The mechanical world of bacteria.

In the wild, bacteria are predominantly associated with surfaces as opposed to existing as free-swimming, isolated organisms. They are thus subject to surface-specific mechanics, including hydrodynamic forces, adhesive forces, the rheology of their surroundings, and transport rules that define their encounters with nutrients and signaling molecules. Here, we highlight the effects of mechanics on bacterial behaviors on surfaces at multiple length scales, from single bacteria to the development of multicellular bacterial communities such as biofilms.

Mitochondrial morphology controls fatty acid utilization by changing CPT1 sensitivity to malonyl-CoA.

Changes in mitochondrial morphology are associated with nutrient utilization, but the precise causalities and the underlying mechanisms remain unknown. Here, using cellular models representing a wide variety of mitochondrial shapes, we show a strong linear correlation between mitochondrial fragmentation and increased fatty acid oxidation (FAO) rates. Forced mitochondrial elongation following MFN2 over-expression or DRP1 depletion diminishes FAO, while forced fragmentation upon knockdown or knockout of MFN2 augments FAO as evident from respirometry and metabolic tracing. Remarkably, the genetic induction of fragmentation phenocopies distinct cell type-specific biological functions of enhanced FAO. These include stimulation of gluconeogenesis in hepatocytes, induction of insulin secretion in islet ß-cells exposed to fatty acids, and survival of FAO-dependent lymphoma subtypes. We find that fragmentation increases long-chain but not short-chain FAO, identifying carnitine O-palmitoyltransferase 1 (CPT1) as the downstream effector of mitochondrial morphology in regulation of FAO. Mechanistically, we determined that fragmentation reduces malonyl-CoA inhibition of CPT1, while elongation increases CPT1 sensitivity to malonyl-CoA inhibition. Overall, these findings underscore a physiologic role for fragmentation as a mechanism whereby cellular fuel preference and FAO capacity are determined.

"Beyond transcription: How post-transcriptional mechanisms drive neural crest EMT".

The neural crest is a stem cell population that originates from the ectoderm during the initial steps of nervous system development. Neural crest cells delaminate from the neuroepithelium by undergoing a spatiotemporally regulated epithelial-mesenchymal transition (EMT) that proceeds in a coordinated wave head-to-tail to exit from the neural tube. While much is known about the transcriptional programs and membrane changes that promote EMT, there are additional levels of gene expression control that neural crest cells exert at the level of RNA to control EMT and migration. Yet, the role of post-transcriptional regulation, and how it drives and contributes to neural crest EMT, is not well understood. In this mini-review, we explore recent advances in our understanding of the role of post-transcriptional regulation during neural crest EMT.

Bacteroides vulgatus SNUG 40005 Restores Akkermansia Depletion by Metabolite Modulation.

BACKGROUND & AIMS: Weight loss and exercise intervention have been reported to increase the interaction between Bacteroides spp and Akkermansiamuciniphila (Am), although the underlying mechanisms and consequences of the interaction remain unknown. METHODS: Using a healthy Korean twin cohort (n = 582), we analyzed taxonomic associations with host body mass index. B vulgatus strains were isolated from mice and human subjects to investigate the strain-specific effect of B vulgatus SNUG 40005 (Bvul) on obesity. The mechanisms underlying Am enrichment by Bvul administration were investigated by multiple experiments: (1) in vitro cross-feeding experiments, (2) construction of Bvul mutants with the N-acetylglucosaminidase gene knocked out, and (3) in vivo validation cohorts with different metabolites. Finally, metabolite profiling in mouse and human fecal samples was performed. RESULTS: An interaction between Bvul and Am was observed in lean subjects but was disrupted in obese subjects. The administration of Bvul to mice fed a high-fat diet decreased body weight, insulin resistance, and gut permeability. In particular, Bvul restored the abundance of Am, which decreased significantly after a long-term high-fat diet. A cross-feeding analysis of Am with cecal contents or Bvul revealed that Am enrichment was attributed to metabolites produced during mucus degradation by Bvul. The metabolome profile of mouse fecal samples identified N-acetylglucosamine as contributing to Am enrichment, which was confirmed by in vitro and in vivo experiments. Metabolite network analysis of the twin cohort found that lysine serves as a bridge between N-acetylglucosamine, Bvul, and Am. CONCLUSIONS: Strain-specific microbe-microbe interactions modulate the mucosal environment via metabolites produced during mucin degradation in the gut.

Reprogramming Filamentous fd Viruses to Capture Copper Ions.

