Expression Pattern of ALOXE3 in Mouse Brain Suggests Its Relationship with Seizure Susceptibility.

Arachidonic acid (AA), a polyunsaturated fatty acid, is involved in the modulation of neuronal excitability in the brain. Arachidonate lipoxygenase 3 (ALOXE3), a critical enzyme in the AA metabolic pathway, catalyzes the derivate of AA into hepoxilins. However, the expression pattern of ALOXE3 and its role in the brain has not been described until now. Here we showed that the levels of Aloxe3 mRNA and protein kept increasing since birth and reached the highest level at postnatal day 30 in the mouse hippocampus and temporal cortex. Histomorphological analyses indicated that ALOXE3 was enriched in adult hippocampus, somatosensory cortex and striatum. The distribution was restricted to the neurites of function-specific subregions, such as mossy fibre connecting hilus and CA3 neurons, termini of Schaffer collateral projections, and the layers III and IV of somatosensory cortex. The spatiotemporal expression pattern of ALOXE3 suggests its potential role in the modulation of neural excitability and seizure susceptibility. In fact, decreased expression of ALOXE3 and elevated concentration of AA in the hippocampus was found after status epilepticus (SE) induced by pilocarpine. Local overexpression of ALOXE3 via adeno-associated virus gene transfer restored the elevated AA level induced by SE, alleviated seizure severities by increasing the latencies to myclonic switch, clonic convulsions and tonic hindlimb extensions, and decreased the mortality rate in the pilocarpine-induced SE model. These results suggest that the expression of ALOXE3 is a crucial regulator of AA metabolism in brain, and potentially acts as a regulator of neural excitability, thereby controlling brain development and seizure susceptibility.

Two ST11 Klebsiella pneumoniae strains exacerbate colorectal tumorigenesis in a colitis-associated mouse model.

Sequence type (ST) 11 is one of the major lineages of carbapenem-resistant Klebsiella pneumoniae (CRKP). Although the gastrointestinal (GI) carriage of CRKP predisposes individuals to subsequent infections, little is known for its impact on gut homeostasis. In this study, we investigated the association between ST11 CRKP colonization and colorectal cancer (CRC). Two ST11 CRKP, KPC160111 (KL47) and KPC160132 (KL64), were selected as the representative strains. We used azoxymethane (AOM) and dextran sodium sulfate (DSS) to initiate a colitis-associated CRC model. Both strains established prolonged colonization in the GI tract of the AOM-DSS-treated BALB/c mice and aggravated gut dysbiosis. Under this AOM-DSS-induced setting, ST11 K. pneumoniae colonization significantly promoted the growth and progression of colorectal adenomas to high-grade dysplasia. Numerous crypts were formed inside the enlarged adenomas, in which CD163+ tumor-associated macrophages accumulated. Similarly, ST11 K. pneumoniae also increased the population size of the CD163+ macrophages with the M2 phenotype in the peritoneal cavity of LPS-primed BALB/c mice. When applied to RAW264.7 cells, ST11 K. pneumoniae polarized the macrophages toward an M2 phenotype through the inhibition of IKK-NFκB and the activation of STAT6-KLF4-IL-10. Through the M2-skewing ability, ST11 K. pneumoniae promoted the accumulation of CD163+ macrophages in the adenomatous crypts to create an immunosuppressive niche, which not only accommodated the extended stay for its own sake but also deteriorated colorectal tumorigenesis.

[Research advances in the mechanism of acupuncture in regulating tumor immunosuppression].

As a characteristic therapy in traditional Chinese medicine, acupuncture has shown potential advantages in anti-tumor therapy, and one of the therapeutic effects of acupuncture is to improve the immunosuppressive conditions in patients with tumor. Based on the immunoregulatory effect of acupuncture, this article summarized the mechanism of acupuncture in regulating tumor immune status from the following aspects: stimulating the activation of natural killer cells, increasing the number of CD8+ T cells, and adjusting the balance between T helper 1 cells and T helper 2 cells and between regulatory T cells and T helper 17 cells. With reference to existing evidence, we believe that acupuncture can regulate the body's immunosuppressive conditions through a variety of targets, but further clinical and basic studies are needed to clarify its regulatory effect on tumor immune microenvironment and related mechanism of action.

Hypothalamic proteome changes in response to nicotine and its withdrawal are potentially associated with alteration in body weight.

