Altered hippocampal functional connectivity in primary Sjögren syndrome: a resting-state fMRI study.

Structural and metabolic abnormalities in the hippocampus have been associated with the pathophysiological mechanism of central nervous system involvement in primary Sjögren syndrome (pSS). Nevertheless, how hippocampal function is altered in pSS remains unknown. The purpose of our study is to investigate the alterations in hippocampal functional connectivity (FC) in pSS by using resting-state functional magnetic resonance imaging (rs-fMRI). Thirty-eight patients with pSS and 38 age- and education level-matched healthy controls (HCs) underwent magnetic resonance imaging examination. Prior to each MRI examination, neuropsychological tests were performed. Left and right hippocampal FCs were analyzed by using seed-based whole-brain correlation and compared between pSS and HCs. Spearman correlation analysis was performed between the z-value of hippocampal FC in brain regions with significant difference between the two groups and neuropsychological tests/clinical data in pSS. Compared with the controls, the patients with pSS showed decreased hippocampal FC between the left hippocampus and the right inferior occipital gray (IOG)/inferior temporal gray (ITG), as well as between the right hippocampus and right IOG/middle occipital gray (MOG), left MOG, and left middle temporal gray. In addition, increased hippocampal FCs were detected between the left hippocampus and left putamen, as well as between the right hippocampus and right cerebellum posterior lobe. Moreover, the visual reproduction score positively correlated with the FC between right hippocampus and right IOG/MOG. The white matter hyperintensity score negatively correlated with the FC between left hippocampus and right IOG/ITG. In conclusion, patients with pSS suffered decreased hippocampal FC mainly sited in the occipital and temporal cortex with right hippocampal laterality. Altered hippocampal FC might be a potential biomarker in detecting brain function changes and guiding neuroprotection in pSS.

Acetylcholinesterase expression mediated by c-Jun-NH2-terminal kinase pathway during anticancer drug-induced apoptosis.

It has been shown that acetylcholinesterase (AChE) expression was induced during apoptosis and the anti-sense oligonucleotides and siRNA of AChE may prevent apoptosis in various cell types. However, the mechanisms underlying AChE upregulation remain elusive. We demonstrated here that c-Jun NH2-terminal kinase (JNK) could mediate AChE expression. In this study, both etoposide and excisanin A, two anticancer agents, induced apoptosis in colon cancer cell line SW620 as determined by Annexin V staining, the cleavage of caspase-3 and the proteolytic degradation of poly (ADP-ribose) polymerase (PARP). The results showed that both the agents upregulated AChE in SW620 cells. In the meantime, JNK was also activated and the expression and phosphorylation of c-Jun increased in SW620 cells exposed to the two agents. The induced AChE mRNA and protein expression could be blocked by SP600125, a specific inhibitor of SAPK/JNK, and small interfering RNA directed against JNK1/2. Transfection with adenovirus-mediated dominant negative c-Jun also blocked the upregulation of AChE expression. Together, these results suggest that AChE expression may be mediated by the activation of JNK pathway during apoptosis through a c-Jun-dependent mechanism.

Senescence and telomere shortening induced by novel potent G-quadruplex interactive agents, quindoline derivatives, in human cancer cell lines.

Agents stabilizing G-quadruplexes have the potential to interfere with telomere replication by blocking the elongation step catalysed by telomerase or telomerase-independent mechanism and could therefore act as antitumor agents. In this study, we found that quindoline derivatives interacted preferentially with intramolecular G-quadruplex structures and were novel potent telomerase inhibitors. Treatment with quindoline derivatives reproducibly inhibited telomerase activity in human leukemia K562 cells and colon cancer SW620 cells. N'-(10H-Indolo [3,2-b] quinolin-11-yl)-N, N-dimethyl-propane-1,3-diamine (SYUIQ-5), (one of quindoline derivatives), when added to K562 and SW620 cell culture at nonacute cytotoxic concentrations, increased time of population doublings of K562 and SW620 cells, induced a marked cessation in cell growth and cellular senescence phenotype after 35 and 18 days, respectively. Growth cessation was accompanied by a shortening of telomere length, and induction of p16, p21 and p27 protein expression. However, another compound SYUIQ-7 with greater IC(50) for telomerase had no obvious cellular effect in nonacute cytotoxic concentrations. These results indicate that quindoline derivatives as novel potent G-quadruplex interactive agents induce senescence and telomere shortening in cancer cells and therefore are promising agents for cancer treatment.

The microbiota-gut-brain axis and its potential therapeutic role in autism spectrum disorder.

