The Overlap Subgroup of Functional Dyspepsia Exhibits More Severely Impaired Gastric and Autonomic Functions.

GOALS: A combination of multiple tests was introduced to noninvasively investigate the differences in pathophysiologies among functional dyspepsia (FD) subgroups, including postprandial distress syndrome (PDS), epigastric pain syndrome (EPS), and overlap. BACKGROUND: It has not been extensively evaluated whether different pathophysiologies are involved in FD subgroups. STUDY: This multicenter study included 364 FD patients fulfilling Rome IV criteria and 47 healthy controls. A combined noninvasive gastric and autonomic function test was performed: The electrogastrogram and electrocardiogram were recorded simultaneously in the fasting state and after a drink test. Symptoms after drinking were recorded using visual analog scale. RESULTS: (1) Compared with HC, FD patients showed a decreased maximum tolerable volume (MTV) ( P <0.01) and percentage of normal gastric slow waves [normal gastric slow waves (%NSW)] ( P <0.01), and increased postdrinking symptoms, anxiety ( P <0.01), and depression ( P <0.01). The drink reduced %NSW in both FD patients and HC; however, the effect was more potent in patients. (2) The PDS and overlap groups displayed a reduced MTV ( P <0.05). The overlap group exhibited a higher symptom score at 30 minutes after drinking, and higher anxiety and depression scores, and a higher sympathovagal ratio than the EPS ( P <0.05 for all) and PDS ( P <0.01 for all). (3) In the PDS subgroup, the MTV, postprandial sympathovagal ratio, and depression were associated with the overall dyspepsia symptom scale (DSS, P =0.034, 0.021, 0.043, respectively). No significant associations were found in the other 2 subgroups. CONCLUSIONS: The combination of multiple tests can detect pathophysiological abnormities in FD patients. Overall, patients with overlap symptoms display more severe pathophysiologies.

Aconitine - A promising candidate for treating cold and mechanical allodynia in cancer induced bone pain.

BACKGROUND AND AIMS: Patients suffering from cancer induced bone pain (CIBP) have a poor quality of life that is exacerbated by the lack of effective therapeutic drugs. Monkshood is a flowering plant that has been used in traditional Chinese medicine where it has been used to relieve cold pain. Aconitine is the active component of monkshood, but the molecular mechanism for how this compound reduces pain is unclear. METHODS AND RESULTS: In this study, we employed molecular and behavioral experiments to explore the analgesic effect of aconitine. We observed aconitine alleviated cold hyperalgesia and AITC (allyl-isothiocyanate, TRPA1 agonist) induced pain. Interestingly, we found aconitine directly inhibits TRPA1 activity in calcium imaging studies. More importantly, we found aconitine alleviated cold and mechanical allodynia in CIBP mice. Both the activity and expression of TRPA1 in L4 and L5 DRG (Dorsal Root Ganglion) neurons were reduced with the treatment of aconitine in the CIBP model. Moreover, we observed aconiti radix (AR) and aconiti kusnezoffii radix (AKR), both components of monkshood that contain aconitine, alleviated cold hyperalgesia and AITC induced pain. Furthermore, both AR and AKR alleviated CIBP induced cold allodynia and mechanical allodynia. CONCLUSIONS: Taken together, aconitine alleviates both cold and mechanical allodynia in cancer induced bone pain via the regulation of TRPA1. This research on the analgesic effect of aconitine in cancer induced bone pain highlights a component of a traditional Chinese medicine may have clinical applications for pain.

A Novel Patient-like Swine Model of Perianal Crohn's Disease.

