Necrostatin-1s Suppresses RIPK1-driven Necroptosis and Inflammation in Periventricular Leukomalacia Neonatal Mice.

Periventricular leukomalacia (PVL), a predominant form of brain injury in preterm survivors, is characterized by hypomyelination and microgliosis and is also the major cause of long-term neurobehavioral abnormalities in premature infants. Receptor-interacting protein kinase 1 (RIPK1) plays a pivotal role in mediating cell death and inflammatory signaling cascade. However, very little is known about the potential effect of RIPK1 in PVL and the underlying mechanism. Herein, we found that the expression level of RIPK1 was drastically increased in the brain of PVL neonatal mice models, and treatment of PVL neonatal mice with Necrostatin-1s (Nec-1s), an inhibitor of RIPK1, greatly ameliorated cerebral ischemic injury, exhibiting an increase of body weights, reduction of cerebral infarct size, neuronal loss, and occurrence of necrosis-like cells, and significantly improved the long-term abnormal neurobehaviors of PVL. In addition, Nec-1s significantly suppressed hypomyelination and promoted the differentiation of oligodendrocyte precursor cells (OPCs), as demonstrated by the increased expression levels of MBP and Olig2, the decreased expression level of GPR17, a significant increase in the number of CC-1-positive cells, and suppression of myelin ultrastructure impairment. Moreover, the mechanism of neuroprotective effects of Nec-1s against PVL is closely associated with its suppression of the RIPK1-mediated necrosis signaling molecules, RIPK1, PIPK3, and MLKL. More importantly, inhibition of RIPK1 could reduce microglial inflammatory injury by triggering the M1 to M2 microglial phenotype, appreciably decreasing the levels of M1 marker CD86 and increasing the levels of M2 markers Arg1 or CD206 in PVL mice. Taken together, inhibition of RIPK1 markedly ameliorates the brain injury and long-term neurobehavioral abnormalities of PVL mice through the reduction of neural cell necroptosis and reversing neuroinflammation.

Effects of selenium-cadmium co-enriched Cardamine hupingshanensis on bone damage in mice.

Selenium (Se) and cadmium (Cd) usually co-existed in soils, especially in areas with Se-rich soils in China. The potential health consequences for the local populations consuming foods rich in Se and Cd are unknown. Cardamine hupingshanensis (HUP) is Se and Cd hyperaccumulator plant that could be an ideal natural product to assess the protective effects of endogenous Se against endogenous Cd-caused bone damage. Male C57BL/6 mice were fed 5.22 mg/kg cadmium chloride (CdCl2) (Cd 3.2 mg/kg body weight (BW)), or HUP solutions containing Cd 3.2 mg/kg BW and Se 0.15, 0.29 or 0.50 mg/kg BW (corresponding to the HUP0, HUP1 and HUP2 groups) interventions. Se-enriched HUP1 and HUP2 significantly decreased Cd-induced femur microstructure damage and regulated serum bone osteoclastic marker levels and osteogenesis-related genes. In addition, endogenous Se significantly decreased kidney fibroblast growth factor 23 (FGF23) protein expression and serum parathyroid hormone (PTH) levels, and raised serum calcitriol (1,25(OH)2D3). Furthermore, Se also regulated gut microbiota involved in skeletal metabolism disorder. In conclusion, endogenous Se, especially with higher doses (the HUP2 group), positively affects bone formation and resorption by mitigating the damaging effects of endogenous Cd via the modulation of renal FGF23 expression, circulating 1,25(OH)2D3 and PTH and gut microbiota composition.

Stabilizing Ultrasmall Ceria-Cluster Nanozyme for Antibacterial and Antibiofouling Applications.

