Oleanolic acid inhibits hypoxic tumor-derived exosomes-induced premetastatic niche formation in hepatocellular carcinoma by targeting ERK1/2-NFκB signaling.

BACKGROUND: Pulmonary premetastatic niche (PMN) formation plays a key role in the lung metastasis of hepatocellular carcinoma (HCC). Hypoxia promotes the secretion of tumor-derived exosomes (TDEs) and facilitates the formation of PMN. However, the mechanisms remain unexplored. METHODS: TDEs from normoxic (N-TDEs) or hypoxic (H-TDEs) HCC cells were used to induce fibroblast activation in vitro and PMN formation in vivo. Oleanolic acid (OA) was intragastrically administered to TDEs-preconditioned mice. Bioinformatics analysis and drug affinity responsive target stability (DARTS) assays were performed to identify targets of OA in fibroblasts. RESULTS: H-TDEs induced activation of pulmonary fibroblasts, promoted formation of pulmonary PMN and subsequently facilitated lung metastasis of HCC. OA inhibited TDEs-induced PMN formation and lung metastasis and suppressed TDEs-mediated fibroblast activation. MAPK1 and MAPK3 (ERK1/2) were the potential targets of OA. Furthermore, H-TDEs enhanced ERK1/2 phosphorylation in fibroblasts in vitro and in vivo, which was suppressed by OA treatment. Blocking ERK1/2 signaling with its inhibitor abated H-TDEs-induced activation of fibroblasts and PMN formation. H-TDEs-induced phosphorylation of ERK1/2 in fibroblasts touched off the activation NF-κB p65, which was mitigated by OA. In addition, the ERK activator C16-PAF recovered the activation of ERK1/2 and NF-κB p65 in H-TDEs-stimulated MRC5 cells upon OA treatment. CONCLUSION: The present study offers insights into the prevention of TDEs-induced PMN, which has been insufficiently investigated. OA suppresses the activation of inflammatory fibroblasts and the development of pulmonary PMN by targeting ERK1/2 and thereby has therapeutic potential in the prevention of lung metastasis of HCC.

Targeting tumor-derived exosome-mediated premetastatic niche formation: The metastasis-preventive value of traditional Chinese medicine.

Tumor-derived exosome (TDE)-mediated premetastatic niche (PMN) formation is a potential mechanism underlying the organotropic metastasis of primary tumors. Traditional Chinese medicine (TCM) has shown considerable success in preventing and treating tumor metastasis. However, the underlying mechanisms remain elusive. In this review, we discussed PMN formation from the perspectives of TDE biogenesis, cargo sorting, and TDE recipient cell alterations, which are critical for metastatic outgrowth. We also reviewed the metastasis-preventive effects of TCM, which act by targeting the physicochemical materials and functional mediators of TDE biogenesis, regulating the cargo sorting machinery and secretory molecules in TDEs, and targeting the TDE-recipient cells involved in PMN formation.

Effects of Different Chemicals on Sexual Regulation in Persimmon (Diospyros kaki Thunb.) Flowers.

Research on crop sexuality is important for establishing systems for germplasm innovation and cultivating improved varieties. In this study, androecious persimmon trees were treated with various concentrations of ethrel (100, 500, and 1,000 mg/L) and zeatin (1, 5, and 10 mg/L) to investigate the morphological, physiological, and molecular characteristics of persimmon. Ethrel at 1,000 mg/L and zeatin at 10 mg/L both significantly reduced the stamen length and pollen grain diameter in androecious trees. Ethrel treatment also led to reduced stamen development with degenerated cellular contents; zeatin treatment promoted the development of arrested pistils via maintaining relatively normal mitochondrial morphology. Both treatments altered carbohydrate, amino acid, and endogenous phytohormone contents, as well as genes associated with hormone production and floral organ development. Thereafter, we explored the combined effects of four chemicals, including ethrel and zeatin, as well as zebularine and 5-azacytidine, both of which are DNA methylation inhibitors, on androecious persimmon flower development. Morphological comparisons showed that stamen length, pollen viability, and pollen grain diameter were significantly inhibited after combined treatment. Large numbers of genes involving in carbohydrate metabolic, mitogen-activated protein kinase (MAPK) signaling, and ribosome pathways, and metabolites including uridine monophosphate (UMP) and cyclamic acid were identified in response to the treatment, indicating complex regulatory mechanisms. An association analysis of transcriptomic and metabolomic data indicated that ribosomal genes have distinct effects on UMP and cyclamic acid metabolites, explaining how male floral buds of androecious persimmon trees respond to these exogenous chemicals. These findings extend the knowledge concerning sexual differentiation in persimmon; they also provide a theoretical basis for molecular breeding, high-yield cultivation, and quality improvement in persimmon.