BACKGROUND: Perianal Crohn's disease is associated with poor outcomes and high medical costs. It is notoriously difficult to treat despite therapeutic advancements for luminal disease. A large animal model that mimics human perianal disease is needed to test innovative therapies. OBJECTIVE: This study aimed to create a swine model that replicates the inflammatory component and therapeutic challenges found in patients with perianal Crohn's disease. DESIGN: This was an animal preclinical study. SETTINGS: The experiments were performed at the animal laboratory at the Johns Hopkins University. PATIENTS: Four sus scrufus female pigs were included in the study. INTERVENTIONS: Four female pigs underwent creation of 3 surgical perianal fistulas each, 1 rectovaginal and 2 perianal. Size 24 French setons were placed to maintain patency of the fistula tracts for 4 weeks. After removal of the setons, trinitrobenzene sulfonic acid was administered into the fistula tract to create and maintain local inflammation mimicking perianal Crohn's disease. MAIN OUTCOMES MEASURES: An MRI was obtained to assess the fistulas and the pigs were euthanized to review histopathology. RESULTS: Three inflammatory chronic fistula tracts were successfully created in each pig as confirmed by MRI and examination under anesthesia. This is the first report of maintaining patent fistulas in swine 2 weeks after removal of setons. For the first time, we reported that 2 pigs developed branching fistulas and small abscesses reminiscent of human perianal Crohn's disease. The corresponding histopathologic examination found significant chronic active inflammation on standard hematoxylin and eosin staining. LIMITATIONS: The fistulas were surgically induced and did not occur naturally. CONCLUSIONS: A chronic perianal fistula model in pigs that strongly resembles human perianal Crohn's disease was successfully created. This model can be used to test novel therapeutics and techniques to pave the path for human trials. See Video Abstract at http://links.lww.com/DCR/B969 . UN NUEVO MODELO PORCINO SIMILAR A UN PACIENTE DE LA ENFERMEDAD DE CROHN PERIANAL ANTECEDENTES: La enfermedad de Crohn perianal se asocia con malos resultados y altos costos médicos. Es notoriamente difícil de tratar a pesar de los avances terapéuticos para la enfermedad luminal. Se precisa de un modelo animal grande que imite la enfermedad perianal humana para probar terapias innovadoras.OBJETIVO:Nuestro objetivo de este estudio fue crear un modelo porcino que replique el componente inflamatorio y los desafíos terapéuticos que se encuentran en los pacientes con enfermedad de Crohn perianal.DISEÑO:Este fue un estudio preclínico en animales.AJUSTES:Los experimentos se realizaron en el laboratorio de animales de la Universidad Johns Hopkins.PACIENTES:Se incluyeron en el estudio cuatro cerdas sus scrofa.INTERVENCIONES:Cuatro cerdas fueron sometidas a la creación de 3 fístulas perianales quirúrgicas cada una: 1 recto vaginal y 2 perianales. Se colocaron sedales de 24 French para mantener la permeabilidad de los trayectos fistulosos durante 4 semanas. Tras el retiro de los sedales, se administró ácido trinitrobenceno sulfónico en el trayecto de la fístula para crear y mantener la inflamación local simulando la enfermedad de Crohn perianal.PRINCIPALES MEDIDAS DE RESULTADOS:Se obtuvo una resonancia magnética para evaluar las fístulas y los cerdos fueron sacrificados para revisar la histopatología.RESULTADOS:Se crearon de manera exitosa tres trayectos fistulosos inflamatorios crónicos en cada cerdo, confirmados por imágenes de resonancia magnética y examen bajo anestesia. Este es el primer informe de preservación de fístulas permeables en cerdos 2 semanas tras el retiro de los setones. Por primera vez, informamos que dos cerdos desarrollaron fístulas ramificadas y pequeños abscesos que recuerdan a la enfermedad de Crohn perianal humana. El examen histopatológico correspondiente encontró una significativa inflamación crónica activa en la tinción estándar de hematoxilina y eosina.LIMITACIONES:Las fístulas se indujeron quirúrgicamente y no se produjeron de forma natural.CONCLUSIONES:Se logro recrear con éxito un modelo de fístula perianal crónica en cerdos que se asemeja mucho a la enfermedad de Crohn perianal humana. Este modelo se puede utilizar para probar nuevas terapias y técnicas para allanar el camino para los ensayos en humanos. Consulte Video Resumen en http://links.lww.com/DCR/B969 . (Traducción-Dr Osvaldo Gauto).

Randomised clinical trial: Efficacy and safety of Qing-Chang-Hua-Shi granules in a multicenter, randomized, and double-blind clinical trial of patients with moderately active ulcerative colitis.

