(D-Ser2) oxyntomodulin recovers hippocampal synaptic structure and theta rhythm in Alzheimer's disease transgenic mice.

In our previous studies, we have shown that (D-Ser2) oxyntomodulin (Oxm), a glucagon-like peptide 1 (GLP-1) receptor (GLP1R)/glucagon receptor (GCGR) dual agonist peptide, protects hippocampal neurons against Aß1-42-induced cytotoxicity, and stabilizes the calcium homeostasis and mitochondrial membrane potential of hippocampal neurons. Additionally, we have demonstrated that (D-Ser2) Oxm improves cognitive decline and reduces the deposition of amyloid-beta in Alzheimer's disease model mice. However, the protective mechanism remains unclear. In this study, we showed that 2 weeks of intraperitoneal administration of (D-Ser2) Oxm ameliorated the working memory and fear memory impairments of 9-month-old 3×Tg Alzheimer's disease model mice. In addition, electrophysiological data recorded by a wireless multichannel neural recording system implanted in the hippocampal CA1 region showed that (D-Ser2) Oxm increased the power of the theta rhythm. In addition, (D-Ser2) Oxm treatment greatly increased the expression level of synaptic-associated proteins SYP and PSD-95 and increased the number of dendritic spines in 3×Tg Alzheimer's disease model mice. These findings suggest that (D-Ser2) Oxm improves the cognitive function of Alzheimer's disease transgenic mice by recovering hippocampal synaptic function and theta rhythm.

Differentiation of lipid-poor adenoma from pheochromocytoma on biphasic contrast-enhanced CT.

PURPOSE: To evaluate the diagnostic performance of biphasic contrast-enhanced CT in differentiation of lipid-poor adenomas from pheochromocytomas. METHODS: 129 patients with 132 lipid-poor adenomas and 93 patients with 97 pheochromocytomas confirmed by pathology were included in this retrospective study. Patients underwent unenhanced abdominal CT scan followed by arterial and venous phase. Quantitative and qualitative imaging features were compared between the two groups using univariate analysis. Risk factors for pheochromocytomas were evaluated by multivariate logistic regression analysis and a diagnostic scoring model was established based on odd ratio (OR) of the risk factors. RESULTS: Pheochromocytomas were larger and showed cystic degeneration more frequently compared with lipid-poor adenomas (p < 0.01). No significant difference was found in peak enhancement phase between the two groups (p = 0.348). Attenuation values on unenhanced phase (CTU), arterial phase (CTA), and venous phase (CTV) of pheochromocytomas were significantly higher than that of lipid-poor adenomas while enhancement ratio on arterial and venous phase (ERA, ERV) of pheochromocytomas was significantly lower than that of lipid-poor adenomas (all p < 0.05). Multivariate analysis revealed lesion size > 29 mm (OR: 5.74; 95% CI 2.51-13.16; p < 0.001), CTA > 81 HU (OR: 2.54; 95% CI 1.04-6.17; p = 0.04), CTV > 97 HU (OR: 11.19; 95% CI 3.21-38.97; p < 0.001), ERV ≤ 1.5 (OR: 20.23; 95% CI 6.30-64.87; p < 0.001), and the presence of cystic degeneration (OR: 6.22, 95% CI 1.74-22.25; p = 0.005) were risk factors for pheochromocytomas. The diagnostic scoring model yielded an area under the curve (AUC) of 0.911. CONCLUSIONS: Biphasic contrast-enhanced CT showed good diagnostic performance in differentiation of lipid-poor adenomas from pheochromocytomas.

Multifocal neuroendocrine cell hyperplasia accompanied by tumorlet formation and pulmonary sclerosing pneumocytoma: A case report.

BACKGROUND: Pulmonary tumorlets are nodular hyperplastic neuroendocrine cells (NECs) that extend beyond the basement membrane. They often coexist with other lung diseases such as fibrosis and bronchiectasis, but rarely accompanied by pulmonary sclerosing pneumocytoma (PSP), which has not been reported in the literature. CASE SUMMARY: A 54-year-old woman was admitted to the hospital because she had symptoms of bloody sputum for more than 4 mo and hemoptysis for 1 wk. Computed tomography images showed atrophy accompanied by infections in the middle lobe of her right lung. Moreover, numerous nodules were identified in the middle lobe of the right lung. The patient underwent thoracoscopic pneumonectomy of the middle lobe of the right lung, and the resected mass was pathologically confirmed to have bronchiectasis, multifocal NEC hyperplasia accompanied by tumorlet, and PSP. CONCLUSION: Our report presents a rare clinical case of bronchiectasis complicated with multifocal NEC hyperplasia, tumorlet, and PSP.

