Two naturally derived small molecules disrupt the sineoculis homeobox homolog 1-eyes absent homolog 1 (SIX1-EYA1) interaction to inhibit colorectal cancer cell growth.

BACKGROUND: Emerging evidence indicates that the sineoculis homeobox homolog 1-eyes absent homolog 1 (SIX1-EYA1) transcriptional complex significantly contributes to the pathogenesis of multiple cancers by mediating the expression of genes involved in different biological processes, such as cell-cycle progression and metastasis. However, the roles of the SIX1-EYA1 transcriptional complex and its targets in colorectal cancer (CRC) are still being investigated. This study aimed to investigate the roles of SIX1-EYA1 in the pathogenesis of CRC, to screen inhibitors disrupting the SIX1-EYA1 interaction and to evaluate the efficiency of small molecules in the inhibition of CRC cell growth. METHODS: Real-time quantitative polymerase chain reaction and western blotting were performed to examine gene and protein levels in CRC cells and clinical tissues (collected from CRC patients who underwent surgery in the Department of Integrated Traditional and Western Medicine, West China Hospital of Sichuan University, between 2016 and 2018, n = 24). In vivo immunoprecipitation and in vitro pulldown assays were carried out to determine SIX1-EYA1 interaction. Cell proliferation, cell survival, and cell invasion were determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, clonogenic assay, and Boyden chamber assay, respectively. The Amplified Luminescent Proximity Homogeneous Assay Screen (AlphaScreen) method was used to obtain small molecules that specifically disrupted SIX1-EYA1 interaction. CRC cells harboring different levels of SIX1/EYA1 were injected into nude mice to establish tumor xenografts, and small molecules were also injected into mice to evaluate their efficiency to inhibit tumor growth. RESULTS: Both SIX1 and EYA1 were overexpressed in CRC cancerous tissues (for SIX1, 7.47 ±â€Š3.54 vs.1.88 ±â€Š0.35, t = 4.92, P = 0.008; for EYA1, 7.61 ±â€Š2.03 vs. 2.22 ±â€Š0.45, t = 6.73, P = 0.005). The SIX1/EYA1 complex could mediate the expression of two important genes including cyclin A1 (CCNA1) and transforming growth factor beta 1 (TGFB1) by binding to the myocyte enhancer factor 3 consensus. Knockdown of both SIX1 and EYA1 could decrease cell proliferation, cell invasion, tumor growth, and in vivo tumor growth (all P < 0.01). Two small molecules, NSC0191 and NSC0933, were obtained using AlphaScreen and they could significantly inhibit the SIX1-EYA1 interaction with a half-maximal inhibitory concentration (IC50) of 12.60 ±â€Š1.15 µmol/L and 83.43 ±â€Š7.24 µmol/L, respectively. Administration of these two compounds could significantly repress the expression of CCNA1 and TGFB1 and inhibit the growth of CRC cells in vitro and in vivo. CONCLUSIONS: Overexpression of the SIX1/EYA1 complex transactivated the expression of CCNA1 and TGFB1, causing the pathogenesis of CRC. Pharmacological inhibition of the SIX1-EYA1 interaction with NSC0191 and NSC0933 significantly inhibited CRC cell growth by affecting cell-cycle progression and metastasis.

Effect of Acupuncture-rehabilitation Therapy on Neural Function and Expression of Forkhead Box P3 and Retinoic Acid-related Orphan Receptor γt in Mice with Cerebral Ischemia / 中国康复理论与实践

