Similar excitability through different sodium channels and implications for the analgesic efficacy of selective drugs.

Nociceptive sensory neurons convey pain-related signals to the CNS using action potentials. Loss-of-function mutations in the voltage-gated sodium channel NaV1.7 cause insensitivity to pain (presumably by reducing nociceptor excitability) but clinical trials seeking to treat pain by inhibiting NaV1.7 pharmacologically have struggled. This may reflect the variable contribution of NaV1.7 to nociceptor excitability. Contrary to claims that NaV1.7 is necessary for nociceptors to initiate action potentials, we show that nociceptors can achieve similar excitability using different combinations of NaV1.3, NaV1.7, and NaV1.8. Selectively blocking one of those NaV subtypes reduces nociceptor excitability only if the other subtypes are weakly expressed. For example, excitability relies on NaV1.8 in acutely dissociated nociceptors but responsibility shifts to NaV1.7 and NaV1.3 by the fourth day in culture. A similar shift in NaV dependence occurs in vivo after inflammation, impacting ability of the NaV1.7-selective inhibitor PF-05089771 to reduce pain in behavioral tests. Flexible use of different NaV subtypes exemplifies degeneracy - achieving similar function using different components - and compromises reliable modulation of nociceptor excitability by subtype-selective inhibitors. Identifying the dominant NaV subtype to predict drug efficacy is not trivial. Degeneracy at the cellular level must be considered when choosing drug targets at the molecular level.

Genome-wide analysis of Chinese keloid patients identifies novel causative genes.

Background: Keloids are benign skin tumors that appears on skin lesions in humans. Keloids are characterized by invasive tumor growth and are highly prone to recurrence after treatment. The incidence of keloids is ethnically specific; however, the molecular mechanism underlying the incidence of keloids in the Chinese population remains unclear. To date, no reports appear to have been published on the molecular characteristics underlying keloids in the Chinese population from the perspective of whole-genome sequencing. Methods: In this study, we collected keloid samples from 9 keloid patients underwent surgery in the Department of Dermatology, The First Affiliated Hospital of Soochow University, paired them to normal skin tissues, and performed whole-exome sequencing. The average depth of the samples was 1,200×, and the average exome coverage was 98.90%. Results: The bioinformatics analysis identified 3,125 single nucleotide variants (SNVs) and 299 insertions/deletions (InDels). The major mutation characteristics of the SNVs were C > A and C > T. The non-synonymous SNV types included stopgain, and stoploss. The non-synonym InDels included frameshift deletion, frameshift insertion, and stopgain. We also found a total of 67,873 copy number variations (CNVs) in the samples. The genes with the highest mutation frequency included mucin 4 (MUC4) (55.6%), tubulin tyrosine ligase like 12 (TTLL12) (33.3%), calcium voltage-gated channel subunit alpha1 (CACNA1C) (33.3%), and mucin 12 (MUC12) (33.3%). The average tumor mutation burden (TMB) was 289 mutations/million base pair (MB). The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the mutated genes were mainly concentrated in micro ribonucleic acids in cancer and the calcium signaling pathway. The Gene Ontology (GO) analysis showed that mutant genes were mainly concentrated in binding cells, cell parts, and cellular processes. Conclusions: Whole-exome sequencing was performed in the Chinese keloid patients and some potential candidate genes related to keloid occurrence and development were identified, which may provide new molecular targets for the clinical diagnosis and treatment of keloid patients.

Electro-Acupuncture Regulates Metabolic Disorders of the Liver and Kidney in Premature Ovarian Failure Mice.

