Gut Distribution, Impact Factor, and Action Mechanism of Bacteriocin-Producing Beneficial Microbes as Promising Antimicrobial Agents in Gastrointestinal Infection.

Gastrointestinal (GI) infection by intestinal pathogens poses great threats to human health, and the therapeutic use of antibiotics has reached a bottleneck due to drug resistance. The developments of antimicrobial peptides produced by beneficial bacteria have drawn attention by virtue of effective, safe, and not prone to developing resistance. Though bacteriocin as antimicrobial agent in gut infection has been intensively investigated and reviewed, reviews on that of bacteriocin-producing beneficial microbes are very rare. It is important to explicitly state the prospect of bacteriocin-producing microbes in prevention of gastrointestinal infection towards their application in host. This review discusses the potential of gut as an appropriate resource for mining targeted bacteriocin-producing microbes. Then, host-related factors affecting the bacteriocin production and activity of bacteriocin-producing microbes in the gut are summarized. Accordingly, the multiple mechanisms (direct inhibition and indirect inhibition) behind the preventive effects of bacteriocin-producing microbes on gut infection are discussed. Finally, we propose several targeted strategies for the manipulation of bacteriocin-producing beneficial microbes to improve their performance in antimicrobial outcomes. We anticipate an upcoming emergence of developments and applications of bacteriocin-producing beneficial microbes as antimicrobial agent in gut infection induced by pathogenic bacteria.

Progranulin released from microglial lysosomes reduces neuronal ferroptosis after cerebral ischemia in mice.

The cellular redox state is essential for inhibiting ferroptosis. Progranulin (PGRN) plays an important role in maintaining the cellular redox state after ischemic brain injury. However, the effect of PGRN on ferroptosis and its underlying mechanism after cerebral ischemia remains unclear. This study assesses whether PGRN affects ferroptosis and explores its mechanism of action on ferroptosis after cerebral ischemia. We found endogenous PGRN expression in microglia increased on day 3 after ischemia. In addition, PGRN agonists chloroquine and trehalose upregulated PGRN expression, reduced brain infarct volume, and improved neurobehavioral outcomes after cerebral ischemia compared to controls (p < 0.05). Moreover, PGRN upregulation attenuated ferroptosis by decreasing malondialdehyde and increasing Gpx4, Nrf2, and Slc7a11 expression and glutathione content (p < 0.05). Furthermore, chloroquine induced microglial lysosome PGRN release, which was associated with increased neuron survival. Our results indicate that PGRN derived from microglial lysosomes effectively inhibits ferroptosis during ischemic brain injury, identifying it as a promising target for ischemic stroke therapy.

Comparison of two different therapeutic approaches for skeletal Class II patients with temporomandibular degenerative joint disease.

OBJECTIVES: To compare two different therapeutic approaches for skeletal Class II patients with temporomandibular degenerative joint disease. MATERIALS AND METHODS: A total of 47 patients were included in this study. Group anterior repositioning splint (ARS) was treated with temporomandibular joint (TMJ) disc surgery followed by an ARS and camouflage orthodontic treatment. Group stabilization splint (SS) was treated with an SS followed by orthodontic treatment combined with orthognathic surgery. Cephalometric analysis of lateral radiographs and measurements of condylar height were evaluated before and after splints. RESULTS: In group ARS, mandibular advancement was observed after treatment in 21 of 24 patients (87.5%). The SNB angle increased by an average of 1.40 ± 1.01°. The ANB angle, overjet, Wits, and convexity decreased. Facial angle and soft tissue N Vert to pogonion increased. Vertically, MP-FH, MP-SN, y-axis, and vertical ratio decreased and ANS-Me/N-Me and S-Go/N-Me increased, suggesting a counterclockwise rotation of the mandible. In group SS, 18 of 23 patients (78.3%) showed a backward change tendency. The SNB angle reduced by 0.90 ± 0.93°. The ANB angle, overjet, Wits, convexity, and y-axis increased. The facial angle and soft tissue N Vert to soft tissue pogonion (ST N Vert to ST pogonion) decreased. Magnetic resonance imaging showed condylar height increased by 1.45 ± 3.05 mm (P = .002) in group ARS. In group SS, condylar height change was not consistent. CONCLUSIONS: TMJ disc surgery followed by ARS promoted condylar bone remodeling and regeneration. The SNB angle increased, and the severity of skeletal Class II was improved. The SS enabled the mandible to withdraw backward and revealed a retrognathic but true mandible position.

