Research advancements on the involvement of E3 ubiquitin ligase UBR5 in gastrointestinal cancers.

E3 ubiquitin ligases comprise a family of ubiquitination-catalyzing enzymes that have been extensively researched and are considered crucial components of the ubiquitin-proteasome system involved in various diseases. The ubiquitin-protein ligase E3 component n-recognition 5 (UBR5) is an E3 ubiquitin-protein ligase that has garnered considerable interest of late. Recent studies demonstrate that UBR5 undergoes high-frequency mutations, chromosomal amplification, and/or abnormalities during expression of various malignant tumors. These alterations correlate with the biological behaviors and prognoses of malignancies, such as tumor invasion, metastasis, and resistance to chemotherapeutic agents. This study aimed to comprehensively elucidate the biological functions of UBR5, and its role and relevance in the context of gastrointestinal cancers. Furthermore, this article expounds a scientific basis to explore the molecular mechanisms underlying gastrointestinal cancers and developing targeted therapeutic strategies for their remediation.

Bismuth-Containing Quadruple Therapy for Helicobacter pylori Eradication: A Randomized Clinical Trial of 10 and 14 Days.

BACKGROUND: Bismuth-containing quadruple therapy is the first-line treatment for eradicating Helicobacter pylori (H. pylori). The optimal duration for H. pylori eradication using bismuth-containing quadruple therapy remains controversial. Therefore, we aimed to compare the clinical effects of the 10- and 14-day bismuth-containing quadruple treatment regimen to eradicate H. pylori. METHODS: Treatment-naïve patients with H. pylori infection (n = 1300) were enrolled in this multicenter randomized controlled study across five hospitals in China. They were randomized into 10- or 14-day treatment groups to receive bismuth-containing quadruple therapy as follows: vonoprazan 20 mg twice daily; bismuth 220 mg twice daily; amoxicillin 1000 mg twice daily; and either clarithromycin 500 mg twice daily or tetracycline 500 mg four times daily. At least 6 weeks after treatment, we performed a 13C-urea breath test to evaluate H. pylori eradication. RESULTS: The per-protocol eradication rates were 93.22% (564/605) and 93.74% (569/607) (p < 0.001) and the intention-to-treat eradication rates were 88.62% (576/650) and 89.38% (581/650) (p = 0.007) for the 10- and 14-day regimens, respectively. Incidence of adverse effects was lower in patients who received 10- vs. 14 days of treatment (22.59% vs. 28.50%, p = 0.016). We observed no significant differences in the compliance to treatment or the discontinuation of therapy because of severe adverse effects between the groups. CONCLUSION: Compared with the 14-day bismuth-containing quadruple regimens, the 10-day regimen demonstrated a non-inferior efficacy and lower incidence of adverse effects. Therefore, the 10-day regimen is safe and tolerated and could be recommended for H. pylori eradication (NCT05049902).

Efficacy and safety of a 14-day modified concomitant therapy for refractory Helicobacter pylori infection: a pilot study.

BACKGROUND AND AIM: After three treatment failures, Helicobacter pylori infection is deemed refractory as antibiotic treatment options become significantly limited. This study evaluated the efficacy and safety of a 14-day modified concomitant therapy for managing refractory H. pylori infection. METHODS: Patients who had failed to respond to three or more rounds of H. pylori therapies were recruited for this study. They received a 14-day modified concomitant therapy, including esomeprazole 40 mg, amoxicillin 1000 mg, and furazolidone 100 mg twice daily and tetracycline 500 mg four times daily. Demographic data, adverse events, and patient compliance were recorded. The presence of H. pylori was reevaluated 6 weeks following treatment. Eradication rate was assessed as the primary outcome. RESULTS: Overall, 59 participants received the 14-day modified concomitant therapy. In the intention-to-treat and per-protocol analyses, the eradication rate was 84.7% (50/59) and 89.3% (50/56), respectively. H. pylori was successfully isolated from 75.0% (12/16) of patients. The resistance rate of H. pylori to metronidazole, levofloxacin, and clarithromycin was 91.7% (11/12), 58.3% (7/12), and 50.0% (6/12), respectively. Resistance to amoxicillin, furazolidone, or tetracycline was not observed. The frequency of adverse events was 35.6% (21/59), with no serious adverse events reported. CONCLUSION: The 14-day modified concomitant therapy appears to be appropriate for refractory H. pylori infection and is particularly promising for the Chinese population. A randomized controlled trial is warranted to verify its efficacy, especially in the current environment of increasing antibiotic resistance.