Nicotine, a major addictive component in tobacco, plays an important role in the changes of body weight upon smoking and its cessation. Here we showed that nicotine-treated mice exhibited weight loss and nicotine withdrawal led to weight gain. Using TMT-based proteomic analysis, we obtained the different hypothalamic protein profiles in response to nicotine and its withdrawal. A total of ~5000 proteins were identified from the hypothalamus with 50 altered proteins upon 28-day nicotine treatment and 28 altered proteins upon 15-day nicotine withdrawal. Of the altered proteins, CASP3, LCMT2, GRIN2D, CCNT2, FADS3 and MRPS18B were inversely changed in response to nicotine and withdrawal, coincidence with the change of body weight. Of them, CASP3, LCMT2, GRIN2D and CCNT2 were found to be associated with several GO terms and KEGG pathways linking with cell apoptosis, neurotransmission and metabolism. Further Western blot and RT-qPCR analyses confirmed that the levels of the 4 proteins CASP3, LCMT2, GRIN2D and CCNT2, instead of their mRNA transcripts, altered in response to nicotine and withdrawal. Thus this study provides nicotine- and withdrawal-induced hypothalamic protein profiles and suggests potential roles of these altered proteins in the change of body weight. SIGNIFICANCE: Cigarette smoking is one of important factors harming human health. Most smokers tend to have lower body weights and smoking cessation often lead to overweight or obesity, which is an important reason for smokers to insist on smoking. It is known that nicotine, a critical component in tobacco, is associated with the alteration in body weight by affecting hypothalamic function. Through TMT-based proteomic analysis, this study identified differential hypothalamic protein profiles in response to nicotine treatment and its withdrawal, and 4 nicotine- and withdrawal-induced contrary proteins CASP3, LCMT2, GRIN2D and CCNT2 are involved in several enriched GO terms and KEGG pathways, which are associated with cell apoptosis, neurotransmission and metabolism. Our study may provide novel targets for further investigation of the molecular mechanisms of nicotine- and withdrawal-induced alteration in body weight.

Cadmium and arsenic accumulation during the rice growth period under in situ remediation.

Rice (Oryza sativa L.) planted in cadmium (Cd)- and arsenic (As)-contaminated soil is considered the main source of dietary Cd and As intake for humans in Southeast Asia and thereby poses a threat to human health. Minimizing the transfer of these pollutants to rice grain is an urgent task for environmental researchers. The main objective of this study was to investigate the effects and the mechanisms of a combined amendment (hydroxyapatite + zeolite + biochar, HZB) on decreasing Cd and As accumulation in rice. In situ remediation and aqueous solution adsorption experiments were conducted. The results showed that after application of HZB, Cd and As concentrations of the exchangeable fraction and TCLP extraction in soil decreased with the growth of rice plants. Cd concentrations in rice tissues were decreased at the tillering, filling and maturing stages after in situ remediation, while As concentrations in rice tissues were decreased only at the maturing stage. When 8 kg·plot-1 (9000 kg ha-1) HZB was applied, concentrations of Cd and inorganic As in brown rice were decreased to 0.18 and 0.16 mg kg-1, respectively, lower than the levels permissible for grain in China, i.e., 0.2 mg kg-1. Application of HZB reduced Cd accumulation in rice tissues, and the suppression of Cd accumulation was significantly greater than that of As. Furthermore, HZB significantly increased rice grain yield. An aqueous solution adsorption experiment demonstrated that HZB could adsorb and covalently bind Cd and As (V) via -OH, -COOH, -Si-O-Si and CO32- groups to produce carboxylates, silicates and carbonates, thereby promoting in situ immobilization of Cd and As in soil solution.

Epigenetic Downregulation of Scn3a Expression by Valproate: a Possible Role in Its Anticonvulsant Activity.

Upregulation of sodium channel SCN3A expression in epileptic tissues is known to contribute to enhancing neuronal excitability and the development of epilepsy. Therefore, certain strategies to reduce SCN3A expression may be helpful for seizure control. Here, we reveal a novel role of valproate (VPA) in the epigenetic downregulation of Scn3a expression. We found that VPA, instead of carbamazepine (CBZ) and lamotrigine (LTG), could significantly downregulate Scn3a expression in mouse Neuro-2a cells. Luciferase assays and CpG methylation analyses showed that VPA induced the methylation at the -39C site in Scn3a promoter which decreased the promoter activity. We further showed that VPA downregulated the expression of methyl-CpG-binding domain protein 2 (MBD2) at the posttranscriptional level and knockdown of MBD2 increased Scn3a expression. In addition, we found that VPA induced the expression of fat mass and obesity-associated (FTO) protein and FTO knockdown abolished the repressive effects of VPA on MBD2 and Nav1.3 expressions. Furthermore, VPA, instead of other two anticonvulsant drugs, induced the expressions of Scn3a and Mbd2 and reduced Fto expression in the hippocampus of VPA-treated seizure mice. Taken together, this study suggests an epigenetic pathway for the VPA-induced downregulation of Scn3a expression, which provides a possible role of this pathway in the anticonvulsant action of VPA.