A dual GLP-1 and Gcg receptor agonist rescues spatial memory and synaptic plasticity in APP/PS1 transgenic mice.

Alzheimer's disease (AD) is a neurodegenerative disease that severely affects the health and lifespan of the elderly worldwide. Recently, the correlation between AD and type 2 diabetes mellitus (T2DM) has received intensive attention, and a promising new anti-AD strategy is the use of anti-diabetic drugs. Oxyntomodulin (Oxm) is a peptide hormone and growth factor that acts on neurons in the hypothalamus. OXM activates glucagon-like peptide 1 (GLP-1) and glucagon (Gcg) receptors, facilitates insulin signaling and has neuroprotective effects against Aß1-42-induced cytotoxicity in primary hippocampal neurons. Here, we tested the effects of the protease-resistant analogue (D-Ser2)Oxm on spatial memory and synaptic plasticity and the underlying molecular mechanisms in the APP/PS1 transgenic mouse model of AD. The results showed that (D-Ser2)Oxm not only alleviated the impairments of working memory and long-term spatial memory, but also reduced the number of Aß plaques in the hippocampus, and reversed the suppression of hippocampal synaptic long-term potentiation (LTP). Moreover, (D-Ser2)Oxm administration significantly increased p-PI3K/p-AKT1 expression and decreased p-GSK3ß levels in the hippocampus. These results are the first to show an in vivo neuroprotective role of (D-Ser2)Oxm in APP/PS1 mice, and this role involves the improvement of synaptic plasticity, clearance of Aß and normalization of PI3K/AKT/GSK3ß cell signaling in the hippocampus. This study suggests that (D-Ser2)Oxm holds promise for the prevention and treatment of AD.

Triptolide reduces ischemia/reperfusion injury in rats and H9C2 cells via inhibition of NF­κB, ROS and the ERK1/2 pathway.

Myocardial ischemia/reperfusion (I/R) induces cardiac cell injury; however, the mechanism underlying cardiac damage remains unclear. A previous study demonstrated that triptolide (TP) exerts protective effects against I/R in cerebral cells. The present study aimed to evaluate the protective effects of TP on cardiac cells, and investigated the potential mechanisms involved in I/R­induced damage. Rats and cardiac H9C2 cells undergoing I/R were pretreated with TP, and cell damage was assessed in vivo and in vitro. Hematoxylin and eosin and terminal deoxynucleotidyl­transferase­mediated dUTP nick end labeling staining were employed to evaluate I/R injury in rat cardiac tissue. Inflammatory factors, including tumor necrosis factor­α, interleukin (IL)­1ß and IL­6, were detected by ELISA. Biochemical analyses were performed to evaluate the bioactivity of superoxide dismutase, malondialdehyde and catalase. In addition, viability of H9C2 cells was measured using the Cell Counting kit 8 assay. Flow cytometry was used to evaluate cell apoptosis and reactive oxygen species (ROS) generation. Furthermore, the expression levels of proteins associated with apoptosis, peroxide and inflammation were measured using western blot analysis. H9C2 cells were also treated with N­acetylcysteine and pyrrolidine dithiocarbamate, and cell injury was assessed after peroxidation or I/R. The results demonstrated that TP exerted a significant protective effect on cardiac cells in vivo and in vitro. TP reduced the inflammatory response, as determined by nuclear factor­κB inhibition. In addition, TP decreased ROS­mediated lipid peroxidation, and reduced ROS generation. TP also inhibited cell apoptosis by activating the extracellular signal­regulated kinase 1/2 pathway. In conclusion, TP may protect cardiac cells from I/R injury; the potential protective mechanisms of TP against I/R include anti­inflammatory action, antioxidation and apoptotic resistance.

Epigallocatechin-3-gallate protects HUVECs from PM2.5-induced oxidative stress injury by activating critical antioxidant pathways.

Endothelial dysfunction and oxidative stress likely play roles in PM2.5-induced harmful effects. Epigallocatechin-3-gallate (EGCG), the major polyphenolic constituent of green tea, is a potent antioxidant that exerts protective effects on cardiovascular diseases (CVDs) in part by scavenging free radicals. The exposure to ambient fine particulate matter (PM2.5) is responsible for certain CVDs. The aim of the present study was to investigate whether EGCG could also inhibit PM2.5-induced oxidative stress by activating the nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway in human umbilical vein endothelial cells (HUVECs). PM2.5 (200 µg/mL) increased both cell death and intracellular ROS levels significantly, whereas EGCG (50-400 µM) inhibited these effects in a concentration-dependent manner. Western blotting and PCR demonstrated that EGCG increased Nrf2 and HO-1 expression in HUVECs that had been exposed to PM2.5. PD98059 (a selective inhibitor of extracellular signal regulated kinase [ERK]-1/2) and SB203580 (a selective inhibitor of p38 MAPK), but not SP600125 (a selective inhibitor of c-jun N-terminal kinase [JNK]), attenuated the EGCG-induced Nrf2 and HO-1 expression. In addition, silencing Nrf2 abolished EGCG-induced Nrf2 and HO-1 upregulation and enhancement of cell viability. The present study suggests that EGCG protects HUVECs from PM2.5-induced oxidative stress injury by upregulating Nrf2/HO-1 via activation of the p38 MAPK and the ERK1/2 signaling pathways.