C-terminal truncated variants (A, VA, NVA, ANVA, FANVA and GFANVA) of our recently identified Cu(II) specific peptide "HGFANVA" were displayed on filamentous fd phages. Wild type fd-tet and engineered virus variants were treated with 100 mM Cu(II) solution at a final phage concentration of 1011 vir/ml and 1012 vir/ml. Scanning electron microscopy (SEM) and atomic force microscopy (AFM) imaging before Cu(II) exposure showed ≈6-8 nm thick filamentous virus layer formation. Cu(II) treatment resulted in aggregated bundle-like assemblies with mineral deposition. HGFANVA phage formed aggregates with an excessive mineral coverage. As the virus concentration was 10-fold decreased, nanowire-like assemblies were observed for shorter peptide variants A, NVA and ANVA. Wild type fd phages did not show any mineral formation. Energy dispersive X-ray spectroscopy (EDX) analyses revealed the presence of C and N peaks on phage organic material. Cu peak was only detected for engineered viruses. Metal ion binding of viruses was next investigated by enzyme-linked immunosorbent assay (ELISA) analyses. Engineered viruses were able to bind Cu(II) forming mineralized intertwined structures although no His (H) unit was displayed. Such genetically reprogrammed virus based biological materials can be further applied for bioremediation studies to achieve a circular economy.

A comprehensive benchmarking of WGS-based deletion structural variant callers.

Advances in whole-genome sequencing (WGS) promise to enable the accurate and comprehensive structural variant (SV) discovery. Dissecting SVs from WGS data presents a substantial number of challenges and a plethora of SV detection methods have been developed. Currently, evidence that investigators can use to select appropriate SV detection tools is lacking. In this article, we have evaluated the performance of SV detection tools on mouse and human WGS data using a comprehensive polymerase chain reaction-confirmed gold standard set of SVs and the genome-in-a-bottle variant set, respectively. In contrast to the previous benchmarking studies, our gold standard dataset included a complete set of SVs allowing us to report both precision and sensitivity rates of the SV detection methods. Our study investigates the ability of the methods to detect deletions, thus providing an optimistic estimate of SV detection performance as the SV detection methods that fail to detect deletions are likely to miss more complex SVs. We found that SV detection tools varied widely in their performance, with several methods providing a good balance between sensitivity and precision. Additionally, we have determined the SV callers best suited for low- and ultralow-pass sequencing data as well as for different deletion length categories.

A mouse xenograft long-term replication yields a SARS-CoV-2 Delta mutant with increased lethality.

We recently established a long-term SARS-CoV-2 infection model using lung-cancer xenograft mice and identified mutations that arose in the SARS-CoV-2 genome during long-term propagation. Here, we applied our model to the SARS-CoV-2 Delta variant, which has increased transmissibility and immune escape compared with ancestral SARS-CoV-2. We observed limited mutations in SARS-CoV-2 Delta during long-term propagation, including two predominant mutations: R682W in the spike protein and L330W in the nucleocapsid protein. We analyzed two representative isolates, Delta-10 and Delta-12, with both predominant mutations and some additional mutations. Delta-10 and Delta-12 showed lower replication capacity compared with SARS-CoV-2 Delta in cultured cells; however, Delta-12 was more lethal in K18-hACE2 mice compared with SARS-CoV-2 Delta and Delta-10. Mice infected with Delta-12 had higher viral titers, more severe histopathology in the lungs, higher chemokine expression, increased astrocyte and microglia activation, and extensive neutrophil infiltration in the brain. Brain tissue hemorrhage and mild vacuolation were also observed, suggesting that the high lethality of Delta-12 was associated with lung and brain pathology. Our long-term infection model can provide mutant viruses derived from SARS-CoV-2 Delta and knowledge about the possible contributions of emergent mutations to the properties of new variants.

Morphology Control of Au-Ni Hybrid Nanoparticles: Exploring Heterostructures and Optical Tuning.

Hybrid nanoparticles (NPs) have attracted considerable attention because of their ability to provide diverse properties by integrating the inherent properties of multiple components; however, synthetic strategies to control their morphology remain unexplored. In this study, a new method was used to control the morphology and optical properties of Au-Ni heterostructure (ANH) NPs. Unique morphological changes were observed by varying the Au/Ni precursor ratio from 2:1 to 1:4, exhibiting a shape transformation from dumbbell-like to quasi-spherical owing to the Ni NP size expansion, whereas the Au NP maintained their size. Moreover, increasing the Ni ratio induced plasmonic band broadening and wavelength redshift, resulting in color changes from red to navy and black. In terms of the structure, the atomic orientation of the crystallite showed that even a large lattice mismatch can result in heterojunctions at the NPs. In addition, the reaction aliquots uncovered heterogeneous nucleation and growth of ANH NPs in the colloidal system, demonstrating Ni reduction on the preformed Au NP owing to the reduction in potential gap. This study provides new insights into controlling the morphology of hybrid NPs using colloidal synthesis and the design of optimized materials for various applications.