Zeb2/Axin2-Enriched BMSC-Derived Exosomes Promote Post-Stroke Functional Recovery by Enhancing Neurogenesis and Neural Plasticity.

Exosomes harvested from bone marrow-derived mesenchymal stromal cells (BMSCs) have shown treatment potential in many diseases. In vitro, Zeb2/Axin2 stimulated endogenous neurogenesis, which induced functional recovery after stroke. Here, we investigated whether the Zeb2/Axin2-enriched exosomes harvested from BMSCs transfected with a Zeb2/Axin2 overexpression plasmid would enhance neurological recovery. Compared with the control, both exosome treatments significantly improved functional recovery, and Zeb2/Axin2-enriched exosomes had significantly more improved effects on neurological function, neurogenesis, and neurite remodeling/neuronal dendrite plasticity than the control BMSC exosome treatment in a middle cerebral artery occlusion MCAO rat model. After stimulation with Zeb2/Axin2-enriched BMSC exosomes, the spatial memory and nerve function of MCAO rats showed marked recovery. The number of neurons was increased in the subventricular zone (SVZ), hippocampus, and cortex area, while the expression of nerve growth factors (NGF, BDNF, etc.) was upregulated. In the ischemic boundary zone, Zeb2/Axin2-enriched exosomes promoted synaptic remodeling by increasing the number of synapses and reversed the axonal loss of phosphorylated neurofilament (SMI-31) and synaptophysin (SYN) caused by ischemic injury, thus alleviating axonal demise and promoting synaptic proliferation. In vitro, Zeb2/Axin2-enriched exosomes significantly increased neurite branching and elongation of cultured cortical embryonic rat neurons under oxygen- and glucose-deprived (OGD) conditions. Moreover, Ex-Zeb2/Axin2-enriched exosomes downregulated the protein level of SOX10, endothelin-3/EDNRB, and Wnt/ß-catenin expression. In conclusion, exosomes harvested from Ex-Zeb2/Axin2 BMSC could improve post-stroke neuroplasticity and functional recovery in MCAO rats by promoting proliferation and differentiation of neural stem cells. The mechanism may be related to the SOX10, Wnt/ß-catenin, and endothelin-3/EDNRB pathways.

Validation of a Gyrolab™ assay for quantification of rituximab in human serum.

INTRODUCTION: Gyrolab™ technology presents a technology breakthrough for large molecule bioanalysis to support biologic drug development. The advantages of this innovative platform include fully automated nanoscale immunoassay capability, better assay reproducibility and data quality, small reagent and sample volumes, and rapid assay development and validation as a result of reduced run time. Although Gyrolab has been increasingly used in method development in discovery environment, few fully validated Gyrolab assays have been reported. Here we report a method validation of a Gyrolab assay to determine rituximab levels in human serum. METHODS: Rituximab is captured on a Bioaffy™ CD by a biotinylated rat anti-idiotypic monoclonal antibody against rituximab and detected by an Alexa Fluor®-labeled anti-human IgG antibody. Assay conditions were optimized to give required sensitivity and dynamic range. The assay validation was conducted according to the current industry standards for GLP-regulated immunoassays. RESULTS: The intrabatch precision and accuracy for the assay were determined using spiked human serum samples and shown to have a coefficient of variation (CV) of <11% with a mean bias <20%. The interbatch precision (CV) and absolute mean bias were both <12% with the total error <25%. Adequate spike recovery was demonstrated in serum samples of healthy individuals and solid tumor patients. The dilutional linearity test showed that the determined concentrations adjusted with various dilution factors had a linear relationship with the expected concentrations and that there was no hook effect. The method has been validated for the quantification of rituximab in human serum from 90 to 60,000 ng/mL with a minimum required dilution of 30. DISCUSSION: The Gyrolab assay was proved to be accurate, precise and selective, with a comparable sensitivity to the ELISA method, but provided an automated nanoscale assay with a significantly wider assay dynamic range for the determination of rituximab in human serum during pharmacokinetics/toxicokinetics studies.