The neuroprotection of Rattin against amyloid ß peptide in spatial memory and synaptic plasticity of rats.

Rattin, a specific derivative of humanin in rats, shares the ability with HN to protect neurons against amyloid ß (Aß) peptide-induced cellular toxicity. However, it is still unclear whether Rattin can protect against Aß-induced deficits in cognition and synaptic plasticity in rats. In the present study, we observed the effects of Rattin and Aß31-35 on the spatial reference memory and in vivo hippocampal Long-term potentiation of rats by using Morris water maze test and hippocampal field potential recording. Furthermore, the probable molecular mechanism underlying the neuroprotective roles of Rattin was investigated. We showed that intra-hippocampal injection of Rattin effectively prevented the Aß31-35-induced spatial memory deficits and hippocampal LTP suppression in rats; the Aß31-35-induced activation of Caspase-3 and inhibition of STAT3 in the hippocampus were also prevented by Rattin treatment. These findings indicate that Rattin treatment can protect spatial memory and synaptic plasticity of rats against Aß31-35-induced impairments, and the underlying protective mechanism of Rattin may be involved in STAT3 and Caspases-3 pathways. Therefore, application of Rattin or activation of its signaling pathways in the brain might be beneficial to the prevention of Aß-related cognitive deficits.

Arginine residues in the C-terminal and their relationship with the analgesic activity of the toxin from the Chinese scorpion Buthus martensii Karsch (BmK AGP-SYPU1).

In this study, we investigated the functional role of arginines in the C-terminal (65-67) of BmK AGP-SYPU1, an analgesic peptide from the Chinese scorpion Buthus martensii Karsch. Using site-directed mutagenesis, arginines at the C-terminal (65-66) were deleted or added to the C-terminal (67). The genes for three mutants of BmK AGP-SYPU1 were obtained by PCR. An analgesic activity assay was used to evaluate the role of arginine residues in the analgesic activity. The three-dimensional structure of BmK AGP-SYPU1 was established by homology modeling. As a result, we showed that the arginines in the C-terminal are crucial for the analgesic activity and may be located at analgesic functional sites. Our work has implications for further modification of scorpion toxins to obtain new analgesic peptides with enhanced activity.

[Regulatory effect of Bushenfang on the serum testosterone level of naturally aging rats and its mechanism].

OBJECTIVE: To study the regulatory effect of Bushenfang on the serum testosterone (T) level of naturally aging rats and its mechanism, in order to provide a theoretical and experimental basis for the clinical treatment of late onset hypogonadism (LOH) in males. METHODS: Thirty-two 18-month-old male SD rats were randomly divided into four groups of equal number, naturally aging model and low-, medium- and high-dose Bushenfang groups, and another eight 4-month-old rats were taken as normal controls. The rats of the aging model and normal control groups were treated with normal saline, while those of the low-, medium- and high-dose Bushenfang groups received intragastrically Bushenfang at 3.25, 7.50 and 15.00 g/kg, respectively, all for 3 weeks. Then the rats were sacrificed, the histomorphologic changes of the testis observed by HE staining, the serum T level measured by radioimmunoassay, and the expressions of the StAR protein, P450scc and 3beta-HSD I determined by RT-PCR. RESULTS: The number of Leydig cells was obviously increased after Bushenfang treatment. The levels of serum T were significantly higher in the low-, medium- and high-dose Bushenfang groups ([6.74 +/- 1.56] nmol/L, [8.50 +/- 1.99] nmol/L and [12.41 +/- 2.91] nmol/L) than in the model group ([3.48 +/- 0.75] nmol/L) (P < 0.05). The three Bushenfang groups also showed a remarkable elevation in the mRNA expressions of StAR (0.74 +/- 0.29, 0.83 +/- 0.32 and 1.35 +/- 0.50), P450scc (0.72 +/- 0.36, 1.023 +/- 0.30 and 1.41 +/- 0.37) and 3beta-HSD I (0.58 +/- 0.14, 0.72 +/- 0.07 and 0.85 +/- 0.18), as compared with the models (StAR: 0.44 +/- 0.09; P450scc: 0.33 +/- 0.05; 3beta-HSD I: 0.34 +/- 0.02), with significant differences in the StAR expression between the high-dose Bushenfang and the model groups, as well as in P450scc and 3beta-HSD I expressions between the medium- and high-dose Bushenfang and the model groups (P < 0.05). CONCLUSION: Bushenfang could improve the pathological status of testicular injury and increase the expression of testosterone synthetase, which might be the mechanism behind its regulatory effect on the serum T level of aging rats.