Analysis of SARS-CoV-2 omicron mutations that emerged during long-term replication in a lung cancer xenograft mouse model.

SARS-CoV-2 Omicron has the largest number of mutations among all the known SARS-CoV-2 variants. The presence of these mutations might explain why Omicron is more infectious and vaccines have lower efficacy to Omicron than other variants, despite lower virulence of Omicron. We recently established a long-term in vivo replication model by infecting Calu-3 xenograft tumors in immunodeficient mice with parental SARS-CoV-2 and found that various mutations occurred majorly in the spike protein during extended replication. To investigate whether there are differences in the spectrum and frequency of mutations between parental SARS-CoV-2 and Omicron, we here applied this model to Omicron. At 30 days after infection, we found that the virus was present at high titers in the tumor tissues and had developed several rare sporadic mutations, mainly in ORF1ab with additional minor spike protein mutations. Many of the mutant isolates had higher replicative activity in Calu-3 cells compared with the original SARS-CoV-2 Omicron virus, suggesting that the novel mutations contributed to increased viral replication. Serial propagation of SARS-CoV-2 Omicron in cultured Calu-3 cells resulted in several rare sporadic mutations in various viral proteins with no mutations in the spike protein. Therefore, the genome of SARS-CoV-2 Omicron seems largely stable compared with that of the parental SARS-CoV-2 during extended replication in Calu-3 cells and xenograft model. The sporadic mutations and modified growth properties observed in Omicron might explain the emergence of Omicron sublineages. However, we cannot exclude the possibility of some differences in natural infection.

A retrospective study for long-term oncologic and obstetric outcomes in cervical intraepithelial neoplasia treated with loop electrosurgical excision procedure: focus on surgical margin and human papillomavirus.

BACKGROUND: The present study aimed to evaluate the long-term oncological and obstetric outcomes following the loop electrosurgical excision procedure (LEEP) in patients with cervical intraepithelial neoplasia (CIN) and investigate the risk factors for recurrence and preterm birth. METHODS: This retrospective cohort study included patients who underwent LEEP for CIN 2-3 between 2011 and 2019. Demographic information, histopathological findings, postoperative cytology, and human papillomavirus (HPV) status were collected and analyzed. The Cox proportional hazards model and Kaplan-Meier curves with the log-rank test were used for risk factor analysis. RESULTS: A total of 385 patients treated with the LEEP were analyzed. Treatment failure, including recurrence or residual disease following surgery, was observed in 13.5% of the patients. Positive surgical margins and postoperative HPV detection were independent risk factors for CIN1 + recurrence or residual disease (HR 1.948 [95%CI 1.020-3.720], p = 0.043, and HR 6.848 [95%CI 3.652-12.840], p-value < 0.001, respectively). Thirty-one patients subsequently delivered after LEEP, and the duration between LEEP and delivery was significantly associated with preterm-related complications, such as a short cervix, preterm labor, and preterm premature rupture of the membrane (p = 0.009). However, only a history of preterm birth was associated with preterm delivery. CONCLUSIONS: Positive HPV status after LEEP and margin status were identified as independent risk factors for treatment failure in patients with CIN who underwent LEEP. However, combining these two factors did not improve the prediction accuracy for recurrence.

In vitro and in vivo suppression of SARS-CoV-2 replication by a modified, short, cell-penetrating peptide targeting the C-terminal domain of the viral spike protein.

