NK007 helps in mitigating paclitaxel resistance through p38MAPK activation and HK2 degradation in ovarian cancer.

Ovarian cancer resistance to available medicines is a huge challenge in dire need of a solution, which makes its recurrence and mortality rate further exacerbated. A promising approach to overcome chemoresistance is drug screening from natural products. Here, we report that NK007, a (±)-tylophorine malate isolated from the Asclepiadaceae family, selectively inhibited the proliferation of A2780 and A2780 (Taxol) cells and migration of paclitaxel-sensitive and -resistant ovarian cancer cells. Interestingly, the decline of cell viability, including cell multiplication, clonality, and migration capacity was independent on cell apoptosis. At the molecular level, NK007 considerably induced G1/S arrest and upregulated the expression of phospho-p38 mitogen-activated protein kinase (p-p38MAPK). In addition, hexokinase 2 (HK2) protein degradation was considerably elevated in the presence of NK007, which resulted in the reduction of oxygen consumption rate and extracellular acidification rate. Altogether, our results indicate that NK007, an analog of tylophorine, can overcome paclitaxel (PTX) resistance through p38MAPK activation and HK2 degradation. As an effective, alternative antiresistance agent, NK007 exhibits a promising potential to treat PTX-resistant ovarian cancer.

Aureane-type sesquiterpene tetraketides as a novel class of immunomodulators with interleukin-17A inhibitory activity.

Interleukin (IL)-17A, a pro-inflammatory cytokine, is a fundamental function in the onset and advancement of multiple immune diseases. To uncover the primary compounds with IL-17A inhibitory activity, a large-scale screening of the library of traditional Chinese medicine constituents and microbial secondary metabolites was conducted using splenic cells from IL-17A-GFP reporter mice cultured under Th17-priming conditions. Our results indicated that some aureane-type sesquiterpene tetraketides isolated from a wetland mud-derived fungus, Myrothecium gramineum, showed remarkable IL-17A inhibitory activity. Nine new aureane-type sesquiterpene tetraketides, myrogramins A-I (1, 4-11), and two known ones (2 and 3) were isolated and identified from the strain. Compounds 1, 3, 4, 10, and 11 exhibited significant IL-17A inhibitory activity. Among them, compound 3, with a high fermentation yield dose-dependently inhibited the generation of IL-17A and suppressed glycolysis in splenic cells under Th17-priming conditions. Strikingly, compound 3 suppressed immunopathology in both IL-17A-mediated animal models of experimental autoimmune encephalomyelitis and pulmonary hypertension. Our results revealed that aureane-type sesquiterpene tetraketides are a novel class of immunomodulators with IL-17A inhibitory activity, and hold great promise applications in treating IL-17A-mediated immune diseases.

Auricular Acupressure for Hemodialysis Patients with Insomnia: A Multicenter Double-Blind Randomized Sham-Controlled Trial.

Background and objectives: The effect of auricular acupressure (AA) for maintenance hemodialysis (MHD) patients with insomnia has been controversial. This study assessed the efficacy and safety of AA for MHD patients with chronic insomnia. Design, setting, participants, and measurements: This was a multicenter, double-blind (participant and assessor), randomized sham-controlled trial. A total of 133 subjects were randomized to receive AA on active points (AA group, n = 64) or on sham auricular acupressure (SAA) points (SAA group, n = 69) for 8 weeks and followed up for 12 weeks. AA was provided by assigned qualified nurses who were not involved in assessment. The primary outcome was the clinical response rate, which was defined as the percentage of participants who reached a reduction of Pittsburgh Sleep Quality Index (PSQI) global score ≥3 in each group. Secondary outcomes included changes in PSQI scores over time, PSQI scores and hypnotics use at each visit, and changes in the weekly dose of hypnotics for drug-dependent subjects. Results: At week 8, the AA group yielded a higher clinical response rate than the SAA group (AA: 55% vs. SAA: 36%, odds ratio: 1.5, 95% confidence interval: 1.0-2.2, p = 0.033). Both groups showed a reduction in PSQI global scores during treatment and follow-up, compared with the baseline, respectively. A significant change of PSQI global score was observed over time (F = 28.387, p < 0.001). PSQI global score of the AA group was relatively lower than that of the SAA group at each visit (p < 0.05 at week 16 and 20). For those depending on hypnotics, AA reduced their consumption of hypnotics. The intervention was safe, and its adherence was satisfactory. Conclusion: AA could serve as a complementary or alternative therapy for MHD patients with insomnia by improving their sleep quality and reducing their use of hypnotics. Clinical trial registration: Clinicaltrials.gov, Identifier: NCT03015766.

