Protective effects of pre-germinated brown rice diet on low levels of Pb-induced learning and memory deficits in developing rat

Lead (Pb) is a known neurotoxicant in humans and experimental animals. Numerous studies have provided evidence that humans, especially young children, and animals chronically intoxicated with low levels of Pb show learning and memory impairments. Unfortunately, Pb-poisoning cases continue to occur in many countries. Because the current treatment options are very limited, there is a need for alternative methods to attenuate Pb toxicity. In this study, the weaning (postnatal day 21, PND21) rats were randomly divided into five groups: the control group (AIN-93G diet, de-ionized water), the lead acetate (PbAC) group (AIN-93G diet, 2 g/L PbAC in de-ionized water), the lead acetate + WR group (white rice diet, 2 g/L PbAC in de-ionized water; PbAC + WR), the lead acetate + BR group (brown rice diet, 2 g/L PbAC in de-ionized water; PbAC + BR) and the lead acetate + PR group (pre-germinated brown rice diet, 2 g/L PbAC in de-ionized water; PbAC + PR). The animals received the different diets until PND60, and then the experiments were terminated. The protective effects of pre-germinated brown rice (PR) on Pb-induced learning and memory impairment in weaning rats were assessed by the Morris water maze and one-trial-learning passive avoidance test. The anti-oxidative effects of feeding a PR diet to Pb-exposed rats were evaluated. The levels of reactive oxygen species (ROS) were determined by flow cytometry. The levels of 8-hydroxy-2-deoxyguanosine (8-OHdG), γ-aminobutyric acid (GABA) and glutamate were determined by HPLC. Our data showed that feeding a PR diet decreased the accumulation of lead and decreased Pb-induced learning and memory deficits in developing rats. The mechanisms might be related to the anti-oxidative effects and large amount of GABA in PR. Our study provides a regimen to reduce Pb-induced toxicity, especially future learning and memory deficits in the developing brain.     

Cyclophilin A binds to AKT1 and facilitates the tumorigenicity of Epstein-Barr virus by mediating the activation of AKT/mTOR/NF-κB positive feedback loop

The AKT/mTOR and NF-κB signalings are crucial pathways activated in cancers including nasopharyngeal carcinoma (NPC), which is prevalent in southern China and closely related to Epstein-Barr virus (EBV) infection. How these master pathways are persistently activated in EBV-associated NPC remains to be investigated. Here we demonstrated that EBV-encoded latent membrane protein 1 (LMP1) promoted cyclophilin A (CYPA) expression through the activation of NF-κB. The depletion of CYPA suppressed cell proliferation and facilitated apoptosis. CYPA was able to bind to AKT1, thus activating AKT/mTOR/NF-κB signaling cascade. Moreover, the use of mTOR inhibitor, rapamycin, subverted the activation of the positive feedback loop, NF-κB/CYPA/AKT/mTOR. It is reasonable that LMP1 expression derived from initial viral infection is enough to assure the constant potentiation of AKT/mTOR and NF-κB signalings. This may partly explain the fact that EBV serves as a tumor-promoting factor with minimal expression of the viral oncoprotein LMP1 in malignancies. Our findings provide new insight into the understanding of causative role of EBV in tumorigenicity during latent infection.     

Different Regional Gray Matter Loss in Recent Onset PTSD and Non PTSD after a Single Prolonged Trauma Exposure

Objective

Gray matter loss in the limbic structures was found in recent onset post traumatic stress disorder (PTSD) patients. In the present study, we measured regional gray matter volume in trauma survivors to verify the hypothesis that stress may cause different regional gray matter loss in trauma survivors with and without recent onset PTSD.

Method

High resolution T1-weighted magnetic resonance imaging (MRI) were obtained from coal mine flood disaster survivors with (n = 10) and without (n = 10) recent onset PTSD and 20 no trauma exposed normal controls. The voxel-based morphometry (VBM) method was used to measure the regional gray matter volume in three groups, the correlations of PTSD symptom severities with the gray matter volume in trauma survivors were also analyzed by multiple regression.

Results

Compared with normal controls, recent onset PTSD patients had smaller gray matter volume in left dorsal anterior cingulate cortex (ACC), and non PTSD subjects had smaller gray matter volume in the right pulvinar and left pallidum. The gray matter volume of the trauma survivors correlated negatively with CAPS scores in the right frontal lobe, left anterior and middle cingulate cortex, bilateral cuneus cortex, right middle occipital lobe, while in the recent onset PTSD, the gray matter volume correlated negatively with CAPS scores in bilateral superior medial frontal lobe and right ACC.

