IL-17A as a new circulating bioindicator for non-small cell lung cancer diagnosis and prognosis.

OBJECTIVE: Lung cancer (LC) is the highest contributor to cancer-associated mortality worldwide. Approximately 85% of all LC incidences involve non-small cell LC (NSCLC). Unfortunately, owing to a significant lack of sensitive and robust bioindicators, most patient diagnoses occur at advanced stages of the disease, thereby resulting in extremely poor patient outcomes. Herein, we elucidated the role of interleukin-17A (IL-17A) among NSCLC patients. MATERIALS AND METHODS: Circulating IL-17A content was measured using enzyme-linked immunosorbent assay (ELISA), and its diagnostic and prognostic abilities were assessed using the receiver operating characteristic (ROC) curve and Kaplan-Meier analysis, respectively. RESULTS: Our analysis revealed that circulating IL-17A levels were significantly augmented among NSCLC vs. control samples. Moreover, based on our area under the curve (AUC) analysis, circulating IL-17A levels fared considerably better than the standard bioindicator carcinoembryonic antigen (CEA) in both testing and validation cohorts. Notably, we also revealed that the circulating IL-17A levels were accurately and reliably predicted in early-stage NSCLC patients. Besides, we demonstrated a strong correlation between elevated circulating IL-17A expression and worse prognosis among NSCLC patients. CONCLUSIONS: Herein, we demonstrated that circulating IL-17A levels can serve as reliable and potent diagnostic and prognostic bioindicators for NSCLC.

Association of arterial stiffness in non-hypertensive offspring with parental hypertension: the Hanzhong adolescent hypertension cohort study.

OBJECTIVE: Arterial stiffness may be an early marker for vascular changes associated with hypertension in young adults. Individuals with a family history of hypertension are at high risk of developing hypertension. We investigated whether arterial stiffness measured, such as mean arterial pressure (MAP) and brachial to ankle pulse wave velocity (baPWV), were increased in normotensive offspring with a parental history of hypertension. PATIENTS AND METHODS: We compared MAP and baPWV in a sample of 1953 non-hypertensive participants (974 men, mean age 42±3 years) recruited in the previous Hanzhong adolescent hypertension cohort study. Standardized questionnaires, physical examinations and laboratory tests were used to obtain information, with a particular focus on family hypertension history, anthropometric, hemodynamic, and biochemical factors. RESULTS: A total of 1039, 759, 155 participants had 0, 1, and 2 parents with hypertension, respectively. Parental hypertension was associated with elevated offspring MAP (in multivariable-adjusted models, B=1.5 mm Hg, 95% CI 0.8-2.2 for 1 parent with hypertension; B=3.0 mm Hg, 95% CI 1.8-4.3, for 2 parents with hypertension; p<0.001 for each). A significant positive correlation was also observed between MAP and baPWV (r=0.543, p<0.001). BaPWV displayed a similar correlation with parental hypertension in age-adjusted, sex-adjusted and body mass index (BMI)-adjusted models (B=23.1 cm/s, 95% CI 8.0-38.1, for 1 parent with hypertension, p<0.01; B=53.0 cm/s, 95% CI 25.8-80.2, p<0.001 for 2 parents with hypertension), but associations were attenuated in multicovariate models after adjustment for MAP. In multivariable-adjusted models, logistic regression analysis showed that the risk of belonging to the upper quartile of MAP was significantly increased for offspring whose parents had hypertension (OR=1.5, 95% CI 1.2-1.9, for 1 parent with hypertension; OR=2.3, 95% CI 1.6-3.4, for 2 parents with hypertension; p<0.001 for each). Similarly, the odds ratios of belonging to the upper quartile of baPWV increased (OR=1.3, 95% CI 1.1-1.6, for 1 parent with hypertension, p<0.05; OR=2.1, 95% CI 1.5-3.0, for 2 parents with hypertension, p<0.001, in age-sex-BMI-adjusted models), and were then brought down in the fully adjusted models including MAP, but the increase remained significant for 2 parents with hypertension (OR=1.6, 95% CI 1.0-2.3, p<0.05). CONCLUSIONS: These findings provide evidence that arterial stiffness is higher in young-to middle-aged normotensive subjects with a family history of hypertension, suggesting that increased arterial stiffness may occur in the early stages during the pathogenesis of hypertension.

