Fucoxanthin inhibits gastric cancer lymphangiogenesis and metastasis by regulating Ran expression.

BACKGROUND: Lymph node metastasis is a key mechanism in gastric cancer (GC) metastasis and lymphangiogenesis is a vital step in the process of lymph node metastasis. Currently, there are no drugs which can treat lymph node metastasis in GC. Previous studies using the drug fucoxanthin have mainly focused on cell cycle arrest, induction of apoptosis, or inhibition of angiogenesis in GC. However, the effects of fucoxanthin on lymphangiogenesis and metastasis in GC have not been studied. METHODS: Cell counting kit 8 and transwell experiments were used to evaluate the inhibitory effect of fucoxanthin on cell proliferation, migration and invasion. HGC-27 and HLEC cells were co-cultured in a transwell chamber and the footpad metastasis model was established to evaluate lymphangiogenesis and lymph node metastasis. The possible regulatory targets of fucoxanthin in GC were analyzed using human tissue microarrays, bioinformatics analysis, and molecular docking. The regulatory pathway of fucoxanthin was verified using confocal laser microscopy, adenovirus transfection and western blotting. RESULTS: Tissue microarray and bioinformatics analyses showed that Ran was highly expressed in metastatic lymph nodes and has some predictive value for metastasis in GC. Molecular docking results revealed that fucoxanthin interacted with Met189 and Lys167 of Ran via hydrogen bonds. Mechanistically, fucoxanthin inhibits the nuclear transport of NF-κB by downregulating protein expression of Ran and importinß, thereby inhibiting VEGF-C secretion, and ultimately inhibiting tumor lymphangiogenesis and lymph node metastasis in vivo and in vitro. CONCLUSIONS: Fucoxanthin suppressed GC-induced lymphangiogenesis and metastasis in vitro and in vivo by regulating Ran expression via the importinß/NF-κB/VEGF-C nuclear transport signaling pathway. These novel findings provide the basis for the research and development of novel treatments using traditional Chinese medicine in treatment of lymph node metastasis, which has important theoretical significance and clinical value.

Metabolomics integrated network pharmacology reveals the mechanism of Ma-Mu-Ran Antidiarrheal Capsules on acute enteritis mice.

Acute enteritis (AE) is a type of digestive disease caused by biochemical factors that irritate the intestinal tract or pathogenic bacteria that infect it. In China, Ma-Mu-Ran Antidiarrheal Capsules (MMRAC) have been applied against diarrhea caused by AE and bacillary dysentery for many years, but the underlying mechanisms of their beneficial effects are not known. In the present study, network pharmacology and metabolomics were performed to clarify the active ingredients of MMRAC and explore the specific mechanism of MMRAC on AE mice. A total of 43 active components of MMRAC with 87 anti-AE target genes were identified, and these target genes were enriched in IL-17 and HIF-1 signaling pathways. Integration analysis revealed that purine metabolism was the critical metabolic pathway by which MMRAC exerted its therapeutic effect against AE. Specifically, MAPK14, MMP9, PTGS2, HIF1A, EGLN1, NOS2 were the pivotal targets of MMRAC for the treatment of AE, and Western blot analysis revealed MMRAC to decrease protein levels of these pro-inflammatory signaling molecules. According to molecular docking, these key targets have a strong affinity with the MMRAC compounds. Collectively, MMRAC relieved the colon inflammation of AE mice via regulating inflammatory signaling pathways to reduce hypoxia and improved energy metabolism.

Determining the protective effects of Ma-Mu-Ran Antidiarrheal Capsules against acute DSS-induced enteritis using 16S rRNA gene sequencing and fecal metabolomics.

Ma-Mu-Ran Antidiarrheal Capsules (MMRAC) is traditional Chinese medicine that has been used to treat diarrhea caused by acute enteritis (AE) and bacillary dysentery in Xinjiang (China) for many years. However, the potential therapeutic mechanism of MMRAC for AE and its regulatory mechanism on host metabolism is unclear. This study used fecal metabolomics profiling with GC/MS and 16S rRNA gene sequencing analysis to explore the potential regulatory mechanisms of MMRAC on a dextran sulfate sodium salt (DSS)-induced mouse model of AE. Fecal metabolomics-based analyses were performed to detect the differentially expressed metabolites and metabolic pathways. The 16S rRNA gene sequencing analysis was used to assess the altered gut microbes at the genus level and for functional prediction. Moreover, Pearson correlation analysis was used to integrate differentially expressed metabolites and altered bacterial genera. The results revealed that six intestinal bacteria and seven metabolites mediated metabolic disorders (i.e., metabolism of amino acid, carbohydrate, cofactors and vitamins, and lipid) in AE mice. Besides, ten altered microbes mediated the differential expression of eight metabolites and regulated these metabolisms after MMRAC administration. Overall, these findings demonstrate that AE is associated with metabolic disorders and microbial dysbiosis. Further, we present that MMRAC exerts protective effects against AE by improving host metabolism through the intestinal flora.