Transmission routes and patterns of helicobacter pylori.

BACKGROUND AND OBJECTIVE: Helicobacter pylori (H. pylori), a gram-negative bacterium that colonizes the stomach, can cause chronic gastritis and peptic ulcers, as well as gastric cancer as a Class I carcinogen. However, the modes of H. pylori transmission are not clear. This review aims to clarify the transmission routes and patterns of H. pylori and identify efficacious prevention measures. METHODS: Studies of H. pylori transmission were identified using PubMed, the Web of Science, and Cochrane Central; the retrieval deadline was October 2022. RESULTS: The transmission routes of H. pylori are discussed, focusing on the five primary transmission routes, namely fecal-oral, oral-oral, gastric-oral, anal-oral, and genital-oral. We propose that H. pylori is contracted through multiple transmission routes. Additionally, we summarize the key transmission patterns of H. pylori, including person-to-person and animal-to-human transmission, as well as foodborne and occupational exposure. CONCLUSION: Fecal-oral appears to be the most common H. pylori transmission routes. Although the oral-oral pathway is also important, the evidence does not support that this route of transmission is universal. The gastric-oral route occurs primarily in children and patients who are prone to vomiting. Meanwhile, the anal-oral and genital-oral routes remain hypothetical. Person-to-person and foodborne infections represent the predominant transmission patterns of H. pylori, whereas strong environmental and occupational limitations are associated with animal-to-human and occupational exposure.

Cardia and non-cardia gastric cancer risk associated with Helicobacter pylori in East Asia and the West: A systematic review, meta-analysis, and estimation of population attributable fraction.

OBJECTIVES: To assess the region-specific relative risk of cardia/non-cardia gastric cancer (CGC/NCGC) associated with Helicobacter pylori (H. pylori) and quantify its contribution to gastric cancer burden using population attributable fraction (PAF). METHODS: PubMed, EMBASE, Web of Science, and Cochrane Central databases were searched by two reviewers until April 20, 2022. The association between H. pylori infection and NCGC/CGC was assessed using pooled odds ratios (ORs) with 95% confidence intervals (CIs). PAF was calculated using the formula of H. pylori prevalence and the pooled OR. RESULTS: One hundred and eight studies were included. A significant association was observed between H. pylori infection and NCGC in East Asia (OR, 4.36; 95% CI: 3.54-5.37) and the West (OR, 4.03; 95% CI: 2.59-6.27). Regarding CGC, a significant association was found only in East Asia (OR, 2.86; 95% CI: 2.26-3.63), not in the West (OR, 0.80; 95% CI: 0.61-1.05). For studies with a follow-up time of ≥10 years, pooled ORs for NCGC and CGC in East Asia were 5.58 (95% CI: 4.08-7.64) and 3.86 (95% CI: 2.69-5.55), respectively. Pooled OR for NCGC was 6.80 (95% CI: 3.78-12.25) in the West. PAFs showed that H. pylori infection accounted for 71.2% of NCGC, 60.7% of CGC in East Asia, and 73.2% of NCGC in the West. CONCLUSIONS: Gastric cancer burden associated with H. pylori infection exhibits important geographical differences. Prolonged follow-up period could overcome the underestimation of the magnitude of the association between H. pylori infection and CGC/NCGC. Customized strategies for H. pylori screening and eradication should be implemented to prevent gastric cancer.

The cure rate of 10-day bismuth-containing quadruple therapy for Helicobacter pylori eradication is equivalent to 14-day: a systematic review and meta-analysis.