Autism spectrum disorder (ASD) is a series of neurodevelopmental disorders that are characterized by deficits in both social and cognitive functions. Although the exact etiology and pathology of ASD remain unclear, a disorder of the microbiota-gut-brain axis is emerging as a prominent factor in the generation of autistic behaviors. Clinical studies have shown that gastrointestinal symptoms and compositional changes in the gut microbiota frequently accompany cerebral disorders in patients with ASD. A disturbance in the gut microbiota, which is usually induced by a bacterial infection or chronic antibiotic exposure, has been implicated as a potential contributor to ASD. The bidirectional microbiota-gut-brain axis acts mainly through neuroendocrine, neuroimmune, and autonomic nervous mechanisms. Application of modulators of the microbiota-gut-brain axis, such as probiotics, helminthes and certain special diets, may be a promising strategy for the treatment of ASD. This review mainly discusses the salient observations of the disruptions of the microbiota-gut-brain axis in the pathogenesis of ASD and reveals its potential therapeutic role in autistic deficits.

Pseudomonas syringae pv tomato induces the expression of tomato EREBP-like genes pti4 and pti5 independent of ethylene, salicylate and jasmonate

The tomato genes Pti4 and Pti5 encode ethylene-responsive element binding protein-like transcription factors that bind to the GCC box, a conserved cis-element in many defense-related genes. The Pti proteins have previously been shown to interact with the tomato disease resistance protein Pto. Here we report that the expression of both Pti4 and Pti5 are induced by a virulent strain of Pseudomonas syringae pv tomato. The expression of Pti5 is further enhanced by the interaction of the Pto gene in tomato and the corresponding avrPto gene in the bacterium. The enhancement of Pti5 expression by Pto-avrPto interaction requires a functional Prf gene in the plant. Pti5 appears to be expressed specifically during biotic stresses, suggesting a specific role in plant defense. Pti4 and several EREBP-like genes are induced by ethylene, salicylate and wounding. However, the Pseudomonas bacterium induced a wild-type level of Pti4 and Pti5 transcripts in tomato plants carrying the nahG transgene, the Nr mutation, or the def1 mutation. In addition, the ethylene action inhibitor norbornadiene did not inhibit the induction of Pti4 and Pti5 either in the compatible or incompatible interactions. The results suggest that the Pseudomonas bacterium induces Pti4 and Pti5 expression through a pathway independent of salicylic acid, ethylene and jasmonic acid.

Intranasal immunisation with Stx2B-Tir-Stx1B-Zot protein leads to decreased shedding in goats after challenge with Escherichia coli O157:H7.

Ruminants are an important reservoir of Escherichia coli O157:H7. To reduce E coli O157:H7 excretion by these animals could play a key role in prevention and control of human infections. In the present study, the authors used 12 three-month-old goats to evaluate the efficacy of intranasal administration of the Stx2B-Tir-Stx1B-Zot protein. These goats were inoculated on days 0 and 21 and infected with 10(10) colony-forming units (cfu) of E coli O157:H7 by oral inoculation on day 36. Faecal shedding was monitored daily for two weeks. All of six goats immunised with recombinant protein elicited significant Stx2b-Tir-Stx1b-Zot-specific serum IgG antibodies, and three of them also showed production of antigen-specific IgA in faeces. The immunised goats showed much less shedding of E coli O157:H7 after challenge. These results demonstrate the potential for the use of Stx2B-Tir-Stx1B-Zot protein in mucosal vaccine formulations to prevent colonisation and shedding of E coli O157:H7 in goats.

Molecular characterization of the surface glycoprotein genes of an H5N1 influenza virus isolated from a human in Guangdong, China.

In March 2006, a human H5N1-infected case was found in Guangdong province, China. Here, we molecularly characterized the hemagglutinin (HA) and neuraminidase (NA) genes of the A/China/GD01/06 (GD01) strain causing the infection. The phylogenetic analyses suggested that the HA and NA genes of GD01 and recent human H5N1 viruses from different provinces of China were probably derived from a common ancestor and the H5N1 human infection was acquired directly from affected poultry. At the cleavage site of HA, GD01 contained multiple basic amino acids, a feature characteristic of highly pathogenic avian influenza A viruses. The virus possessed Gln222, Gly224, Ser223, Asn182, Gln192 residues adjacent to the receptor-binding site, preferential for recognizing SAalpha2, 3Gal. In addition, the GD01 NA amino acid sequence possessed Asn344 and Phe466, which might be related to the low-pH stability of the sialidase activity and gastrointestinal symptoms of the patient.