NIR-responsive magnesium phosphate cement loaded with simvastatin-nanoparticles with biocompatibility and osteogenesis ability.

The insufficient osteogenesis of magnesium phosphate cement (MPC) limits its biomedical application. It is of great significance to develop a bioactive MPC with osteogenic performance. In this study, an injectable MPC was reinforced by the incorporation of a near infrared (NIR)-responsive nanocontainer, which was based on simvastatin (SIM)-loaded mesoporous silica nanoparticles (MSNs) modified with a polydopamine (PDA) bilayer, named SMP. In addition, chitosan (CHI) was introduced into MPC (K-struvite) to enhance its mechanical properties and cytocompatibility. The results showed that nanocontainer-incorporated MPC possessed a prolonged setting time, almost neutral pH, excellent injectability, and enhanced compressive strength. Immersion tests indicated that SMP-CHI MPC could suppress rapid degradation. Based on its physicochemical features, the SMP-CHI MPC had good biocompatibility and osteogenesis properties, as shown via in vitro and in vivo experiments. These findings can provide a simple way to produce a multifunctional MPC with improved osteogenesis for further orthopedic applications.

An Injectable Magnesium-Based Cement Stimulated with NIR for Drug-Controlled Release and Osteogenic Potential.

Magnesium phosphate bone cement (MPC) has gained widespread usage in orthopedic implantation due to its fast-setting and high initial strength benefits. However, the simultaneous attainment of drug-controlled release and osteogenic potential in MPC remains a significant challenge. Herein, a strategy to create a smart injectable cement system using nanocontainers and chondroitin sulfate is proposed. It employs nanocontainers containing alendronate-loaded mesoporous silica nanoparticles, which are surface-modified with polypyrrole to control drug release in response to near-infrared (NIR) stimulation. The alendronate-incorporated cement (ACMPC) exhibits improved compressive strength (70.6 ± 5.9 MPa), prolonged setting time (913 s), and exceptional injectability (96.5% of injection rate and 242 s of injection time). It also shows the capability to prevent degradation, thus preserving mechanical properties. Under NIR irradiation, the cement shows good antibacterial properties due to the combined impact of hyperthermia, reactive oxygen species, and alendronate. Furthermore, the ACMPC (NIR) group displays good biocompatibility and osteogenesis capabilities, which also lead to an increase in alkaline phosphatase activity, extracellular matrix mineralization, and the upregulation of osteogenic genes. This research has significant implications for developing multifunctional biomaterials and clinical applications.

Self-Assembled Multilayered Coatings with Multiple Cyclic Self-Healing Capability, Bacteria Killing, Osteogenesis, and Angiogenesis Properties on Magnesium Alloys.

Self-healing coatings improve the durability of magnesium (Mg) implants, but rapid corrosion still poses a challenge in the healing stage. Moreover, Mg-based materials with acceptable bacteria killing, osteogenic and angiogenic properties are challenging in biomedical applications. Herein, the self-healing polymeric coatings are fabricated on Mg alloys using the spin-assisted layer-by-layer (SLbL) assembly of hyaluronic acid (HA) and branched polyethyleneimine (bPEI) followed by chemical crosslinking treatment. The self-healing coatings show excellent adhesion strength and structure stability. The corrosion resistance is improved due to the physical barrier of polymer coatings, which also promotes the formation of hydroxyapatite (HAp) during degradation for further protection of Mg substrate. Owing to the dynamic reversible hydrogen bonds existing between HA and bPEI, the crosslinked multilayered coatings possess fast, substantial, and cyclic self-healing capabilities leading to restoration of the original structure and functions. In vitro investigations reveal that the self-healing coatings have multiple functionalities pertaining to bacteria killing, cytocompatibility, osteogenesis, as well as angiogenesis. In addition, the self-healing coatings stimulate alkaline phosphatase activity (ALP), extracellular matrix (ECM) mineralization, and the expression of osteogenesis-related genes of mBMSCs and HUVECs. This study reveals a feasible strategy to design and prepare versatile self-healing coatings on Mg implants for biomedical applications.

NIR-responsive injectable magnesium phosphate bone cement loaded with icariin promotes osteogenesis.