[CHU Hao-ran's experience in treatment of diarrhea-predominant irritable bowel syndrome with acupuncture and moxibustion].

Professor CHU Hao-ran believes that the clinical diagnosis and treatment of diarrhea-predominant irritable bowel syndrome with acupuncture and moxibustion should concentrate on the integration of disease and syndrome differentiation. According to the evolution of pathogenesis, this disease is divided into 4 stages, i.e. invasion of exogenous pathogens, liver stagnation and spleen deficiency, spleen and kidney yang deficiency and interaction of cold and heat. Hence, the treatment should be provided by stages. Focusing on regulating the spleen and stomach, a specific acupuncture-moxibustion prescription is proposed, including Tianshu (ST 25), Zhongwan (CV 12), Zusanli (ST 36) and Shangjuxu (ST 37). Additionally, the combination of distal and nearby acupoints is considered and an unique needling manipulation, named the fight between dragon and tiger, is exerted. On the base of syndrome and meridian differentiation, the modern medicine is combined, stressing on the mind regulation and the mutual application of acupuncture and moxibustion in treatment. Eventually, a distinctive treatment system with acupuncture and moxibustion is formed for "regulating the spleen and stomach and differentiating meridians".

Determining the protective effects of Ma-Mu-Ran Antidiarrheal Capsules against acute DSS-induced enteritis using 16S rRNA gene sequencing and fecal metabolomics / 中国天然药物

Ma-Mu-Ran Antidiarrheal Capsules (MMRAC) is traditional Chinese medicine that has been used to treat diarrhea caused by acute enteritis (AE) and bacillary dysentery in Xinjiang (China) for many years. However, the potential therapeutic mechanism of MMRAC for AE and its regulatory mechanism on host metabolism is unclear. This study used fecal metabolomics profiling with GC/MS and 16S rRNA gene sequencing analysis to explore the potential regulatory mechanisms of MMRAC on a dextran sulfate sodium salt (DSS)-induced mouse model of AE. Fecal metabolomics-based analyses were performed to detect the differentially expressed metabolites and metabolic pathways. The 16S rRNA gene sequencing analysis was used to assess the altered gut microbes at the genus level and for functional prediction. Moreover, Pearson correlation analysis was used to integrate differentially expressed metabolites and altered bacterial genera. The results revealed that six intestinal bacteria and seven metabolites mediated metabolic disorders (i.e., metabolism of amino acid, carbohydrate, cofactors and vitamins, and lipid) in AE mice. Besides, ten altered microbes mediated the differential expression of eight metabolites and regulated these metabolisms after MMRAC administration. Overall, these findings demonstrate that AE is associated with metabolic disorders and microbial dysbiosis. Further, we present that MMRAC exerts protective effects against AE by improving host metabolism through the intestinal flora.

CHU Hao-ran's experience in treatment of diarrhea-predominant irritable bowel syndrome with acupuncture and moxibustion / 中国针灸

Professor CHU Hao-ran believes that the clinical diagnosis and treatment of diarrhea-predominant irritable bowel syndrome with acupuncture and moxibustion should concentrate on the integration of disease and syndrome differentiation. According to the evolution of pathogenesis, this disease is divided into 4 stages, i.e. invasion of exogenous pathogens, liver stagnation and spleen deficiency, spleen and kidney yang deficiency and interaction of cold and heat. Hence, the treatment should be provided by stages. Focusing on regulating the spleen and stomach, a specific acupuncture-moxibustion prescription is proposed, including Tianshu (ST 25), Zhongwan (CV 12), Zusanli (ST 36) and Shangjuxu (ST 37). Additionally, the combination of distal and nearby acupoints is considered and an unique needling manipulation, named the fight between dragon and tiger, is exerted. On the base of syndrome and meridian differentiation, the modern medicine is combined, stressing on the mind regulation and the mutual application of acupuncture and moxibustion in treatment. Eventually, a distinctive treatment system with acupuncture and moxibustion is formed for "regulating the spleen and stomach and differentiating meridians".