Objective To explore the effect of acupuncture-rehabilitation therapy on the expression of transcription factor forkheadbox P3 (Foxp3) and retinoic acid-related orphan receptor γt (RORγt) protein in cerebral ischemic mice. Methods Forty-five female C57BL/6 mice were randomly assigned to sham operation group, model group, acupuncture group, rehabilitation group, and acupuncture-rehabilitation group, with nine mice in each group. Subsequently, each group was divided into three days, seven days and 14 days subgroups. The permanent middle cerebral artery occlusion models were established by the suture method, except the sham operation group. The sham operation group and the model group received no treatment. The acupuncture group received scalp cluster acupuncture, the rehabilitation group received treadmill training, and the acupuncture-rehabilitation group received scalp cluster acupuncture combined with treadmill training. Three days, seven days and 14 days after modeling, the modified Neurological Severity Score (mNSS) was obtained, and the expression of Foxp3 and RORγt in brain tissue of ischemic side was analyzed by Western blotting. Results The mNSS in the sham operation group was 0, and was higher in the model group than in the sham operation group at each postoperative time point. Three days after operation, the mNSS decreased in the rehabilitation group and the acupuncture-rehabilitation group, compared to the model group (P < 0.05). Fourteen days after operation, the mNSS decreased in the acupuncture-rehabilitation group, compared to the model group and acupuncture group (P < 0.05). The expression of Foxp3 protein was significantly lower in the acupuncture-rehabilitation group than in other groups at all time points after surgery( P < 0.05). Three days after operation, the expression of RORγt was higher in the acupuncture-rehabilitation group than in other groups (P < 0.05). Seven days after operation, the expression of RORγt was higher in the acupuncture-rehabilitation group than in the acupuncture group and sham operation group (P < 0.05). Conclusion Acupuncture-rehabilitation therapy may improve the tissue injury of cerebral ischemia mice, and promote the recovery of neural function, possibly by regulating Foxp3 and RORγT expression to reduce the level of inflammation, and then exert neuroprotective effects.

Effect of Acupuncture-rehabilitation Therapy on Neural Function and Expression of Forkhead Box P3 and Retinoic Acid-related Orphan Receptor γt in Mice with Cerebral Ischemia / 中国康复理论与实践

Objective To explore the effect of acupuncture-rehabilitation therapy on the expression of transcription factor forkheadbox P3 (Foxp3) and retinoic acid-related orphan receptor γt (RORγt) protein in cerebral ischemic mice. Methods Forty-five female C57BL/6 mice were randomly assigned to sham operation group, model group, acupuncture group, rehabilitation group, and acupuncture-rehabilitation group, with nine mice in each group. Subsequently, each group was divided into three days, seven days and 14 days subgroups. The permanent middle cerebral artery occlusion models were established by the suture method, except the sham operation group. The sham operation group and the model group received no treatment. The acupuncture group received scalp cluster acupuncture, the rehabilitation group received treadmill training, and the acupuncture-rehabilitation group received scalp cluster acupuncture combined with treadmill training. Three days, seven days and 14 days after modeling, the modified Neurological Severity Score (mNSS) was obtained, and the expression of Foxp3 and RORγt in brain tissue of ischemic side was analyzed by Western blotting. Results The mNSS in the sham operation group was 0, and was higher in the model group than in the sham operation group at each postoperative time point. Three days after operation, the mNSS decreased in the rehabilitation group and the acupuncture-rehabilitation group, compared to the model group (P < 0.05). Fourteen days after operation, the mNSS decreased in the acupuncture-rehabilitation group, compared to the model group and acupuncture group (P < 0.05). The expression of Foxp3 protein was significantly lower in the acupuncture-rehabilitation group than in other groups at all time points after surgery( P < 0.05). Three days after operation, the expression of RORγt was higher in the acupuncture-rehabilitation group than in other groups (P < 0.05). Seven days after operation, the expression of RORγt was higher in the acupuncture-rehabilitation group than in the acupuncture group and sham operation group (P < 0.05). Conclusion Acupuncture-rehabilitation therapy may improve the tissue injury of cerebral ischemia mice, and promote the recovery of neural function, possibly by regulating Foxp3 and RORγT expression to reduce the level of inflammation, and then exert neuroprotective effects.

Modified Van Assche magnetic resonance imaging-based score for assessing the clinical status of anal fistulas.

The modified Van Assche magnetic resonance imaging (MRI)-based score is a feasible system to assess the clinical status of anal fistulas in Crohn disease. In this study, we evaluated this score's association with clinical status in patients with anal fistulas (AFs).We included all patients with AF who underwent contrast-enhanced pelvic MRI and surgery between January 2011 and December 2016. The score was evaluated retrospectively preoperatively and 1, 3, and 6 months postoperatively. Univariate and multivariate analyses of the risk factors for AF recurrence were also performed.We retrospectively analyzed data for 104 patients. Twelve (11.5%) patients developed AF recurrence. We classified patients' preoperative clinical status into three grades: 52 (50.0%) grade A, 31 (29.8%) grade B, and 21 (20.2%) grade C. The preoperative MRI-based score was significantly correlated with patients' preoperative clinical status grade (Pearson correlation: 0.547; P < .001). The 3 preoperative clinical status grades showed significant (F = 23.303, P < .001) tendencies for associations with lower respective MRI-based scores. The incidence of AF recurrence decreased with the MRI-based score to 1-month postoperatively, then gradually increased (F = 60.863, P = .000). Long duration of disease, prior interventions, and high MRI-based score were independent risk factors for AF recurrence.The MRI-based score objectively assessed the clinical status and disease activity of patients with AFs, with a high score being associated with severe clinical status and long recovery time.