Segmentation of Prefrontal Lobe Based on Improved Clustering Algorithm in Patients with Diabetes.

Diabetics are prone to postoperative cognitive dysfunction (POCD). The occurrence may be related to the damage of the prefrontal lobe. In this study, the prefrontal lobe was segmented based on an improved clustering algorithm in patients with diabetes, in order to evaluate the relationship between prefrontal lobe volume and COPD. In this study, a total of 48 diabetics who underwent selective noncardiac surgery were selected. Preoperative magnetic resonance imaging (MRI) images of the patients were segmented based on the improved clustering algorithm, and their prefrontal volume was measured. The correlation between the volume of the prefrontal lobe and Z-score or blood glucose was analyzed. Qualitative analysis shows that the gray matter, white matter, and cerebrospinal fluid based on the improved clustering algorithm were easy to distinguish. Quantitative evaluation results show that the proposed segmentation algorithm can obtain the optimal Jaccard coefficient and the least average segmentation time. There was a negative correlation between the volume of the prefrontal lobe and the Z-score. The cut-off value of prefrontal lobe volume for predicting POCD was <179.8, with the high specificity. There was a negative correlation between blood glucose and volume of the prefrontal lobe. From the results, we concluded that the segmentation of the prefrontal lobe based on an improved clustering algorithm before operation may predict the occurrence of POCD in diabetics.

Nanoparticle-Mediated Delivery of Emodin via Colonic Irrigation Attenuates Renal Injury in 5/6 Nephrectomized Rats.

Our previous study showed that emodin enema modulates gut microbiota and delays CKD progression. However, the poor solubility, limited colonic irrigation retention time, and inadequate colon adhesion of emodin hinder its clinical application. Based on the deficiencies of emodin, we prepared monomethoxy-poly (ethylene glycol)-poly (lactic acid)-chitosan-2-mercaptobenzimidazole nanoparticles with incorporated emodin (emodin-NP) and studied their efficacy in delaying CKD progression. 5/6 nephrectomized Male Sprague Dawley rats were administered via colonic irrigation with emodin-NP every two days for eight weeks. We found that treatment with emodin-NP improved the kidney function of the rats and limited the expansion of tubulointerstitial fibrosis. Treatment with emodin-NP once every two days is comparable to emodin treatment once a day. Furthermore, emodin-NP via colonic irrigation remarkably reduced IL-1ß, IL-6, and LPS levels in serum, improved intestinal barrier functions, and downregulated the key proteins (TLR4, MyD88, and NF-κB) expression in intestinal TLR4 signaling pathway. 16S rDNA analyses showed that emodin-NP can regulate microbiota disturbance in CKD. Taken together, these results suggest that emodin-NP alleviates kidney dysfunction and tubulointerstitial fibrosis by mediation through the modification of gut microbiota disorders. Emodin-NP may be a new method to treat CKD.

Auricular acupressure for insomnia in hemodialysis patients: study protocol for a randomized controlled trial.

BACKGROUND: Patients on maintenance hemodialysis (MHD) frequently complain of insomnia. Poor sleep quality impairs their quality of life and adversely affects long-term outcome. Previously we applied auricular acupressure therapy (AAT) for MHD patients with insomnia and yielded favorable results. AAT probably improves sleep quality by stimulating the vagus nerve and inhibiting sympathetic overactivity. However, the efficacy of AAT for insomnia in this population is still lacking. The proposed randomized controlled trial (RCT) will evaluate the efficacy and safety of AAT for improvement of sleep quality in MHD patients with insomnia. METHODS/DESIGN: The proposed study is a multi-center, double-blind (participants and assessors), parallel-group RCT. A total of 112 participants with insomnia will be recruited from six hemodialysis centers in Guangzhou, China, and randomly allocated in a 1:1 ratio to receive auricular acupressure on either active points (AA group) or control points (points irrelevant to insomnia management, SAA group). The treatment will last for 8 weeks prior to a follow-up period of 12 weeks. Evaluation by blinded assessors at baseline, at 8 weeks (end of treatment) as well as at 4-week, 8-week and 12-week follow-ups (after intervention) will include Pittsburgh Sleep Quality Index (PSQI) scores and average weekly dose of hypnotics. The primary endpoint is clinical response rate (percentage of participants who reach a reduction of PSQI global score ≥ 3 in each group) at 8 weeks from baseline. Secondary endpoints include the changes in PSQI scores over time from baseline, as well as the changes in weekly dose of hypnotics. DISCUSSION: This paper describes the rationale and design of a double-blind RCT that aims to determine the efficacy and safety of AAT for insomnia of hemodialysis patients. If successful, this project will provide evidence of the efficacy and safety of AAT for insomnia of hemodialysis patients. TRIAL REGISTRATION: ClinicalTrials.gov , Identifier: NCT03015766 . Registered on 22 December 2016.