There were defects like limited osteogenesis and fast drug release in traditional magnesium phosphate bone cement (MPC). In this study, we loaded icariin in a mesoporous nano silica container modified by polydopamine and then added it and citric acid into MPC (IHP-CA MPCs). The results indicate that IHP-CA MPCs have a long curing time, almost neutral pH value, excellent injectability, and compressive strength. In vitro experiments have shown that IHP-CA MPCs have good biocompatibility and bone promoting ability. These improvements provide feasible solutions and references for the clinical application of MPCs as implants.

Genome-wide association study in Alzheimer's disease: a bibliometric and visualization analysis.

Background: Thousands of research studies concerning genome-wide association studies (GWAS) in Alzheimer's disease (AD) have been published in the last decades. However, a comprehensive understanding of the current research status and future development trends of GWAS in AD have not been clearly shown. In this study, we tried to gain a systematic overview of GWAS in AD by bibliometric and visualization analysis. Methods: The literature search terms are: ("genome-wide analysis" or "genome-wide association study" or "whole-genome analysis") AND ("Alzheimer's Disease" or "Alzheimer Disease"). Relevant publications were extracted from the Web of Science Core Collection (WoSCC) database. Collected data were further analyzed using VOSviewer, CiteSpace and R package Bibliometrix. The countries, institutions, authors and scholar collaborations were investigated. The co-citation analysis of publications was visualized. In addition, research hotspots and fronts were examined. Results: A total of 1,350 publications with 59,818 citations were identified. The number of publications and citations presented a significant rising trend since 2013. The United States was the leading country with an overwhelming number of publications (775) and citations (42,237). The University of Washington and Harvard University were the most prolific institutions with 101 publications each. Bennett DA was the most influential researcher with the highest local H-index. Neurobiology of Aging was the journal with the highest number of publications. Aß, tau, immunity, microglia and DNA methylation were research hotspots. Disease and causal variants were research fronts. Conclusion: The most frequently studied AD pathogenesis and research hotspots are (1) Aß and tau, (2) immunity and microglia, with TREM2 as a potential immunotherapy target, and (3) DNA methylation. The research fronts are (1) looking for genetic similarities between AD and other neurological diseases and syndromes, and (2) searching for causal variants of AD. These hotspots suggest noteworthy directions for future studies on AD pathogenesis and genetics, in which basic research regarding immunity is promising for clinical conversion. The current under-researched directions are (1) GWAS in AD biomarkers based on large sample sizes, (2) studies of causal variants of AD, and (3) GWAS in AD based on non-European populations, which need to be strengthened in the future.

Global trends and prospects about synaptic plasticity in Alzheimer's disease: a bibliometric analysis.

Background and purpose: In recent years, synaptic plasticity disorders have been identified as one of the key pathogenic factors and the early pathological characteristics of Alzheimer's disease (AD). In this study, we tried to use bibliometric analysis to gain a systematic understanding about synaptic plasticity in Alzheimer's disease. Methods: We extracted relevant publications from the Web of Science Core Collection (WoSCC) on August 29th, 2022. Then, we used CiteSpace, VOSviewer and other online bibliometric platforms to further analyze the obtained data. Results: A total of 2,348 published articles and reviews about synaptic plasticity in AD from 2002 to 2022 were identified. During the past two decades, the overall trends of the numbers and citations of manuscripts were on the rise. The United States was the leading country with the largest number of publications which showed its crucial role in this field. The collaboration network analysis showed that the United States and China had the most frequent collaboration. In addition, Harvard University was the institution with the greatest number of publications and cited times. Among all authors, Selkoe DJ was the most influential author with the greatest cited times. The journal of Alzheimer's disease published the maximum number of documents in the field of synaptic plasticity in AD within 20 years. Furthermore, the results of keywords burst detection showed that the hot topics have shifted from the synaptic transmission, precursor protein and plaque formation to neuroinflammation, microglia and alpha synuclein. Conclusion: This study analyzed 2,348 publications with 82,025 references covering the topic of synaptic plasticity in AD and presented the research trends. The results indicated that neuroinflammation, microglia and alpha synuclein were the current research hotspots, which implied the potential clinical applications to AD.

pH/NIR-responsive and self-healing coatings with bacteria killing, osteogenesis, and angiogenesis performances on magnesium alloy.