Silence of lncRNA BCAR4 alleviates the deterioration of osteoporosis.

OBJECTIVE: To illustrate the biological function of long non-coding RNA (lncRNA) BCAR4 in triggering osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), thus mediating the progression of osteoporosis. MATERIALS AND METHODS: Relative levels of BCAR4 in BMSCs undergoing indicated time points of osteogenic differentiation were examined by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). After intervening BCAR4 levels in osteogenically differentiated BMSCs, the relative levels of serum osteocalcin (OCN) and osteopontin (OPN) were detected, as well as ALP activity and mineralization capacity. Female Sprague Dawley (SD) rats were classified into sham group, BMSCs group (administration with BMSCs), RNAi group (administration with BMSCs transfected with si-BCAR4), and control group, with 10 rats per group. Osteoporosis model was generated in the latter three groups by resection of bilateral ovaries. Positive expressions of procollagen type I N propeptide (PINP) and ß-C-terminal telopeptide (ß-CTx), and ß-CTx in rats were determined by enzyme-linked immunosorbent assay (ELISA). Bone density in rat femurs and bone biomechanics were examined using the dual energy X-ray bone densitometer and the three-point bending test, respectively. RESULTS: BCAR4 was downregulated on the 3rd and 7th day of osteogenic differentiation in BMSCs. Overexpression of BCAR4 downregulated OCN and OPN. In the meantime, BCAR4 was able to weaken alkaline phosphatase (ALP) activity and mineralization capacity in BMSCs. The promotive effects of silenced BCAR4 on osteogenic potentials in BMSCs were abolished by overexpression of GLI2. In rats of RNAi group, positive expression of PINP and bone biomechanics were remarkably higher than BMSCs group, whereas they were lower than the sham group. Positive expression of ß-CTx was declined in RNAi group compared with that of BMSCs group, and it was still higher than that of sham group. CONCLUSIONS: BCAR4 is involved in the osteogenic differentiation of BMSCs. The knockdown of BCAR4 can alleviate the progression of osteoporosis.

Correlation between Helicobacter pylori infection and Crohn's disease: a meta-analysis.

OBJECTIVE: Researches on the potential correlation between Helicobacter pylori (Hp) infection and Crohn's disease (CD) are controversial. This study aims to clarify their correlation and provide a new theoretical basis for uncovering the pathogenesis of inflammatory bowel diseases (IBD). MATERIALS AND METHODS: Relevant literature has been searched reporting the correlation between Hp infection and susceptibility to CD in Medline, PubMed, and Cochrane Collaboration database published from 1991 to 2019. Data of the eligible literature were extracted and analyzed for the OR and the corresponding 95% CI using the Review Manager (RevMan) software. RESULTS: A total of 20 pieces of literature involving 2055 cases of CD patients and 3442 cases of controls were enrolled. Hp infection rate in CD patients and controls was 30.6% and 42.7%, respectively. There was a significant difference in Hp infection rate between CD patients and controls [OR=0.42, 95% CI (0.33-0.54), p<0.00001], showing a negative correlation. Heterogeneity existed between the included studies. CONCLUSIONS: Hp infection is a protective factor for CD. However, heterogeneity and publication bias may restrict the accuracy of the conclusions. It is necessary to further explore the potential influence of the Hp infection on CD.

LncRNA MALAT1 expression inhibition suppresses tongue squamous cell carcinoma proliferation, migration and invasion by inactivating PI3K/Akt pathway and downregulating MMP-9 expression.