Qing-Chang-Hua-Shi (QCHS) is a Chinese herbal formula, which is composed of 11 herbs. Studies have also shown that QCHS granules can alleviate colitis in animal models by preventing inflammatory responses and suppressing apoptosis through the MEK/ERK signaling pathway. To determine the efficacy and safety of QCHS granules in patients with moderately active UC. We performed a multicenter, randomized, placebo-controlled, double-blind study of patients with moderately active UC who did not respond to 4 weeks of mesalazine therapy at the maximum dose. Patients were randomly assigned to groups and administered QCHS granules (125 g/day, n = 59) or an identical placebo, which was similar to the QCHS granules in color and taste (125 g/day, n = 60), with continued 5-ASA 4 g/d therapy for 12 weeks. The primary outcome was the rate of clinical response and clinical remission at week 12. The secondary outcomes were health-related quality of life, endoscopic response rate, and mucosal healing rate. Any changes in mucus/bloody stool and diarrhea were recorded. Out of the 119 enrolled patients at 10 different centers in China, 102 patients completed the trial. Clinical remission and clinical response were seen in 31.48% and 92.59% of QCHS-treated patients, and 12.50% and 72.92% of placebo-treated patients, respectively. There was a significant difference between the two treatment groups. More patients receiving QCHS granules vs. placebo achieved remission of mucus/bloody stool (70.37% vs. 47.92%, P = 0.0361). Adverse event rates were similar (QCHS granules 38.33%; placebo 25.42%). In conclusion, QCHS granules were superior to the placebo in introducing clinical remission and mucosal healing, as well as in relieving mucus/blood stool in patients with moderately active and 5-ASA-refractory UC.

Transcutaneous auricular vagal nerve stimulation improves functional dyspepsia by enhancing vagal efferent activity.

This study was designed to investigate whether transcutaneous auricular vagal nerve stimulation (taVNS) would be able to improve major pathophysiologies of functional dyspepsia (FD) in patients with FD. Thirty-six patients with FD (21 F) were studied in two sessions (taVNS and sham-ES). Physiological measurements, including gastric slow waves, gastric accommodation, and autonomic functions, were assessed by the electrogastrogram (EGG), a nutrient drink test and the spectral analysis of heart rate variability derived from the electrocardiogram (ECG), respectively. Thirty-six patients with FD (25 F) were randomized to receive 2-wk taVNS or sham-ES. The dyspeptic symptom scales, anxiety and depression scores, and the same physiological measurements were assessed at the beginning and the end of the 2-wk treatment. In comparison with sham-ES, acute taVNS improved gastric accommodation (P = 0.008), increased the percentage of normal gastric slow waves (%NSW, fasting: P = 0.010; fed: P = 0.007) and vagal activity (fasting: P = 0.056; fed: P = 0.026). In comparison with baseline, 2-wk taVNS but not sham-ES reduced symptoms of dyspepsia (P = 0.010), decreased the scores of anxiety (P = 0.002) and depression (P < 0.001), and improved gastric accommodation (P < 0.001) and the %NSW (fasting: P < 0.05; fed: P < 0.05) by enhancing vagal efferent activity (fasting: P = 0.015; fed: P = 0.048). Compared with the HC, the patients showed increased anxiety (P < 0.001) and depression (P < 0.001), and decreased gastric accommodation (P < 0.001) and %NSW (P < 0.001) as well as decreased vagal activity (fasting: P = 0.047). The noninvasive taVNS has a therapeutic potential for treating nonsevere FD by improving gastric accommodation and gastric pace-making activity via enhancing vagal activity.NEW & NOTEWORTHY Treatment of functional dyspepsia is difficult due to various pathophysiological factors. The proposed method of transcutaneous auricular vagal nerve stimulation improves symptoms of both dyspepsia and depression/anxiety, and gastric functions (accommodation and slow waves), possibly mediated via the enhancement of vagal efferent activity. This noninvasive and easy-to-implement neuromodulation method will be well received by patients and healthcare providers.

Electroacupuncture at ST36 Relieves Visceral Hypersensitivity via the NGF/TrkA/TRPV1 Peripheral Afferent Pathway in a Rodent Model of Post-Inflammation Rectal Hypersensitivity.