Helicobacter pylori (H. pylori) infection is a major cause of duodenal ulcers, gastric ulcers, and gastric cancer. However, the optimal duration for H. pylori eradication therapy remains controversial. Most studies have mainly focused on triple therapy, and there is insufficient research on bismuth-containing quadruple therapy. The aim of this study was to compare the clinical effect of the 10-day bismuth-containing quadruple treatment regimen with the 14-day regime in eradicating H. pylori. We searched PubMed, Embase, Web of Science, and the Cochrane Library for randomized controlled trials published in English until May 2022 according to the eligibility criteria. Summary risk ratios (RRs) and 95% confidence intervals (CIs) for eradication rates, adverse effects, and compliance were calculated for included studies. Four studies, involving 1173 patients, were eligible for inclusion. The eradication rate was similar in the 10-day treatment group and the 14-day treatment group in the intention-to-treat analysis (RR 0.97, 95% CI 0.93 to 1.01). Meanwhile, the incidence of adverse effects was lower in patients who received 10 days of treatment than in those who received 14 days of treatment and patients' compliance was almost the same between two groups. Compared to the 14-day bismuth-containing quadruple regimens, 10-day regimens had similar efficacy and lower incidence of adverse effects. Therefore, the 10-day regimen is safe and well-tolerated and should be recommended for H. pylori infection.

Efficacy of bismuth for antibiotic-resistant Helicobacter pylori strains eradication: A systematic review and meta-analysis.

BACKGROUND & AIMS: Antibiotic resistance of Helicobacter pylori (H. pylori) is increasing worldwide, and bismuth quadruple therapy has been recommended as a first-line regimen in many areas. This study aimed to investigate whether bismuth would improve the eradication rate (ER) of clarithromycin-/metronidazole-/levofloxacin-resistant H. pylori strains and how much additional efficacy bismuth could achieve. METHODS: PubMed, EMBASE, Web of Science, and Cochrane Central databases for randomized controlled trials were systematically searched by two independent reviewers until 15 January 2022. Pooled ERs of clarithromycin-/metronidazole-/levofloxacin-resistant H. pylori strains were compared between bismuth-containing and non-bismuth therapies. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using a random-effects model. RESULTS: Eight studies enrolling 340 individuals were included. The RRs of pooled ERs compared between bismuth-containing and non-bismuth therapies were 1.83 for clarithromycin-resistant strains (95% CI 1.16-2.89, pooled ER: 76.9% vs. 36.6%, p = .009, I2  = 0%), 1.39 for metronidazole-resistant strains (95% CI 1.09-1.78, pooled ER: 86.8% vs. 60.9%, p = .008, I2  = 37%), 2.75 for dual clarithromycin/metronidazole-resistant strains (95% CI 1.01-7.52, pooled ER: 76.9% vs. 18.2%, p = .05, I2  = 0%), and 1.04 for levofloxacin-resistant strains (95% CI 0.56-1.93, pooled ER: 63.4% vs. 54.3%, p = .90; I2  = 60%). Bismuth significantly increased the ERs of clarithromycin-, metronidazole-, and dual-resistant strains by 40%, 26%, and 59%, respectively. Subgroup analysis of treatment duration showed that the significantly higher eradication rate for antibiotic-resistant strains in bismuth-containing therapy than non-bismuth therapy was only observed in 14-day treatment regimens and not in 7-day regimens (p = .02 and .17, respectively). CONCLUSIONS: Bismuth was most effective in improving the ERs of dual-resistant H. pylori strains, followed by clarithromycin- and metronidazole-resistant strains. Prolonged treatment duration might effectively improve the efficacy of bismuth in overcoming antibiotic resistance.

Low compliance to post-screening recommendations in a family-based Helicobacter pylori screening and treatment program: A prospective cohort study.

