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Microglia is the innate immune cell in central nervous system (CNS) and plays an important role in neuroinflammation. Microglia mediated neuroinflammation is the key factor affecting the development of neurodegenerative diseases. Although there was evidence that paraquat (PQ) could induce inflammatory response, its mechanism was not clear. The present study investigated the mechanisms of PQ-induced inflammatory responses in BV-2 microglia cells, and tried to reveal the role of ROS/Akt1 pathway. The results showed that the cell activation markers (iNOS and CD206) of BV-2 cells were increased after PQ treatment, suggesting that BV-2 microglia were activated. PQ induced the reactive oxygen species (ROS) and inhibited the AKT1 phosphorylation in BV-2 cells. Besides, the M1 markers expression (IL-6, TNF-α and IL-1β) were significantly increased after PQ treatment, which suggested that PQ induced the increase of M1 phenotype of BV-2 microglia. Pre-treated with NAC (ROS scavenger), the M1 phenotype was decreased while the p-Akt1 was restored compared to PQ stimulation. Furthermore, we built an Akt1(S473E)-overexpression BV-2 cell line. The Akt1 (S473E) partially attenuated the PQ induced increase in M1 phenotype, while ROS did not significantly change. These results indicated that PQ induced BV-2 microglia activation by increased ROS mediated Akt1 activation inhibition, leading to neuroinflammation.

Paraquat (PQ), a widely used herbicide, could cause neurodegenerative diseases, yet the mechanism remains incompletely understood. This study aimed to investigate the direct effect of PQ on NSC in vivo and its possible mechanism. Adult C57BL/6 mice were subcutaneously injected with 2 mg/kg PQ, 20 mg/kg PQ or vehicle control once a week for 2 weeks, and sacrificed 1 week after the last PQ injection. Furthermore, extra experiments with Tauroursodeoxycholic Acid (TUDCA) intervention were performed to observe the relationship between ER stress, neuroinflammation and the neural stem cell (NSC) impairment. The results showed that 20 mg/kg PQ caused the NSC number decrease in both subgranular zones (SGZ) and subventricular zone (SVZ). Further analysis indicated that the 20 mg/kg PQ suppressed the proliferation of NSC, without affecting the apoptosis. Moreover, 20 mg/kg PQ also induced ER stress in microglia and caused neuroinflammation in SGZ and SVZ. Interestingly, the ER stress inhibitor could simultaneously ameliorate the neuroinflammation and NSC reduction. These data suggested that increased ER stress in microglia might be a possible pathway for PQ-induced neuroinflammation and NSC impairment. That is a previously unknown mechanism for PQ neurotoxicity.

A new type of film packaging made from natural polysaccharide materials, with its environmental safety and friendliness, is considered as a potential substitute for plastics. Novel polysaccharide composite films based upon citrus pectin (CP) and sodium alginate (SA) were successfully prepared and characterized, containing pterostilbene (PTE) at various concentrations (0.2, 0.4, 0.8, 1.6, 3.2 mM). The rheological analysis displayed that all film-forming liquids performed no gelation behavior with G" > G' at low frequency and weak gelation with G" < G' at high frequency. The SA-CP films had good tensile strength (TS) and elongation at break (EB), while adding PTE as an antioxidant to the film reduced both the values. Of note, the SA-CP films with PTE had better moisture resistance than that of the pure SA-CP films, which was related to the changes of its microstructure. The increased roughness of the films containing PTE was observed by microscope. After calcium chloride cross-linking, the water solubility of the films was reduced, while its thermal stability was improved. Notably, the accretion of PTE expressively enhanced the antioxidant properties of the SA-CP films. Thus, the SA-CP composite films containing PTE could be utilized as an excellent antioxidant packaging material.