As per the theory of traditional Chinese medicine (TCM), the liver and kidney dysfunction are important pathogenies for premature ovarian failure (POF). POF is a common gynecological disease that reduced the pregnancy rate. Electro-acupuncture (EA) is a useful non-pharmaceutical therapy that supposedly regulates the function of the liver and kidney in the treatment of POF with TCM. However, the underlying mechanism of EA in the treatment of POF has not been adequately studied through metabonomics with reference to the theory of TCM. Accordingly, we investigated the effect of EA on the liver and kidney metabolites in POF mice through metabolomics. POF mice were established via intraperitoneal injection of cisplatin. Both Sanyinjiao (SP6) and Guanyuan (CV4) were stimulated by EA for 3 weeks. The biological samples (including the serum and the ovary, liver, and kidney tissues) were evaluated by histopathology, molecular biology, and hydrogen-1 nuclear magnetic resonance (1HNMR)-based metabolomics to assess the efficacy of EA. 1HNMR data were analyzed by the orthogonal partial least squares discriminant analysis (OPLS-DA). The results revealed that EA was beneficial to ovarian function and the menstrual cycle of POF. Both the energy metabolism and neurotransmitter metabolism in the liver and kidney were regulated by EA. Notably, EA played an important role in regulating energy-related metabolism in the kidney, and the better effect of neurotransmitter-related metabolism in the liver was regulated by EA. These findings indicated that the ovarian functions could be improved and the metabolic disorder of the liver and kidney caused by POF could be regulated by EA. Our study results thus suggested that the EA therapy, based on the results for the liver and kidney, were related to POF in TCM, as preliminarily confirmed through metabolomics.

Genome-wide identification and genetic characterization of the CaMYB family and its response to five types of heavy metal stress in hot pepper (Capsicum annuum cv. CM334).

MYB proteins play a crucial role in plant growth and development and stress responses. In this study, 160 members of the MYB gene family from the pepper genome database were used to analyze gene structures, chromosome localization, collinearity, genetic affinity and expression in response to heavy metals. The results identified R2R3-MYB members and further phylogenetically classified them into 35 subgroups based on highly conserved gene structures and motifs. Collinearity analysis showed that segmental duplication events played a crucial role in the functional expansion of the CaMYB gene family by intraspecific collinearity, and at least 12 pairs of CaMYB genes existed between species prior to the differentiation between monocots and dicots. Moreover, the upstream CaMYB genes were mainly localized to the phytohormone elements ABRE and transcription factor elements MYB and MYC. Further analysis revealed that MYB transcription factors were closely associated with a variety of abiotic stress-related proteins (e.g., MAC-complex and SKIP). Under the stress of five metal ions, Cd2+, Cu2+, Pb2+, Zn2+, and Fe3+, the expression levels of some CaMYB family genes were upregulated. Of these genes, pairing homologous 1 (PH-1), PH-13, and PH-15 in the roots of Capsicum annuum were upregulated to the greatest extent, indicating that these three MYB family members are particularly sensitive to these five metals. This study provides a theoretical reference for the analysis of the molecular regulatory mechanism of MYB family genes in mediating the response to heavy metals in plants. This study reveals the mode of interaction between MYB and a variety of abiotic stress proteins and clarifies the biological functions of CaMYB family members in the regulation of heavy metal stress.

[Nuclear magnetic resonance-based metabolomics revealed metabolite profiles participate in intervention effect of refined moxibustion in gastric ulcer model rats].

OBJECTIVE: To investigate the effect of refined moxibustion on expression of gastric mucosal epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), and changes of metabolite profiles in gastric ulcer (GU) rats, so as to analyze its mechanism underlying improvement of GU. METHODS: Male SD rats were randomized into control, model, acupoint moxibustion groups (n=6 per group). The GU model was induced by cold-restraint stress. The ignited refined moxa was applied to bilateral "Liangmen" (ST21) and "Zusanli" (ST36) for 3 cones/acupoint, once daily for 7 days. Then, we employed 1H NMR-based metabolomics approach to analyze the metabolic profiles of serum and stomach tissue samples. The conventional histopathological changes of the gastric mucosa were observed by H.E. stain and the expressions of EGFR and VEGF in the gastric mucosa were detected by immunohistochemistry. RESULTS: Compared to the control group, the expression levels of EGFR and VEGF were significantly increased in the model group (P<0.01, P<0.05), and further notably up-regulated in the acupoint moxibustion group (P<0.001, P<0.01). Results of H.E. staining showed damage of the folds of gastric mucosa, disordered arrangement of the glands, infiltration of inflammatory cells and unclear structure of gastric mucosa in the model group, which was relatively milder in the acupoint moxibustion group. 1H-NMR technical analysis showed that in comparison with the control group, 11 and 11 metabolites in the stomach extract and plasma were increased, 10 in the gastric tissue and 3 in the plasma were decreased in the GU model group; while in comparison with the model group, 17 differently expressed metabolites in the gastric extract and 10 metabolites in the plasma restored to their levels of control group after the acupoint moxibustion intervention. These metabolites participate in 12 metabolic pathways including glycine, serine and threonine metabolism, glutathione metabolism, glycine metabolism, alanine, aspartic acid and glutamic acid metabolism, purine metabolism, glyoxylic acid and digarboxylic acid metabolism, biosynthesis of aminoacyl-tRNA, amino sugar and nucleotide sugar metabolism, cysteine and methionine metabolism, citrate cycle, pyruvate metabolism, and the mutual conversion of pentose and glucuronate，suggesting their involvement in moxibustion-induced improvement of GU. CONCLUSION: Refined moxibustion at ST21 and ST36 can up-regulate the expression of EGFR and VEGF in the gastric mucosa and lessen gastric mucosal injury, which may be related to its effects in reducing GU-induced metabolic disorders, including sugar, purine, amino acid, and phospholipid metabolism and antioxidant defense system.