Research progress on icariin, a traditional Chinese medicine extract, in the treatment of asthma.

Bronchial asthma is a common chronic airway disease, and long-term management of asthma is the focus and challenge of clinical treatment. Glucocorticoids are often used as the first choice for the treatment of asthma. However, the occurrence of hormone dependence, hormone resistance, and local and systemic adverse reactions caused by hormone application also creates problems for the treatment of asthma. Finding new, safe, and effective therapeutic drugs is an important research direction at present. Icariin is an effective ingredient of the traditional Chinese medicine, Epimedium. It has various biological attributes such as anti-inflammatory and antioxidative activities, and immune regulation. It has high safety and a wide range of clinical applications. Icariin has the characteristics of multitargeted intervention in the treatment of asthma. Here, we review the specific mechanisms of icariin in treating asthma, and icariin is considered a novel therapy in controlling asthma; however, the mechanism is still worth further investigation.

Curcumin Can Improve Spinal Cord Injury by Inhibiting TGF-ß-SOX9 Signaling Pathway.

Spinal cord injury (SCI) is a severe nervous system disease with high morbidity and disability rate. Signaling pathways play a key role in the neuronal restorative mechanism following SCI. SRY-related high mobility group (HMG)-box gene 9 (SOX9) affects glial scar formation via Transforming growth factor beta (TGF-ß) signaling pathway. Activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is transferred into nucleus to upregulate TGF-ß-SOX9. Curcumin exhibits potent anti-inflammatory and anti-oxidant properties. Curcumin can play an important role in SCI recovery by inhibiting the expression of NF-κB and TGF-ß-SOX9. Herein, we review the potential mechanism of curcumin-inhibiting SOX9 signaling pathway in SCI treatment. The inhibition of NF-κB and SOX9 signaling pathway by curcumin has the potentiality of serving as neuronal regenerative mechanism following SCI.

Effect of Chinese herbal compound on liver fibrosis in rabbits with schistosomiasis by B-ultrasound.

OBJECTIVE: To explore the value of B-ultrasound on the evaluation of the effects of traditional Chinese medicine compound of Radix astragali, Salvia miltiorrhiza and Angelica sinensis, and TCM + praziquantel on liver fibrosis in rabbits with schistosomiasis. METHODS: The hepatic fibrosis model in rabbits with schistosomiasis was established. The experimental animals (24 rabbits) were randomly divided into four groups (group A, B, C and D, n=6). Group A (control group) was only treated by praziquantel; Group B was treated by mixture of Radix astragali and Salvia miltiorrhiza + praziquantel; Group C was treated by mixture of Radix astragali and Angelica sinensis + praziquantel; Group D was treated by mixture of Radix astragali, Salvia miltiorrhiza and Angelica sinensis + praziquantel. Then B-ultrasonogram was used to evaluate the effects. RESULTS: Each group showed certain curative effect on liver fibrosis in rabbits with schistosomiasis. The efficacy of group B, C and D was better than group A, and that of group D was the best. The differences in long diameter, thickness diameter, transverse diameter and portal vein inner diameter of liver before and after treatment were statistically significant (P<0.05). The liver function indexes and liver fibrosis indexes were significantly improved after treatment (P<0.05). CONCLUSIONS: The mixture of Radix astragali, Salvia miltiorrhiza and Angelica sinensis combined with Western medicine treatment can obviously improve the efficacy on liver fibrosis of schistosomiasis.