Although biodegradable polymer coatings can impede corrosion of magnesium (Mg)-based orthopedic implants, they are prone to excessive degradation and accidental scratching in practice. Bone implant-related infection and limited osteointegration are other factors that adversely impact clinical application of Mg-based biomedical implants. Herein, a self-healing polymeric coating is constructed on the Mg alloy together with incorporation of a stimuli-responsive drug delivery nanoplatform by a spin-spray layer-by-layer (SSLbL) assembly technique. The nanocontainers are based on simvastatin (SIM)-encapsulated hollow mesoporous silica nanoparticles (S@HMSs) modified with polydopamine (PDA) and polycaprolactone diacrylate (PCL-DA) bilayer. Owing to the dynamic reversible reactions, the hybrid coating shows a fast, stable, and cyclical water-enabled self-healing capacity. The antibacterial assay indicates good bacteria-killing properties under near infrared (NIR) irradiation due to synergistic effects of hyperthermia, reactive oxygens species (ROS), and SIM leaching. In vitro results demonstrate that NIR laser irradiation promotes the cytocompatibility, osteogenesis, and angiogenesis. The coating facilitates alkaline phosphatase activity and expedites extracellular matrix mineralization as well as expression of osteogenesis-related genes. This study reveals a useful strategy to develop multifunctional coatings on bioabsorbable Mg alloys for orthopedic implants.

Psychological Capital and Self-Acceptance Modified the Association of Depressive Tendency with Self-Rated Health of College Students in China during the COVID-19 Pandemic.

BACKGROUND: To explore the association between the self-reported health status, depressive tendency, psychological capital, and self-acceptance of college students in China during the COVID-19 pandemic. METHODS: Using the online survey platform "questionnaire star", a two-phase cross-sectional study was conducted on a total number of 1438 undergraduates with informed consents. The questionnaires of Self-Rated Health Measurement Scale (SRHMS), the Center for Epidemiological Studies-Depression Scale (CES-D), Psychological Capital Questionnaire (PCQ-24), and self-acceptance questionnaire were administered to each participant. RESULTS: Male college students had significantly higher depressive tendency scores than female (17.59 vs. 15.82) (p < 0.01). College students having no siblings had significantly higher psychological capital scores than those having siblings (108.63 vs. 105.60) (p < 0.05). Exercise had significantly positive associations with self-rated health, psychological capital, and self-acceptance scores, while online time per day had significantly negative associations. Multivariate analysis showed that the interaction between depressive tendency, psychological capital, and self-acceptance was statistically significant (ß = 0.004, p = 0.013 for phase 1 and ß = 0.002, p = 0.025 for phase 2) in health status with depressive tendency ranking the top (ß = -0.54 for phase 1 and -0.41 for phase 2, p < 0.001). Mediation analysis showed that psychological capital and self-acceptance modified the association of depressive tendency with health status. CONCLUSION: Physical exercise is beneficial to both physical and psychological health. Depressive tendency is the main risk factor that associates with self-rated health. Regardless of depressive tendency level, high psychological capital and self-acceptance could improve college students' health.

Gα13-Mediated Signaling Cascade Is Related to the Tau Pathology Caused by Anesthesia and Surgery in 5XFAD Transgenic Mice.

BACKGROUND: Our previous studies indicated that anesthesia and surgery could aggravate cognitive impairment of 5XFAD transgenic (Tg) mice, and this aggravation was associated with tau hyperphosphorylation. We previously identified that GNA13 (the gene encoding Gα13) was a hub gene with tau hyperphosphorylation. OBJECTIVE: This study aims to further investigate the mechanism that whether the Gα13-mediated signaling pathway acts as an instigator to regulate cofilin activation and autophagy impairment in this process. METHODS: 5XFAD Tg mice and their littermate (LM) mice were randomly allocated into four groups: LM Control group, LM Anesthesia/Surgery group, AD Control group, and AD Anesthesia/Surgery group. For mice in the Anesthesia/Surgery groups, abdominal surgery was performed under 1.4% isoflurane anesthesia followed by sustaining anesthetic inhalation for up to 2 h. RESULTS: Compared with the AD Control group, protein levels of Gα13, ROCK2, LPAR5, and p-tau/tau46 ratio were increased, while p-cofilin/cofilin protein expression ratio was decreased in the AD Anesthesia/Surgery group. However, the differences in these protein levels were not significant among LM groups. CONCLUSION: This study demonstrated that anesthesia and surgery might exacerbate p-tau accumulation in 5XFAD Tg mice but not in LM mice. And this might be closely related to cofilin activation via Gα13-mediated signaling cascade.