PURPOSE: The aim of the study was to investigate the effects of electroacupuncture (EA) at ST36 on rectal hypersensitivity and compliance in DSS-treated post-inflammation rats. In addition, we explored the involvement of mast cells-triggered NGF/TrkA/TRPV1 peripheral afferent pathway. METHODS: Rats were provided water with 5% dextran sulphate sodium (DSS) for 7 days. Two weeks after the DSS treatment they were subjected to initial and repetitive EA. Different sets of parameters were compared in the initial test and then EA with the selected parameters were performed for 2 weeks. Rectal compliance was assessed by colorectal distension while visceral sensitivity was evaluated by abdominal withdraw reflexes (AWR) and electromyogram (EMG). Masson's trichrome staining was performed to stain collagen and toluidine blue staining was applied to assess the degranulation of mast cells. Nerve growth factor (NGF), tryptase, TrkA and TRPV1 were measured by Western blot or immunofluorescence staining. RESULTS: EA at 100 Hz was more effective in improving rectal compliance and visceral hypersensitivity. Daily EA improved visceral hypersensitivity but not rectal compliance. Five weeks after DSS treatment, fibrosis was noted in both sham-EA and EA groups. The expression and activation of mast cells were significantly reduced after the 2-week EA treatment with a concurrent decrease in the expression of colonic NGF/TrkA and TRPV1 in both colon and dorsal root ganglions. CONCLUSION: EA at ST36 with a special set of parameters has no effect on reduced rectal compliance but relieves visceral hypersensitivity via the mast cells-triggered NGF/TrkA/TRPV1 peripheral afferent pathway in DSS-treated post-inflammation rats.

Effects of Salvia miltiorrhiza and Radix astragali on the TGF-ß/Smad/Wnt pathway and the pathological process of liver fibrosis in rats.

Traditional Chinese medicine has made some progress in the study of liver fibrosis, and provides valuable experience for clinical treatment of liver fibrosis. The aim of this study was to investigate the rationality of compatibility use of Salvia miltiorrhiza and Radix astragali on liver fibrosis in rats. For this purpose, the rat model of liver fibrosis was treated with single or different compatibilities of herbals extracts for 4 weeks. Saline and colchicine were set as a negative and positive control, respectively. Liver histopathology, liver function, and expressions of key proteins in the TGF-ß/Smad/Wnt pathway were assessed. Results showed that compared with colchicine, herbal extracts showed better ability to reduce deposition of α-SMA and type I collagen, and improve liver function. The effect of R. astragali extracts and 1:1 compound on improving liver fibrosis and liver function was relatively better than other treatment options. The compound groups showed a particularly significant effect on reducing Cyclin D1 expression. It was concluded that the 1:1 compatibility use of S. miltiorrhiza extracts and R. astragali extracts can preferably attenuate liver fibrosis by regulating the expression of TGF-ß1 and Cyclin D1.

Baicalin alleviates TNBS-induced colitis by inhibiting PI3K/AKT pathway activation.

Inflammatory bowel diseases (IBDs) are chronic immunological disorders of the intestinal tract characterized by persistent inflammation. Baicalin, a type of flavonoid, has exhibited a wide range of pharmacological activities, including immunomodulation and anti-inflammation. However, little is known about the therapeutic role of baicalin in IBD. The aim of the present study was to ascertain whether baicalin could be a therapeutic drug of IBD and investigate its specific mechanisms. In the present study, the results revealed that baicalin not only significantly alleviated TNBS-induced colitis by reducing the release of IL-6, TNF-α and IL-1ß and increasing the level of IL-10, but promoted the expression of tight-junction proteins ZO-1 and ß-catenin, which may have been achieved by blockage of the PI3K/AKT signaling pathway. In vitro, the results demonstrated that baicalin clearly inhibited the release of TNF-α, IL-6 and IL-1ß and promoted the expression of IL-10 in LPS-induced HT-29 cells, and significantly decreased LPS-induced HT-29 cell apoptosis by blockage of the PI3K/AKT signaling pathway. In conclusion, the present research revealed for the first time that baicalin acted as a therapeutic drug in IBD by suppression of the PI3K/AKT signaling pathway.

Artificial Neural Network-Based Automatic Detection of Food Intake for Neuromodulation in Treating Obesity and Diabetes.

PURPOSE: Neuromodulation, such as vagal nerve stimulation and intestinal electrical stimulation, has been introduced for the treatment of obesity and diabetes. Ideally, neuromodulation should be applied automatically after food intake. The purpose of this study was to develop a method of automatic food intake detection through dynamic analysis of heart rate variability (HRV). MATERIALS AND METHODS: Two experiments were conducted: (1) a small sample series with a standard test meal and (2) a large sample series with varying meal size. Electrocardiograms (ECGs) were collected in the fasting and postprandial states. Each ECG was processed to compute the HRV. For each HRV segment, time- and frequency-domain features were derived and used as inputs to train and test an artificial neural network (ANN). The ANN was trained and tested with different cross-validation methods. RESULTS: The highest classification accuracy reached with leave-one-subject-out-leave-one-sample-out cross-validation was 0.93 in experiment 1 and 0.88 in experiment 2. Retraining the ANN on recordings of a subject drastically increased the achieved accuracy for that subject to values of 0.995 and 0.95 in experiments 1 and 2, respectively. CONCLUSIONS: Automatic food intake detection by ANNs, using features from the HRV, is feasible and may have a great potential for neuromodulation-based treatments of meal-related disorders.