GAPDH-mediated posttranscriptional regulations of sodium channel Scn1a and Scn3a genes under seizure and ketogenic diet conditions.

Abnormal expressions of sodium channel SCN1A and SCN3A genes alter neural excitability that are believed to contribute to the pathogenesis of epilepsy, a long-term risk of recurrent seizures. Ketogenic diet (KD), a high-fat and low-carbohydrate treatment for difficult-to-control (refractory) epilepsy in children, has been suggested to reverse gene expression patterns. Here, we reveal a novel role of GAPDH on the posttranscriptional regulation of mouse Scn1a and Scn3a expressions under seizure and KD conditions. We show that GAPDH binds to a conserved region in the 3' UTRs of human and mouse SCN1A and SCN3A genes, which decreases and increases genes' expressions by affecting mRNA stability through SCN1A 3' UTR and SCN3A 3' UTR, respectively. In seizure mice, the upregulation and phosphorylation of GAPDH enhance its binding to the 3' UTR, which lead to downregulation of Scn1a and upregulation of Scn3a. Furthermore, administration of KD generates ß-hydroxybutyric acid which rescues the abnormal expressions of Scn1a and Scn3a by weakening the GAPDH's binding to the element. Taken together, these data suggest that GAPDH-mediated expression regulation of sodium channel genes may be associated with epilepsy and the anticonvulsant action of KD.

Damxungmacin A and B, Two New Amicoumacins with Rare Heterocyclic Cores Isolated from Bacillus subtilis XZ-7.

Two new amicoumacins, named Damxungmacin A (1) and B (2), were isolated from the culture broth of a soil-derived bacterium Bacillus subtilis XZ-7. Their chemical structures were elucidated by spectroscopic studies (UV, IR, NMR and HR-ESI-MS). Compound 1 possessed a 1,4-diazabicyclo[2.2.1]heptane-2-one ring system in its structure, which was reported for the first time, while 2 had a 1-acetylmorpholine-3-one moiety, which was naturally rare. Compound 1 exhibited moderate to weak cytotoxic activities against three human tumor cell lines (A549, HCT116 and HepG2) with IC50 values of 13.33, 14.34 and 13.64 µM, respectively. Meanwhile, compound 1 showed weak antibacterial activities against some strains of Staphylococcus epidermidis, while compound 2 at 16 µg/mL did not show antibacterial activity.

The Clinical Features and Prognosis of Gastric Remnant Carcinoma after Treatment.

BACKGROUND/AIMS: The incidence of gastric remnant carcinoma does not decrease after partial gastrectomy The aim of this study was to evaluate the clinical features and prognosis of gastric remnant carcinoma after treatment. METHODOLOGY: Among 412 gastric carcinoma patients who were admitted to our hospital 21 were found to have gastric remnant carcinoma. We analyzed their clinicopathological features and prognosis. RESULTS: Prognosis did not differ significantly in terms of gender, age, tumor-lymph node-metastasis stage, tumor location, and time interval between first and subsequent operations. However, it was influenced by intensive curative gastrectomy with or without resection of local lymph nodes. CONCLUSION: Long-term follow-up after gastrectomy, appropriate curative resection, as well as prevention and management of hypertensive disease co-mobility are important to improve survival rate of gastric remnant carcinoma operation.

The clinical features and prognosis of gastric remnant carcinoma after treatment.

Introduction. The incidence of gastric remnant carcinoma does not decrease after partial gastrectomy. The aim of this study was to evaluate the clinical features and prognosis of gastric remnant carcinoma after treatment. Methods. Among 412 gastric carcinoma patients who were admitted to our hospital, 21 were found to have gastric remnant carcinoma. We analyzed their clinicopathological features and prognosis. Results. Prognosis did not differ significantly in terms of gender, age, tumor lymph node metastasis stage, tumor location, and time interval between first and subsequent operations. However, it was influenced by intensive curative gastrectomy with resection of local lymph nodes. Conclusion. Long-term follow-up after gastrectomy, appropriate curative resection, and prevention and management of comorbidities are important to detect gastric remnant carcinoma at an early stage.