The generation of undesired biofouling in medical and engineering applications results in a reduction in function and durability. Copying functionalities of natural enzymes to combat biofouling by artificial nanomaterials is highly attractive but still challenged by the inferior catalytic activity and specificity principally because of low densities of active sites. Here, an innovate strategy is demonstrated to stabilize high-density ultrasmall ceria clusters on zirconia for biofouling prevention. Benefiting from the unique structure, CeO2 @ZrO2 nanozyme can significantly enhance the haloperoxidase-mimicking activity in catalyzing the oxidation of bromide with H2 O2 into biocidal hypobromous acid as a result of abundant defects and surface strong acidity sites, inducing impressive antibacterial and antibiofouling capacity compared with that of pristine CeO2 . This work is expected to open a new avenue for the rational design of cluster catalysts for various targeting catalytic applications.

ME-NBI combined with endoscopic ultrasonography for diagnosing and staging the invasion depth of early esophageal cancer: a diagnostic meta-analysis.

BACKGROUND: Several methods can assist in detecting early esophageal cancer (EEC) and staging esophageal cancer (EC) invasion depth. OBJECTIVE: To evaluate the accuracy of magnifying endoscopy with narrow-band imaging (ME-NBI) plus endoscopic ultrasonography (EUS) for diagnosing EC. METHODS: We searched the PubMed, Embase, Cochrane Library, and China National Knowledge Infrastructure (CNKI) databases for relevant studies. The Quality Assessment of Diagnostic Accuracy Studies 2 (QADAS2) was used to assess the studies' methodological quality. The sensitivity, specificity, positive likelihood (LR+), negative likelihood (LR-), and diagnostic odds ratio (DOR) were calculated, and the summary receiver operating characteristic (SROC) curves were drawn to evaluate the diagnostic performance. RESULTS: Seven studies were included. The meta-analysis suggested that the pooled sensitivity, specificity, LR+, LR-, and DOR of ME-NBI plus EUS for diagnosing EC were 0.947 (95% confidence interval [CI], 0.901-0.975), 0.894 (95% CI, 0.847-0.931), 7.989 (95% CI, 4.264-14.970), 0.066 (95% CI, 0.035-0.124), and 137.96 (95% CI, 60.369-315.27), respectively. Those values for staging the invasive depth were 0.791 (95% CI, 0.674-0.881), 0.943 (95% CI, 0.906-0.968), 13.087 (95% CI, 7.559-22.657), 0.226 (95% CI, 0.142-0.360), and 61.332 (95% CI, 27.343-137.57). The areas under the curves (AUCs) for diagnosis and staging were 0.97 and 0.95, respectively. CONCLUSIONS: ME-NBI plus EUS might be an adequate diagnostic and staging modality for EC. Due to the study limitations, more large-scale, high-quality studies are needed to confirm the diagnostic accuracy of ME-NBI plus EUS.

Aggravated behavioral and neurochemical deficits and redox imbalance in mice with enhanced neonatal iron intake: improvement by biochanin A and role of microglial p38 activation.

Objectives: We aim to investigate the joint effect of iron (enhanced neonatal iron intake), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and biochanin A (BA, oral administration) and possible mechanisms for action on behavioral and neurochemical indicators in the mice. Methods: Rotarod test, pole test and swim test were used to evaluate animal behavior. The neurochemical analysis was conducted by HPLC-ECD. Oxidative stress was determined in this study. Further mechanism was investigated through in vitro experiments. Results: Iron and MPTP co-administration significantly induced behavioral deficits and decreased striatal dopamine content in the male and female mice. The co-administration of iron and MPTP also significantly induced redox imbalance in the substantia nigra (SN) of mice. Furthermore, BA significantly improved behavioral deficits and increased striatal dopamine content in the mice co-treated with iron and MPTP. BA also significantly improved redox imbalance in the SN of mice co-administered with iron and MPTP. Finally, we showed that iron and 1-Methyl-4-phenylpyridinium (MPP+) co-treatment significantly increased superoxide production in microglial cultures by inducing p38 mitogen-activated protein kinase (MAPK) activation. BA also significantly decreased superoxide production and p38 MAPK phosphorylation in the cultures co-treated with iron and MPP+. Conclusion: Iron and MPTP co-treatment may result in worsened behavioral and neurochemical deficits and aggravated redox imbalance through inducing microglial p38 MAPK activation. BA may improve behavioral and neurochemical deficits and redox imbalance through repressing microglial p38 MAPK activation.