BACKGROUND: Intra-family transmission is an important Helicobacter pylori (H. pylori) infection route. Family-based screening and treatment of H. pylori is a promising strategy. However, limited data are available on patient compliance with post-screening recommendations for such a strategy. MATERIALS AND METHODS: A prospective cohort study of families from six regions in Shandong, China, from July 2021 to February 2022 was conducted. Demographic characteristics, prior testing, and treatment for H. pylori, prior gastroscopy, symptoms, and family history were collected. Infection status of participants was determined using the 13 C-urea breath test. Infected participants were recommended to undergo eradication treatment, confirmation testing, and gastroscopy per expert consensus. Participants were monitored for 6 months to record recommendation compliance in a real-world setting. Logistic regression models were used to analyze the factors influencing compliance with the recommendations. RESULTS: The study included 1173 individuals from 386 families with the overall infection rate of 36.7%. The recommendation compliance for eradication treatment, confirmation testing, and gastroscopy was 69.3% (271/391), 32.5% (88/271), and 6.1% (19/309), respectively. Factors that increased the risk of lower compliance were male sex (odds ratio [OR], 1.917, 95% confidence interval [CI], 1.233-2.981), and living in a non-urban area (OR, 1.954, 95% CI, 1.241-3.074), for treatment recommendations; having more than one infected family member (OR, 2.138, 95% CI, 1.237-3.698), and a lower family income (¥100,000-¥300,000 per year, OR, 7.247, 95% CI, 1.788-29.363; or <¥100,000 per year, OR, 7.294, 95% CI, 1.832-29.042), for confirmation testing recommendations; and being asymptomatic (OR, 3.009, 95% CI, 1.105-8.196), for gastroscopy recommendations. CONCLUSIONS: Post-screening recommendation compliance for this family-based H. pylori screening and treatment program was unsatisfactory. Further studies focusing on pre-screening education are warranted to improve compliance.

Physicochemical and antioxidant activity of fruit harvested from eight jujube (Ziziphus jujuba Mill.) cultivars at different development stages.

Jujube is a crop highly resistant to drought and salinity, making it one of the main fruit trees in Xinjiang. The present study evaluated the changes in the physicochemical and antioxidant activities of jujube fruit of eight different cultivars from Xinjiang, China. The developmental stages were selected according to the days after full bloom and fruit peel colour during ripening; these stages included young (S1), fruit core-hardening (S2), green ripening (S3), half-red maturity (S4) and complete red. In present study, different cultivars of jujube fruit showed similar chemical profiles, but their amounts showed great variation. HZ had the highest content of sugars, and JY had the highest content of cAMP and cGMP, while relatively higher levels of ascorbic acid, catechin, epicatechin, rutin, proanthocyanidin and antioxidant activity were found in 'FS' than in other cultivars, indicating that 'FS' could be used as a potential natural antioxidant. Regarding the development stages of jujube fruit, the moisture, ascorbic acid, total polyphenol, catechin, epicatechin, proanthocyanidin and rutin contents decreased during the development of all jujube cultivars, while the fructose, glucose, sucrose, cAMP, and cGMP contents greatly increased. The antioxidant activity determined by DPPH and ABTS radical scavenging decreased as the fruits matured. Therefore, the results suggest that green jujube (S1) could be used for natural antioxidants (catechin, epicatechin, proanthocyanidin) and that the advanced ripening stage(S5) is the proper picking period for fresh fruit and commercial processing.

Two Different 1-Week Quadruple Therapies Given Back-to-Back Consecutive Therapy for Difficult-to-Treat Helicobacter pylori Infection: A Pilot Study.