OBJECTIVE: LncRNA MALAT1 has been proved to be involved in the development of various types of human cancers while the involvement of MALAT1 in tongue squamous cell carcinoma has not been reported. In view of this, our study aimed to investigate the functionality of MALAT1 in tongue squamous cell carcinoma. PATIENTS AND METHODS: The expression of MALAT1 in tumor tissues and adjacent healthy tissues of tongue cancer patients, and the serum from tongue cancer patients as well as healthy controls, were detected by quantitative Real Time-PCR (qRT-PCR). ROC curve analysis was performed to analyze the diagnostic value of plasma MALAT1 for tongue cancer. Survival curves were plotted using the Kaplan-Meier method to evaluate the prognostic value of plasma MALAT1 for tongue cancer. CCK-8 assay, transwell migration and invasion assay were performed to investigate the effects of MALAT1 knockdown on the proliferation, migration and invasion of tongue cancer cells, respectively. The effects of MALAT1 overexpression on the PI3K/Akt pathway and MMP-9 expression were detected by Western blot. RESULTS: The expression level of MALAT1 was remarkably higher in tumor tissues than that in adjacent healthy tissues. Serum MALAT1 was significantly higher in tongue cancer patients than in healthy controls. MALAT1 knockdown markedly inhibits the proliferation, migration and invasion of tongue cancer cells. MALAT1 knockdown also reduced the phosphorylation level of Akt as well as the expression level of MMP-9. It showed no significant effects on Akt expression, while PI3K activator treatment reduced the inhibitory effects of MALAT1 knockdown on the proliferation, migration and invasion of tongue cancer cells. CONCLUSIONS: LncRNA MALAT1 expression inhibition can inhibit the proliferation, migration and invasion of tongue cancer cells by inactivating the PI3K/Akt pathway and downregulating MMP-9. MALAT1 may serve as a target for the treatment of tongue squamous cell carcinoma.

Inhibition of microRNA-218 promotes oral squamous cell carcinoma growth by targeting GLUT1 to affect glucose metabolism.

OBJECTIVE: Glucose transporter 1 (GLUT1) is a key player in glucose metabolism that has important roles in oral squamous cell carcinoma (OSCC), while microRNA-218 can target GLUT1 to achieve its biological roles. Therefore, we hypothesize that microRNA-218 may target GLUT1 to participate in OSCC. PATIENTS AND METHODS: Tumor tissues and adjacent healthy tissues were collected from OSCC patients, and blood samples were collected from both OSCC patients and healthy controls. Expression of microRNA-218 and GLUT1 in those tissues was detected by qRT-PCR. All patients were followed up for 5 years. Diagnostic and prognostic values of serum microRNA-218 for OSCC were investigated by ROC curve analysis and survival curve analysis, respectively. MicroRNA-218 knockdown OSCC cell lines were established. The effects on cell proliferation, glucose uptake as well as GLUT1 expression were detected by CCK-8 assay, glucose uptake assay and Western blot. RESULTS: MicroRNA-218 expression level was decreased while GLUT1 expression level was increased in tumor tissues compared with adjacent healthy tissues. Serum level of microRNA-218 was lower, while serum level of GLUT1 was higher in cancer patients than that in healthy control. Serum microRNA-218 and GLUT1 can be used to accurately predict OSCC and its prognosis. MicroRNA-218 knockdown promoted tumor cell proliferation, increased glucose uptake and promoted GLUT1 expression. CONCLUSIONS: Inhibition of microRNA-218 can promote oral cancer cell growth by targeting GLUT1 to affect glucose metabolism.

The complete genomic sequence of Sugarcane mosaic virus from Canna spp. in China.

BACKGROUND: Sugarcane mosaic virus (SCMV) is the prevalent virus inducing maize dwarf mosaic and sugarcane mosaic diseases in China. According to the phylogenetic results of the complete genomic and coat protein gene sequences, SCMV was divided into four or five molecular groups, respectively. Previously, we detected SCMV isolates of group SO from Canna spp. in Ji'nan, Shandong province, China. FINDINGS: In this study, we collected two SCMV isolates infecting Canna spp. in Ji'nan (Canna-Ji'nan) and Tai'an (Canna-Tai'an) of Shandong, China. Their complete genome sequences had genome of 9576 nucleotides and contained a large open reading frame encoding a polyprotein of 3063 amino acids. The phylogenetic analysis showed that the both Canna-Ji'nan and Canna-Tai'an were clustered into an independent group based on the complete genome sequence. CONCLUSION: In this study, we report the complete genome sequences of SCMV infecting Canna spp. from Ji'nan and Tai'an. This is the first report on SCMV belonging to SO group.