Body mass index, waist circumference, and risk of hearing loss: a meta-analysis and systematic review of observational study.

BACKGROUND: Emerging evidence implicates excess weight as a potential risk factor for hearing loss. However, this association remained inconclusive. Therefore, we aimed to systematically and quantitatively review the published observational study on the association between body mass index (BMI) or waist circumference (WC) and hearing loss. METHODS: The odds ratios (ORs) or relative risks (RRs) with their 95% confidence intervals (CIs) were pooled under a random-effects model. Fourteen observational studies were eligible for the inclusion in the final analysis. RESULTS: In the meta-analysis of cross-sectional studies, the ORs for prevalent hearing loss were 1.10 (95% CI 0.88, 1.38) underweight, 1.14 (95% CI 0.99, 1.32) for overweight, OR 1.40 (95% CI 1.14, 1.72) for obesity, 1.14 (95% CI 1.04, 1.24) for each 5 kg/m2 increase in BMI, and 1.22 (95% CO 0.88. 1.68) for higher WC. In the meta-analysis of longitudinal studies, the RRs were 0.96 (95% CI 0.52, 1.79) for underweight, 1.15 (95% CI 1.04, 1.27) for overweight, 1.38 (95% CI 1.07, 1.79) for obesity, 1.15 (95% CI 1.01, 1.30) for each 5 kg/m2 increase in BMI, and 1.11 (95% CI 1.01, 1.22) for higher WC. CONCLUSIONS: In summary, our findings add weight to the evidence that elevated BMI and higher WC may be positively associated with the risk of hearing loss.

Protein Interacting with C-Kinase 1 Deficiency Impairs Glutathione Synthesis and Increases Oxidative Stress via Reduction of Surface Excitatory Amino Acid Carrier 1.

Protein interacting with C-kinase 1 (PICK1) has received considerable attention, because it interacts with a broad range of neurotransmitter receptors, transporters, and enzymes and thereby influences their localization and function in the CNS. Although it is suggested that putative partners of PICK1 are involved in neurological diseases such as schizophrenia, Parkinson's disease, chronic pain, and amyotrophic lateral sclerosis, the functions of PICK1 in neurological disorders are not clear. Here, we show that oxidative stress, which is tightly associated with neurological diseases, occurs in PICK1(-/-) mice. The oxidation in PICK1(-/-) mice was found selectively in neurons and was age dependent, leading to microglial activation and the release of inflammatory factors. Neurons in the cortex and hippocampus from PICK1(-/-) mice showed increased vulnerability to oxidants and reduced capacity to metabolize reactive oxygen species (ROS); this was caused by reduced glutathione content and impaired cysteine transport. The dysregulated expression of glutathione was attributed to a decrease of the surface glutamate transporter excitatory amino acid carrier 1 (EAAC1). Overexpression of PICK1 could rescue the surface expression of EAAC1 and ameliorate the glutathione deficit in PICK1(-/-) neurons. Finally, reduced surface EAAC1 was associated with defective Rab11 activity. Transfection with dominant-negative Rab11 effectively suppressed surface EAAC1 and increased ROS production. Together, these results indicate that PICK1 is a crucial regulator in glutathione homeostasis and may play important roles in oxidative stress and its associated neurodegenerative diseases.

Protein Interacting C-Kinase 1 Modulates Surface Expression of P2Y6 Purinoreceptor, Actin Polymerization and Phagocytosis in Microglia.