A Cost-Efficient 5G Non-Public Network Architectural Approach: Key Concepts and Enablers, Building Blocks and Potential Use Cases.

The provision of high data rate services to mobile users combined with improved quality of experience (i.e., zero latency multimedia content) drives technological evolution towards the design and implementation of fifth generation (5G) broadband wireless networks. To this end, a dynamic network design approach is adopted whereby network topology is configured according to service demands. In parallel, many private companies are interested in developing their own 5G networks, also referred to as non-public networks (NPNs), since this deployment is expected to leverage holistic production monitoring and support critical applications. In this context, this paper introduces a 5G NPN architectural approach, supporting among others various key enabling technologies, such as cell densification, disaggregated RAN with open interfaces, edge computing, and AI/ML-based network optimization. In the same framework, potential applications of our proposed approach in real world scenarios (e.g., support of mission critical services and computer vision analytics for emergencies) are described. Finally, scalability issues are also highlighted since a deployment framework of our architectural design in an additional real-world scenario related to Industry 4.0 (smart manufacturing) is also analyzed.

[Professor CHU Hao-ran's experience of acupuncture and moxibustion of regulating spleen-stomach and differentiating meridians-collaterals].

Professor CHU Hao-ran successively followed famous doctors of acupuncture and spleen-stomach disease, such as ZHOU Mei-sheng, inherited their academic thoughts and clinical experience, and studied the classics to summarize and propose the clinical academic proposition regulating spleen-stomach, differentiating meridians-collaterals. In clinical practice, professor CHU focuses on individual differences of patients, carefully examines syndrome and refines acupoint selection; he pays attention to regulating spleen-stomach, and actively uses Zusanli (ST 36); he simultaneously uses acupuncture-moxibustion and acupoints with efficacy; he inherits traditional reinforcing and reducing methods, and extends the scope of acupoint diagnosis and treatment, while he emphasizes keeping spirit and treating spirit, and the combination of mind and qi, in order to improve clinical diagnosis and treatment effect.

High-throughput screening yields several small-molecule inhibitors of repeat-associated non-AUG translation.

Repeat-associated non-AUG (RAN) translation is a noncanonical translation initiation event that occurs at nucleotide-repeat expansion mutations that are associated with several neurodegenerative diseases, including fragile X-associated tremor ataxia syndrome (FXTAS), ALS, and frontotemporal dementia (FTD). Translation of expanded repeats produces toxic proteins that accumulate in human brains and contribute to disease pathogenesis. Consequently, RAN translation constitutes a potentially important therapeutic target for managing multiple neurodegenerative disorders. Here, we adapted a previously developed RAN translation assay to a high-throughput format to screen 3,253 bioactive compounds for inhibition of RAN translation of expanded CGG repeats associated with FXTAS. We identified five diverse small molecules that dose-dependently inhibited CGG RAN translation, while relatively sparing canonical translation. All five compounds also inhibited RAN translation of expanded GGGGCC repeats associated with ALS and FTD. Using CD and native gel analyses, we found evidence that three of these compounds, BIX01294, CP-31398, and propidium iodide, bind directly to the repeat RNAs. These findings provide proof-of-principle supporting the development of selective small-molecule RAN translation inhibitors that act across multiple disease-causing repeats.

Professor 's experience of acupuncture and moxibustion of regulating spleen-stomach and differentiating meridians-collaterals / 中国针灸

Professor - successively followed famous doctors of acupuncture and spleen-stomach disease, such as -, inherited their academic thoughts and clinical experience, and studied the classics to summarize and propose the clinical academic proposition regulating spleen-stomach differentiating meridians-collaterals. In clinical practice, professor focuses on individual differences of patients, carefully examines syndrome and refines acupoint selection; he pays attention to regulating spleen-stomach, and actively uses Zusanli (ST 36); he simultaneously uses acupuncture-moxibustion and acupoints with efficacy; he inherits traditional reinforcing and reducing methods, and extends the scope of acupoint diagnosis and treatment, while he emphasizes keeping spirit and treating spirit, and the combination of mind and , in order to improve clinical diagnosis and treatment effect.