Alterations in the gut barrier and involvement of Toll-like receptor 4 in murine postoperative ileus.

BACKGROUND: The changes in the gut barrier (GB) and associated mechanisms in postoperative ileus (POI) are still unclear. Toll-like receptor 4 (TLR4) is involved in inflammation, which may cause GB dysfunction and POI. Here, the roles of the GB in POI in relation to TLR4-dependent signaling pathways were explored. METHODS: POI was induced by small bowel manipulation in wild-type (WT) and TLR4-knockout (TLR4-/-) mice. Twenty-four hours after manipulation, indices of gastrointestinal (GI) transit, GB structure and function, inflammation, and related signaling pathways were analyzed. KEY RESULTS: Normal GI motility and GB function were not affected by TLR4 knockout. Compared with WT POI mice, TLR4-/-POI mice showed milder GI transit retardation, GB dysfunction, and inflammatory responses. In WT mice, GB disorder was characterized by colonic goblet cells depletion, increased gut claudin-2 expression, and decreased CD4+/CD8+ ratios in intestinal Peyer's patches. Green fluorescent protein-tagged Escherichia coli in the gut was detected in plasma and extraintestinal organs, followed with increased plasma lipopolysaccharide. These changes displayed in WT POI mice were less severe in TLR4-/-POI mice. Furthermore, the mRNA and protein expression of interleukin-6, monocyte chemotactic protein-1, pp38 and pJNK in the intestine, and TNF-α level in plasma were significantly increased in WT, but not TLR4-/-POI mice. CONCLUSIONS & INFERENCES: These results indicate that GB is impaired in the experimental POI, with inflammation being involved in this pathological process. TLR4 deficiency alleviated GB dysfunction and suppressed inflammation by disrupting the activation of mitogen-activated protein kinase signaling pathways, thereby ameliorating POI.

High prevalence of fosfomycin resistance gene fosA3 in bla CTX-M-harbouring Escherichia coli from urine in a Chinese tertiary hospital during 2010-2014.

Fosfomycin has become a therapeutic option in urinary tract infections. We identified 57 fosfomycin-resistant Escherichia coli from 465 urine-derived extended-spectrum ß-lactamase (ESBL)-producing isolates from a Chinese hospital during 2010-2014. Of the 57 fosfomycin-resistant isolates, 51 (89·5%) carried fosA3, and one carried fosA1. Divergent pulsed-field gel electrophoresis profiles and multi-locus sequence typing results revealed high clonal diversity in the fosA3-positive isolates. Conjugation experiments showed that the fosA3 genes from 50 isolates were transferable, with IncFII or IncI1 being the most prevalent types of plasmids. The high prevalence of fosA3 was closely associated with that of bla CTX-M. Horizontal transfer, rather than clonal expansion, might play a central role in dissemination. Such strains may constitute an important reservoir of fosA3 and bla CTX-M, which may well be readily disseminated to other potential human pathogens. Since most ESBL-producing E. coli have acquired resistance to fluoroquinolones worldwide, further spread of fosA3 in such E. coli isolates should be monitored closely.