Background Early life exposure to triclosan, an emerging endocrine disrupting chemical, may adversely impact childhood neurodevelopment, but limited epidemiologic studies have examined the associations. Objective We evaluated the associations between prenatal and postnatal triclosan exposure and child neurodevelopment at 3 years. Methods The study included 377 mother-child pairs who participated in Sheyang Mini Birth Cohort Study (SMBCS), a longitudinal birth cohort in China. Triclosan concentrations in maternal and 3-year-old child urine samples were quantified using gas chromatography-tandem mass spectrometry (GC-MS/MS). Gesell Developmental Schedules (GDS) were used to assess child neurodevelopment at 3 years of age. Multivariate linear regression models were applied to estimate associations of prenatal and postnatal urinary triclosan concentrations with children's developmental quotients (DQs). Results Detection frequencies of triclosan in maternal and childhood urine samples were 100% and 99.5%, respectively. The median values of prenatal and postnatal urinary triclosan levels were 0.65 and 0.44 μg/L, respectively. One ln-unit increase of maternal urinary triclosan concentration was associated with increase of DQ scores in motor area of children (regression coefficient, β = 0.28, 95% confidence interval, CI: 0.03, 0.54; p = 0.03). In sex-stratified analyses, maternal urinary triclosan levels were significantly related to increases in DQ scores in motor area among boys (β = 0.25, 95%CI: 0.01, 0.50; p = 0.04), while postnatal urinary triclosan concentrations were inversely associated with DQ scores in social area in boys (β = -0.37, 95%CI: -0.72, -0.03; p = 0.03). Conclusions The findings suggested that prenatal triclosan exposure predicted increases in motor scores, while postnatal triclosan exposure was related to reductions in social scores of 3-year-old children. These associations were only observed in boys. The biological mechanisms linking triclosan exposure to neurodevelopment await further studies.

Bisphenol A (BPA) exposure during early life may increase risk of childhood obesity, however, prospective evidence of birth cohort is limited and inconclusive. We aimed to explore the associations of maternal and childhood BPA exposure with child adiposity measures, including body mass index, waist circumference and skinfold thickness and waist to height ratio of children at 7 years. 430 mother-child pairs were examined from a population-based prospective cohort in a rural area of East China. BPA concentrations of spot urine samples were quantified in mothers and their children aged 3 and 7 years. Maternal urinary BPA concentration was significantly positively associated with waist circumference in children aged 7 years (β = 0.508 cm, 95% CI: 0.067, 0.950). These significant associations were not modified by child sex, but they were only observed among girls in sex-stratified analyses. Risk of central obesity related to prenatal BPA exposure was significantly higher in the second and the third tertile than those in the first tertile (odds ratio, OR = 2.510, 95% CI = 1.146, 5.499; OR = 2.584, 95% CI = 1.186, 5.631, respectively; p for trend = 0.022). The present findings suggested that prenatal exposure to BPA may enhance waist circumference of children and thereby increase risk of central obesity in school-age girls.

To examine sex-specific associations of neonatal and childhood exposure to eight trace elements with cognitive abilities of school-age children. The association between exposure and effects was assessed among 296 school-age children from a population-based birth cohort study, who had manganese (Mn), cadmium (Cd), and lead (Pb) exposure measured in cord blood and chromium (Cr), manganese, cobalt (Co), copper (Cu), arsenic (As), selenium (Se), cadmium, and lead exposure quantified in spot urine. Cognitive abilities were assessed using the Wechsler Intelligence Scale for Children-Chinese Revised (WISC-CR). Generalized linear models were performed to analyze associations of intelligence quotient (IQ) with trace element concentrations in cord blood and urinary trace element levels. General linear models were used to evaluate association between exposure fluctuation and children’s IQ. Urinary Cd concentrations were negatively associated with full-scale IQ (β = − 3.469, 95% confidence interval (CI) − 6.291, − 0.647; p = 0.016) and performance IQ (β = − 4.012, 95% CI − 7.088, − 0.936; p = 0.011) in girls; however, neonatal Cd exposure expressed as Cd concentrations in cord blood was in inverse associations with verbal IQ (β = − 2.590, 95% CI − 4.570, − 0.609; p = 0.010) only in boys. Positive association between urinary Mn concentrations and performance IQ (β = 1.305, 95% CI 0.035, 2.575; p = 0.044) of children was observed, especially in girls. In addition, inverse association of urinary Cu concentrations with verbal IQ (β = − 2.200, 95% CI − 4.360, − 0.039; p = 0.046) was only found in boys. Childhood Cd exposure may adversely affect cognitive abilities, while Mn exposure may beneficially modify cognitive abilities of school-age children, particularly in girls.