Ultrasound-guided transversus thoracic muscle plane-pectoral nerve block for postoperative analgesia after modified radical mastectomy: a comparison with the thoracic paravertebral nerve block.

BACKGROUND: Modified radical mastectomy (MRM) is the most effective and common type of invasive surgery for breast cancer. However, it causes moderate to severe acute pain and even lasts for a long postoperative period. Transversus thoracic muscle plane-pectoral nerve block (TTP-PECS) is a novel and promising interfacial plane block which can provide analgesia for MRM while thoracic paravertebral nerve block (TPVB) is also widely used for this purpose. This study compared the postoperative analgesia between the ultrasound-guided TTP-PECS and TPVB in patients undergoing MRM. METHODS: In this randomized controlled trial, eighty female breast cancer patients undergoing unilateral MRM with sentinel lymph node dissection (SLND) and axillary dissection (ALND) were enrolled. Patients were randomized to receive either ultrasound-guided TTP-PECS (TTP-PECS group, n = 40) or TPVB (TPVB group, n = 40) with 0.5% ropivacaine 30 ml. Evaluated variables included 24 h postoperative total PCA fentanyl consumption, including PCA background consumption and PCA press consumption (per bolus dosage multiply by the effective pressing times), and intraoperative fentanyl consumption, as well as postoperative flurbiprofen axetil requirement, duration of analgesia, blocking area, pain intensity at rest and during activity, ability to reduce the inflammatory response, and the quality of recovery 40 (QoR-40) score of patients. RESULTS: Compared with the TPVB, the main blocking area was T2-T6 in the TTP-PECS group, which was more suitable for the MRM. TTP-PECS has a longer analgesia duration than TPVB; 24 h postoperative total PCA fentanyl consumption, especially the PCA press consumption, and the postoperative flurbiprofen axetil requirement were decreased in the TTP-PECS group than those in the TPVB group. Furthermore, the VAS scores at rest and during activity and inflammatory response were lower in the TTP-PECS group compared with the TPVB group at 12 h postoperatively. Finally, the total QoR-40 score, especially for the scores of pain; emotional state; and patient support were better in the TTP-PECS group. CONCLUSION: Compared with the TPVB, TTP-PECS can provide better postoperative analgesia in patients undergoing MRM, simultaneously reduce the inflammatory response, and prompt early recovery. These results suggest that TTP-PECS is an attractive alternative to TPVB for postoperative analgesia of modified radical mastectomy.

Construction of a ternary system: a strategy for the rapid formation of porous poly(lactic acid) fibers.

Combining electrospinning technology with nonsolvent induced phase separation (ESP-NIPS), 10 wt% poly(lactic acid) (PLA) spinning solutions are prepared by using chloroform as a good solvent and absolute ethanol as a nonsolvent. The "PLA/CHCl3/C2H5OH" ternary system is constituted to realize the rapid preparation of porous-structured PLA fibers. The morphologies, thermal properties and crystalline structures of the obtained fibers are characterized and the rapid forming mechanism of PLA porous fibers is investigated and discussed. The interaction parameters between the substances of the "PLA/CHCl3/C2H5OH" ternary system, binodal line, spinodal line and critical point are obtained by theoretical calculation and experiment, and the "PLA/CHCl3/C2H5OH" ternary phase diagram model is established. The results show that, when the mass ratio of chloroform/ethanol is around 75/25, the rapid "in situ" formation of the PLA fibers can be realized with porous structures within 5-10 s. The establishment of a "nonsolvent-solvent-polymer" ternary phase diagram model has laid a theoretical foundation for the rapid formation of polymer porous fibers by ESP-NIPS. The ESP-NIPS for the porous PLA fibers preparation provides a new resolution for the rapid formation of porous polymer materials, which is vital to further expand the application of electrospun fibers in emergency situations such as isolation, protection, insulation and flame retardant usage.

Develop a Clinical Prediction Model for Postoperative Cognitive Dysfunction after Major Noncardiac Surgery in Elderly Patients: A Protocol for a Prospective Observational Study.

