BIX-01294, a G9a inhibitor, suppresses cell proliferation by inhibiting autophagic flux in nasopharyngeal carcinoma cells.

G9a, a histone methyltransferase, has been found to be upregulated in a range of tumor tissues, and contributes to tumor growth and metastasis. However, the impact of G9a inhibition as a potential therapeutic target in nasopharyngeal carcinoma (NPC) is unclear. In the present study we aimed to investigate the anti-proliferative effect of G9a inhibition in the NPC cell lines CNE1 and CNE2, and to further elucidate the molecular mechanisms underlying these effects. The expression of G9a in NPC tumor tissues was significantly higher than that in normal nasopharyngeal tissues. The pharmacological inhibition of G9a by BIX-01294 (BIX) inhibited proliferation and induced caspase-independent apoptosis in NPC cells in vitro. Treatment with BIX induced autophagosome accumulation, which exacerbated the cytotoxic activity of BIX in NPC cells. Mechanistic studies have found that BIX impairs autophagosomes by initiating autophagy in a Beclin-1-independent way, and impairs autophagic degradation by inhibiting lysosomal cathepsin D activation, leading to lysosomal dysfunction. BIX was able to suppress tumor growth, possibly by inhibiting autophagic flux; it might therefore constitute a promising candidate for NPC therapy.

Mechanism of Gynostemmae Pentaphylli Herba in the treatment of ischemic stroke based on network pharmacology and molecular docking.

OBJECTIVES: To analyze the mechanism of Gynostemmae Pentaphylli Herba in the treatment of ischemic stroke based on network pharmacology and molecular docking. METHODS: We used various databases and software, including Cytoscape, Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, Pubchem, Swiss Target Prediction, GenCards, String, and WebGestalt to identify the active components and targets of Gynostemmae Pentaphylli Herba, as well as the targets associated with ischemic stroke. The mechanism of Gynostemmae Pentaphylli Herba in treating ischemic stroke was analyzed from the perspective of protein-protein interaction (PPI) co-expression, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and AutoDock was used for molecular docking. RESULTS: A total of 12 active components were identified, and 276 potential targets of Gynostemmae Pentaphylli Herba were obtained. There were 3151 disease targets associated with ischemic stroke. The top 5 active components of Gynostemmae Pentaphylli Herba were Ruvoside_qt, quercetin, 3'-methyleriodictyol, Spinasterol, and Cholesterin (CLR) according to the node degree value. There were 186 common targets between the disease targets of cerebral ischemic stroke and drug targets of Gynostemmae Pentaphylli Herba, with 21 key targets obtained by PPI network analysis. KEGG analysis revealed enrichment in 45 signaling pathways. Biological process increased 139 biological processes. Molecular function enriched 17 cell functions. Cellular component enriched 20 cell components. Molecular docking found that the binding energy of other protein molecules to ligand small molecules was less than -5 kal·mol-1, except that the binding energy of AKT1 to 3'-methyleriodictyol was greater than -5 kal·mol-1. CONCLUSIONS: Gynostemmae Pentaphylli Herba may play a role in treating ischemic stroke by affecting various pathways through its active ingredients such as Ruvoside_qt, quercetin, 3'-methyleriodictyol, Spinasterol and CLR.

Efficacy of nasal irrigation with hypertonic saline on chronic rhinosinusitis: systematic review and meta-analysis.

INTRODUCTION: Currently, several different concentrations of saline are recommended for use in nasal irrigation. Increasing studies show that nasal irrigation with hypertonic saline is more effective than traditional saline in the treatment of rhinosinusitis, but there have been few systematic analyses of the effect of nasal irrigation with hypertonic saline on chronic rhinosinusitis. OBJECTIVE: We sought to compare the effects of hypertonic saline and isotonic saline in the treatment of rhinosinusitis in order to provide a reference for clinical nasal irrigation for chronic rhinosinusitis treatment. METHODS: Medline, cochrane library, EMBASE, PubMed, Chinese biomedical journal database, China national knowledge infrastructure, Wanfang database, and other databases were searched, and the searching was supplemented by manual searches for relevant references to treatment of rhinosinusitis by saline nasal irrigation. The last retrieval date was March 2018. The included studies were evaluated for quality, and data were extracted for meta-analysis using RevMan 5.3. RESULTS: Seven studies were included. Effects favoring hypertonic saline on nasal symptoms were greater in 4 subgroups. These were (1) patients with nasal secretion (SMD=1.52; 95% CI: 1.04, 2.00; p<0.01), (2) patients with congestion (SMD=1.52; 95% CI: 1.04, 2.00; p<0.01), (3) patients with headache (SMD=0.82; 95% CI: 0.38, 1.26; p<0.01), (4) patients with overall symptomatic relief (SMD=1.63; 95% CI: 0.83, 2.44; p<0.01). However, no difference was shown in smell improvement (SMD=0.47; 95% CI: -0.65, 1.59; p=0.41) and radiologic scores improvement (SMD=2.44; 95% CI: -3.14, 8.02; p<0.01). Besides, hypertonic saline showed greater improvement in mucociliary clearance time scores than did the isotonic saline group (SMD=1.19; 95% CI: 0.78, 1.60; p<0.01). Hypertonic saline brought greater minor adverse effects. CONCLUSION: Compared with isotonic saline, hypertonic saline nasal irrigation for the treatment of chronic rhinosinusitis is significantly more effective and has mild side effects in improving nasal symptoms and ciliary movement, but there is no significant difference in imaging findings and smell improvement. Although hypertonic saline is worthy of widespread use in clinical practice, it is still necessary to further study the exact manner and concentration of nasal irrigation.