Poststroke Constipation Is Associated With Impaired Rectal Sensation.

OBJECTIVES: Constipation is prevalent in individuals after stroke. However, the pathophysiological mechanisms of poststroke constipation remain unclear. This study was designed (i) to investigate the difference in anorectal motility and rectal sensation among stroke patients with constipation, stroke patients without constipation, and healthy controls (HC), (ii) to evaluate the impact of stroke sites on constipation and rectal sensation, (iii) to explore the role of autonomic functions, and (iv) to determine the independent risk factors for poststroke constipation. METHODS: Seventy-one stroke patients and 24 HC were recruited. General information, clinical characteristics, and relevant questionnaires were collected. Meanwhile, an anorectal manometry test was performed to assess functions of anorectal motility and rectal sensation, and an electrocardiogram was recorded to evaluate autonomic functions. RESULTS: (i) Constipation patients exhibited increased rectal sensation thresholds, compared with patients without constipation or HC (P < 0.001). Almost no difference was detected in anorectal motility parameters among 3 groups. Constipation-associated clinical characteristics, such as spontaneous bowel movements, were weakly or moderately correlated with rectal sensation thresholds (P < 0.05 to P < 0.001 for various parameters). (ii) Patients with brainstem lesions had increased prevalence of constipation and first sensation threshold, compared with patients without brainstem lesions (P = 0.045, P = 0.025, respectively). (iii) There was a weak positive correlation between sympathetic activity and stroke severity and a weak negative one between vagal activity and stroke severity. Rectal sensation thresholds were positively and weakly correlated with sympathetic activity but negatively with vagal activity. (iv) The desire of defecation threshold and the physical activity were independent risk factors for poststroke constipation (P = 0.043, P = 0.025, respectively). DISCUSSION: Poststroke constipation is characterized by elevated thresholds for rectal sensation, rather than altered anorectal motility. Patients with brainstem lesions are predisposed to constipation possibly because of the disruption of afferent pathway from the rectum to the brain. Moreover, the desire of defecation threshold and the physical activity level are factors independently associated with poststroke constipation.

Potential of Electrical Neuromodulation for Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a common chronic inflammatory disease of the digestive tract that is often debilitating. It affects patients' quality of life and imposes a financial burden. Despite advances in treatment with medications such as biologics, a large proportion of patients do not respond to medical therapy or develop adverse events. Therefore, alternative treatment options such as electrical neuromodulation are currently being investigated. Electrical neuromodulation, also called bioelectronic medicine, is emerging as a potential new treatment for IBD. Over the past decade, advancements have been made in electrical neuromodulation. A number of electrical neuromodulation methods, such as vagus nerve stimulation, sacral nerve stimulation, and tibial nerve stimulation, have been tested to treat IBD. A series of animal and clinical trials have been performed to evaluate efficacy with promising results. Although the exact underlying mechanisms of action for electrical neuromodulation remain to be explored, this modality is promising. Further randomized controlled trials and basic experiments are needed to investigate efficacy and clarify intrinsic mechanisms.

Qing Chang Hua Shi granule ameliorate inflammation in experimental rats and cell model of ulcerative colitis through MEK/ERK signaling pathway.

Ulcerative colitis (UC), a bowel disease with significant morbidity, is associated with inflammation. In this study, the effect of Qingchang Huashi granule (QCHS) on UC and its underlying mechanisms were explored using both animal and cell culture experiments. A rat UC model was induced with trinitro-benzene-sulfonic acid (TNBS), concentrations of the cytokines IL-1α, IL-6, IL-8, IL-1ß, and TNF-α were significantly up-regulated and the concentrations of IL-4, IL-10, and IL-13 were significantly down-regulated compared with the control group (P < 0.05). In contrast, the QCHS and salicylazosulfapyridine (SASP) groups reversed these modulations (P < 0.05). A UC cell model in HT-29 cells was generated using TNF-α combined with lipopolysaccharide treatment. Cells treated with QCHS were used to investigate the possible mechanisms. The expression of apoptosis-related proteins, including Bax/Bcl-2, caspase-3, caspase-9, Fas/Fas-L, and Rafl in the QCHS and SASP groups, were significantly lower than that in the control group in both animal and cell experiments (P < 0.05). In addition, the in vitro results indicate changes in these indicators mediate the MEK/ERK signaling pathways via SGK1. Our results suggested that QCHS could be beneficial in preventing UC progression as an alternative drug for UC treatment.