Microglia clean up dead cells and debris through phagocytosis in the central nervous system. UDP-activated P2Y6 receptors (P2Y6Rs) induce the formation of phagocytic cup-like structure and P2Y6R expression is increased during the phagocytosis. However, it remains unclear how surface expression of P2Y6R is increased. PICK1 (protein interacting with C-kinase-1) interacts with various neurotransmitter receptors, transporters, and enzymes. We here report that PICK1 might interact with P2Y6R. Surface P2Y6R was reduced in microglia from PICK1-knockout mice and PICK1-knockdown BV2 cells, which was also confirmed by electrophysiological recordings, showing that P2Y6R-mediated current was increased by PICK1 overexpression but was reduced by PICK1-knockdown in BV2 microglia. Finally, PICK1 was sufficient to affect cytoskeletal aggregation and phagocytosis both in primary microglia and BV2 cells. These results indicate that PICK1 is an important regulator of P2Y6R expression and microglial phagocytosis.

Grifola frondosa Glycoprotein GFG-3a Arrests S phase, Alters Proteome, and Induces Apoptosis in Human Gastric Cancer Cells.

GFG-3a is a novel glycoprotein previously purified from the fermented mycelia of Grifola frondosa with novel sugar compositions and protein sequencing. The present study aims to investigate its effects on the cell cycle, differential proteins expression, and apoptosis of human gastric cancer SGC-7901 cells. Our findings revealed that GFG-3a induced the cell apoptosis and arrested cell cycle at S phase. GFG-3a treatment resulted in the differential expression of 21 proteins in SGC-7901 cells by upregulating 10 proteins including RBBP4 associated with cell cycle arrest and downregulating 11 proteins including RUVBL1, NPM, HSP90AB1, and GRP78 involved in apoptosis and stress response. qRT-PCR and Western blot analysis also suggested that GFG-3a could increase the expressions of Caspase-8/-3, p53, Bax, and Bad while decrease the expressions of Bcl2, Bcl-xl, PI3K, and Akt1. These results indicated that the stress response, p53-dependent mitochondrial-mediated, Caspase-8/-3-dependent, and PI3k/Akt pathways were involved in the GFG-3a-induced apoptosis process in SGC-7901 cells. These findings might provide a basis to prevent or treat human gastric cancer with GFG-3a and understand the tumor-inhibitory molecular mechanisms of mushroom glycoproteins.

Covered metal stent or multiple plastic stents for refractory pancreatic ductal strictures in chronic pancreatitis: a systematic review.

BACKGROUND AND AIMS: Refractory chronic pancreatitis has been proposed as a challenge for endoscopists following routine single plastic stenting. However, data on the efficacy and safety of further endoscopic stenting are still controversial. The current systematic review aimed to assess the efficacy and safety of placement of fully covered self-expandable metal stent (FCSEMS) and multiple plastic stents. METHODS: Databases including MEDLINE, EMBASE, the Cochrane Library, CBM, CNKI, VIP, and WANFANG Database were used to search relevant trials. Published studies were assessed by using well-defined inclusion and exclusion criteria. The process was independently performed by two investigators. RESULTS: A total of 5 studies provided data of 80 patients. Forest plots and publication bias were not carried out because few studies were relevant and screened studies were all case series. The technical success rate was 100% both in placement of FCSEMS and multiple plastic stents. The functional success rate after placement of FCSEMS was 100%, followed by multiple plastic stents (94.7%). Complications occurred 26.2% after FCSEMS placement, which was not described in detail in multiple plastic stents. The stent migration rate was 8.2% for FCSEMS and 10.5% for multiple plastic stents. Reintervention rate was 9.8% for FCSEMS and 15.8% for multiple plastic stents. Pain improvement rate was 85.2% for FCSEMS and 84.2% for multiple plastic stents. CONCLUSIONS: FCSEMS appeared to be no significant difference with multiple plastic stents in treatment of refractory chronic pancreatitis. We need to develop more investigations.

Effects of Lactobacillus plantarum supplementation on glucose and lipid metabolism in type 2 diabetes mellitus and prediabetes: A systematic review and meta-analysis of randomized controlled trials.