Bioinformatics analysis of biomarkers and transcriptional factor motifs in Down syndrome

In this study, biomarkers and transcriptional factor motifs were identified in order to investigate the etiology and phenotypic severity of Down syndrome. GSE 1281, GSE 1611, and GSE 5390 were downloaded from the gene expression ominibus (GEO). A robust multiarray analysis (RMA) algorithm was applied to detect differentially expressed genes (DEGs). In order to screen for biological pathways and to interrogate the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database, the database for annotation, visualization, and integrated discovery (DAVID) was used to carry out a gene ontology (GO) function enrichment for DEGs. Finally, a transcriptional regulatory network was constructed, and a hypergeometric distribution test was applied to select for significantly enriched transcriptional factor motifs. CBR1, DYRK1A, HMGN1, ITSN1, RCAN1, SON, TMEM50B, and TTC3 were each up-regulated two-fold in Down syndrome samples compared to normal samples; of these, SON and TTC3 were newly reported. CBR1, DYRK1A, HMGN1, ITSN1, RCAN1, SON, TMEM50B, and TTC3 were located on human chromosome 21 (mouse chromosome 16). The DEGs were significantly enriched in macromolecular complex subunit organization and focal adhesion pathways. Eleven significantly enriched transcription factor motifs (PAX5, EGR1, XBP1, SREBP1, OLF1, MZF1, NFY, NFKAPPAB, MYCMAX, NFE2, and RP58) were identified. The DEGs and transcription factor motifs identified in our study provide biomarkers for the understanding of Down syndrome pathogenesis and progression.

Postprandial effects of two Chinese liquors on selected cardiovascular disease risk factors in young men.

The aim of this study was to investigate postprandial effects of two Chinese liquors on s elected cardiovascular disease risk factors in humans. Sixteen healthy men were randomized into three groups in a three-way crossover study: tea-flavor liquor (TFL), traditional Chinese liquor (TCL) and water control (WC). Every subject consumed 60 mL of either liquor (45% (v/v) ethanol) or water together with a high-fat meal, respectively. Compared with baseline, serum uric acid was significantly increased in TFL group (0.5-hour: P = 0.012; 1-hour: P = 0.001; 2-hour: P = 0.008) and it was significantly decreased in WC group (1-hour: P = 0.001; 2-hour: P = 0.001; 4-hour: P < 0.001), while uric acid was non-significantly increased in the TCL group. High-sensitive C-reactive protein (hs-CRP) was significantly increased in the TCL (P = 0.014) and WC (P = 0.008) groups at postprandial 4 hours compared with baseline. There was no significant difference between groups during the postprandial period for these two parameters or other biochemical parameters. In conclusion, both liquors increased postprandial uric acid, and no significant difference was observed for the effects of TFL and TCL on the measured biochemical parameters.

Genetic and sex influence on neuropathic pain-like behaviour after spinal cord injury in the rat.

BACKGROUND: Chronic pain of neuropathic nature after spinal cord injury (SCI) is common and its underlying mechanisms are poorly understood. Genes, as well as sex, have been implicated, but not thoroughly investigated in experimental genetic models for complex traits. We have previously found that inbred Dark-Agouti (DA) rats develop more severe SCI pain-like behaviour than a major histocompatibility complex-congenic Piebald Virol Glaxo (PVG)-RT1(av1) strain in a model of photochemically induced SCI. METHODS: In this study, a genome-wide linkage study in an F2 cross between the susceptible DA and resistant PVG-RT1(av1) strains was performed in order to explore the influence of genes and sex for SCI pain. RESULTS: A consistent finding was that female rats in parental, F1 and F2 generations displayed increased pain sensitivity at testing before injury and also developed mechanical hypersensitivity more rapidly and to a greater extent than male rats. In addition, we could identify three quantitative trait loci (QTLs) associated with pain-like behaviour: a sex-specific QTL on chromosome 2, one on chromosome 15 and on chromosome 6. Animals carrying DA alleles at each of these loci were more susceptible to development of mechanical hypersensitivity compared with rats with PVG alleles. CONCLUSION: This is the first whole genome QTL mapping of neuropathic pain-like behaviour in a model of SCI. The results provide strong support for a significant genetic and sex component in development of pain after SCI and provide the basis for further genetic dissection and positional cloning of the underlying genes.

Effect of small interfering RNA targeting wild-type FLT3 in acute myeloid leukaemia cells in vitro and in vivo.