Design and Implementation of Wearable Cephalic Stimulator / 中国康复理论与实践

Objective:To design a type of wearable cephalic stimulator and verify its feasibility, safety and effectiveness. Methods:The wearable cephalic stimulator was designed based on transcranial electric stimulation and the meridian. From June 2015 to February 2018, 80 patients with ischemic stroke were randomly divided into control group (n = 40) and treatment group (n = 40). The control group accepted routine rehabilitation, and the treatment group was treated with the wearable cephalic stimulator additionally, for four weeks. They were assessed with Fugl-Meyer Assessment (FMA) and modified Barthel index (MBI) before and after treatment. While, the safety and stability of the device were observed, and the temperature, pulse, respiration, blood pressure, etc. of the patient were recorded. Results:The prototype was successfully produced. There was no significant difference in the scores of FMA and MBI between two groups before treatment (P > 0.05). The scores of FMA and MBI significantly increased in both groups (t > 2.448, P < 0.05), and they were higher in the observation group than in the control group (|t| > 2.202, P < 0.05) after treatment. The temperature, pulse, and breathing did not change during the treatment with this device, and blood pressure did not increase. Conclusion:The wearable cephalic stimulator is safe, reliable and operability, and could effectively improve the motor function and activities of daily living in patients with acute ischemic stroke.

Effect of Acupuncture-rehabilitation Therapy on Homocysteine and Cognitive Function for Patients with Ischemic Stroke / 中国康复理论与实践

Objective:To investigate the effects of acupuncture-rehabilitation therapy on homocysteine (Hcy) and cognitive function in patients with cognitive impairment after ischemic stroke. Methods:From July, 2017 to June, 2018, 88 patients with cognitive impairment after ischemic stroke were randomly divided into group A (n = 29, cluster needling), group B (n = 30, cognitive training) and group C (n = 29, acupuncture-rehabilitation). Their serum Hcy content was measured and they were assessed with Montreal Cognitive Assessment (MoCA) before and 30 days after treatment. Results:The serum Hcy content was the least in group C after treatment (F = 6.570, P < 0.01), with the most score of MoCA (F = 31.526, P < 0.001). Conclusion:Acupuncture-rehabilitation therapy is more effective than simple cluster needling or cognitive training for patients with cognitive impairment after ischemic stroke.

Effects of Exercise Preconditioning on Blood-brain Barrier Permeability in Rats after Cerebral Ischemia-reperfusion Injury / 中国康复理论与实践

Objective:To observe the effects of exercise preconditioning on blood-brain barrier (BBB) permeability, and connexin 43 (Cx43) and pannexin 1 (Panx1) protein after cerebral ischemia-reperfusion injury in rats. Methods:Fifty-four male Sprague-Dawley rats were randomly divided into sham group (n = 18), model group (n = 18) and exercise preconditioning group (n = 18). The exercise preconditioning group was trained with treadmill for three weeks before modeling. The middle cerebral arteries were occluded in the model group and the exercise preconditioning group using the modified Koizumi suture. After reperfusion of 24 hours, the rats were assessed with modified Neurological Severity Score (mNSS). The permeability of BBB was observed with Evans blue (EB). The expression of Cx43 and Panx1 was detected with Western blotting and immunohistochemistry in the ischemic tissues. Results:Compared with the model group, the mNSS score decreased in the exercise preconditioning group (P < 0.05), while the Evans blue content and the expression of Cx43 and Panx1 decreased (P < 0.05), as well as the the positive areas of Cx43 and Panx1 (P < 0.05). Conclusion:Exercise preconditioning can improve the permeability of BBB in cerebral ischemia-reperfusion rats, which may associate with down-regulation of Cx43 and Panx1, to protect brain from injury.