Lactobacillus plantarum has been shown to improve glucose and lipid metabolism in mouse models of type 2 diabetes mellitus (T2DM). However, it remains unclear whether such benefits extend to humans. A systematic review and meta-analysis of randomized controlled trials (RCTs) was performed to clarify the effect of L. plantarum supplementation on glucose and lipid metabolism in T2DM and prediabetes. The PubMed, Cochrane, and Web of Science databases were searched. A random-effects model was used to estimate the pooled mean difference with 95% CI (confidence interval). L. plantarum supplementation reduced the levels of fasting plasma glucose (-0.41, 95%CI -0.63, -0.19 mg/dL; n = 5) and hemoglobin A1c (-0.2, 95%CI: -0.3, 0%; n = 4). A non-statistically significant tendency towards improvements in the Homeostatic Model Assessment for Insulin Resistance (MD: -0.74, 95%CI: -1.72, 0.25; n = 3), low-density lipoprotein cholesterol (-6.87; 95%CI: -15.03, 1.29 mg/dL; n = 3), high-density lipoprotein cholesterol (MD: 1.34; 95%CI: -0.78, 3.46 mg/dL; n = 3), triglyceride (MD: -3.90; 95%CI: -11.05, 3.24 mg/dL; n = 3), and total cholesterol (MD: -4.88; 95%CI: -11.84, 2.07 mg/dL; n = 3) was observed with the supplementation. In summary, while the evidence from the currently available RCTs provides a crude indication that L. plantarum supplementation might improve glucose and lipid metabolism in patients with T2DM and prediabetes, the benefits of the supplementation are likely subtle, and its clinical significance requires further investigation.

Protective effects and mechanism of chemical- and plant-based selenocystine against cadmium-induced liver damage.

Although selenium (Se) and cadmium (Cd) often coexist naturally in the soil of China, the health risks to local residents consuming Se-Cd co-enriched foods are unknown. In the present study, we investigated the effects of chemical-based selenocystine (SeCys2) on cadmium chloride-induced human hepatocarcinoma (HepG2) cell injury and plant (Cardamine hupingshanensis)-derived SeCys2 against Cd-induced liver injury in mice. We found that chemical- and plant-based SeCys2 showed protective effects against Cd-induced HepG2 cell injury and liver damage in mice, respectively. Compared with Cd intervention group, co-treatment with chemical- or plant-based SeCys2 both alleviated liver toxicity and ferroptosis by decreasing ferrous iron, acyl-CoA synthetase long-chain (ACSL) family member 4, lysophosphatidylcholine acyltransferase 3, reactive oxygen species and lipid peroxide levels, and increasing ACSL3, peroxisome proliferator-activated receptor α, solute carrier family 7 member 11 (SLC7A11) and glutathione and glutathione peroxidase 4 (GPX4) levels. In conclusion, chemical- and plant-based SeCys2 alleviated Cd-induced hepatotoxicity and ferroptosis by regulating SLC7A11/GPX4 signaling and lipid peroxidation. Our findings indicate that potential Cd toxicity from consuming foods grown in Se- and Cd-rich soils should be re-evaluated. This study offers a new perspective for the development of SeCys2-enriched agricultural products.

An Antisweat Interference and Highly Sensitive Temperature Sensor Based on Poly(3,4-ethylenedioxythiophene)-Poly(styrenesulfonate) Fiber Coated with Polyurethane/Graphene for Real-Time Monitoring of Body Temperature.

Body temperature is an important indicator of human health. The traditional mercury and medical electronic thermometers have a slow response (≥1 min) and can not be worn for long to achieve continuous temperature monitoring due to their rigidity. In this work, we prepared a skin-core structure polyurethane (PU)/graphene encapsulated poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT:PSS) temperature-sensitive fiber in one step by combining wet spinning technology with impregnation technology. The composite fiber has high sensitivity (-1.72%/°C), super-resolution (0.1 °C), fast time response (17 s), antisweat interference, and high linearity (R2 = 0.98) in the temperature sensing range of 30-50 °C. The fiber is strong enough to be braided into the temperature-sensitive fabric with commercial cotton yarns. The fabric with good comfort and durability can be arranged in the armpit position of the cloth to realize real-time body temperature monitoring without interruption during daily activities. Through Bluetooth wireless transmission, body temperature can be monitored in real-time and displayed on mobile phones to the parents or guardians. Overall, the fiber-based temperature sensor will significantly improve the practical applications of wearable temperature sensors in intelligent medical treatment due to its sensing stability, comfort, and durability.