[Effects of eicosapentaenoic acid on biological activity and inflammatory factor expression of human gingival fibroblasts].

PURPOSE: To explore the effects of eicosapentaenoic acid (EPA) on biological activity and inflammatory factor expression of human gingival fibroblasts (HGFs). METHODS: The effects of EPA on the activity, morphology and cell cycle of HGFs were observed by living and dead cell staining, immunofluorescence staining and flow cytometry, respectively. HGFs were stimulated by lipopolysaccharides (LPS) of Porphyromonas gingivalis (P. gingivalis) or heat inactivated P. gingivalis, after which the effects of EPA on mRNA and protein expression of IL-6, IL-8 and IL-1ß were observed by real-time PCR and ELISA, respectively. The gene and protein expression of heme oxygenase-1(HO-1) was also detected by real-time PCR and Western blotting, respectively. The data were analyzed with SPSS 22.0 software package. RESULTS: 200 µmol/L EPA inhibited cell activity of HGFs; 100 µmol/L EPA did not affect cell activity and morphology of HGFs, and had no significant effect on cell cycle (P>0.05). EPA significantly downregulated gene expression of IL-6 and IL-1ß, and protein expression of IL-6 stimulated by P. gingivalis LPS and heat-killed P.gingivalis(P<0.05), in a dose-dependent manner. EPA increased gene expression of HO-1 in a dose dependent manner(P<0.05), and upregulated HO-1 protein expression. CONCLUSIONS: EPA significantly inhibits the expression of inflammatory factors without affecting the biological activity of HGFs, which may be related to the induction of HO-1, suggesting the potential role of EPA in the prevention and treatment of periodontitis.

Organoamine-Directed Assembly of 5p-4f Heterometallic Cluster Substituted Polyoxometalates: Luminescence and Proton Conduction Properties.

The assembly of heterometallic cluster substituted polyoxometalates (POMs) remains a great challenge for inorganic synthetic chemistry up to now. Herein, a series of 5p-4f heterometallic cluster substituted POMs were successfully isolated by a facile one-step hydrothermal reaction method, namely H17(H2en)3[SbIII9SbVLn3O14(H2O)3][(SbW9O33)3(PW9O34)]·28H2O(1-Ln, Ln = Ce, Sm, Eu, Gd, Tb, Dy) (en = ethylenediamine). Interestingly, by replacing en with imidazole, another series of 5p-4f heterometallic cluster substituted POMs H13(HIm)4K2Na4(H2O)9[SbIII9SbVLn3O14(H2O)3][(SbW9O33)3(PW9O34)]·26H2O (2-Ln, Ln = Sm, Eu, Gd, Tb, Dy, Im = imidazole) were obtained. Structural analyses indicate that both 1-Ln and 2-Ln are made up of an unprecedented 5p-4f heterometallic {Sb10Ln3O14(H2O)3} cluster stabilized simultaneously by mixed trilacunary heteropolyanions including {A-α-PW9O34} and {B-α-SbW9O33}. Impedance measurements indicate that both compounds exhibit different proton conduction properties, and the conductivity of 2 can reach up to 1.64 × 10-2 S cm-1 at 85 °C under 98% relative humidity. Moreover, the fluorescence emission behaviors of both compounds have been studied.