Therapeutic strategies of thromboembolic events in patients with inflammatory bowel diseases: Two case reports.

RATIONALE: Inflammatory bowel disease (IBD), including Crohn disease (CD) and ulcerative colitis (UC), is characterized by chronic inflammatory condition and immunological abnormalities, which probably develop into venous thromboembolic events (VTEs). VTE in IBD patients mostly occurs at deep venous thrombosis (DVT) and pulmonary embolism (PE). The complications are extremely important in clinical practice considering the high mortality rate. Hence, an early diagnosis of IBD and the control of complications play an important role in therapy of thromboembolic events (TEEs). PATIENT CONCERNS: Case 1 was a 31-year-old man with chronic UC who presented with signs of thromboembolism. Case 2 was a 43-year-old woman with CD complicated by fistulas. DIAGNOSES: Computed tomography (CT) and digital subtraction angiography (DSA) of the patient (case 1) suggested a thrombus in cerebral vein. The patient (case 2) developed acute ischemia of her right arm; B ultrasonography revealed a thrombus in the distal of the right subclavian artery accompanied by stenosis. INTERVENTIONS: To lower blood viscosity and overcome the risk of deep thrombosis, the patient (case 1) was treated with a combination of low-molecular-weight heparin and dextran as anticoagulation. For the patient (case 2), anticoagulation treatment with 75 mg qd clopidogrel (plavix) and 1.25 mg qd warfarin was performed. OUTCOMES: In both patients, no further TEE occurred during follow-up 1 year and one and a half years, respectively. LESSONS: It is important to pay attention to IBD patients especially those with high coagulation state.

Inflammatory Bowel Disease and Risk of Ischemic Heart Disease: An Updated Meta-Analysis of Cohort Studies.

BACKGROUND: Several immune-mediated diseases have been shown to be associated with an increased risk of cardiovascular disease. However, studies evaluating the association between inflammatory bowel disease and risk of cardiovascular disease reported inconsistent results. We assessed the association between inflammatory bowel disease and risk of ischemic heart disease in a meta-analysis of cohort studies. METHODS AND RESULTS: We conducted a literature search of PubMed and Embase up to October 2016 to identify relevant studies. The summary relative risks were calculated using the random-effects models. To explore the source of heterogeneity, we performed subgroup and sensitivity analysis. We included 10 cohort studies that satisfied our inclusion criteria. Patients with inflammatory bowel disease were associated with an increased risk of ischemic heart disease (relative risk: 1.244; 95% CI, 1.142-1.355). Considerable heterogeneity was observed. Crohn's disease showed a significantly increased risk of ischemic heart disease (relative risk=1.243; 95% CI, 1.042-1.482) and a positive association was also observed in ulcerative colitis (relative risk=1.206; 95% CI, 1.170-1.242). CONCLUSIONS: Based on meta-analysis of cohort studies, we found an increased risk of ischemic heart disease in patients with inflammatory bowel disease. Large long-term prospective studies are warranted to confirm our results.

[Effect of Jianpi Bushen Qingchang Huashi Recipe on Proliferation of Bone Marrow Mesenchymal Stem Cells].

OBJECTIVE: To observe the effect of Jianpi Bushen Qingchang Huashi Recipe (JBQHR) on proliferation and migration of bone marrow mesenchymal stem cells (BMSCs). METHODS: BMSCs were isolated and cultured in vitro with adherence screening method to prepare cell suspension. No drug intervention was given to BMSCs in the vehicle control group. JBQHR at 0.39, 0.78, 1.56 µg/mL was added in BMSCs of low, mid, and high dose JBQHR groups for co-incubation. Its effect on the proliferation of BMSCs was detected by CCK-8. BMSCs migration and chemotactic ability was detected using Transwell method. Each dose JBQHR combined ERK kinase inhibitor U0126 was set up as control. The phosphorylation of extracellular regulated protein kinase (ERK) and CAMP responsive element-binding protein (CREB) were detected by Western blot. RESULTS: Compared with the vehicle control group, the proliferation of BMSCs and BMSCs migration number could be promoted in the 3 JBQHR groups (P < 0.05). Besides, the proliferation of BMSCs was better in mid and high dose JBQHR groups than in the low dose JBQHR group (P < 0.05). Compared with the vehicle control group, the phosphorylation of ERK and CREB could be elevated in the 3 JBQHR groups (P < 0.05), and could be inhibited by U0126 (P < 0.01). Compared with the low dose JBQHR group, the phosphorylation of ERK increased in mid and high dose JBQHR groups with statistical difference (P < 0.05). CONCLUSION: JBQHR could promote the proliferation and migration of BMSCs, and its mechanism might be related to ERK/CREB signaling pathway