Auricular Acupressure Helps Alleviate Xerostomia in Maintenance Hemodialysis Patients: A Pilot Study.

BACKGROUND: Xerostomia is one of the most common complaints in maintenance hemodialysis (MHD) patients. This problem contributes to excess fluid intake and results in poor survival outcome. Based on Traditional Chinese Medicine (TCM) theory and literature studies, the authors have been practicing auricular acupressure therapy (AAT) to help patients with xerostomia. This pilot study was conducted to demonstrate the potential of AAT for xerostomia in MHD patients. METHODS: Eligible subjects who agreed to participate in this study were recruited and provided with AAT for 4 weeks. The Summated Xerostomia Inventory (SXI), as well as measurement of inter-dialytic weight gain (IDWG), daily inter-dialytic weight gain (daily IDWG), percentage of inter-dialytic weight gain (IDWG%), blood pressure, and biochemical parameters, were completed at baseline and after a 4-week intervention. RESULTS: A total of 26 eligible participants were recruited. Of them, 10 men and 16 women (Mage = 52.92 ± 11.80 years; dialysis vintage 81.86 ± 46.05 months) completed the study. After the 4-week AAT intervention, the SXI scores were significantly decreased compared with baseline (from 10.08 ± 2.26 to 9.04 ± 2.14; p < 0.05). However, the IDWG, daily IDWG, IDWG%, blood pressure, and biochemical parameters did not change significantly after the intervention. CONCLUSION: This study provides preliminary evidence that AAT may be effective in reducing xerostomia intensity for MHD patients.

[Effect of glutamine on apoptosis of the small intestine in young rats with endotoxemia and its mechanism].

OBJECTIVE: To study the effect of glutamine on intestinal epithelial apoptosis by examining changes regarding Bcl-2 and Bax mRNA expressions in the small intestine of young rats with endotoxemia and to explore the protective mechanism that glutamine may have. METHODS: A total of 120 18-day-old rats were randomly assigned into Endotoxemia, Glutamine-treated and Control groups (n = 40 each). The endotoxemia model was established by intraperitoneal injection of endotoxin (4 mg/kg of O55B5 Escherichia coli lipopolysaccharide). Rats in the Glutamine-treated group were intraperitoneally injected with N (2)-L-alanyl-L-glutamine (2 g/kg) along with endotoxin. Rats in the Control group were intraperitoneally injected with an equal volume of normal saline. The entire ileum was collected at 2, 4, 6, 24, and 72 hrs after injection. Bcl-2 and Bax mRNA expressions were detected by semi-quantities reverse transcriptase chain reaction. RESULTS: Bcl-2 mRNA was not expressed in the Control and the Endotoxemia groups but increased in the Glutamine-treated group at each time point. Bax mRNA expression was weak in the Control group, and significantly increased in the Endotoxemia group at each time point. The Glutamine-treated group showed noticeably reduced Bax mRNA expression at 2 hrs post-injection while other time points were similar to the Control group. The ratio of Bax and Bcl-2 mRNA expression at each time point in the Endotoxemia group was significantly higher than that in the Control group while the Glutamine-treated group demonstrated significantly lower ratio of Bax and Bcl-2 mRNA expression than both. CONCLUSIONS: Glutamine treatment increased Bcl-2 mRNA expression and decreased Bax mRNA expression, as a result, the ratio of Bax and Bcl-2 mRNA expression decreased. The effects of glutamine resulted in a suppression of intestinal epithelial apoptosis and maintained the integrity of the gut barrier structure.

Auricular acupressure on specific points for hemodialysis patients with insomnia: a pilot randomized controlled trial.