Perioperative neurocognitive disorders (PNDs) refer to cognitive decline identified in the preoperative or postoperative period. It has been reported that the incidence of postoperative neurocognitive impairment after noncardiac surgery in patients older than 65 at 1 week was 25.8∼41.4%, and at 3 months 9.9∼12.7%. PNDs will last months or even develop to permanent dementia, leading to prolonged hospital stays, reduced quality of life, and increased mortality within 1 year. Despite the high incidence and poor prognosis of PNDs in the aged population, no effective clinical prediction model has been established to predict postoperative cognitive decline preoperatively. To develop a clinical prediction model for postoperative neurocognitive dysfunction, a prospective observational study (Clinical trial registration number: ChiCTR2000036304) will be performed in the Shanghai General Hospital during January 2021 to October 2022. A sample size of 675 patients aged >65 years old, male or female, and scheduled for elective major noncardiac surgery will be recruited. A battery of neuropsychological tests will be used to test the cognitive function of patients at 1 week, 1 month, and 3 months postoperatively. We will evaluate the associations of PNDs with a bunch of candidate predictors including general characteristics of patients, blood biomarkers, indices associated with anesthesia and surgery, retinal nerve-fiber layer thickness, and frailty index to develop the clinical prediction model by using multiple logistic regression analysis and least absolute shrinkage and the selection operator (LASSO) method. The k-fold cross-validation method will be utilized to validate the clinical prediction model. In conclusion, this study was aimed to develop a clinical prediction model for postoperative cognitive dysfunction of old patients. It is anticipated that the knowledge gained from this study will facilitate clinical decision-making for anesthetists and surgeons managing the aged patients undergoing noncardiac surgery.

Bibliometric analysis of global research profile on ketogenic diet therapies in neurological diseases: Beneficial diet therapies deserve more attention.

Background: The protective effects of Ketogenic Diet Therapies (KDTs) on neurological diseases have been extensively studied over the past two decades. The purpose of this study was to quantitatively and qualitatively analyze the publication of KDTs in the neurological field from 2000 to 2021. Methods: A literature search was performed on June 7th, 2022, using the search terms: (("ketone" OR "ketogenic" OR "*hydroxybuty*") AND ("neuro*")) in the WoSCC database. Collected data were further analyzed using VOSviewer, CiteSpace and other online bibliometric websites. The annual publication volume and citation trends were summarized. The collaborations among highly cited countries, institutions, authors and journals were visualized. The co-citation analysis of highly cited references and journals were also visualized. Moreover, the research focuses and fronts were revealed by co-occurrence analysis and burst keywords detection. Results: A total of 2808 publications with 88,119 citations were identified. From 2000-2021, the number of publications and citations presented rising trends. The United States was the country with an overwhelming number of publications and cited times. Johns Hopkins University was the most contributory institution. Kossoff Eric H was the author with the largest number of publications. And Epilepsia was both the largest publisher and the most frequently cited journal. The keywords of intense interest involved "Modified Atkins Diet", "Temporal Lobe Epilepsy", "Alzheimer's Disease", "Parkinson's Disease", "Cerebral Blood Flow", "Neuroinflammation", "Oxidative Stress", "Metabolism" and "Mitochondria". Conclusion: We presented the global trend of KDTs in neurological diseases and provided important information for relevant researchers in a bibliometric way. This bibliometric study revealed that treating epilepsy, neuroprotection and functional effects of KDTs on mitochondria and oxidative stress have been the spotlight from 2000 to 2021. These have emerged as the basis for transformation from basic research to clinical application of KDTs.

Stress Granules Modulate SYK to Cause Tau-Associated Neurocognitive Deterioration in 5XFAD Mouse After Anesthesia and Surgery.

BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia. However, no curative therapy has been found effective to slow down the process of AD. It is reported that anesthesia and surgery will induce neurocognitive deterioration in AD, but the mechanism is not quite clear. In this study, we aim to compare the cognitive impairment between 5XFAD transgenic (Tg) mice and its littermate (LM) after isoflurane anesthesia and surgery to clarify the specific impacts of anesthesia and surgery on individuals with AD and to explore the mechanisms. METHODS: We performed abdominal surgery in cognitively impaired, 4-month-old female 5XFAD mice and LM control mice. Isoflurane anesthesia (1.4%) was induced and maintained over 2 h. Open field and fear conditioning tests were conducted on 1, 3 and 7 days after anesthesia and surgery. The total distance, velocity and freezing time were the major outcomes. P-tau (AT8), tau oligomers (T22), stress granules (SGs), the SYK tyrosine kinase and p-SYK in the hippocampus at postoperative day 1 were evaluated by Western Blot assays. The colocalization of SGs, SYK, p-SYK, and neurons in the hippocampus section was assessed using qualitative immunofluorescence. RESULTS: In the open field test, no difference between the distance moved and the velocity of LM mice and 5XFAD Tg mice were found on day 1 after anesthesia and surgery. 5XFAD Tg mice exhibited reduced freezing time of fear conditioning context test on postoperative day 3, but not on day 7; the LM mice showed no changes in FCTs. Furthermore, p-tau, tau oligomers, SGs, SYK and p-SYK were evident in the hippocampus region of 5XFAD Tg mice on a postoperative day 1. In addition, SGs, SYK, p-SYK were colocalized with hippocampus neurons, as shown by immunofluorescence. CONCLUSION: This study demonstrates that anesthesia and surgery may induce tau-associated neurocognitive deterioration in individuals with AD. The mechanism under it may be associated with SGs and the tyrosine kinase, SYK. After anesthesia and surgery, in 5XFAD Tg mice, SGs were formed and SYK was phosphorylated, which may contribute to the phosphorylation of tau protein. This study provided hints that individuals with AD may be more vulnerable to anesthesia and surgery.

Identification of key transcriptome biomarkers based on a vital gene module associated with pathological changes in Alzheimer's disease.

Dysregulation of transcriptome expression has been reported to play an increasingly significant role in AD. In this study, we firstly identified a vital gene module associated with the accumulation of ß-amyloid (Aß) and phosphorylated tau (p-tau) using the WGCNA method. The vital module, named target module, was then employed for the identification of key transcriptome biomarkers. For coding RNA, GNA13 and GJA1 were identified as key biomarkers based on ROC analysis. As for non-coding RNA, MEG3, miR-106a-3p, and miR-24-3p were determined as key biomarkers based on analysis of a ceRNA network and ROC analysis. Experimental analyses firstly confirmed that GNA13, GJA1, and ROCK2, a downstream effector of GNA13, were all increased in 5XFAD mice, compared to littermate mice. Moreover, their expression was increased with aging in 5XFAD mice, as Aß and p-tau pathology developed. Besides, the expression of key ncRNA biomarkers was verified to be decreased in 5XFAD mice. GSEA results indicated that GNA13 and GJA1 were respectively involved in ribosome and spliceosome dysfunction. MEG3, miR-106a-3p, and miR-24-3p were identified to be involved in MAPK pathway and PI3K-Akt pathway based on enrichment analysis. In summary, we identified several key transcriptome biomarkers, which promoted the prediction and diagnosis of AD.

[D-Ala2, D-Leu5] Enkephalin Inhibits TLR4/NF-κB Signaling Pathway and Protects Rat Brains against Focal Ischemia-Reperfusion Injury.

BACKGROUND: Cerebral ischemia-reperfusion (I/R) injury is the main cause of acute brain injury, which is a life-threatening disease due to the lack of effective treatments. [D-Ala2, D-Leu5] enkephalin (DADLE) is a synthetic delta-opioid receptor agonist that is reported to confer neuroprotective effect; however, the underlying mechanism is still being explored. The purpose of the present study is to determine whether DADLE administrated intracerebroventricularly could attenuate the cerebral I/R injury, to determine if this is through inhibiting the toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling pathway and therefore inhibiting neuroinflammation in an ischemic stroke model. METHODS: Rats were subjected to 120 minutes of ischemia by transient middle cerebral artery occlusion (MCAO). At 45 minutes after ischemia, DADLE or control vehicle (artificial cerebrospinal fluid, ACSF) was given to the rats intracerebroventricularly. Neurological deficit, cerebral infarct volume, and histopathological changes were assessed at 24 hours after reperfusion. Brain inflammation was assessed by measuring tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the ischemic penumbra by ELISA. The expression of TLR4 was determined by immunohistochemistry staining and western blotting. The expression of NF-κB was investigated by western blotting. RESULTS: Compared with the vehicle-treatment (ACSF), DADEL improved neurological deficit (9.6 ± 2.1 versus 13.8 ± 1.9), reduced cerebral infarct volume (18.74 ± 3.30% versus 10.57 ± 2.50%), and increased the number of normal neurons (29.72 ± 8.53% versus 51.37 ± 9.18%) after cerebral I/R injury in rats (all P < 0.05). Expressions of inflammatory molecules including TNF-α and IL-6 were highly expressed in the vehicle-treated rats, whereas treatment with DADLE downregulated these expressions (P < 0.05). Additionally, cerebral I/R injury significantly increased the TLR4 and NF-κB expression in vehicle-control group, which was markedly inhibited by DADLE (P < 0.05). CONCLUSIONS: DADLE, administrated intracerebroventricularly at 45 minutes after cerebral ischemia, significantly ameliorated I/R-induced brain damage in rats. This kind of neuroprotective effect appears to be related to the downregulation of TLR4-mediated inflammatory responses.