Background Early-life carbamate exposure during developmental period has been linked with adverse health effects and attracted attention. Methods Three hundred and three children at age of seven were included in the current study. Urinary carbofuranphenol concentrations were measured using gas chromatography-tandem mass spectrometry. Verbal, performance and full-scale intelligence quotients (IQV, IQP, and IQFS) were assessed using Wechsler Intelligence Scale for Children-Chinese Revised. Generalized linear models were used to explore the associations between carbofuranphenol levels and IQs. Generalized estimating equations were used to explore long-term health effect and sensitive time window. Results Carbofuranphenol was detected in 96.6% of the seven-year-old urinary samples, the geometric mean, median, and inter quartile range of the carbofuranphenol concentrations were 0.67 μg/L, 0.30 μg/L, and 0.09–3.72 μg/L, respectively, which were similar with the level of three-year-old children from the SMBCS cohort. Seven-year-old carbofuranphenol level was negatively associated with IQP [β = −0.044; 95% confidence interval (CI): −0.087, −0.001; p = 0.045]. Three-year-old carbofuranphenol level was negatively associated with IQP (β = −0.100; 95% CI: −0.186, −0.014; p = 0.022) and IQFS (β = −0.087; 95% CI: −0.173, −0.001; p = 0.047). Carbamate exposure of maternal and children at both three and seven years old had negative associations with IQP (β = −0.089; 95% CI: −0.171, −0.007; p = 0.034), and IQFS (β = −0.064; 95% CI: −0.127, −0.000; p = 0.049) of children at age of seven. Conclusion Results of the present study verify that children in an agricultural region of China were widely exposed to carbamate pesticides. Carbamate exposure in utero and at three and seven years may adversely impact children’s neurodevelopment.

Paraquat (1,1′-dimethyl-4,4′-bipyridium dichloride, PQ), a non-selective and efficient herbicide, causes neuroinflammation, neurodegeneration and memory dysfunction. However, adverse effects of PQ on the neuroimmune interactions have rarely been investigated. Female adult C57/BL6 mice were divided into 3 groups and treated with PQ (intraperitoneal injection, 1 mg/kg or 5 mg/kg) or the vehicle (an equivalent volume of 0.9% saline) every two days, at day 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, for a total of 14 doses. We evaluated blood-brain barrier (BBB) integrity and PQ concentrations during the course of PQ exposure and tested interleukin-1β (IL-1β) concentrations in dentate gyrus (DG) after 28 days PQ exposure. In addition, memory function, neural stem cells (NSCs) proliferation, neurogenesis and microglia polarization were analyzed after PQ exposure. Furthermore, mice were intraperitoneal injections of anti-IL-1β during 5 mg/kg PQ exposure to test the rule of IL-1β. Blood-brain barrier (BBB) permeability and PQ concentrations increased gradually during PQ exposure (n = 6). Moreover, memory function, NSCs proliferation and neurogenesis were impaired after 5 mg/kg PQ exposure (n = 6). Further analyses revealed that ‘classically’ activated (M1) microglia and IL-1β concentrations in DG were increased after 5 mg/kg PQ treatment (n = 6). Moreover, we found that neutralization of IL-1β partly restored PQ-induced NSCs impairments and memory dysfunction (n = 6). In conclusion, our results revealed that PQ induced NSCs impairments and memory dysfunction in adult mice, which was related to the release of IL-1β by M1-polarized microglia in DG. These findings may help understand the neurotoxic effect of PQ.

Acellular nerves are composed of a basal lamina tube, which retains sufficient bioactivity to promote axon regeneration, thereby repairing peripheral nerve gaps. However, the clinical application of acellular allografts has been restricted due to its limited availability. To investigate whether xenografts, a substitute to allograft acellular nerves in abundant supply, could efficiently promote nerve regeneration, rabbit and rat acellular nerve grafts were used to reconstruct 1 cm defects in Wistar rat facial nerves. Autologous peroneal nerve grafts served as a positive control group. A total of 12 weeks following the surgical procedure, the axon number, myelinated axon number, myelin sheath thickness, and nerve conduction velocity of the rabbit and rat‑derived acellular nerve grafts were similar, whereas the fiber diameter of the rabbit‑derived acellular xenografts decreased, as compared with those of rat‑derived acellular allografts. Autografts exerted superior effects on nerve regeneration; however, no significant difference was observed between the axon number in the autograft group, as compared with the two acellular groups. These results suggested that autografts perform better than acellular nerve grafts, and chemically extracted acellular allografts and xenografts have similar effects on the regeneration of short facial nerve defects.