Conclusion

The present study identified gray matter loss in different regions in recent onset PTSD and non PTSD after a single prolonged trauma exposure. The gray matter volume of left dorsal ACC associated with the development of PTSD, while the gray matter volume of right pulvinar and left pallidum associated with the response to the severe stress. The atrophy of the frontal and limbic cortices predicts the symptom severities of the PTSD.     

Unexpected Neuronal Protection of SU5416 against 1-Methyl-4-Phenylpyridinium Ion-Induced Toxicity via Inhibiting Neuronal Nitric Oxide Synthase

SU5416 was originally designed as a potent and selective inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) for cancer therapy. In this study, we have found for the first time that SU5416 unexpectedly prevented 1-methyl-4-phenylpyridinium ion (MPP⁺)-induced neuronal apoptosis in cerebellar granule neurons, and decreased 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced loss of dopaminergic neurons and impairment of swimming behavior in zebrafish in a concentration-dependent manner. However, VEGFR-2 kinase inhibitor II, another specific VEGFR-2 inhibitor, failed to reverse neurotoxicity at the concentration exhibiting anti-angiogenic activity, strongly suggesting that the neuroprotective effect of SU5416 is independent from its anti-angiogenic action. SU5416 potently reversed MPP⁺-increased intracellular nitric oxide level with an efficacy similar to 7-nitroindazole, a specific neuronal nitric oxide synthase (nNOS) inhibitor. Western blotting analysis showed that SU5416 reduced the elevation of nNOS protein expression induced by MPP⁺. Furthermore, SU5416 directly inhibited the enzyme activity of rat cerebellum nNOS with an IC₅₀ value of 22.7 µM. In addition, knock-down of nNOS expression using short hairpin RNA (shRNA) abolished the neuroprotective effects of SU5416 against MPP⁺-induced neuronal loss. Our results strongly demonstrate that SU5416 might exert its unexpected neuroprotective effects by concurrently reducing nNOS protein expression and directly inhibiting nNOS enzyme activity. In view of the capability of SU5416 to cross the blood-brain barrier and the safety for human use, our findings further indicate that SU5416 might be a novel drug candidate for neurodegenerative disorders, particularly those associated with NO-mediated neurotoxicity.     

The miR156‐SPL9‐DFR pathway coordinates the relationship between development and abiotic stress tolerance in plants

Young organisms have relatively strong resistance to diseases and adverse conditions. When confronted with adversity, the process of development is delayed in plants. This phenomenon is thought to result from the rebalancing of energy, which helps plants to coordinate the relationship between development and stress tolerance; however, the molecular mechanism underlying this phenomenon remains mysterious. In this study, we found that miR156 integrates environmental signals to ensure timely flowering, thus enabling the completion of breeding. Under stress conditions, miR156 is induced to maintain the plant in the juvenile state for a relatively long period of time, whereas under favorable conditions, miR156 is suppressed to accelerate the developmental transition. Blocking the miR156 signaling pathway in Arabidopsis thaliana with 35S::MIM156 (via target mimicry) increased the sensitivity of the plant to stress treatment, whereas overexpression of miR156 increased stress tolerance. In fact, this mechanism is also conserved in Oryza sativa (rice). We also identified downstream genes of miR156, i.e. SQUAMOSA PROMOTER BINDING PROTEIN‐LIKE 9 (SPL9) and DIHYDROFLAVONOL‐4‐REDUCTASE (DFR), which take part in this process by influencing the metabolism of anthocyanin. Our results uncover a molecular mechanism for plant adaptation to the environment through the miR156‐SPLs‐DFR pathway, which coordinates development and abiotic stress tolerance.     

Phenolic compounds and their anti-oxidative properties and protein kinase inhibition from the Chinese mangrove plant Laguncularia racemosa

Phenolic compounds, named integracin D (1), (7′R, 8′S, 8S)-8-hydroxyisoguaiacin (3), (2R, 3R) pinobanksin-3-caffeoylate (5) and threo-8S-7-methoxysyringylglycerol (6), respectively, were isolated from the Chinese mangrove plant Laguncularia racemosa (L) Gaertn. f. (Combretaceae), together with 23 known phenolic metabolites. Their structures were elucidated on the basis of extensive spectroscopic analyses including that of IR, UV, MS, CD, 1D and 2D NMR spectra as well as by comparison with literature data. Compound 5 showed significant anti-oxidative activity in the DPPH and TEAC free-radical-scavenging assays, while several of the phenolic compounds were tested for protein kinase inhibitory activity in an assay involving 24 different human tumor related protein kinases. Compounds 5, 7, and 23 showed potential inhibition with IC₅₀ values between 2.2 and 3.6 μg/mL toward individual kinases. The ellagic acid derivatives were tested for insecticidal activity.     