Cytokine evaluation in liver cirrhosis and hepatocellular carcinoma.

BACKGROUND/AIMS: The purpose of this study was to examine the roles of tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-18, and alpha-fetoprotein (AFP) in patients with liver cirrhosis (LC) and hepatocellular carcinoma (HCC). METHODOLOGY: AFP and cytokine serum concentrations were determined via EIA or ELISA. RESULTS: In total, 81 patients were included, including 9 healthy controls, 36 LC patients, and 36 HCC patients. Significant differences in AFP, TNF-alpha, IL-6, and IL-18 between the three groups were noted (p < 0.001). AFP was lowest in the healthy subjects, intermediate in LC patients and highest in HCC patients (all p < 0.001). 11-6 and 11-18 concentrations were significantly higher in the HCC group than the other two groups. HCC and LC patients with AFP concentration > 7ng/ml had increased IL-18 concentrations compared to both the other groups p < 0.001). In contrast to previously published studies, TNF-alpha was highest in the healthy group, intermediate in the HCC group, and lowest in the LC group (p < 0.001). CONCLUSIONS: IL-18 may be a potential tumour marker in combination with IL-6 and AFP in the diagnosis of HCC, but further research including a larger population of patients is essential. Further research is warranted.

[Effects of arsenic on reproductive and endocrine system of female rats].

OBJECTIVE: Effects of arsenic on the levels of estradiol (E2), follicle stimulating hormone (FSH), luteinizing hormone (LH) and prolactin (PRL) in serum of female rats, as well as histopathological changes of ovary and adrenal gland were researched. METHODS: The hormone levels of female rats were determined by RIA exposing arsenic for 10 weeks, and histopathological examination of ovary and adrenal gland were performed with light microscope. RESULTS: In spite of LH, there was no levels of three hormones (P > 0.05). However, different extents of histopathological changes in ovary and adrenal gland were found. CONCLUSION: LH is a sensitive index on hormones of female rats, but it may directly damage the reproductive system.

Serum IL-8 as a possible marker for determining the status of Helicobacter pylori infection in patients with untreated and treated peptic ulcer.

Failure to eradicate Helicobacter pylori can lead to peptic ulcer recurrence and gastric malignancy. Therefore, the objective of this study was to develop a noninvasive method for determining whether H. pylori infection was eradicated with antibiotic-based triple therapy. A total of 17 patients with duodenal ulcer (DU) and 17 with gastric ulcer (GU) were evaluated both before and after treatment. Outcomes included serum levels of interleukin-8 (IL-8), pepsinogen I, and gastrin, and the Wilcoxon signed rank test was used to test significance. Changes in these parameters were also correlated with disease status. In those patients where both GU and DU healing occurred as a result of treatment, most showed an increase in serum IL-8 and a decrease in serum pepsinogen. Serum gastrin levels were not significantly changed in either group. Posttreatment increases in serum IL-8 were seen in 15 of 17 (88%) recovered DU patients and 14 of 17 (82%) recovered GU patients (P<.05 for each). Posttreatment decreases in pepsinogen I were found in 15 of 17 DU and 15 of 17 GU patients (P<.05 for each). These preliminary findings suggest that an increase in serum IL-8 and possibly a decrease in pepsinogen I may be useful in identifying the successful eradication of H. pylori infection in patients with peptic ulcer treated with antibiotics. A more systematic analysis of these putative diagnostic markers is now warranted.

Phosphorylation of Helicobacter pylori CagA in patients with gastric ulcer and gastritis.

The effects of Helicobacter pylori infection are strongly associated with chronic gastritis, gastric and duodenal ulcer, gastric cancer, and MALT lymphoma. The microorganism has been classified as a type I carcinogen by the World Health Organization. Varying clinical results from H. pylori infection are believed due, in part, to differences in virulence among species. The cag pathogenicity island is a complex of virulent genes and a coding region for the type IV phosphorylated secretion system. Through this system, many virulent gene products or proteins are phosphorylated into the host cells. This study demonstrated the positive CagA-phosphorylation effect of H. pylori in patients with chronic gastritis and benign gastric ulcer and revealed significantly different rates of CagA phosphorylation between these two diseases (P<.05).