Purpose The titanium-nickel shape-memory alloy distractor is a new kind of alveolar ridge distraction device that can be completely buried and self-activated. To evaluate this new device, the present study compared the effects of 2 osteotomy techniques and investigated the osteogenesis outcome by measuring the bone mineral density and biomechanical properties of newly generated bone tissues. Materials and Methods Adult mongrel canines (n = 18) were randomly divided into 3 groups. All the mandibular teeth were extracted. Group I received a complete osteotomy, whereas groups II and III received a partial osteotomy with preservation of the glossal cortical bones. The left mandible served as the experimental site for each group, and the right side served as the internal control. Groups I and II were sacrificed 3 months after the completion of distraction, whereas group III was sacrificed 6 months after the completion of distraction. Radiographs were taken. Dual-energy x-ray absorptiometric results and compressive biomechanics of the distracted and control bone masses were examined for groups II and III (partial osteotomy group). Results The complete osteotomy group exhibited a larger distraction space initially; however, the distracted area showed a remarkable depression on the buccal-glossal side. In contrast, the partial osteotomy groups exhibited a nearly normal mandibular morphology. The bone mineral density, compressive strength, and elastic modulus were decreased in the distracted side compared with the control side 3 months after distraction. These 3 parameters increased in the distracted side 6 months after distraction, which did not differ significantly from those in the control side. Conclusions Partial osteotomy with preservation of the glossal cortical bones is more suitable for alveolar ridge augmentation using the shape-memory alloy distraction device. The newly generated bone exhibited adequate strength, which can satisfy the requirements of subsequent implantation.

Purpose To investigate the use of an internal self-activated distraction device made of titanium-nickel memory alloy to augment the mandibular alveolar ridge. Materials and Methods Twelve adult mongrel canines were randomly divided into 4 groups. Groups I and II were sacrificed 1 month and 3 months after distraction, respectively. In group III (distraction-planting group), 2 implants were placed on both sides of the mandible 3 months after distraction. In group IV (control group), no implants were placed. X-rays were taken and histologic research was performed. Results When the distraction device was in place, the transport segments were lifted up 3.0 to 4.5 mm immediately, and a range of 7.5 to 11.5 mm of augmentation was reached after 3 to 5 days of device activation. X-rays showed that bone mineral density increased, and new bone formed in the distraction area 1 month after distraction. Three months later, the bone mineral density of the distraction area was close to that of the surrounding alveolar bone. Histologic observation showed that collagen bundles initially formed in the distraction region and were followed by calcification and osteogenesis. X-rays showed that the implants were well integrated 3 months after implant placement. The implant-bone interface showed bony integration, and there was no significant difference in the implant-bone contact rate between the distraction and control sides. Conclusion The titanium-nickel memory alloy distractor can be used successfully to augment the posterior mandibular alveolar ridge of canines. New bone formed between the buccal and lingual periosteal layers. A conventional implant surgical procedure could be performed 3 months later and the desirable implant-bone integration was produced.

Purpose To assess the clinical efficacy of the repair of facial nerve defects by allograft transplantation using acellular facial nerves. Materials and Methods Seven patients with facial nerve defects, ranging from damage to 1 facial nerve branch to combined defects of all branches, were enrolled. Defects ranged from 3 to longer than 4 cm. All defects were repaired by transplantation of acellular facial nerve allografts. Static and dynamic symmetry and facial expressions were evaluated using the House-Brackmann classification and the functional status of the facial nerve was assessed electromyographically. No patient received immunosuppressive therapy. Results All wounds healed well, with no swelling or inflammatory exudation. The patients recovered facial nerve function to various extents. Six months postoperatively, 4 of 7 patients showed static facial asymmetry. Twelve months postoperatively, 3 patients had static facial asymmetry with normal eye closure, and only careful observation could detect slight asymmetry of forehead movement. Two of 7 patients showed moderate facial nerve dysfunction. Ipsilateral facial movement and facial asymmetry were obvious in the patient whose defect affected the common trunk and all facial nerve branches. Two years postoperatively, 5 of 7 patients had mild facial nerve dysfunction, with symmetric faces and incomplete eye occlusion. Six years postoperatively, these patients continued to show symmetric faces and incomplete ipsilateral eye occlusion, but facial muscle function was considerably restored. Follow-up electromyography showed neurologic recovery in all patients. Conclusion The repair of a facial nerve defect by transplantation of an acellular facial nerve allograft is feasible.