Efficacy of nasal irrigation with hypertonic saline on chronic rhinosinusitis: systematic review and meta-analysis / Eficácia da irrigação nasal com solução salina hipertônica na rinossinusite crônica: revisão sistemática e metanálise

Abstract Introduction: Currently, several different concentrations of saline are recommended for use in nasal irrigation. Increasing studies show that nasal irrigation with hypertonic saline is more effective than traditional saline in the treatment of rhinosinusitis, but there have been few systematic analyses of the effect of nasal irrigation with hypertonic saline on chronic rhinosinusitis. Objective: We sought to compare the effects of hypertonic saline and isotonic saline in the treatment of rhinosinusitis in order to provide a reference for clinical nasal irrigation for chronic rhinosinusitis treatment. Methods: Medline, cochrane library, EMBASE, PubMed, Chinese biomedical journal database, China national knowledge infrastructure, Wanfang database, and other databases were searched, and the searching was supplemented by manual searches for relevant references to treatment of rhinosinusitis by saline nasal irrigation. The last retrieval date was March 2018. The included studies were evaluated for quality, and data were extracted for meta-analysis using RevMan 5.3. Results: Seven studies were included. Effects favoring hypertonic saline on nasal symptoms were greater in 4 subgroups. These were (1) patients with nasal secretion (SMD = 1.52; 95% CI: 1.04, 2.00; p < 0.01), (2) patients with congestion (SMD = 1.52; 95% CI: 1.04, 2.00; p < 0.01), (3) patients with headache (SMD = 0.82; 95% CI: 0.38, 1.26; p < 0.01), (4) patients with overall symptomatic relief (SMD = 1.63; 95% CI: 0.83, 2.44; p < 0.01). However, no difference was shown in smell improvement (SMD = 0.47; 95% CI: −0.65, 1.59; p = 0.41) and radiologic scores improvement (SMD = 2.44; 95% CI: -3.14, 8.02; p < 0.01). Besides, hypertonic saline showed greater improvement in mucociliary clearance time scores than did the isotonic saline group (SMD = 1.19; 95% CI: 0.78, 1.60; p < 0.01). Hypertonic saline brought greater minor adverse effects. Conclusion: Compared with isotonic saline, hypertonic saline nasal irrigation for the treatment of chronic rhinosinusitis is significantly more effective and has mild side effects in improving nasal symptoms and ciliary movement, but there is no significant difference in imaging findings and smell improvement. Although hypertonic saline is worthy of widespread use in clinical practice, it is still necessary to further study the exact manner and concentration of nasal irrigation.

Resumo Introdução: Atualmente, o uso de várias concentrações diferentes de solução salina é recomendado na irrigação nasal. Um número crescente de estudos mostra que a irrigação nasal com solução salina hipertônica é mais eficaz do que a solução salina tradicional no tratamento de rinossinusite, mas existem poucas análises sistemáticas do efeito da irrigação nasal com solução salina hipertônica em rinossinusite crônica. Objetivo: Comparar os efeitos da solução salina hipertônica com a solução salina isotônica no tratamento da rinossinusite, para fornecer uma referência clínica de irrigação nasal no tratamento da rinossinusite crônica. Método: Foram pesquisados os bancos de dados Medline, Cochrane Library, Embase, PubMed, Chinese biomedical journal database, China national knowledge infrastructure, Wanfang database e outros, e a pesquisa foi complementada por pesquisas manuais de referências relevantes ao tratamento da rinossinusite por irrigação nasal com solução salina. A data da última recuperação de dados foi março de 2018. Os estudos incluídos foram avaliados quanto à qualidade e os dados foram extraídos para a metanálise com o software RevMan 5.3. Resultados: Sete estudos foram incluídos. Os efeitos favoráveis à solução salina hipertônica nos sintomas nasais foram maiores em quatro subgrupos. Esses foram (1) pacientes com secreção nasal (DMP = 1,52; IC95%: 1,04, 2,00; p ˂ 0,01); (2) pacientes com congestão (DMP = 1,52; IC95%: 1,04, 2,00; p ˂ 0,01); (3) Pacientes com dor de cabeça (DMP = 0,82; IC95%: 0,38, 1,26; p ˂ 0,01); (4) Pacientes com alívio sintomático geral (DMP = 1,63; IC95%: 0,83, 2,44; p ˂ 0,01). Entretanto, não houve diferença na melhoria do olfato (DMP = 0,47; IC95%: -0,65, 1,59; p = 0,41) e na melhoria dos escores radiológicos (DMP = 2,44; IC95%: -3,14, 8,02; p < 0,01). Além disso, o grupo solução salina hipertônica mostrou maior melhoria nos escores do tempo de clearence mucociliar do que o grupo solução salina isotônica (DMP = 1,19; IC95%: 0,78, 1,60; p ˂ 0,01). A solução salina hipertônica causou efeitos adversos menores. Conclusão: Em comparação com a solução salina isotônica, a irrigação nasal com solução salina hipertônica para o tratamento da rinossinusite crônica é significantemente mais eficaz e apresenta efeitos colaterais mais leves, melhoria mais acentuada dos sintomas nasais e no movimento ciliar, mas não há diferença significante nos achados de imagem e na melhoria do olfato. Embora a solução salina hipertônica seja digna de uso generalizado na prática clínica, ainda são necessários mais estudos sobre a forma de uso e a concentração ideal da solução nasal.