Peptides are promising therapeutic agents for COVID-19 because of their specificity, easy synthesis, and ability to be fine-tuned. We previously demonstrated that a cell-permeable peptide corresponding to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike C-terminal domain (CD) inhibits the interaction between viral spike and nucleocapsid proteins that results in SARS-CoV-2 replication in vitro. Here, we used docking studies to design R-t-Spike CD(D), a more potent short cell-penetrating peptide composed of all D-form amino acids and evaluated its inhibitory effect against the replication of SARS-CoV-2 S clade and other variants. R-t-Spike CD(D) was internalized into Vero cells and Calu-3 cells and suppressed the replication of SARS-CoV-2 S clade, delta variant, and omicron variant with higher potency than the original peptide. In hemizygous K18-hACE2 mice, intratracheal administration of R-t-Spike CD(D) effectively delivered the peptide to the trachea and lungs, whereas intranasal administration delivered the peptide mostly to the upper respiratory system and stomach, and a small amount to the lungs. Administration by either route reduced viral loads in mouse lungs and turbinates. Furthermore, intranasally administered R-t-Spike CD(D) mitigated pathological change in the lungs and increased the survival of mice after infection with the SARS-CoV-2 S clade or delta variant. Our data suggest that R-t-Spike CD(D) has potential as a therapeutic agent against SARS-CoV-2 infection.

Effect of Nanoparticles in LiFePO4 Cathode Material Using Organic/Inorganic Composite Solid Electrolyte for All-Solid-State Batteries.

Herein, we report the effect of using nanoparticles of LiFePO4 on the electrochemical properties of all-solid-state batteries (ASSBs) with a solid electrolyte. LiFePO4 (LFP) cathode materials are promising cathode materials in polymer-based composite solid electrolytes because of their limited electrochemical window range. However, LFP cathodes exhibit poor electric conductivity and sluggish lithium ion diffusion. In addition, there is a disadvantage in that the interfacial resistance increases due to poor contact between the LFP cathode material and the solid electrolyte when composing the composite cathode. The nano-sized LFP cathode material increases the contact area between solid electrolyte in the positive electrode and enhances lithium ion diffusion. Therefore, the structural differences and electrochemical performance of these nanoscale LFP cathode materials in the ASSB were studied by X-ray diffraction, scanning electron microscopy, and electrochemical analysis.

Immunohistochemical characteristics of local sites that trigger atrial arrhythmias in response to high-frequency stimulation.

AIMS: The response to high frequency stimulation (HFS) is used to locate putative sites of ganglionated plexuses (GPs), which are implicated in triggering atrial fibrillation (AF). To identify topological and immunohistochemical characteristics of presumed GP sites functionally identified by HFS. METHODS AND RESULTS: Sixty-three atrial sites were tested with HFS in four Langendorff-perfused porcine hearts. A 3.5 mm tip quadripolar ablation catheter was used to stimulate and deliver HFS to the left and right atrial epicardium, within the local atrial refractory period. Tissue samples from sites triggering atrial ectopy/AF (ET) sites and non-ET sites were stained with choline acetyltransferase (ChAT) and tyrosine hydroxylase (TH), for quantification of parasympathetic and sympathetic nerves, respectively. The average cross-sectional area (CSA) of nerves was also calculated. Histomorphometry of six ET sites (9.5%) identified by HFS evoking at least a single atrial ectopic was compared with non-ET sites. All ET sites contained ChAT-immunoreactive (ChAT-IR) and/or TH-immunoreactive nerves (TH-IR). Nerve density was greater in ET sites compared to non-ET sites (nerves/cm2: 162.3 ± 110.9 vs. 69.65 ± 72.48; P = 0.047). Overall, TH-IR nerves had a larger CSA than ChAT-IR nerves (µm2: 11 196 ± 35 141 vs. 2070 ± 5841; P < 0.0001), but in ET sites, TH-IR nerves were smaller than in non-ET sites (µm2: 6021 ± 14 586 vs. 25 254 ± 61 499; P < 0.001). CONCLUSIONS: ET sites identified by HFS contained a higher density of smaller nerves than non-ET sites. The majority of these nerves were within the atrial myocardium. This has important clinical implications for devising an effective therapeutic strategy for targeting autonomic triggers of AF.

Ablation versus anti-arrhythmic therapy for reducing all hospital episodes from recurrent atrial fibrillation: a prospective, randomized, multi-centre, open label trial.