INTRODUCTION: We aim to evaluate the efficacy of 2 different 1-week quadruple therapies given back-to-back consecutive therapy in patients with difficult-to-treat Helicobacter pylori infection. METHODS: Patients with proven H. pylori infection were recruited after >3 failed standard quadruple eradication. They received consecutive therapy consisting of esomeprazole 40 mg or rabeprazole 20 mg twice daily, amoxicillin 1,000 mg twice daily, tetracycline 500 mg 4 times daily, and furazolidone 100 mg 3 times daily for the first 7 days, followed by colloidal bismuth pectin 200 mg twice daily in place of furazolidone 100 mg for another 7 days. Eradication rates, treatment-emergent adverse events (TEAEs), and compliance were assessed. RESULTS: Sixty-five patients were enrolled. The mean number of previous eradications was 3.6 (range: 3-7). The intention-to-treat and per-protocol eradication rates were 90.8% (59/65) and 95.1% (58/61). In total, 23.4% (15/64) of patients experienced drug-related TEAEs. No serious adverse events were observed. None of the patients required treatment for TEAEs, and 95.3% (61/64) showed good compliance. Overall, 51 patients (78.5%) were with the available antimicrobial susceptibility testing results. The resistance rates to clarithromycin, metronidazole, levofloxacin, and amoxicillin were 60.8% (31/51), 100% (51/51), 70.6% (36/51), and 2.0% (1/51), respectively. No resistance was detected to either furazolidone or tetracycline. However, in 54.9% of patients (28/51), H. pylori was resistant to 3 antibiotics (metronidazole, levofloxacin, and clarithromycin). DISCUSSION: Consecutive therapy, including amoxicillin, tetracycline, and furazolidone, achieved a good eradication rate (>90%), with desirable compliance and tolerability in difficult-to-treat H. pylori infection.

Clarithromycin versus furazolidone for naïve Helicobacter pylori infected patients in a high clarithromycin resistance area.

BACKGROUND AND AIM: The increase in antibiotic resistance makes the eradication of Helicobacter pylori more difficult. Considering the limitations of the application of susceptibility-guided therapy, it is important to find an effective empirical regimen. The aim of the study is to compare the efficacy, safety, and cost-effectiveness of clarithromycin-based bismuth-containing quadruple therapy (C-BQT) and furazolidone-based bismuth-containing quadruple therapy (F-BQT) in naïve H. pylori positive patients. METHODS: This was an open-label, randomized controlled, crossover trial. The trial comprised two phases. In C-F group, patients received C-BQT in the first phase; those who were still positive for H. pylori infection after the first phase entered the second phase to receive F-BQT as rescue treatment. In F-C group, patients were treated with F-BQT firstly and rescued with C-BQT. RESULTS: As first-line treatments, the eradication rates of C-BQT and F-BQT were 89.7% (157/175) and 92.0% (161/175) (P = 0.458) in intention-to-treat analysis and 93.4% (156/167) and 95.8% (161/168) (P = 0.327) in per-protocol analysis, respectively. The cumulative eradication rates of the C-F group and the F-C group were both 94.3% in intention-to-treat analysis (P = 1.000). Cost-effectiveness indexes of F-BQT and C-BQT were 0.54 and 1.24 in first-line treatments. Frequencies of adverse events in F-BQT and C-BQT had no differences (36.0% in C-BQT vs 32.6% in F-BQT, P = 0.499). CONCLUSIONS: Furazolidone-based bismuth-containing quadruple therapy should be preferred for its excellent cost-effectiveness and acceptable safety.

Chronic restraint stress increases social interaction in C57BL/6J mice monitoring through MiceProfiler analysis.

The social deficit is a prevailing symptom in stress-induced depression. Although social interaction behavior has been widely studied in humans and rodents, it is imprecise to record the social behavior between two free-moving mice via perusal. In the present study, we applied an approach to analyze the social behavior in mice using a software named "MiceProfiler." C57BL/6J mice were stressed via chronic restraint stress (CRS) and housed in three populations of different sizes as follows: single, three in a cage, and six in a cage. The MiceProfiler was used to analyze the video of behavioral repertoire and, the result showed that stressed and single housed mice exhibited more social interaction both in the contact time and contact activities. Furthermore, we investigated the effect of CRS on social behavior when the mice were housed in larger populations size (three or six in a cage) and found that, the CRS procedure promoted social interaction. However, the larger population size resulted in the less total contact time, less time of head-tail, and moving in an opposite way. Besides, the CRS mice showed less social avoidance while the mice from a larger population presented less active contact. And the CRS mice also exhibited a higher social hierarchy compared with the control. Our data indicated that mild restraint stress might increase the intercommunication between mice. Collectively, our findings provided a new evidence for social behavior study and the MiceProfiler could be a new tool to measure the social behaviors of rodents.

