Effect of traditional Chinese medicine in osteosarcoma: Cross-interference of signaling pathways and potential therapeutic targets.

Osteosarcoma (OS) has a high recurrence rate, disability rate, mortality and metastasis, it brings great economic burden and psychological pressure to patients, and then seriously affects the quality of life of patients. At present, the treatment methods of OS mainly include radiotherapy, chemotherapy, surgical therapy and neoadjuvant chemotherapy combined with limb salvage surgery. These treatment methods can relieve the clinical symptoms of patients to a certain extent, and also effectively reduce the disability rate, mortality and recurrence rate of OS patients. However, because metastasis of tumor cells leads to new complications, and OS cells become resistant with prolonged drug intervention, which reduces the sensitivity of OS cells to drugs, these treatments still have some limitations. More and more studies have shown that traditional Chinese medicine (TCM) has the characteristics of "multiple targets and multiple pathways," and can play an important role in the development of OS through several key signaling pathways, including PI3K/AKT, Wnt/ß-catenin, tyrosine kinase/transcription factor 3 (JAK/STAT3), Notch, transforming growth factor-ß (TGF-ß)/Smad, nuclear transcription factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), nuclear factor E2-related factor 2 (Nrf2), Hippo/YAP, OPG/RANK/RANKL, Hedgehog and so on. In this paper, the signaling pathways of cross-interference between active ingredients of TCM and OS were reviewed, and the development status of novel OS treatment was analyzed. The active ingredients in TCM can provide therapeutic benefits to patients by targeting the activity of signaling pathways. In addition, potential strategies for targeted therapy of OS by using ferroptosis were discussed. We hope to provide a unique insight for the in-depth research and clinical application of TCM in the fields of OS growth, metastasis and chemotherapy resistance by understanding the signaling crosstalk between active ingredients in TCM and OS.

Comparing high-dose dual therapy with bismuth-containing quadruple therapy for the initial eradication of Helicobacter pylori infection on Hainan Island: A randomized, multicenter clinical trial.

BACKGROUND: Traditional bismuth-containing quadruple therapy, as a first-line eradication treatment for Helicobacter pylori (H. pylori), has several disadvantages, including drug side effects, low medication adherence, and high costs. Trials of high-dose dual treatment have demonstrated its advantages, which include good safety and adherence profiles. In this study, we investigated the efficacy, safety, and compliance of a high-dose dual therapy when compared with bismuth-based quadruple treatment for the initial eradication of H. pylori infection on Hainan Island, China. METHODS: We randomized 846 H. pylori-infected patients into two groups. A bismuth-containing quadruple therapy group was administered the following: esomeprazole 20 mg, amoxicillin 1000 mg, and clarithromycin 500 mg twice daily, and colloidal bismuth pectin in suspension 150 mg three times/day for 2 weeks. A high-dose dual therapy group was administered the following: esomeprazole 20 mg four times/day and amoxicillin 1000 mg three times/day for 2 weeks. Patients were given a 13C urea breath test at 4 weeks at treatment end. Adverse effects and compliance were evaluated at follow-up visits. RESULTS: Eradication rates in the high-dose dual therapy group were: 90.3% (381/422, 95% confidence interval [CI]: 87.1%-92.9%) in intention-to-treat (ITT) and 93.6% (381/407, 95% CI: 90.8%-95.8%) in per-protocol (PP) analyses. Eradication rates were 87.3% in ITT (370/424, 95% CI: 83.7%-90.3%) and 91.8% in PP analyses (370/403, 95% CI: 88.7%-94.3%) for quadruple therapy, with no statistical differences (P = 0.164 in ITT and P = 0.324 in PP analyses). Adverse effects were 13.5% (55/407) in the dual group and 17.4% (70/403) in the quadruple group (P = 0.129). Compliance was 92.4% (376/407) in the dual group and 86.6% (349/403) in the quadruple group (P = 0.007). CONCLUSIONS: High-dose dual therapy had high eradication rates comparable with bismuth-based quadruple treatment, with no differences in adverse effects, however higher adherence rates were recorded.

Integration of Hormonal and Nutritional Cues Orchestrates Progressive Corolla Opening.

Flower opening is essential for pollination and thus successful sexual reproduction; however, the underlying mechanisms of its timing control remain largely elusive. We identify a unique cucumber (Cucumis sativus) line '6457' that produces normal ovaries when nutrients are under-supplied, and super ovaries (87%) with delayed corolla opening when nutrients are oversupplied. Corolla opening in both normal and super ovaries is divided into four distinct phases, namely the green bud, green-yellow bud, yellow bud, and flowering stages, along with progressive color transition, cytological tuning, and differential expression of 14,282 genes. In the super ovary, cell division and cell expansion persisted for a significantly longer period of time; the expressions of genes related to photosynthesis, protein degradation, and signaling kinases were dramatically up-regulated, whereas the activities of most transcription factors and stress-related genes were significantly down-regulated; concentrations of cytokinins (CKs) and gibberellins were higher in accordance with reduced cytokinin conjugation and degradation and increased expression of gibberellin biosynthesis genes. Exogenous CK application was sufficient for the genesis of super ovaries, suggesting a decisive role of CKs in controlling the timing of corolla opening. Furthermore, 194 out of 11,127 differentially expressed genes identified in pairwise comparisons, including critical developmental, signaling, and cytological regulators, contained all three types of cis-elements for CK, nitrate, and phosphorus responses in their promoter regions, indicating that the integration of hormone modulation and nutritional regulation orchestrated the precise control of corolla opening in cucumber. Our findings provide a valuable framework for dissecting the regulatory pathways for flower opening in plants.

Epigenetic modification of spinal miR-219 expression regulates chronic inflammation pain by targeting CaMKIIγ.

Emerging evidence has shown that miRNA-mediated gene expression modulation contributes to chronic pain, but its functional regulatory mechanism remains unknown. Here, we found that complete Freund's adjuvant (CFA)-induced chronic inflammation pain significantly reduced miRNA-219 (miR-219) expression in mice spinal neurons. Furthermore, the expression of spinal CaMKIIγ, an experimentally validated target of miR-219, was increased in CFA mice. Overexpression of spinal miR-219 prevented and reversed thermal hyperalgesia and mechanical allodynia and spinal neuronal sensitization induced by CFA. Concurrently, increased expression of spinal CaMKIIγ was reversed by miR-219 overexpression. Downregulation of spinal miR-219 in naive mice induced pain-responsive behaviors and increased p-NMDAR1 expression, which could be inhibited by knockdown of CaMKIIγ. Bisulfite sequencing showed that CFA induced the hypermethylation of CpG islands in the miR-219 promoter. Treatment with demethylation agent 5'-aza-2'-deoxycytidine markedly attenuated pain behavior and spinal neuronal sensitization, which was accompanied with the increase of spinal miR-219 and decrease of CaMKIIγ expression. Together, we conclude that methylation-mediated epigenetic modification of spinal miR-219 expression regulates chronic inflammatory pain by targeting CaMKIIγ.