Neuregulin-1ß Protects the Rat Diaphragm during Sepsis against Oxidative Stress and Inflammation by Activating the PI3K/Akt Pathway.

Sepsis-induced diaphragm dysfunction (SIDD) which is mainly characterized by decrease in diaphragmatic contractility has been identified to cause great harms to patients. Therefore, there is an important and pressing need to find effective treatments for improving SIDD. In addition, acetylcholinesterase (AChE) activity is a vital property of the diaphragm, so we evaluated both diaphragmatic contractility and AChE activity. Though neuregulin-1ß (NRG-1ß) is known to exert organ-protective effects in some inflammatory diseases, little is known about the potential of NRG-1ß therapy in the diaphragm during sepsis. Our study was aimed at exploring the effects of NRG-1ß application on diaphragmatic contractility and AChE activity during sepsis. Proinflammatory cytokines, muscle injury biomarkers in serum, contractile force, AChE activity, proinflammatory cytokines, oxidative parameters, histological condition, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and expression of phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB/Akt) signaling proteins in the diaphragm were measured and compared between nonseptic and septic groups with or without NRG-1ß treatment. In vitro, the effects of NRG-1ß on reactive oxygen species (ROS) production in the lipopolysaccharide- (LPS-) stimulated L6 rat muscle skeletal cells with or without the Akt inhibitor MK-2206 were detected. NRG-1ß inhibited proinflammatory cytokine release and muscle injury biomarkers soaring in serum and improved the sepsis-induced diaphragm dysfunction and AChE activity decrease significantly during sepsis. Meanwhile, the inflammatory response, oxidative stress, pathological impairment, and cell apoptosis in the diaphragm were mitigated by NRG-1ß. And NRG-1ß activated the PI3K/Akt signaling in the diaphragm of septic rats. Elevated ROS production in the LPS-stimulated L6 rat skeletal muscle cells was reduced after treatment with NRG-1ß, while MK-2206 blocked these effects of NRG-1ß. In conclusion, our findings underlined that NRG-1ß could reduce circulating levels of proinflammatory cytokines in rats with sepsis, adjust diaphragmatic proinflammatory cytokine level, mitigate diaphragmatic oxidative injury, and lessen diaphragm cell apoptosis, thereby improving diaphragmatic function, and play a role in diaphragmatic protection by activating PI3K/Akt signaling.

Regionally infused lidocaine can dose-dependently protect the ischemic spinal cord in rabbits and may be associated with the EAA changes.