This study investigated the effect of using small interfering RNA (siRNA) to silence the wild-type FMS-like tyrosine kinase 3 (FLT3) gene in acute myeloid leukaemia (AML) cells, in vitro and in vivo. FLT3 siRNA was introduced into the human AML cell line, THP1, and into a THP1 xenograft tumour model in BALB/c nude mice. FLT3 siRNA effectively reduced both the mRNA and the protein levels of FLT3, arrested cells in G(0)/G(1) phase, inhibited THP1 cell proliferation and increased apoptosis. Intraperitoneal injection of FLT3 siRNA suppressed tumour growth in BALB/c nude mice. FLT3 siRNA treatment also reduced cyclin D1 and Bcl-2 protein levels, and increased the nuclear level of silencing mediator for retinoic acid and thyroid hormone receptors protein both in vitro and in vivo. These data suggest that FLT3 siRNA is a strong inhibitor of FLT3 expression in vitro and in vivo, and may provide a new therapeutic target for AML.

Haemodynamic brain response to visual sexual stimuli is different between homosexual and heterosexual men.

The underlying neurobiological factors involved in sexual orientation are largely unknown. This study investigated whether neural circuits or different cognitive processes accounted for differences in brain activation in 14 heterosexual and 14 homosexual males. Brain scans were undertaken in each subject using functional magnetic resonance imaging while they viewed different sexual stimuli, i.e. heterosexual couple stimuli (HCS), gay couple stimuli (GCS), lesbian couple stimuli (LCS) and neutral stimuli (NS). Ratings of sexual attractiveness of the stimuli were assessed. Subjective sexual arousal was induced by HCS and GCS in heterosexual and homosexual men, respectively. Sexual disgust was induced by GCS and LCS in heterosexual and homosexual men, respectively. Compared with viewing NS, viewing sexual stimuli induced significantly different brain activations, most of which had the characteristics of cognitive processes. These observations suggest that different cognitive patterns may be the major cause of different subjective responses to sexual stimuli between heterosexual and homosexual men.

Peripheral blood stem cell transplantation compared with bone marrow transplantation from unrelated donors in patients with leukemia: a single institutional experience.

We analyzed data for 89 patients with leukemia undergoing bone marrow transplantation (BMT) (n=44) or peripheral blood stem cell transplantation (PBSCT) (n=45) from unrelated donors between May 2000 and February 2009 in our institution. PBSCT resulted in faster hematopoietic engraftment, compared with BMT (P<0.001). There was no difference between BMT and PBSCT in infectious episodes and CMV antigenemia within the first 100 days post-transplantation. The frequency of acute graft-versus-host disease (GVHD) grades II-IV was 49.7% and 47.0% (P=0.838) and of chronic GVHD 42.4% and 43.9% (P=0.827) in BMT and PBSCT. The 5-year cumulative percent of relapse was 18.5 in BMT and 48.6 in PBSCT (P=0.041), and the transplant-related mortality (TRM) was 40% and 29.5% (P=0.800), respectively. The 5-year cumulative percent of disease-free survival (DFS) was 50.8 and 38.9 (P=0.439); overall survival (OS) was 55.3% and 48.5% (P=0.447) in BMT and PBSCT, respectively. The reconstitution of T and B cells at 1, 3, 6, 9, and 12 months post-transplantation was not different between BMT and PBSCT, except that the level of regulatory T cells (T-regs) was higher after PBSCT than after BMT at 1 month (P=0.001).

KCNJ11 Lys23Glu and TCF7L2 rs290487(C/T) polymorphisms affect therapeutic efficacy of repaglinide in Chinese patients with type 2 diabetes.