Advance in Relationship between Autism Spectrum Disorders and Microbiome (review) / 中国康复理论与实践

It has been increasingly recognized that the presence of a healthy and diverse gut microbiota is important to the development of central nervous system and emotional processing for children with autism spectrum disorders (ASD). The interconnection of gut microbiome and brain function has significantly contributed to establishing the microbiota-gut-brain axis as an extension of the well-accepted gut-brain axis concept. The bidirectional interaction between the gut microbiota and the brain occurs through various pathways including serotonin, hypothalamus-pituitary-adrenal axis, neurotrophin, and the immune system. The microbiota-gut-brain axis has been shown to influence the behaviors associated with neuropsychiatric conditions. Modulation of this gut microbiota as a novel therapy for ASD is gaining interest. This paper summarized the status of neuropsychological microbiome, which provided evidence supporting the role of gut microbiota in modulating neuropsychological functions of the central nervous system and exploring the potential underlying mechanisms.

Effects of Enriched Environment on Apoptosis and Brain-derived Neurotrophic Factor /Tyrosine Kinase Receptor B Signaling Pathway in Hippocampal Neurons of Neonatal Rats with Hypoxic-ischemic Brain Damage / 中国康复理论与实践

Objective:To investigate the effects of enriched environment on hippocampal neuronal apoptosis and brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) signaling pathway in neonatal rats with hypoxic-ischemic brain damage. Methods:Forty-eight newborn Wistar rats aged seven days were randomly divided into sham operation group, model group and enriched environment group, each group was divided in to 14 days group and 28 days group, with eight in each subgroup. The model was established with the Rice method. The sham operation group and the model group did not receive any intervention, and the enriched environment group received enriched environment stimulation 24 hours after modeling. Fourteen days and 28 days after modeling, the levels of neuronal apoptosis in hippocampus were detected by TUNEL and double immunofluorescence staining; BDNF and TrkB proteins in hippocampus were detected by immunohistochemical staining. Results:Fourteen days and 28 days after modeling, the numbers of TUNEL positive cells, double immunofluorescence positive cells, BDNF and TrkB positive cells were significantly more in the model group than in the sham operation group (t > 27.214, P < 0.001), while the numbers of TUNEL positive cells, double immunofluorescence positive cells were significantly less in the enriched environment group than in the model group (t > 12.687, P < 0.001); and the number of BDNF and TrkB positive cells were significantly more in the enriched environment group than in the model group 28 days after modeling (t > 137.998, P < 0.001). Conclusion:Enriched environmental stimulation could reduce the apoptosis of hippocampal neurons, and up-regulate the expression of BDNF and TrkB proteins in the neonatal rats with hypoxic-ischemic brain damage.

Effect of lateral internal sphincterotomy in patients undergoing excisional hemorrhoidectomy.

BACKGROUND: Excisional hemorrhoidectomy (EH) is the major surgical option for high-grade symptomatic hemorrhoids, but it has some shortcomings, especially postoperative pain. This study was performed to assess the effect of lateral internal sphincterotomy (LIS) in patients undergoing excisional hemorrhoidectomy. METHODS: A systematic literature search (Medline, Embase, Cochrane Library, Science Citation Index, Science Direct, Springer Link, Ovid Journals, and EBSCO) was performed to identify all eligible articles. Randomized controlled trials (RCTs) published until July 7, 2017 comparing EH combined with LIS (experimental group) with EH only (control group) were eligible for inclusion. The primary outcome of interest was postoperative pain. RESULTS: Ten RCTs involving 1560 patients were identified for inclusion. The pooled analysis revealed that patients undergoing EH and LIS were associated with lower pain score [standardized mean difference (SMD), -0.75; 95% confidence interval (CI), -1.14 to -0.36; z = 3.76; P = .0002] and resting anal pressure [odds ratio (OR), -17.19; 95% CI, -25.66 to -8.72; z = 3.98; P < .0001], and lower incidence of anal stricture (OR, 0.12; 95% CI, 0.03-0.53; z = 2.85; P = .004). However, the differences of urinary retention, bleeding and length of hospital stay were similar between the 2 methods. CONCLUSION: Our meta-analysis suggests that LIS effectively relieves postoperative pain and reduces patient's postoperative analgesic requirements. LIS also reduces the incidence of anal stenosis but increases the incidence of fecal incontinence.