Rapid SNP discovery and a RAD-based high-density linkage map in jujube (Ziziphus Mill.).

BACKGROUND: Ziziphus Mill. (jujube), the most valued genus of Rhamnaceae, comprises of a number of economically and ecologically important species such as Z. jujuba Mill., Z. acidojujuba Cheng et Liu and Z. mauritiana Lam. Single nucleotide polymorphism (SNP) markers and a high-density genetic map are of great benefit to the improvement of the crop, mapping quantitative trait loci (QTL) and analyzing genome structure. However, such a high-density map is still absent in the genus Ziziphus and even the family Rhamnaceae. The recently developed restriction-site associated DNA (RAD) marker has been proven to be most powerful in genetic map construction. The objective of this study was to construct a high-density linkage map using the RAD tags generated by next generation sequencing. RESULTS: An interspecific F1 population and their parents (Z. jujuba Mill. 'JMS2' × Z. acidojujuba Cheng et Liu 'Xing 16') were genotyped using a mapping-by-sequencing approach, to generate RAD-based SNP markers. A total of 42,784 putative high quality SNPs were identified between the parents and 2,872 high-quality RAD markers were grouped in genetic maps. Of the 2,872 RAD markers, 1,307 were linked to the female genetic map, 1,336 to the male map, and 2,748 to the integrated map spanning 913.87 centi-morgans (cM) with an average marker interval of 0.34 cM. The integrated map contained 12 linkage groups (LGs), consistent with the haploid chromosome number of the two parents. CONCLUSION: We first generated a high-density genetic linkage map with 2,748 RAD markers for jujube and a large number of SNPs were also developed. It provides a useful tool for both marker-assisted breeding and a variety of genome investigations in jujube, such as sequence assembly, gene localization, QTL detection and genome structure comparison.

The complex jujube genome provides insights into fruit tree biology.

The jujube (Ziziphus jujuba Mill.), a member of family Rhamnaceae, is a major dry fruit and a traditional herbal medicine for more than one billion people. Here we present a high-quality sequence for the complex jujube genome, the first genome sequence of Rhamnaceae, using an integrated strategy. The final assembly spans 437.65 Mb (98.6% of the estimated) with 321.45 Mb anchored to the 12 pseudo-chromosomes and contains 32,808 genes. The jujube genome has undergone frequent inter-chromosome fusions and segmental duplications, but no recent whole-genome duplication. Further analyses of the jujube-specific genes and transcriptome data from 15 tissues reveal the molecular mechanisms underlying some specific properties of the jujube. Its high vitamin C content can be attributed to a unique high level expression of genes involved in both biosynthesis and regeneration. Our study provides insights into jujube-specific biology and valuable genomic resources for the improvement of Rhamnaceae plants and other fruit trees.

Leukemia inhibitory factor in the neuroimmune communication pathways in allergic asthma.

In the pathogenesis of asthma, central sensitization is suggested to be an important neural mechanism, and neurotrophins and cytokines are likely to be the major mediators in the neuroimmune communication pathways of asthma. However, their impact on the central nervous system in allergic asthma remains unclear. We hypothesize that central neurogenic inflammation develops in the pathogenesis of allergic asthma, and nerve growth factor (NGF) and leukemia inhibitory factor (LIF) are important mediators in its development. An asthma model of rats was established by sensitization and challenged with ovalbumin (OVA). For further confirmation of the role of LIF in neurogenic inflammation, a subgroup was pretreated with intraperitoneally (i.p.) LIF antibody before OVA challenge. The levels of LIF and NGF were measured with reverse transcription and polymerase chain reaction (RT-PCR), in situ hybridization (ISH) and immunohistochemistry stain in lung tissue, airway-specific dorsal root ganglia (DRG, C7-T5) and brain stem of asthmatic rats, anti-LIF pretreated rats and controls. A significantly increased number of LIF- and NGF-immunoreactive cells were detected in lung tissue, DRG and the brain stem of asthmatic rats. In the asthma group a significantly increase level of mRNA encoding LIF and NGF in lung tissue was detected, but not in DRG and the brain stem. Pretreatment with LIF antibody decreased the level of LIF and NGF in all tissues. LIF is an important mediator in the crosstalk between nerve and immune systems. Our study demonstrate that the increased level of LIF and NGF in DRG and brain stem may be not based on result from de novo synthesis, but rather on result from retrograde nerve transport or passage across the blood-brain-barrier.