[Endogenous metabolites involving effects of moxibustion on injured gastric mucosal tissue in rats with stomach heat or cold syndrome based on nuclear magnetic resonance spectroscopy].

OBJECTIVE: To investigate the profile of metabolites of gastric mucosa involving the effectiveness of moxibustion in the treatment of syndromes of stomach heat (SH) and stomach cold (SC) by 1H-nuclear magnetic resonance (1H-NMR) spectroscopy in rats, so as to reveal its mechanisms underlying improvement of gastric disorders. METHODS: Male SD rats were randomly divided into control, SH-model, SC-model, SH-moxibustion and SC-moxibustion groups (n＝6 rats/group). The SH-model and SC-model were established by gavage of pepper liquid plus ethanol, and ice water plus NaOH, respectively. Moxibustion was applied to bilateral "Zusanli" (ST36) and "Liangmen"(ST21) for 20 min, once daily for 7days. Histopathological changes of the gastric tissue were observed by H．E. staining. Differential metabolites in the gastric mucosal tissue were detected and the relevant metabolic pathways analyzed by using 1H-NMR, pattern recognition method，and online MetPA (http: //www.metaboanalyst.ca). RESULTS: Compared with the control group, the body mass was decreased significantly from the 4th to 14th day after modeling (P<0.05，P<0.01). After the treatment, the body mass was obviously increased from the 10th day on in both SH-EA and SC-EA groups relevant to the SH and SC model group, respectively (P<0.05，P<0.01). H．E. staining showed severe damage of the columnar epithelial structure of the gastric mucosa and inflammatory cell infiltration in the SH group, and inflammatory cell infiltration in the SC model group, which were relatively milder in both moxibustion groups. 1H-NMR analysis displayed a total of 16 potential biomarkers in the injured gastric mucosa of SH syndrome and 14 biomarkers for the SC syndrome after mode-ling, and 13 metabolites related to SH moxibustion and 8 metabolites related to SC moxibustion after moxibustion interventions, respectively. After moxibustion, among the 13 differential metabolites of the SH syndrome, the effectively up-regulated candidates were isoleucine, creatinine, choline and lactate (P<0.05), and the down-regulated ones were choline phosphate, glycine, alanine, urine pyrimidine, tyrosine, phenylalanine, hypoxanthine, adenosine and nicotinamide (P<0.05). Among the 8 metabolites related to the SC syndrome, creatinine, ethanolamine, choline, adenosine and nicotinamide were markedly increased (P<0.05), and glycine, creatine phosphate and tyrosine remarkably decreased in their levels after moxibustion (P<0.05). MetPA showed that moxibustion could regulate 10 metabolic pathways for SH syndrome and 7 metabolic pathways for SC syndrome. Metabolites and metabolic pathways are mainly involved in functions of amino acid metabolism, energy metabolism and inflammatory response. CONCLUSION: The idea of "moxibustion could be used for heat syndrome" has metabolic substance basis, and its efficacy in repairing the injured gastric mucosa involves regulation of amino acid metabolism, energy balance and inflammation response, and moxibustion for SH and SC syndromes has both generality and specificity in regulating metabolic activities.

[Analysis on adolescent depression treated with acupuncture based on the theory of "taking shaoyang as the pivot"].

Depression is related to qi stagnation in the body. At present, the treatment with acupuncture for depression focuses on the theories of the governor vessel, liver, spleen, stomach and the entity of five zang organs, especially for the adult group. However, the attention to adolescent depression is insufficient. It is recorded in Internal Classic that shaoyang meridian is taken as the pivot of three yang meridians, dominates the regulating of the ascending and dispersing of yang qi and plays the key role in treatment. The authors believe that yang qi starts growing at the period of youth, to which shaoyang meridian is corresponded. It is viewed that adolescent depression is closely related to the pivot function of shaoyang. In this paper, based on the theory of "taking shaoyang as the pivot", the mechanism of adolescent depression and the acupoint selection in acupuncture treatment are explored so as to utilize this theory in the treatment of adolescent depression with acupuncture.

Selective Activation of Cholecystokinin-Expressing GABA (CCK-GABA) Neurons Enhances Memory and Cognition.