OBJECTIVE: In our previous study, we found that lidocaine, infused through the abdominal aorta, could protect the spinal cord against the ischemia-reperfusion (I/R) injury caused by aortic occlusion. However, whether lidocaine protective effects have dose-dependent properties and its underlying mechanisms still remain unclear. This study was designed to investigate whether regionally infused lidocaine could dose-dependently protect spinal cord against I/R injury in rabbits and its underlying mechanism. METHODS: 46 New Zealand white rabbits were randomized into six groups: Group NS (normal saline control); Group L10 (lidocaine 10 mg/kg); Group L20 (lidocaine 20 mg/kg); Group L40 (lidocaine 40 mg/kg); Group L80 (lidocaine 80 mg/kg) and Group Sham. In Group NS, Group L10, Group L20, Group L40 and Group L80, spinal cord ischemia was induced by infrarenal aortic occlusion for 30 min. The sham group did not receive spinal cord ischemia. During the occlusion, normal saline or lidocaine at different doses was infused continuously through a catheter into the clamped abdominal aorta respectively. Neurologic behavior functions were assessed according to the Tarlov scale system at the moments of 0, 6, 24 and 48 h after reperfusion. The neural injuries were evaluated by the histological examination and the count of normal α-motor neurons in the ventral horn. The levels of excitatory amino acids (EAAs) in the spinal cord, including glutamate (Glu) and aspartic acid (Asp), were analyzed by high performance liquid chromatography with fluorescence detection. RESULTS: The Tarlov scales in the Group L20 and the Group L40 were significantly higher than those in the Group NS at 24 and 48 h after reperfusion (P < 0.05). 12.5 % animals in Group L40 and 25 % animals in Group L20 were paraplegic versus 75 % animals in Group NS at 48 h after reperfusion (P < 0.05). The median of normal α-motor neurons in the L20, L40 and L80 groups was 7.5, 9 and 5 respectively which was significantly higher than in the NS group (count 0, P < 0.05). The levels of L-ASP and L-Glu remarkably decreased in the Group L10 and the Group L40 compared to Group NS (P < 0.05). CONCLUSIONS: These data revealed that regional administration of lidocaine through the abdominal aorta can provide dose-dependent protection on spinal cord I/R in rabbits. Inhibition of EAA release may be one of the underlying mechanisms.

Effects of D­Ala2, D­Leu5­Enkephalin pre­ and post­conditioning in a rabbit model of spinal cord ischemia and reperfusion injury.

It has recently been revealed that during the aorta­clamped period, D­Ala2, D­Leu5­Enkephalin (DADLE) infusion can protect the spinal cord against ischemia and reperfusion (I/R) injury. However, the protective effects of DADLE administration prior to ischemia or at the time of early reperfusion have not yet been investigated. Drug pre­ or post­conditioning can serve as a more valuable clinical strategy. Therefore, the present study was designed to investigate the neuroprotective effect of DADLE infusion at different time intervals in order to determine the optimum time point for ischemic spinal cord protection. A total of 40 New Zealand white rabbits were randomly divided into 5 groups: Sham­operated (Sham), normal saline pre­conditioning (NS), DADLE per­conditioning (Dper), DADLE pre­conditioning (Dpre) and DADLE post­conditioning (Dpost). All animals were subjected to spinal cord ischemia for 30 min followed by 48 h reperfusion. Hind limb motor functions were assessed according to the Tarlov criterion when the animals regained consciousness, 6, 24 and 48 h after reperfusion. Histological analysis and the number of viable α­motor neurons were also used to assess the extent of spinal cord injury. Compared with the NS group, the Tarlov scores and the number of normal neurons were significantly higher in the Dper group (P<0.05), which were consistent with the results of a previous study. In addition, the paraplegia rate and loss of normal motor neurons were lower in the DADLE per­ and post­conditioning groups compared with the DADLE pre­conditioning; however, these were not statistically significant. DADLE 0.05 mg/kg administration at three time points all mitigated normal motor neuron injury in the anterior horn and decreased the paraplegia rates in rabbits. The therapeutic benefits appeared best in the post­conditioning group with DADLE, and worst in the pre­conditioning group.

Fabrication and characterization of electrospun PLLA/PANI/TSA fibers.

Poly(l-lactic acid)/polyaniline/p-toluene sulfonic acid composites (PLLA/PANI/TSA) were synthesized via an emulsion polymerization-composition method with TSA as the dopant for PANI, and the structures and properties of the composites were characterized and analyzed. Conductive fiber tubes of PLLA/PANI/TSA were fabricated using electrospinning-knitting technology, and the effects of electrical stimulation on the growth and proliferation of osteoblast cells over the fiber tubes were investigated. The polymerization of PANI and the preparation of the PLLA/PANI/TSA composites were carried out via a one-step emulsion polymerization-composition or two-step method, where the reaction time of the two-step method was shorter and its yield higher than that of the one-step method. The addition of TSA improved the electrical conductivity of the PLLA/PANI composite and promoted chain propagation in the emulsion polymerization of the aniline oligomers and increased the degree of PANI polymerization. The PLLA/PANI/TSA fiber tubes obtained by electrospinning possessed regular morphologies and hydrophilic properties. Osteoblast cells grew and proliferated strongly with the PLLA/PANI/TSA fiber mats as a tissue scaffold and the electrical concentrating material under the condition of electrical stimulation of rectangular wave pulse signals with the appropriate stimulation current.