Purpose To investigate the feasibility of repairing whole facial nerve defects with chemically extracted acellular whole facial allografts nerves and its effect on motor conductivity recovery. Materials and Methods Whole nerve defects (branches and trunk) were made in 4 rabbit groups (n = 18), and the nerve defect was bridged using 1) acellular facial nerve allografts, 2) facial nerve isografts, 3) acellular peroneal nerve allografts, and 4) peroneal nerve isografts. Six months later, cell morphology, nerve microbeam distribution, angiogenesis, and collagen were observed in the distal and center of the grafts with special trichrome staining. The regenerated nerve fibers and Schwann cells in the anastomosis site were immunohistochemically stained. Nerve axon numbers and passing rates were analyzed with computer-captured images. The regenerated nerve ultrastructure was analyzed by transmission electron microscopy. Results Regenerated nerve fibers and vessels were found in the grafts, with no differences between groups A and B. Groups C and D had poor nerve continuity with little vascular regeneration. The distal segments of nerve transplants in groups A and B showed strong positive neurofilament staining, higher than in groups C and D. In groups A and B, many long spindle-shaped Schwann cells proliferated longitudinally in the nerve transplant, but less in groups C and D. Myelinated nerve fibers were found in the distal facial nerve. There were no differences between groups A and B in fiber number and myelin sheath thickness, which were much lower than normal, whereas little myelin sheath regeneration was observed in groups C and D. Conclusion Chemically extracted acellular whole facial nerve allografts are feasible for repairing whole facial nerve defects.

Protein delivery systems focus on protecting the protein that directly affects release kinetics. This study was carried out to determine the effect of surface polar group and fiber structure in a recombinant human bone morphogenetic protein-2 (rhBMP-2) protecting system based on a collagen matrix on its pharmacokinetics (PK) and osteoinductive activity In this study, two types of collagen carriers were made for rhBMP-2 protecting system. The PKs of rhBMPs within collagen (Col) and collagen-chondroitin sulfate (Col-CS) carriers were determined using (125)I-labeled proteins in rat ectopic assay. The two carriers were characterized with surface energy and hydrophilicity. We observed that the osteoinductivity of these two scaffolds seemed to depend on two parameters: the nature of the carrier material and the release kinetics of the carriers. Results indicated that with CS modification, the initial burst release of rhBMP-2 from Col-CS scaffold was much higher than collagen scaffold. The subsequent PKs at longer times were not strongly dependent on the carriers. These differences were expected to affect the osteoinductive activity of the implants. It was concluded that surface energy played a significant role in the release PK of implanted rhBMP and higher initial burst is favorable to bone regeneration near the matrix.

In this study, a new artificial bone matrix was constructed with collagen and Ca5(PO4)3OH (hydroxyapatite/HA) which are the main components of natural bone. To improve the property of the artificial bone matrix, chitosan (CS), a kind of positive charged polysaccharide, was crosslinked into the scaffolds. Solid–liquid phase separation method was used to shape 3D porous structure benefited for cells growing into. The artificial bone matrix was investigated by transmission electron microscopy, scanning electron microscopy, and electron spectroscopy for chemical analysis, etc. for structures and characteristics. And its ability of bone repair was investigated by orthotope bone defect reparation in vivo. The results showed that the artificial bone matrix was a porousscaffold with three-dimension interconnected fiber microstructure. HA particles were dispersed evenly among collagen fiber and CS was modified on the surface of collagen fiber. It was indicated that this artificial bone matrix could be used as a bone substitute with outstanding properties. © 2007 Wiley Periodicals, Inc. J Biomed Mater Res, 2008