Cholecystokinin-expressing GABAergic (CCK-GABA) neurons are perisomatic inhibitory cells that have been argued to regulate emotion and sculpt the network oscillations associated with cognition. However, no study has selectively manipulated CCK-GABA neuron activity during behavior in freely-moving animals. To explore the behavioral effects of activating CCK-GABA neurons on emotion and cognition, we utilized a novel intersectional genetic mouse model coupled with a chemogenetic approach. Specifically, we generated triple transgenic CCK-Cre;Dlx5/6-Flpe;RC::FL-hM3Dq (CCK-GABA/hM3Dq) mice that expressed the synthetic excitatory hM3Dq receptor in CCK-GABA neurons. Results showed that clozapine-N-oxide (CNO)-mediated activation of CCK-GABA neurons did not alter open field (OF) or tail suspension (TS) performance and only slightly increased anxiety in the elevated plus maze (EPM). Although CNO treatment had only modestly affected emotional behavior, it significantly enhanced multiple cognitive and memory behaviors including social recognition, contextual fear conditioning, contextual discrimination, object recognition, and problem-solving in the puzzle box. Collectively, these findings suggest that systemic activation of CCK-GABA neurons minimally affects emotion but significantly enhances cognition and memory. Our results imply that CCK-GABA neurons are more functionally diverse than originally expected and could serve as a potential therapeutic target for the treatment of cognitive/memory disorders.

Statistical Analysis of Current Oral Health Care and Dental Education Resources in China.

OBJECTIVE: To collect information and statistical data regarding the current oral health care and dental education resources in China. METHODS: Electronic databases were searched and a literature review conducted. The homepages of relevant universities and colleges were visited to collect dental education information. In addition, private conversations with related experts were conducted. RESULTS: Compared with the 3rd National Oral Health Survey (2005), the ratio of gingival bleeding in individuals aged 33 to 44 years has increased in the last 10 years. The average percentage of residents visiting departments of dentistry in public hospitals is less than 10%. The total number of dentists and assistant dentists increased to 167,227 in 2016, with a ratio of 1.21 per 10,000 people. There is a great imbalance in the distribution of dental practitioners among the provinces. There are 101 dental schools or departments of stomatology that provide 5-year dental training courses and offer bachelor's degrees in dentistry, with another 93 dental institutions offering shorter 3-year training courses for assistant dentists. CONCLUSION: The results of the present study show that there has been significant change during recent years in China. However, the ratio of dental practitioners to the population as well as the number of dental visits carried out is still much lower than in developed countries and does not satisfy the demand for dental care in China. The quality and quantity of dental education, including continuing dental education, calls for improvement in the future.

[Effect of exogenous ATP on NLRP3 inflammasome activation in gingival fibroblasts cells].

PURPOSE: To investigate exogenous ATP-dependent activation of NLRP3 inflammasome and interleukin-1ß ( IL-1ß) secretion in P.gingivalis infected and heat-killed P.gingivalis induced gingival fibroblasts cells ( hGFs) in vitro. METHODS: Gingival tissues were obtained from healthy patients and hGFs were cultured in vitro with tissue block method to harvest primary cells. HGFs was simulated by being treated with 100 MOI live P.gingivalis or 100 MOI heat-killed P.gingivalis (HP.gingivalis) after 5 mmol/L ATP pre-treatment. Real-time PCR was carried out to assess mRNA expression of NLRP3, ASC, caspase-1 and IL-1ß. The protein level of NLRP3 , caspase-1 and IL-1ß was evaluated by Western blot. IL-1ß secretion was measured using ELISA. Statistical analysis was performed using Graphpad prism 6 statistical package and the measurement data were analyzed by t test or one-way ANOVA. RESULTS: Compared with the control group, P.gingivalis downregulated NLRP3 mRNA and ASC mRNA while upregulated IL-1ß mRNA. Moreover, the protein expression of NLRP3 and IL-1ß was decreased. The gene and protein expression of NLRP3, ASC and IL-1ß was induced by HP.gingivalis, while caspase-1mRNA and IL-1ßsecretion was free from P.gingivalis or HP.gingivalis stimulus. All those genes as well as intracellular protein expression and IL-1ßsecretion were significantly potentiated with ATP/P.gingivalis or ATP/HP.gingivalis stimuli in hGFs. CONCLUSIONS: Exogenous ATP may be a potential stimulus signal in favour of NLRP3 inflammasome activation of hGFs and mediated inflammatory factor IL-1ß secretion.