[The proarrhythmic effects of autoantibody against beta1 adrenergic receptor].

OBJECTIVE: To investigate the distribution characteristics of autoantibody against beta1 adrenergic receptor (beta1 AR) in the sera of arrhythmia patients and whether the autoantibody could induce arrhythmia. METHODS: Healthy subjects and patients with arrhythmia or coronary artery disease were chosen. The autoantibody against beta1 AR in the sera was screened by enzyme-linked immunosorbent assay (ELISA). IgG in the positive autoantibody sera from arrhythmia patients were purified and administrated to normal rats; then the ECGs were dynamic monitored. RESULTS: The positive rate of autoantibody against beta1 AR in arrhythmia patients was 52.8%, which was significantly higher than that in coronary heart disease group (24%, P < 0.01) and healthy people group (5%, P < 0.01), respectively. Moreover, the autoantibody against beta1 AR could lead to the occurring of arrhythmia in normal rats, most of which were ventricular arrhythmia. CONCLUSION: In the sera of arrhythmia patients, the autoantibody against beta1 AR has a high titer and it could lead to the arrhythmia of rats in vivo.

[Establishment and application of double-antibody sandwich ELISA for determination of 3-nitrotyrosine].

AIM: To prepare the working standards of 3-nitrotyrosine (3-NT) and establish a two-antibody-sandwich ELISA for determining the concentration of peroxynitrite in the tissue. METHODS: Nitrated bovine serum albumin was prepared by additions of an alkaline stock solution of peroxynitrite which was synthesized by a quenched-flow reactor. The monoclone anti-3-NT antibody from mouse was used as coating antibody and the polyclone anti-3-NT antibody from as labeling antibody to prepare the standard work curve by orthogonal design. The concentrations of 3-NT in cardiac tissue from rats subjected to myocardial ischemia and reperfusion (MI/R) were analyzed. RESULTS: A two-antibody-sandwich ELISA method for measuring 3-NT content in biological fluids and homogenates was successfully established. The detecting limit was 0.1 ng x ml(-1) and the linear range of standard work curve was 0.15 - 7.50 ng x ml(-1) (r2 = 0.995). The 3-NT concentration in cardiac tissue from rats subjected to MI/R (1022.42 +/- 97.35 ng x mg pro(-1)) was significantly higher than that in the sham group (246.58 +/- 56.52 ng x mg pro(-1), P < 0.01). CONCLUSION: A two-antibody-sandwich ELISA was established for determining the 3-NT concentration in the tissue and conveniently, quickly, accurately quantitative analysis of the content of 3-NT. The assay provides a new method for quantitative analysis of the peroxyinitrite in the future.

[Ultrasound-guided percutaneous radiofrequency ablation of hepatic malignancies with cool-tip needle].

OBJECTIVE: To investigate the efficacy, indication and complication of radiofrequency ablation (RFA) with cool-tip needle in patients with hepatic malignancies. METHODS: 421 patients with hepatic malignancies underwent ultrasound-guided RFA with cool-tip needle under local anaesthesia. The tumor size was from 1.0 to 15 cm in diameter with an average diameter of 4.3 cm. RESULTS: The complete ablation (CA) rate was 91.4% (382/418) in the patients with a tumor < 3 cm, 78.9% (97/123) in those with a tumor of 3 to 5 cm and 37.6% (35/93) in the patients with a tumor > 5 cm. No patient died or changed to celiotomy during the 1121 times of RFA for 634 lesions in 421 patients. No hemorrhage occurred in any of these patients after the RFA treatment. The complications included abdominal pain in 32.3% (136/421), nausea in 9.0% (38/421), fever in 34.9% (147/421) and biliary leakage in 0.2% (1/421) of the patients. CONCLUSION: Ultrasound-guided percutaneous radiofrequency ablation with cool-tip needle is effective and safe in the treatment of liver tumors.

Abdominal splenosis: CT and MRI features of 2 cases.

Splenosis is ectopic autotransplantation of splenic tissue after splenic trauma or surgery.(1) The most frequent locations are the surface of visceral peritoneum and parietal peritoneum. Liver and retroperitoneum are rarely involved.(1,2) We present here 2 cases of splenosis involving the liver and retroperitoneum with clinical information, imaging findings, and literature review.