VEGF-PLGA controlled-release microspheres enhanced angiogenesis in encephalomyosynangiosis-based chronic cerebral hypoperfusion.

Treatments enhancing angiogenesis for chronic cerebral hypoperfusion (CCH) are still in the research stage. Although encephalomyosynangiosis (EMS) is a common indirect anastomosis for the treatment of CCH, the effectiveness to promote angiogenesis is not satisfactory. Vascular endothelial growth factors (VEGF) is a cytokine found to specifically act directly on vascular endothelial cells, promote neovascularization, and enhance capillary permeability. However, the short half life and unstable property of VEGF underlies the need to explore available delivery system. In this study, poly (lactide-co-glycolide) (PLGA) was used to prepare VEGF controlled-release microspheres. In vitro and in vivo analysis of release kinetics showed that the microspheres could release VEGF continuously within 30 days. Then, modified chronic cerebral hypoperfusion rat model was established by ligation of bilateral internal carotid artery and one vertebral artery. At 14 days after ischemia, the EMS and the VEGF microspheres injection were performed. At 30 days after the injection, the result of Morris water maze displayed that combinating VEGF microspheres and EMS significantly ameliorated cognitive deficit after ischemia. We observed that combinating VEGF microspheres and EMS could further significantly increase cerebral blood flow. We speculated that this enhancement of cerebral blood flow was attributed to more angiogenesis induced by combination of VEGF microspheres and EMS, which verified by more collateral circulation with cerebral angiography and higher expression of CD31 or α-SMA. Our study demonstrated that combinating VEGF-PLGA controlled-release microspheres could significantly promote angiogenesis in EMS-based CCH rats model, providing new ideas for clinical treatment of CCH.

Injury-preconditioning secretome of umbilical cord mesenchymal stem cells amplified the neurogenesis and cognitive recovery after severe traumatic brain injury in rats.

Traumatic brain injury (TBI) is a dominant cause of death and permanent disability worldwide. Although TBI could significantly increase the proliferation of adult neural stem cells in the hippocampus, the survival and maturation of newborn cells is markedly low. Increasing evidence suggests that the secretome derived from mesenchymal stem cells (MSCs) would be an ideal alternative to MSC transplantation. The successive and microenvironmentally responsive secretion in MSCs may be critical for the functional benefits provided by transplanted MSCs after TBI. Therefore, it is reasonable to hypothesize that the signaling molecules secreted in response to local tissue damage can further facilitate the therapeutic effect of the MSC secretome. To simulate the complex microenvironment in the injured brain well, we used traumatically injured brain tissue extracts to pretreat umbilical cord mesenchymal stem cells (UCMSCs) in vitro and stereotaxically injected the secretome from traumatic injury-preconditioned UCMSCs into the dentate gyrus of the hippocampus in a rat severe TBI model. The results revealed that compared with the normal secretome, the traumatic injury-preconditioned secretome could significantly further promote the differentiation, migration, and maturation of newborn cells in the dentate gyrus and ultimately improve cognitive function after TBI. Cytokine antibody array suggested that the increased benefits of secretome administration were attributable to the newly produced proteins and up-regulated molecules from the MSC secretome preconditioned by a traumatically injured microenvironment. Our study utilized the traumatic injury-preconditioned secretome to amplify neurogenesis and improve cognitive recovery, suggesting this method may be a novel and safer candidate for nerve repair. Cover Image for this issue: doi: 10.1111/jnc.14741.

Intravenously Infusing the Secretome of Adipose-Derived Mesenchymal Stem Cells Ameliorates Neuroinflammation and Neurological Functioning After Traumatic Brain Injury.

The secretome of mesenchymal stem cell (MSC) offers a series of immunoregulatory properties and is regarded as an effective method of mitigating secondary neuroinflammation induced by traumatic brain injury (TBI). The secretome of adipose-derived MSCs (ASC-ST) was collected under hypoxia conditions. Proteomics data were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and concentrations of major components were tested. After the TBI caused by an electric cortical contusion impactor, rats were injected ASC-ST through caudal veins for 7 days. The neurological functional prognosis of TBI rats was significantly improved, and the vasogenic edema of brain tissues that was measured 14 days after TBI was relieved by ASC-ST, corresponding to brain water content levels. ASC-ST ameliorated TBI-induced neuroinflammatory environments that caused the edema, the apoptosis of the neural cells, and the nerve fiber damage by increasing the number of M2 phenotypes present while reducing the number of M1 phenotype microglia present. Furthermore, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) levels were reduced, whereas transforming growth factor-beta (TGF-ß) and tumor necrosis factor-stimulated gene 6 protein (TSG-6) levels were increased after secretome treatment. Altogether, ASC-ST is capable of improving neural functioning by modulating TBI-induced neuroinflammation and its related secondary insults. ASC-ST may be one of the most promising candidates for regulating the secondary inflammatory reactions of central nervous systems for clinical use.

Model-Informed Drug Development, Pharmacokinetic/Pharmacodynamic Cutoff Value Determination, and Antibacterial Efficacy of Benapenem against Enterobacteriaceae.

