobials against various infections. Here, we first found DC exerted a killing effect on planktonic and biofilm cells. Moreover, DC showed a synergistic effect with fluconazole (FLC) and amphotericin B (AMB). Notably, near-to-complete eradication of AMB-tolerant biofilm persisters was achieved upon DC treatment. Next, the mechanism of action of DC was explored through mapping the genes and proteomic profiles of DC-treated . The multi-omics analysis, quantitative real-time PCR and assay of reactive oxygen species (ROS) demonstrated DC exerted an antifungal effect on by increasing cellular oxidative stress. As revealed by multiple analyses (e.g., protein assay based on absorbance at 280 nm and rhodamine 6G assay), DC was able to enhance membrane permeability, inhibit drug efflux and increase cellular FLC/AMB concentration of , thereby mediating its synergism with the antifungals. Furthermore, DC inhibited superoxide dismutase 2 (SOD2) expression and manganese-containing SOD (Mn SOD) activity, leading to ROS production and enhanced killing of biofilm persisters. The current findings demonstrate that the adjunctive use of DC in combination with antifungals is a promising strategy for effective control of infections and management of antifungal resistance/tolerance in biofilms.
PubMed: 38927187
DOI: 10.3390/antibiotics13060521