Adaptively capturing the heterogeneity of expression for cancer biomarker identification.

BACKGROUND: Identifying cancer biomarkers from transcriptomics data is of importance to cancer research. However, transcriptomics data are often complex and heterogeneous, which complicates the identification of cancer biomarkers in practice. Currently, the heterogeneity still remains a challenge for detecting subtle but consistent changes of gene expression in cancer cells. RESULTS: In this paper, we propose to adaptively capture the heterogeneity of expression across samples in a gene regulation space instead of in a gene expression space. Specifically, we transform gene expression profiles into gene regulation profiles and mathematically formulate gene regulation probabilities (GRPs)-based statistics for characterizing differential expression of genes between tumor and normal tissues. Finally, an unbiased estimator (aGRP) of GRPs is devised that can interrogate and adaptively capture the heterogeneity of gene expression. We also derived an asymptotical significance analysis procedure for the new statistic. Since no parameter needs to be preset, aGRP is easy and friendly to use for researchers without computer programming background. We evaluated the proposed method on both simulated data and real-world data and compared with previous methods. Experimental results demonstrated the superior performance of the proposed method in exploring the heterogeneity of expression for capturing subtle but consistent alterations of gene expression in cancer. CONCLUSIONS: Expression heterogeneity largely influences the performance of cancer biomarker identification from transcriptomics data. Models are needed that efficiently deal with the expression heterogeneity. The proposed method can be a standalone tool due to its capacity of adaptively capturing the sample heterogeneity and the simplicity in use. SOFTWARE AVAILABILITY: The source code of aGRP can be downloaded from https://github.com/hqwang126/aGRP .

Dexmedetomidine Prevents Excessive γ-Aminobutyric Acid Type A Receptor Function after Anesthesia.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Postoperative delirium is associated with poor long-term outcomes and increased mortality. General anesthetic drugs may contribute to delirium because they increase cell-surface expression and function of α5 subunit-containing γ-aminobutyric acid type A receptors, an effect that persists long after the drugs have been eliminated. Dexmedetomidine, an α2 adrenergic receptor agonist, prevents delirium in patients and reduces cognitive deficits in animals. Thus, it was postulated that dexmedetomidine prevents excessive function of α5 γ-aminobutyric acid type A receptors. METHODS: Injectable (etomidate) and inhaled (sevoflurane) anesthetic drugs were studied using cultured murine hippocampal neurons, cultured murine and human cortical astrocytes, and ex vivo murine hippocampal slices. γ-Aminobutyric acid type A receptor function and cell-signaling pathways were studied using electrophysiologic and biochemical methods. Memory and problem-solving behaviors were also studied. RESULTS: The etomidate-induced sustained increase in α5 γ-aminobutyric acid type A receptor cell-surface expression was reduced by dexmedetomidine (mean ± SD, etomidate: 146.4 ± 51.6% vs. etomidate + dexmedetomidine: 118.4 ± 39.1% of control, n = 8 each). Dexmedetomidine also reduced the persistent increase in tonic inhibitory current in hippocampal neurons (etomidate: 1.44 ± 0.33 pA/pF, n = 10; etomidate + dexmedetomidine: 1.01 ± 0.45 pA/pF, n = 9). Similarly, dexmedetomidine prevented a sevoflurane-induced increase in the tonic current. Dexmedetomidine stimulated astrocytes to release brain-derived neurotrophic factor, which acted as a paracrine factor to reduce excessive α5 γ-aminobutyric acid type A receptor function in neurons. Finally, dexmedetomidine attenuated memory and problem-solving deficits after anesthesia. CONCLUSIONS: Dexmedetomidine prevented excessive α5 γ-aminobutyric acid type A receptor function after anesthesia. This novel α2 adrenergic receptor- and brain-derived neurotrophic factor-dependent pathway may be targeted to prevent delirium.

Optogenetic exploration and modulation of pain processing.