Benapenem is a novel carbapenem. The objective of this study was to determine the pharmacokinetic (PK)/pharmacodynamic (PD) cutoff values and evaluate the optimal administration regimens of benapenem for the treatment of bacterial infections via PK/PD modeling and simulation. Ertapenem was used as a control. Infected mice received an intravenous (i.v.) injection of benapenem or ertapenem of 14.6, 58.4, or 233.6 mg/kg of body weight, and the PK/PD profiles were evaluated. The MICs were determined by using a 2-fold agar dilution method. Mathematical models were developed to characterize the pharmacokinetic profile of benapenem in humans and mice. Monte Carlo simulations were employed to determine the cutoff values and the appropriate benapenem dosing regimens for the treatment of infections caused by clinical isolates of Enterobacteriaceae Two 2-compartment models were developed to describe the PK profiles of benapenem in humans and mice. A two-site binding model was applied to fit the protein binding in mouse plasma. Through correlation analysis, the percentage of the time that the free drug concentration remains above the MIC (%fT>MIC) was determined to be the indicator of efficacy. Results from the simulation showed that the probability of target attainment (PTA) against the tested isolates was over 90% with the dosing regimens studied. The PK/PD cutoff value of benapenem was 1 mg/liter at a %fT>MIC of 60% when given at a dose of 1,000 mg/day by i.v. drip for 0.5 h. The established model provides a better understanding of the pharmacological properties of benapenem for the treatment of Enterobacteriaceae infections. The proposed PK/PD cutoff value suggests that benapenem is a promising antibacterial against the Enterobacteriaceae The cutoff value of 1 mg/liter may be a useful guide for the clinical use of benapenem and for surveillance for benapenem resistance.

3D printing collagen/chitosan scaffold ameliorated axon regeneration and neurological recovery after spinal cord injury.

Spinal cord injury (SCI) is a disaster that can cause severe motor, sensory, and functional disorders. Implanting biomaterials have been regarded as hopeful strategies to restore neurological function. However, no optimized scaffold has been available. In this study, a novel 3D printing technology was used to fabricate the scaffold with designed structure. The composite biomaterials of collagen and chitosan were also adopted to balance both compatibility and strength. Female Sprague-Dawley rats were subjected to a T8 complete-transection SCI model. Scaffolds of C/C (collagen/chitosan scaffold with freeze-drying technology) or 3D-C/C (collagen/chitosan scaffold with 3D printing technology) were implanted into the lesion. Compared with SCI or C/C group, 3D-C/C implants significantly promoted locomotor function with the elevation in Basso-Beattie-Bresnahan (BBB) score and angle of inclined plane. Decreased latency and increased amplitude were observed both in motor-evoked potential and somatosensory-evoked potential in 3D-C/C group compared with SCI or C/C group, which further demonstrated the improvement of neurological recovery. Fiber tracking of diffusion tensor imaging (DTI) showed the most fibers traversing the lesion in 3D-C/C group. Meanwhile, we observed that the correlations between the locomotor (BBB score or angle of inclined plane) and the DTI parameters (fractional anisotropy values) were positive. Although C/C implants markedly enhanced biotin dextran amine (BDA)-positive neural profiles compared with SCI group, rats implanted with 3D-C/C scaffold displayed the largest degree of BDA profiles regeneration. Collectively, our 3D-C/C scaffolds demonstrated significant therapeutic effects on rat complete-transected spinal cord model, which provides a promising and innovative therapeutic approach for SCI. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1898-1908, 2019.

[Protective effect of Xingnaojing injection on traumatic brain injury].

OBJECTIVE: To investigate the protective effect and mechanism of Xingnaojing(Traditional Chinese Medicine) injection on brain injury in rats. METHODS: Sixty-three healthy adult male SD rats were randomly divided into 3 groups (n = 21): sham operation group, model group, xingnaojing group. The model of traumatic brain injury model group and Xingnaojing group used the free fall impact injury method, the sham operation group underwent craniotomy, did not cause brain damage. Xingnaojing group in rats after 10 min by tail vein injection Xingnaojing injection 10 ml/(kg x d), model group and sham operation group were intravenously injected with 0.9% sodium chloride solution, three groups were administered continuously for 7 days. At administration of the seventh days compared the S-100B protein in the serum and neuro specific enolase (NSE) level, the water content of brain tissue, serum superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione peroxidase (GSH-Px) content, and neurological function of rats among groups. RESULTS: Compared with the sham operation group, the nerve defect, brain water content, MDA, S100B protein and NSE levels were obvigusly increased in Xingnaojing group and model group; SOD, GSH-Px content decreased significantly; In Xingnaojing group nerve impairment and brain moisture were significantly lower than those of model group, the serum MDA, S-100B protein and NSE levels were significantly lower than those in the model group, the SOD, GSH-Px activity was significantly higher than that in the model group. CONCLUSION: Xingnaojing injection has protective effects on rat brain injury, and its mechanism may be related to reduce brain edema after traumatic brain injury and inhibit the reaction of oxygen free radical, protect nerve cells.