Protective effect and mechanism of lactoferrin combined with hypoxia against high-fat diet induced obesity and non-alcoholic fatty liver disease in mice.

Obesity is a global epidemic, it can induce glucose and lipid metabolism disorder and non-alcoholic fatty liver disease (NAFLD). This study explored a new way to control weight and improve fatty liver, namely, living in hypoxia environment and supplement with lactoferrin (Lf). Sixty male C57BL/6J mice were divided into six groups, namely, control, hypoxia, high-fat diet, hypoxia + high-fat diet, hypoxia + high-fat diet + low dose Lf intervention, and hypoxia + high-fat diet + high-dose Lf intervention. Mice in the hypoxia treatment groups were treated with approximately 11.5 % oxygen for 6 h every day for 8 weeks. Results showed that interventions combining Lf and hypoxia treatments showed better effect against obesity and NAFLD than hypoxia treatment alone. The interventions controlled weight gain in mice, improved glucolipid metabolism in mice. The combination intervention reduced cholesterol absorption by reducing the level of hydrophobic bile acids, and elevating the level of hydrophilic bile acids. Gut microbiota analysis revealed that the combination intervention considerably elevated short chain fatty acids (SCFAs)-producing bacteria level, and reduced the Desulfovibrionaceae_unclassified level. Thus, Lf combined with hypoxia intervention effectively prevents obesity and NAFLD by restoring gut microbiota composition and bile acid profile.

Correction to: Amelioration of radiation­induced liver damage by p-coumaric acid in mice.

[This corrects the article DOI: 10.1007/s10068-022-01118-8.].

Photothermal-enabled single-atom catalysts for high-efficiency hydrogen peroxide photosynthesis from natural seawater.

Hydrogen peroxide (H2O2) is a powerful industrial oxidant and potential carbon-neutral liquid energy carrier. Sunlight-driven synthesis of H2O2 from the most earth-abundant O2 and seawater is highly desirable. However, the solar-to-chemical efficiency of H2O2 synthesis in particulate photocatalysis systems is low. Here, we present a cooperative sunlight-driven photothermal-photocatalytic system based on cobalt single-atom supported on sulfur doped graphitic carbon nitride/reduced graphene oxide heterostructure (Co-CN@G) to boost H2O2 photosynthesis from natural seawater. By virtue of the photothermal effect and synergy between Co single atoms and the heterostructure, Co-CN@G enables a solar-to-chemical efficiency of more than 0.7% under simulated sunlight irradiation. Theoretical calculations verify that the single atoms combined with heterostructure significantly promote the charge separation, facilitate O2 absorption and reduce the energy barriers for O2 reduction and water oxidation, eventually boosting H2O2 photoproduction. The single-atom photothermal-photocatalytic materials may provide possibility of large-scale H2O2 production from inexhaustible seawater in a sustainable way.

Inhibition of inflammatory factor TNF-α by ferrostatin-1 in microglia regulates necroptosis of oligodendrocyte precursor cells.