OBJECTIVES: To assess the feasibility and acceptability of a randomized controlled trial compared auricular acupressure (AA) on specific acupoints with AA on non-specific acupoints for treating maintenance hemodialysis (MHD) patients with insomnia. METHODS: Sixty three (63) eligible subjects were randomly assigned into either AA group received AA on specific acupoints (n=32), or sham AA (SAA) group received AA on points irrelevant to insomnia treatment (n=31) for eight weeks. All participants were followed up for 12 weeks after treatments. The primary outcome was clinical response at eight weeks after randomization, defined as a reduction of Pittsburgh Sleep Quality Index (PSQI) global score by 3 points and more. RESULTS: Fifty-eight (58) participants completed the trial and five dropped out. Twenty participants in AA group (62.5%) and ten in SAA group (32.3%) responded to the eight-week interventions (χ2 = 5.77, P = 0.02). PSQI global score declined 3.75 ± 4.36 (95%CI -5.32, -2.18) and 2.26 ± 3.89 (95%CI -3.68, -0.83) in AA group and SAA group respectively. Three participants died during the follow-up period. No evidence supported their deaths were related to the AA intervention. No other adverse event was observed. CONCLUSION: Feasibility and logistics of patient recruitment, randomization procedure, blinding approach, interventions application and outcome assessment had been tested in this pilot trial. The preliminary data appeared to show a favorable result on AA treatment. A full-scale trial is warranted. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-TRC-12002272.

Auricular acupressure helps improve sleep quality for severe insomnia in maintenance hemodialysis patients: a pilot study.

BACKGROUND: Insomnia is common in patients undergoing maintenance hemodialysis (MHD). Long-term use of sedative-hypnotic agents is often correlated with increasing adverse effects. Auricular acupressure therapy (AAT) applied to specific auricular acupoints for managing insomnia has achieved favorable outcomes in a hemodialysis unit. This pilot study was performed to demonstrate the potential of AAT for insomnia in MHD patients and to prepare for a future randomized controlled trial. METHODS: Eligible patients were enrolled into this descriptive pilot study and received AAT designed to manage insomnia for 4 weeks. Questionnaires that used the Pittsburgh sleep quality index (PSQI) were completed at baseline, after a 4-week intervention, and 1 month after completion of treatment. Sleep quality and other clinical characteristics, including sleeping pills taken, were statistically compared between different time points. RESULTS: A total of 22 patients were selected as eligible participants and completed the treatment and questionnaires. The mean global PSQI score was significantly decreased after AAT intervention (p<0.05). Participants reported improved sleep quality (p<0.01), shorter sleep latency (p<0.05), less sleep disturbance (p<0.01), and less daytime dysfunction (p=0.01). They also exhibited less dependency on sleep medications, indicated by the reduction in weekly estazolam consumption from 6.98±4.44 pills to 4.23±2.66 pills (p<0.01). However, these improvements were not preserved 1 month after treatment. CONCLUSION: In this single-center pilot study, complementary AAT for MHD patients with severe insomnia was feasible and well tolerated and showed encouraging results for sleep quality.

Active reranking for web image search.

Image search reranking methods usually fail to capture the user's intention when the query term is ambiguous. Therefore, reranking with user interactions, or active reranking, is highly demanded to effectively improve the search performance. The essential problem in active reranking is how to target the user's intention. To complete this goal, this paper presents a structural information based sample selection strategy to reduce the user's labeling efforts. Furthermore, to localize the user's intention in the visual feature space, a novel local-global discriminative dimension reduction algorithm is proposed. In this algorithm, a submanifold is learned by transferring the local geometry and the discriminative information from the labelled images to the whole (global) image database. Experiments on both synthetic datasets and a real Web image search dataset demonstrate the effectiveness of the proposed active reranking scheme, including both the structural information based active sample selection strategy and the local-global discriminative dimension reduction algorithm.

Correlative linear neighborhood propagation for video annotation.

Recently, graph-based semisupervised learning methods have been widely applied in multimedia research area. However, for the application of video semantic annotation in multilabel setting, these methods neglect an important characteristic of video data: The semantic concepts appear correlatively and interact naturally with each other rather than exist in isolation. In this paper, we adapt this semantic correlation into graph-based semisupervised learning and propose a novel method named correlative linear neighborhood propagation to improve annotation performance. Experiments conducted on the Text REtrieval Conference VIDeo retrieval evaluation data set have demonstrated its effectiveness and efficiency.