[Experimental study on the mechanisms of regulating airway neurogenic inflammation in asthma by never growth factor and leukemia inhibitory factor].

OBJECTIVE: To study the mechanisms of regulating airway neurogenic inflammation in asthma by never growth factor (NGF) and leukemia inhibitory factor (LIF), and then to explore new targets in treating asthma. METHODS: Adult male SD rats (n 36) were divided into the normal group, the asthmatic group and the anti-NGF group at random. There were 12 rats in each group. The asthma models were established by sensitization and challenge with ovalbumin, and the asthma model was treated with anti-NGF. The expression of NGF, LIF and substance P (SP) in lung tissue or in doral root ganglion of each rat were detected by immunohistochemistry and hybridisation in situ. RESULTS: (1) The gray-levels of NGF protein/NGF mRNA, LIF protein/LIF mRNA in the lungs were 157 +/- 7, 138 +/- 8, 156 +/- 6, 141 +/- 10 for the asthmatic group respectively, 183 +/- 7, 190 +/- 7, 187 +/- 7, 181 +/- 8 for the normal control group respectively, and 177 +/- 6, 169 +/- 9, 178 +/- 7, 172 +/- 9 for the asthmatic group with anti-NGF treatment. There were significant differences in gray-level of NGF protein/NGF mRNA, LIF protein/LIF mRNA among those three groups (t = 19.40, 15.80, 20.38, [corrected] 14.79, all P < 0.01). (2) The gray-levels of NGF protein/LIF protein, SP protein/SP mRNA in the doral root ganglions were 136 +/- 8, 148 +/- 6, 140 +/- 8, 128 +/- 8 for the asthmatic group respectively, 185 +/- 7, 187 +/- 8, 174 +/- 7, 180 +/- 8 for the normal control group respectively, and 164 +/- 6, 170 +/- 8, 163 +/- 9, 157 +/- 7 for the asthmatic group with anti-NGF treatment. There were also significant differences in gray-level of NGF protein/LIF protein, SP protein/SP mRNA among those three groups (t = 29.50, 22.65, 23.12, 28.71, all P < 0.01). CONCLUSION: Enhancing the synthesis and release of SP in doral root ganglion may be one of the mechanisms by which NGF and LIF regulate airway neurogenic inflammation in asthmatic rats, and this mechanism can be depressed by the intervention of anti-NGF.

[Regulation effect of nerve growth factor on Ras-MAPK signal transduction pathway in neurogenic inflammation of asthma].

OBJECTIVE: To investigate the regulatory effect of nerve growth factor (NGF) on Ras-MAPK signal transduction pathway in neurogenic inflammation of asthma. METHODS: Thirty-six Sprague-Dawley rats were randomly divided into 3 groups (control group, asthma group and anti-NGF group). The asthmatic model was established by ovalbumin inhalation and injection. The protein expressions of pan-Ras, pERK and c-fos in the dorsal root ganglion and lung of the asthma group and the control group were examined by immunohischemical method. Anti-NGF antibody was used to investigate how it affected the protein expression of pan-Ras, pERK and c-fos in the dorsal root ganglion and the lung of the asthma group. PD98059 (the inhibitor of MAPK) and PMA (the enhancer of PKC) were used to culture the NHBEC. Cell extracts were analyzed for pERK, total-ERK and c-fos by Western blot. RESULTS: The protein expressions of pan-Ras, pERK and c-fos in the lung and dorsal root ganglion of the asthma group were significantly higher than those of the control group (P < 0.01). The protein expressions of pan-Ras, pERK and c-fos were decreased by the anti-NGF treatment (P < 0.01) . The expressions of epithelial pERK and c-fos in the NGF group were significantly higher than those in the control group, and PD98059 could inhibit NGF inducing NHBEC to produce pERK and c-fos. PMA could enhance the effects of NGF. CONCLUSION: NGF may play a role in the pathogenesis of neurogenic inflammation in asthma through Ras-MAPK signal transduction pathway.