OBJECTIVE: Inflammation of the surrounding environment is a major reason causing loss or injury of oligodendrocyte precursor cells (OPCs) in myelin-associated diseases. Lipopolysaccharide-activated microglia can release various inflammatory factors such as tumor necrosis factor-α (TNF-α). One of the ways of OPC death is necroptosis, which can be triggered by TNF-α, a death receptor ligand, by activating receptor-interacting protein kinase 1 (RIPK1)/RIPK3/mixed lineage kinase domain-like protein (MLKL) signaling pathway. This study investigated whether inhibiting microglia ferroptosis can decrease TNF-α release to alleviate OPC necroptosis. METHODS: Lipopolysaccharide and Fer-1 stimulate BV2 cells. The expressions of GPX4 and TNF-α were detected by western blot and quantitative real-time PCR; malondialdehyde, glutathione, iron, and reactive oxygen species were measured by the assay kits. After lipopolysaccharide stimulation of BV2 cells, the supernatant was taken to culture OPC. The protein expression levels of RIPK1, p-RIPK1, RIPK3, p-RIPK3, MLKL, and p-MLKL were detected by western blot. RESULTS: Lipopolysaccharide administration could induce ferroptosis in microglia by decreasing ferroptosis marker GPX4, while ferroptosis inhibitor Fer-1 could significantly increase GPX4 level. Fer-1 prevented oxidative stress and iron concentration elevation and alleviated mitochondrial damage in lipopolysaccharide-induced BV2 cells. The results revealed that Fer-1 downregulated the release of lipopolysaccharide-induced TNF-α in microglia and attenuated OPC necroptosis by significantly decreasing the expression levels of RIPK1, p-RIPK1, MLKL, p-MLKL, RIPK3, and p-RIPK3. CONCLUSION: Fer-1 may be a potential agent for inhibiting inflammation and treating myelin-related diseases.

Lrp6-mediated canonical Wnt signaling is required for lip formation and fusion.

Neither the mechanisms that govern lip morphogenesis nor the cause of cleft lip are well understood. We report that genetic inactivation of Lrp6, a co-receptor of the Wnt/beta-catenin signaling pathway, leads to cleft lip with cleft palate. The activity of a Wnt signaling reporter is blocked in the orofacial primordia by Lrp6 deletion in mice. The morphological dynamic that is required for normal lip formation and fusion is disrupted in these mutants. The expression of the homeobox genes Msx1 and Msx2 is dramatically reduced in the mutants, which prevents the outgrowth of orofacial primordia, especially in the fusion site. We further demonstrate that Msx1 and Msx2 (but not their potential regulator Bmp4) are the downstream targets of the Wnt/beta-catenin signaling pathway during lip formation and fusion. By contrast, a ;fusion-resistant' gene, Raldh3 (also known as Aldh1a3), that encodes a retinoic acid-synthesizing enzyme is ectopically expressed in the upper lip primordia of Lrp6-deficient embryos, indicating a region-specific role of the Wnt/beta-catenin signaling pathway in repressing retinoic acid signaling. Thus, the Lrp6-mediated Wnt signaling pathway is required for lip development by orchestrating two distinctively different morphogenetic movements.

[Protective effects and mechanisms of OSR on primary cultured hippocampus neurons subjected to anoxic injury in neonatal rat].

OBJECTIVE: To investigate the protective effects of oxysophoridine (OSR) on primary cultured hippocampus neurons subjected to anoxia injury in neonatal rats and its mechanism. METHOD: The model of anoxia injury of hippocampus neurons in neonatal rats were primarily cultured in vitro by physical oxygen deficiency using glucose-free culture fluid. The survival rate of neurons, the leaking rate of lactate dehydrogenase (LDH), the intracellular contents of malondialdehyde (MDA) and nitric oxide (NO), the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-PX) and nitric oxide synthase (NOS) were measured. The intracellular free calcium concentration ([Ca2+]i) in hippocampus neurons were detected with Ca(2+)-sensitive dual wavelength fluorescence spectrophotometer. RESULT: Neuron death occurred in the anoxia injury model group with increase of LDH leaking rate, the contents of NO, MDA, intracellular [Ca2+] and the elevated activity of NOS while decreased activities of SOD and GSH-PX. The hippocampus neurons subjected to anoxia injury were alleviated in OSR (0.625, 5, 10 microg x L(-1)) group. CONCLUSION: OSR has significant protective effects on hippocampus neurons subjected to anoxic injury. The mechanism of its protective effect may relate to its reduction of calcium overload and against oxidation injury.