This study showed that the polymorphisms KCNJ11 Lys23Glu and TCF7L2 rs290487(C/T) are associated with a heightened risk of developing type 2 diabetes mellitus (T2DM). We also explored the effects of these polymorphisms on the efficacy of repaglinide therapy in Chinese patients with T2DM. A total of 259 patients with T2DM and 188 healthy controls were genotyped. Forty patients with various genotypes were randomly selected to undergo an 8-week repaglinide treatment regimen. Patients with the G allele of the KCNJ11 Lys23Glu polymorphism showed higher levels of fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) (P < 0.05). After repaglinide treatment, patients with the GA or AA genotype showed higher levels of FPG, PPG, and glycated hemoglobin (HbA(1c)) compared with patients with the GG genotype (P < 0.05). Patients with the C allele of TCF7L2 rs290487(C/T) had higher total cholesterol levels and lower body mass index (BMI) (P < 0.05). In patients with the TT genotype, the drug showed better efficacy with respect to levels of fasting insulin, triglycerides, and low-density lipoprotein cholesterol (LDL-c) than in patients with the CC or CT genotype (P < 0.05). The KCNJ11 and TCF7L2 polymorphisms were associated with repaglinide efficacy.

Repression of NFAT3 transcriptional activity by estrogen receptors.

Nuclear factor of activated T cells 3 (NFAT3) activities have been implicated in many biological processes, such as breast cancer, cardiac hypertrophy, learning and memory, and adipocyte differentiation. However, how protein factors regulate NFAT3 transcriptional activity is poorly understood. Here, we report that regardless of estrogen, overexpression of estrogen receptor alpha and beta (ERalpha and ERbeta) suppresses NFAT3 transcriptional activity, whereas knockdown of endogenous ERalpha and ERbeta enhances the activity. Estrogen further enhances ER inhibition of NFAT3-dependent transcription. ERalpha and ERbeta interact with NFAT3 independently of the NFAT agonists phorbol myristate acetate (PMA) and ionomycin, and ERalpha is recruited to an NFAT3 target gene promoter. Phosphorylation of ERalpha at different sites differentially affects ERalpha modulation of NFAT3 transcriptional activity. These results suggest that ER may play a critical role in regulation of NFAT3 transcriptional activity.

Galanin and spinal pain mechanisms: where do we stand in 2008?

Since the discovery of galanin in 1983, one of the most frequently mentioned possible physiological functions for this peptide is spinal pain modulation. This notion, initially based on the preferential presence of galanin in dorsal spinal cord, has been supported by results from a large number of morphological, molecular and functional studies in the last 25 years. It is generally agreed that spinally applied galanin produces a biphasic dose-dependent effect on spinal nociception through activation of GalR1 (inhibitory) or GalR2 (excitatory) receptors. Galanin also appears to have an inhibitory role endogenously, particularly after peripheral nerve injury when the synthesis of galanin is increased in sensory neurons. In recent years, small-molecule ligands of galanin receptors have been developed, raising the hope that drugs affecting galaninergic transmission may be used as analgesics.

Hyperalgesia and increased neuropathic pain-like response in mice lacking galanin receptor 1 receptors.

The neuropeptide galanin may have a role in modulation of nociception, particularly after peripheral nerve injury. The effect of galanin is mediated by at least three subtypes of receptors. In the present study, we assessed the nociceptive sensitivity in mice lacking the galanin receptor 1 gene (Galr1) and the development of neuropathic pain-like behaviours after photochemically induced partial sciatic nerve ischaemic injury. Under basal condition, Galr1 knock-out (Galr1(-/-)) mice had shortened response latency on the hot plate, but not tail flick and paw radiant heat, tests. The mechanical sensitivity was not different between Galr1(-/-) and wild type (Galr1(+/+)) mice, whereas the cold response was moderately enhanced in Galr1(-/-) mice. Both Galr1(-/-) mice and Galr1(+/+) controls developed mechanical and heat hypersensitivity after partial sciatic nerve injury. The duration of such pain-like behaviours was significantly increased in Galr1(-/-). The Galr1(-/-) mice and Galr1(+/+) mice did not differ in their recovery from deficits in toe-spread after sciatic nerve crush. The results provide some evidence for an inhibitory function for the neuropeptide galanin acting on galanin receptor 1 (GALR1) in nociception and neuropathic pain after peripheral nerve injury in mice.