Intractable pain is the single most common cause of disability, affecting more than 20% of the population world-wide. There is accordingly a global effort to decipher how changes in nociceptive processing in the peripheral and central nervous systems contribute to the onset and maintenance of chronic pain. The past several years have brought rapid progress in the adaptation of optogenetic approaches to study and manipulate the activity of sensory afferents and spinal cord neurons in freely behaving animals, and to investigate cortical processing and modulation of pain responses. This review discusses methodological advances that underlie this recent progress, and discusses practical considerations for the optogenetic modulation of nociceptive sensory processing.

A regulation probability model-based meta-analysis of multiple transcriptomics data sets for cancer biomarker identification.

BACKGROUND: Large-scale accumulation of omics data poses a pressing challenge of integrative analysis of multiple data sets in bioinformatics. An open question of such integrative analysis is how to pinpoint consistent but subtle gene activity patterns across studies. Study heterogeneity needs to be addressed carefully for this goal. RESULTS: This paper proposes a regulation probability model-based meta-analysis, jGRP, for identifying differentially expressed genes (DEGs). The method integrates multiple transcriptomics data sets in a gene regulatory space instead of in a gene expression space, which makes it easy to capture and manage data heterogeneity across studies from different laboratories or platforms. Specifically, we transform gene expression profiles into a united gene regulation profile across studies by mathematically defining two gene regulation events between two conditions and estimating their occurring probabilities in a sample. Finally, a novel differential expression statistic is established based on the gene regulation profiles, realizing accurate and flexible identification of DEGs in gene regulation space. We evaluated the proposed method on simulation data and real-world cancer datasets and showed the effectiveness and efficiency of jGRP in identifying DEGs identification in the context of meta-analysis. CONCLUSIONS: Data heterogeneity largely influences the performance of meta-analysis of DEGs identification. Existing different meta-analysis methods were revealed to exhibit very different degrees of sensitivity to study heterogeneity. The proposed method, jGRP, can be a standalone tool due to its united framework and controllable way to deal with study heterogeneity.

MiR-155 up-regulated by TGF-ß promotes epithelial-mesenchymal transition, invasion and metastasis of human hepatocellular carcinoma cells in vitro.

It has previously been reported that microRNA (miR)-155 is linked to the recurrence and prognosis of hepatocellular carcinoma (HCC) following liver transplantation. However, the role of miR-155 in the invasion and metastasis of HCC cells remains largely unclear. The aim of this study was to investigate the expression of miR-155 in HCC cells and its role in the invasion and migration of HCC cells in vitro. We found that the level of expression of miR-155 in HCC tissues and cells was significantly increased compared with non-tumorous adjacent tissues. Further study revealed that recombinant human transforming growth factor-ß (TGF-ß1) up-regulated the expression of miR-155 in HCC cells in vitro. Further, the overexpression of miR-155 in HCC cell line Huh-7 led to increased levels of cell invasion and migration compared with untreated control Huh-7 cells. MiR-155-overexpressed Huh-7 cells also exhibited altered levels of expression of certain cellular adhesion molecules related to epithelial-mesenchymal transition (EMT), including low levels of CDH1 and higher levels of FN1, SNAI1 and ZEB1, compared with control Huh-7 cells. Moreover, it was found that the overexpression of miR-155 and of TGF-ß1 protein decreased the expression of E-Cadherin and increased the expression of Vimentin in Huh-7 cells. These results indicate that an increased level of miR-155 in HCC cells, possibly due to stimulation by TGF-ß1, accelerates the process of EMT, promotes cellular invasion and migration in vitro, and thereby further promotes the progression of HCC.

MOXIBUSTION ALLEVIATES GASTRIC PRECANCEROUS LESIONS IN RATS BY PROMOTING CELL APOPTOSIS AND INHIBITING PROLIFERATION-RELATED ONCOGENES.