AIMS: There is rising healthcare utilization related to the increasing incidence and prevalence of atrial fibrillation (AF) worldwide. Simplifying therapy and reducing hospital episodes would be a valuable development. The efficacy of a streamlined AF ablation approach was compared to drug therapy and a conventional catheter ablation technique for symptom control in paroxysmal AF. METHODS AND RESULTS: We recruited 321 patients with symptomatic paroxysmal AF to a prospective randomized, multi-centre, open label trial at 13 UK hospitals. Patients were randomized 1:1:1 to cryo-balloon ablation without electrical mapping with patients discharged same day [Ablation Versus Anti-arrhythmic Therapy for Reducing All Hospital Episodes from Recurrent (AVATAR) protocol]; optimization of drug therapy; or cryo-balloon ablation with confirmation of pulmonary vein isolation and overnight hospitalization. The primary endpoint was time to any hospital episode related to treatment for atrial arrhythmia. Secondary endpoints included complications of treatment and quality-of-life measures. The hazard ratio (HR) for a primary endpoint event occurring when comparing AVATAR protocol arm to drug therapy was 0.156 (95% CI, 0.097-0.250; P < 0.0001 by Cox regression). Twenty-three patients (21%) recorded an endpoint event in the AVATAR arm compared to 76 patients (74%) within the drug therapy arm. Comparing AVATAR and conventional ablation arms resulted in a non-significant HR of 1.173 (95% CI, 0.639-2.154; P = 0.61 by Cox regression) with 23 patients (21%) and 19 patients (18%), respectively, recording primary endpoint events (P = 0.61 by log-rank test). CONCLUSION: The AVATAR protocol was superior to drug therapy for avoiding hospital episodes related to AF treatment, but conventional cryoablation was not superior to the AVATAR protocol. This could have wide-ranging implications on how demand for AF symptom control is met. TRIAL REGISTRATION: Clinical Trials Registration: NCT02459574.

Effect of sphingosine and inoculum concentrations on Staphylococcus aureus and Staphylococcus epidermidis biofilms.

Atopic dermatitis (AD) is a chronic inflammatory skin disease where patients are more susceptible to infection and inflammation. The most salient symptoms of atopic dermatitis (AD) are skin dysbiosis and ceramide deficiency. Here, the effect of AD conditions on S. aureus resilience was investigated. S. aureus and S. epidermidis biofilms were co-inoculated at healthy and AD bacterial ratios and exposed to various sphingosine dosing regimens. In both healthy (S. epidermidis dominant) and AD (S. aureus dominant) conditions the viability of the non-dominant bacterial species was affected. Quorum sensing (QS)-impaired S. aureus was overall more susceptible to sphingosine. Despite the general resilience of QS-intact S. aureus against sphingosine, modulation of S. epidermidis (healthy ratio) and sphingosine (healthy Sph) led to a lack of recovery from its initial killing. Overall, it was found that when in biofilms, S. epidermidis increases S. aureus resilience to sphingosine, possibly enhancing the pathogen's recalcitrance in AD skin.

Genome-Wide Identification and Comprehensive Analysis of the GASA Gene Family in Peanuts (Arachis hypogaea L.) under Abiotic Stress.

Peanut (Arachis hypogaea L.) is a globally cultivated crop of significant economic and nutritional importance. The role of gibberellic-acid-stimulated Arabidopsis (GASA) family genes is well established in plant growth, development, and biotic and abiotic stress responses. However, there is a gap in understanding the function of GASA proteins in cultivated peanuts, particularly in response to abiotic stresses such as drought and salinity. Thus, we conducted comprehensive in silico analyses to identify and verify the existence of 40 GASA genes (termed AhGASA) in cultivated peanuts. Subsequently, we conducted biological experiments and performed expression analyses of selected AhGASA genes to elucidate their potential regulatory roles in response to drought and salinity. Phylogenetic analysis revealed that AhGASA genes could be categorized into four distinct subfamilies. Under normal growth conditions, selected AhGASA genes exhibited varying expressions in young peanut seedling leaves, stems, and roots tissues. Notably, our findings indicate that certain AhGASA genes were downregulated under drought stress but upregulated under salt stress. These results suggest that specific AhGASA genes are involved in the regulation of salt or drought stress. Further functional characterization of the upregulated genes under both drought and salt stress will be essential to confirm their regulatory roles in this context. Overall, our findings provide compelling evidence of the involvement of AhGASA genes in the mechanisms of stress tolerance in cultivated peanuts. This study enhances our understanding of the functions of AhGASA genes in response to abiotic stress and lays the groundwork for future investigations into the molecular characterization of AhGASA genes.

Scale-up issues for commercial depth filters in bioprocessing.

Significant increases in cell density and product titer have led to renewed interest in the application of depth filtration for initial clarification of cell culture fluid in antibody production. The performance of these depth filters will depend on the local pressure and velocity distribution within the filter capsule, but these are very difficult to probe experimentally, leading to challenges in both process design and scale-up. We have used a combination of carefully designed experimental studies and computational fluid dynamics (CFD) to examine these issues in both lab-scale (SupracapTM 50) and pilot-scale (StaxTM ) depth filter modules, both employing dual-layer lenticular PDH4 media containing diatomaceous earth. The SupracapTM 50 showed a more rapid increase in transmembrane pressure and a more rapid DNA breakthrough during filtration of a Chinese Hamster Ovary cell culture fluid. These results were explained using CFD calculations which showed very different flow distributions within the modules. CFD predictions were further validated using measurements of the residence time distribution and dye binding in both the lab-scale and pilot-plant modules. These results provide important insights into the factors controlling the performance and scale-up of these commercially important depth filters as well as a framework that can be broadly applied to develop more effective depth filters and depth filtration processes.