Randomized control trail of eye movement desensitization and reprocessing versus cognitive behavior therapy for treating posttraumatic stress disorder / 重庆医学

Objective To investigate the effects of eye movement desensitization and reprocessing (EMDR) versus cognitive behavior therapy (CBT) for treating adult posttraumatic stress disorder (PTSD) .Methods A total of 81 patients with PTSD con‐forming to the including standard were randomly allocated to the EMDR group ,CBT group ,and control group ,27 cases per group . The PTSD symptoms ,anxiety and depression moods in 3 groups were assessed before and after treatment by adopting the Clinician‐administered PTSD Scale (CAPS) ,Hamilton Anxiety Scale (HAMA) and Hamilton Depression Scale (HAMD) .Results The drop‐out rates were 29 .63% for the EMDR group ,7 .41% for the CBT group and 7 .41% for the control group respectively ;the re‐experience symptoms score of CAPS in the EMDR group was lower than that in the CBT group with statistical difference (P=0 . 036) .Conclusion Both EMDR and CBT are the effective psychological therapeutic method ,EMDR has more effective than CBT in the reproving the re‐experience symptoms of PTSD .The future studies should pay more attention to the application of stabilization technologies for reducing the dropout rate of EMDR .

Ran signaling in melanoma: implications for the development of alternative therapeutic strategies.

We performed a comparative study between two human metastatic melanoma cell lines (A375 and 526), and melanocytes (FOM78) by gene expression profiling and pathway analysis, using Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) software. Genes involved in Ran signaling were significantly over-represented (p ≤ 0.001) and up-regulated in melanoma cells. A melanoma-associated molecular pathway was identified, where Ran, Aurora Kinase A (AurkA) and TERT were up-regulated, while c-myc and PTEN were down-regulated. A consistent high Ran and AurkA gene expression was detected in about 48% and 53%, respectively, of 113 tissue samples from metastatic melanoma patients. AurkA down-regulation was observed in melanoma cells, by Ran knockdown, suggesting AurkA protein is a Ran downstream target. Furthermore, AurkA inhibition, by exposure of melanoma cells to MLN8054, a specific AurKA inhibitor, induced apoptosis in both melanoma cell lines and molecular alterations in the IPA-identified molecular pathway. These alterations differed between cell lines, with an up-regulation of c-myc protein level observed in 526 cells and a slight reduction seen in A375 cells. Moreover, Ran silencing did not affect the A375 invasive capability, while it was enhanced in 526 cells, suggesting that Ran knockdown, by AurkA down-regulation, resulted in a Ran-independent enhanced melanoma cell invasion. Finally, AurK A inhibition induced a PTEN up-regulation and its action was independent of B-RAF mutational status. These findings provide insights relevant for the development of novel therapeutic strategies as well as for a better understanding of mechanisms underlying therapy resistance in melanoma.

Divergent evolution of potato immune receptor CC domain interactions with the Ran GTPase-activating protein 2.

Effector-triggered immunity mediated by immune receptors in plants provides powerful defense against specific pathogens. Solanum tuberosum Ran GTPase-Activating Protein 2 (StRanGAP2) interacts with immune receptors Rx and Gpa2 through their coiled-coil (CC) domains. We assayed additional CC domains from other Solanaceous immune receptors and observed interaction by co-immunoprecipitation between StRanGAP2 and a novel immune receptor, STR5. A CC domain very similar to Rx and Gpa2, STR4, failed to interact, likely due to sequence divergence in the region implicated in StRanGAP2 binding. Like Rx and Gpa2, STR5 interacted with the StRanGAP2 N-terminal WPP domain. Our findings substantiate the importance of RanGAPs as common CC-interacting proteins of multiple immune receptors requiring further study to define their roles in pathogen perception.

Systematic Review of Randomized Controlled Study Comparing Traditional Chinese Medicine with Western Medicine in the Treatment of Diabetes / 中国药房

OBJECTIVE:To evaluate the curative efficacy of Chinese medicine vs. western medicine in the treatment of diabetes. METHODS:The randomized controlled trials(RCTs) comparing western medicine with traditional Chinese medicine alone or combination of Chinese medicine and western medicine in the treatment of diabetes were systematically evaluated. Meta-analysis of the cited trials was performed by evidence-based medicine method with Revman 4.2 software for statistical analysis. RESULTS:A total of 14 RCTs met our inclusion criteria. Meta-analysis showed that there was no significant difference between traditional Chinese medicine and western medicine in clinical efficacy in the treatment of diabetes; however,the diabetic patients treated with integrated Chinese medicine and western medicine showed much better efficacy than those treated with western medicine alone. CONCLUSION:Treatment of diabetes with traditional Chinese medicine plus western medicine has more advantages; however,this conclusion remains to be confirmed further by studies of high quality given the low quality in test methodology.