BACKGROUND: It is well known that gastric mucosa dysplasia and intestinal metaplasia are gastric precancerous lesions (GPL). Moxibustion treatment of Liangmen (ST21) and Zusanli (ST36) alleviated the inflammatory response and dysplasia of gastric mucosa in our previous study. The purpose of this study was to further examine the underlying mechanism of moxibustion treatment of ST21 and ST36 on GPL. MATERIALS AND METHODS: Sixty SD rats were divided into five groups and rats with GPL were treated with either moxibustion (ST), moxibustion (Sham), or vitacoenzyme. B-cell lymphoma 2 (bcl-2), tumor protein p53 (P53) and cellular Myc (C-MYC), which are related to cell apoptosis, proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor (VEGF), argyrophilic nucleolar organizer region proteins (Ag-NORs), which are associated with cell proliferation, and cell signaling proteins, nuclear factor kappa B (NF-κB), epidermal growth factor receptor (EGFR) and phosphorylated extracellular signal regulated kinase (p-ERK), were measured after moxibustion treatment. RESULTS: Compared with Control group, gastric mucosa in GPL group showed abnormal mucosal proliferation and pathological mitotic figure, the mRNA expression of bcl-2, P53 and C-MYC increased significantly (P < 0.01), the protein expression of PCNA, VEGF, Ag-NORs and the activity of NF-κß as well as EGFR/ERK signaling proteins also increased significantly (P < 0.01). Moxibustion treatment decreased gastric mucosal proliferation and pathological mitotic figure, down-regulated the mRNA expression of bcl-2, P53, C-MYC (P < 0.01), decreased the protein expression of PCNA, VEGF, Ag-NORs and the activity of NF-κß as well as EGFR/ERK signaling proteins significantly (P < 0.01). But moxibustion treatment of Sham didn't show the same effect on GPL. CONCLUSION: Moxibustion treatment inhibited cell apoptosis and reduced gastric mucosa dysplasia by inhibiting the expression of bcl-2, P53, C-MYC and decreased the activity of NF-κß as well as EGFR/ERK signaling proteins.

Disrupting GluA2-GAPDH Interaction Affects Axon and Dendrite Development.

GluA2-containing AMPA receptors (AMPARs) play a critical role in various aspects of neurodevelopment. However, the molecular mechanisms underlying these processes are largely unknown. We report here that the interaction between GluA2 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is necessary for neuron and cortical development. Using an interfering peptide (GluA2-G-Gpep) that specifically disrupts this interaction, we found that primary neuron cultures with peptide treatment displayed growth cone development deficits, impairment of axon formation, less dendritic arborization and lower spine protrusion density. Consistently, in vivo data with mouse brains from pregnant dams injected with GluA2-G-Gpep daily during embryonic day 8 to 19 revealed a reduction of cortical tract axon integrity and neuronal density in post-natal day 1 offspring. Disruption of GluA2-GAPDH interaction also impairs the GluA2-Plexin A4 interaction and reduces p53 acetylation in mice, both of which are possible mechanisms leading to the observed neurodevelopmental abnormalities. Furthermore, electrophysiological experiments indicate altered long-term potentiation (LTP) in hippocampal slices of offspring mice. Our results provide novel evidence that AMPARs, specifically the GluA2 subunit via its interaction with GAPDH, play a critical role in cortical neurodevelopment.

Glia and TRPM2 Channels in Plasticity of Central Nervous System and Alzheimer's Diseases.

Synaptic plasticity refers to the ability of neurons to strengthen or weaken synaptic efficacy in response to activity and is the basis for learning and memory. Glial cells communicate with neurons and in this way contribute in part to plasticity in the CNS and to the pathology of Alzheimer's disease (AD), a neurodegenerative disease in which impaired synaptic plasticity is causally implicated. The transient receptor potential melastatin member 2 (TRPM2) channel is a nonselective Ca(2+)-permeable channel expressed in both glial cells (microglia and astrocytes) and neurons. Recent studies indicated that TRPM2 regulates synaptic plasticity as well as the activation of glial cells. TRPM2 also modulates oxidative stress and inflammation through interaction with glial cells. As both oxidative stress and inflammation have been implicated in AD pathology, this suggests a possible contribution of TRPM2 to disease processes. Through modulating the homeostasis of glutathione, TRPM2 is involved in the process of aging which is a risk factor of AD. These results potentially point TRPM2 channel to be involved in AD through glial cells. This review summarizes recent advances in studying the contribution of TRPM2 in health and in AD pathology, with a focus on contributions via glia cells.