[Effect of ulinastatin in traumatic brain injury with multiple injuries].

OBJECTIVE: To investigate the effect of ulinastatin (UTI) in traumatic brain injury (TBI) with multiple injuries. METHODS: A prospective analysis of TBI patients with multiple injuries was performed. Sixty cases of cranial trauma with multiple injuries patients were randomly divided into two groups. There were 28 cases in control group while 32 cases in treatment group. Control group underwent conventional treatment while intravenous infusion of UTI was performed in treatment group. The dose of UTI was 200 kU every 8 hours. Patients' intracranial cerebral pressure (ICP) were monitored at admission and 10 days after treatment. At the same time levels of white blood cell (WBC), C-reactive protein (CRP), procalcitonin (PCT), alanine aminotransferase (ALT), aspartate amino transfer enzymes (AST), creatinine (Cr), blood urea nitrogen (BUN), tumor necrosis factor-α (TNF-α), interleukin (IL-2, IL-6) were detected. RESULTS: ICP was down trend after treatment in UTI group, but there was no statistical difference compared with the control group. Hepatic and renal function and inflammation factor levels were significantly decreased in both groups. WBC, CRP, PCT, ALT, AST, Cr, BUN, TNF-α, IL-2, IL-6 were significantly lower in UTI group than those in control group (WBC:12.3±4.5×10(9)/L vs. 15.9±6.3×10(9)/L, CRP:46.12±11.47 mg/L vs. 64.24±18.31 mg/L, PCT:4.51±1.27 µg/L vs. 10.51±4.27 µg/L, ALT:47.26±8.23 U/L vs. 60.94±8.39 U/L, AST:42.67±7.63 U/L vs. 68.51±10.17 U/L, Cr:79.62±15.36 µmol/L vs. 102.36±16.82 µmol/L, BUN:6.35±2.36 mmol/L vs. 8.39±1.67 mmol/L, TNF-α:93.6±31.5 µg/L vs. 195.8±23.9 µg/L, IL-2:12.3±4.5 µg/L vs. 15.9±6.3 µg/L, IL-6:52.36±12.46 µg/L vs. 69.34±26.13 µg/L, all P<0.05). The incidence of systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) in UTI group were significantly lower than those in control group (21.88% vs. 46.43%, 9.38% vs. 28.57%, both P<0.05). CONCLUSION: Application of UTI treatment in TBI with multiple trauma patients can potentially protect the brain, liver and other organ function, thus significantly reduce incidence rate of SIRS and MODS by reducing the release of inflammatory mediators and systemic reaction to the trauma invasion.

[Clinical analysis of linezolid in treatment of infection with methicillin--resistant Staphylococcus in 14 neurosurgical patients].

OBJECTIVE: To evaluate the efficacy and safety of linezolid in the treatment of post-neurosurgical intracranial methicillin-resistant Staphylococcus (MRS) infection. METHODS: The data from 14 patients, admitted to neurological intensive care unit (ICU) of Medical College of Chinese People's Armed Police Forces between March 2009 and November 2011, were retrospectively analyzed. All these cases suffered from post-neurosurgical intracranial infection by MRS and received linezolid treatment. Blood and cerebrospinal fluid (CSF) were collected before and 7 days and 14 days after treatment for routine and bacteriological examinations to assess clinical efficacy and adverse reactions of linezolid. RESULTS: After 14-day treatment with linezolid, the clinical and laboratory parameters showed significant improvement: glucose (mmol/L) in CSF rose from 1.00 (0.65) to 3.15 (1.60), protein (mg/L) in CSF dropped from 2238.50 (2072.50) to 606.50 (217.30), white blood cell count [×106/L] in CSF fell from 920.00 (1587.50) to 30.00 (40.00), and the number of patients with CSF neutrophil ratio>0.20 was reduced from 14 to 1 (all P < 0.01). In addition, serum procalcitonin level (µg/L) was significantly reduced from 0.65 (1.16) to 0.08 (0.09) after linezolid therapy (P < 0.01). Total effective rate was 85.7% (12/14), and CSF bacterial clearance rate reached 100%. No adverse events were found during the treatment. CONCLUSION: Linezolid could effectively control post--neurosurgical intracranial MRS infection and alleviate the inflammatory responses with safety.

Particle swarm algorithm trained neural network for QSAR studies of inhibitors of platelet-derived growth factor receptor phosphorylation.

The multilayer feed-forward artificial neural network (ANN) has been widely used in QSAR studying. Back-propagation algorithm (BP) and the use of evolutionary search as an ANN training method has some limitations associated with overfitting, local optimum problems and slow convergence rate. In this paper, particle swarm optimization (PSO) as a relatively new optimization technique has been used in ANN training. Compared to ANN trained by BP algorithm and evolutionary search, ANN training by PSO algorithm (PSONN) show satisfactory performance, converges quickly towards the optimal position and can avoid overfitting in some extent. The PSONN has been testified by using in QSAR modeling for inhibitory activity of 4-[4-(N-substituted (thio) carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline derivatives.