Cascaded processing in naming and reading: Evidence from Chinese and Korean.

Previous studies have shown that the ability to simultaneously process multiple items when these appear in serial format (called "cascaded" processing) is an important element of reading fluency. However, most evidence in support of cascaded processing comes from studies conducted in European orthographies. Thus, the purpose of the current study was to examine whether the same findings generalize to nonlinear and nonalphabetic orthographies (i.e., Korean and Chinese). Serial and discrete naming of digits and objects were measured in a sample of 610 Chinese and Korean children from Grades 1, 3, 5, and 6. Children were also assessed on discrete word reading and on word- and text-reading fluency. Results of hierarchical regression analysis showed that discrete naming was the main predictor of discrete word reading in both languages as early as Grade 1. Serial digit naming was the main predictor of word-reading fluency across grades and languages. Finally, serial object naming made a unique contribution to word- and text-reading fluency in Chinese upper grades. Taken together, these findings suggest that, beyond accurate and fast word recognition, there is a universal multi-item (or cascaded) processing skill involved in serial naming and reading fluency.

Role of Nuclear-Receptor-Related 1 in the Synergistic Neuroprotective Effect of Umbilical Cord Blood and Erythropoietin Combination Therapy in Hypoxic Ischemic Encephalopathy.

Neonatal hypoxic-ischemic encephalopathy (HIE) results in neurological impairments; cell-based therapy has been suggested as a therapeutic avenue. Previous research has demonstrated the synergistically potentiated therapeutic efficacy of human umbilical cord blood (UCB) by combining recombinant human erythropoietin (EPO) treatment for recovery from HIE. However, its molecular mechanism is not entirely understood. In the present study, we analyzed the mechanisms underlying the effect of combination treatment with EPO and UCB by transcriptomic analysis, followed by gene enrichment analysis. Mouse HIE model of the neonate was prepared and randomly divided into five groups: sham, HIE, and UCB, EPO, and UCB+EPO treatments after HIE. A total of 376 genes were differentially expressed when |log2FC| ≥ 1-fold change expression values were considered to be differentially expressed between UCB+EPO and HIE. Further assessment through qRT-PCR and gene enrichment analysis confirmed the expression and correlation of its potential target, Nurr1, as an essential gene involved in the synergistic effect of the UCB+EPO combination. The results indicated the remarkable activation of Wnt/ß-catenin signaling by reducing the infarct size by UCB+EPO treatment, accompanied by Nurr1 activity. In conclusion, these findings suggest that the regulation of Nurr1 through the Wnt/ß-catenin pathway exerts a synergistic neuroprotective effect in UCB and EPO combination treatment.

Therapeutic Effect of Erythropoietin on Alzheimer's Disease by Activating the Serotonin Pathway.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by memory impairment in patients. Erythropoietin (EPO) has been reported to stimulate neurogenesis. This study was conducted to determine the regenerative effects of EPO in an AD model and to assess its underlying mechanism. Recombinant human EPO was intraperitoneally administered to AD mice induced by intracerebroventricular Aß oligomer injection. Behavioral assessments with novel object recognition test and passive avoidance task showed improvement in memory function of the EPO-treated AD mice compared to that of the saline-treated AD mice (p < 0.0001). An in vivo protein assay for the hippocampus and cortex tissue indicated that EPO treatment modulated neurotransmitters, including dopamine, serotonin, and adrenaline. EPO treatment also restored the activity of serotonin receptors, including 5-HT4R, 5-HT7R, and 5-HT1aR (p < 0.01), at mRNA levels. Furthermore, EPO seemed to exert an anti-inflammatory influence by downregulating TLR4 at mRNA and protein levels (p < 0.05). Finally, an immunohistochemical assay revealed increments of Nestin(+) and NeuN(+) neuronal cells in the CA3 region in the EPO-treated AD mice compared to those in the saline-treated AD mice. The conclusion is that EPO administration might be therapeutic for AD by activating the serotonergic pathway, anti-inflammatory action, and neurogenic characteristics.