益坤宁对围绝经期大鼠卵巢细胞凋亡率及caspase-3表达的影响

目的:研究中药益坤宁(yikunning,YKN)对围绝经期大鼠卵巢细胞凋亡率及凋亡相关基因caspase-3基因表达的影响,探讨益坤宁治疗围绝经期综合征的作用机理。方法:选用30只自然衰老的围绝经期雌性大鼠,随机分为中药益坤宁实验组、围绝经期对照组和利维爱(livial)对照组,另选10只青年雌性大鼠作为青年对照组。连续灌胃处理4周后,采用原位脱氧核糖核苷酸末端转移酶介导的缺口末端标记(TUNEL)法检测大鼠卵巢细胞凋亡率,采用逆转录-聚合酶链反应(RT-PCR)和蛋白印迹(Western blot)检测大鼠卵巢中caspase-3 mRNA和蛋白表达。结果:益坤宁组大鼠卵巢细胞凋亡率显著低于围绝经期对照组(P0.01);益坤宁组大鼠卵巢中caspase-3 mRNA和蛋白表达低于围绝经期对照组,高于青年对照组,差异有统计学意义(P0.01)。结论:中药益坤宁通过降低围绝经期大鼠卵巢细胞凋亡率,下调卵巢中凋亡相关基因caspase-3的表达,从而延缓卵巢衰老,这可能是其治疗围绝经期综合征的分子机制之一。     

Mash2基因在体细胞克隆牛肺脏中DNA甲基化状态分析

体细胞核移植(体细胞克隆)技术在动物生产、医药工业、治疗性克隆以及对珍稀濒危动物的拯救有重要意义,然而克隆效率低下以及克隆动物发育异常,严重制约了克隆技术的发展和应用．在体细胞核克隆中,供体核来自高度分化了的体细胞,发生在核移植后几小时内供体核的重编程,决定了克隆胚胎的发育能力．印记基因是由等位基因表观遗传修饰的不对称导致的基因表达具有亲本选择性,而DNA甲基化是调控印记的一个主要方式．印记基因Mash2在胚胎发育和器官形成过程中起着非常重要的作用．为了探求核移植过程中Mash2基因DNA 甲基化的表观重编程是否充分,利用亚硫酸氢盐测序法对出生48 h内死亡的体细胞核移植牛和正常对照牛肺脏中Mash2基因的DNA甲基化状态进行分析．结果显示,尽管位于Mash2基因启动子和第一个外显子处的CpG岛在正常牛和克隆牛中甲基化水平都不高(20.04%,5.55%),但克隆组的甲基化水平仍显著低于正常对照组 (P < 0.05)．甲基化模式正常组中9N3有5种不同的形式,9N4仅1种;而克隆组9C3和9C5也分别是1种．推测Mash2基因的异常DNA甲基化很可能是导致克隆牛肺脏发育异常的一个重要原因．     

Endoscopic Biopsy in Gastrointestinal Neuroendocrine Neoplasms: A Retrospective Study

Background

Gastrointestinal neuroendocrine neoplasms (GI-NENs) are often located in the deep mucosa or submucosa, and the efficacy of endoscopic biopsy for diagnosis and treatment of GI-NENs is not fully understood.

Objective

The current study analyzed GI-NENs, especially those diagnosed pathologically and resected endoscopically, and focused on the biopsy and cold biopsy forceps polypectomy (CBP) to analyze their roles in diagnosing and treating GI-NENs.

Methods

Clinical data of all GI-NENs were reviewed from January 2006 to March 2012. Histopathology was used to diagnose GI-NENs, which were confirmed by immunohistochemistry.

Results

67.96% GI-NENs were diagnosed pathologically by endoscopy. Only 26.21% were diagnosed pathologically by biopsies before treatment. The diagnostic rate was significantly higher in polypoid (76.47%) and submucosal lesions (68.75%), than in ulcerative lesions (12.00%). However, biopsies were only taken in 56.31% patients, including 51.52% of polypoid lesions, 35.56% of submucosal lesions and 100.00% of ulcerative lesions. Endoscopic resection removed 61.76% of GI-NENs, including six by CBP, 14 by snare polypectomy with electrocauterization, 28 by endoscopic mucosal resection (EMR) and 15 by endoscopic submucosal dissection (ESD). 51.52% polypoid GI-NENs had infiltrated the submucosa under microscopic examination. CBP had a significantly higher rate of remnant (33.33%) than snare polypectomy with electrocauterization, EMR and ESD (all 0.00%).

Conclusions

Biopsies for all polypoid and submucosal lesions will improve pre-operative diagnosis. The high rate of submucosal infiltration of polypoid GI-NENs determined that CBP was inadequate in the treatment of GI-NENs. Diminutive polypoid GI-NENs that disappeared after CBP had a high risk of remnant and should be closely followed up over the long term.