[Insulin-like growth factor 1 regulates expression of stem cell factor through ERKMAPK signaling pathway in gastric smooth muscle cell].

OBJECTIVE: To explore the effect and the intracellular signal transduction pathway of insulin-like growth factor 1 (IGF-1) on the expression of stem cell factor (SCF) in gastric smooth muscle cells (SMC). METHODS: Gastric SMC from SD rats were cultured by enzymolysis and identified by α-actin immunofluorescence methods. Western blot and quantitative reverse transcription-polymerase chain reaction were used to examine the expression of SCF in gastric SMC:(1) The level of SCF after gastric SMC were cultured with IGF-1. (2) The level of SCF after IGF-1 receptor (IGF-1Rα) monoclonal antibody were added. (3) Another SMC were pretreated with specific mitogen-activated protein kinase (MEK) inhibitor PD-98059 and phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor LY-294002, and investigate expression of SCF in gastric SMC. RESULTS: A very low level of SCF was expressed in gastric SMC cultured in bovine serum free medium. A low concentration of IGF-1 (5 and 10 µg/L) had no effect on the expression of SCF (both P>0.05), but the expressions of SCF mRNA and protein increased in IGF-1 at a higher concentration (50, 100 and 150 µg/L) (2.79, 5.51 and 5.35-fold in protein respectively, 1.81, 2.54 and 2.38-fold in mRNA respectively, all P<0.05), and IGF-1 in 100 µg/L may be the effective final concentration (all P<0.05). The peak of SCF increment was at the 16th hour with IGF-1 (2.36-fold in protein, 5.51-fold in mRNA, all P<0.05). The expression of SCF could be inhibited by IGF-1 receptor monoclonal antibody in a dose-dependent manner (all P<0.05). The IGF-1-induced SCF expression was reduced significantly by a pretreatment of PD-98059 (23% in protein and 48% in mRNA, P<0.05). And LY-294002 had no effect on the expression of SCF (P>0.05). CONCLUSION: The SCF expression in gastric SMC is stimulated by IGF-1 in both dose- and time-dependent manners through IGF-1R in which ERKMAPK signal transduction may play an important role.

T300A polymorphism of ATG16L1 and susceptibility to inflammatory bowel diseases: a meta-analysis.

AIM: To evaluate the association of the autophagy-related 16-like 1 (ATG16L1) T300A polymorphism (rs2241880) with predisposition to inflammatory bowel diseases (IBD) by means of meta-analysis. METHODS: Publications addressing the relationship between rs2241880/T300A polymorphism of ATG16L1 and Crohn's disease (CD) and ulcerative colitis (UC) were selected from the MEDLINE and EMBASE databases. To make direct comparisons between the data collected in these studies, the individual authors were contacted when necessary to generate a standardized set of data from these studies. From these data, odds ratio (OR) with 95% confidence interval (CI) were calculated. RESULTS: Twenty-five studies of CD were analyzed, 14 of which involved cases of UC. The variant G allele of ATG16L1 was positively associated with CD (OR = 1.32, 95% CI: 1.26-1.39, P < 0.00001) and UC (OR = 1.06, 95% CI: 1.01-1.10, P = 0.02). For child-onset IBD, a higher G allele frequency was found for cases of CD (OR = 1.35, 95% CI: 1.16-1.57, P = 0.0001) than for cases of UC (OR = 0.98, 95% CI: 0.81-1.19, P = 0.84) relative to controls. CONCLUSION: The ATG16L1 T300A polymorphism contributes to susceptibility to CD and UC in adults, but different in children, which implicates a role for autophagy in the pathogenesis of IBD.