LIF upregulates expression of NK-1R in NHBE cells.

Leukemia inhibitory factor (LIF), a cytokine at the interface between neurobiology and immunology, is mainly mediated through JAK/STAT pathway and MAPK/ERK pathway. Evidence suggested LIF is related to the higher expression of neurokinin-1 receptor (NK-1R) in asthma. In this study, the immunohistochemistry stain showed the expressions of NK-1R, LIF, p-STAT3, and p-ERK1/2 in the lung tissues of allergic rats were increased compared with the controls, and the main positive cell type was airway epithelial cell. Normal human bronchial epithelial cells were treated with LIF in the presence or absence of AG490 (JAK2 inhibitor), PD98059 (MEK inhibitor), and the siRNA against STAT3. Western blot and RT-PCR indicated that LIF induced the expression of NK-1R, which was inhibited by the inhibitors mentioned above. No significant interaction was found between JAK/STAT pathway and MAPK/ERK pathway. In summary, bronchial epithelial cell changes in asthma are induced by LIF which promotes the expression of NK-1R, and JAK/STAT pathway and MAPK/ERK pathway may participate in this process.

[The relationship between leukemia inhibitory factor and neurokinin receptors in a rat model of asthma].

OBJECTIVE: To study the expression of leukemia inhibitory factor (LIF) and neurokinin receptors (NKR) in the lungs of asthmatic rats, and to evaluate the role of LIF in airway neurogenic inflammation. METHODS: Twenty-four Wistar rats were randomly divided into a control group (group A, n = 8), an asthma group (group B, n = 8) and a dexamethasone treated group (group C, n = 8). The rat asthmatic model was made by intraperitoneal injection and nebulized aspiration of ovalbumin (OVA) at the concentrations of 10% and 1% respectively. Expression levels of lung LIF, NK-1R and NK-2R were detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot two weeks after challenge, and the localization of NK-1R was determined by immunohistochemistry. RESULTS: After challenge, the expressions of lung LIF mRNA in group A, B and C were 0.240 +/- 0.020, 0.510 +/- 0.130, 0.180 +/- 0.050, and protein levels were 23 110 +/- 8 018, 40 832 +/- 12 964, 16 160 +/- 2 108 respectively. The expressions of lung NK-1R mRNA in group A, B and C were 0.240 +/- 0.020, 1.040 +/- 0.480, 0.170 +/- 0.040, and protein levels were 16 538 +/- 4 342, 32 292 +/- 4 564, 15 018 +/- 1 488 respectively. The mRNA and protein levels of LIF and NK-1R in group B were significantly elevated as compared with group A and C (all P < 0.01). The expressions of lung NK-2R mRNA in group A, B and C were 0.240 +/- 0.040, 0.200 +/- 0.030 and 0.210 +/- 0.040, and no difference was found among three groups (all P > 0.05). In group B, there was a positive correlation between LIF and NK-1R at mRNA (r = 0.850, P < 0.01) and protein (r = 0.868, P < 0.01) levels respectively. NK-1R immunoreactivity was observed primarily in bronchial epithelial cells. CONCLUSION: LIF and NK-1R were excessively expressed and closely correlated in lungs of the rat asthmatic model, suggesting that LIF may be involved in modulating airway neurogenic inflammation.