Huanglian Jiedu plaster ameliorated X-ray-induced radiation dermatitis injury by inhibiting HMGB1-mediated macrophage-inflammatory interaction.

ETHNOPHARMACOLOGICAL RELEVANCE: Huanglian Jiedu plaster (HJP) is a kind of Chinese patent medicine that contains four medicinal plants. It has been clinically proven to be beneficial for the treatment of tumor-associated radiation dermatitis. However, the underlying mechanism of HJP on radiation dermatitis remains unclear. AIM OF THE STUDY: This study aims to investigate the therapeutic effect of HJP on X-ray-induced radiation dermatitis, and how HJP improves the inflammatory response and skin damage of radiation dermatitis. MATERIALS AND METHODS: In this study, We selected a case of esophageal cancer as a clinical demonstration of the efficacy of radiation dermatitis. The patient received a total radiation dose of 7000cGY, and treatment by HJP for 14 days.RD mouse models were established through continuous irradiation with X-ray (800cGY) on the right hind limb of mice for 5 days, and the treatment group mice was applied HJP to the irradiated skin for 15 days from modeling. An inflammatory cellular model was induced through irradiation with X-ray (100cGY) in JB6 cells and a co-culture system of JB6 cell and macrophage was established to examine the effect and mechanism of HJP on the inflammatory interaction of these two cells. The activation of HMGB1-TLR4-NF-κB signaling pathway, and the levels of epidermal injury related factors and inflammatory cytokins were subsequently detected. RESULTS: The results showed that HJP can significantly alleviate X-ray-induced skin injury, inhibiting skin inflammation and reducing the expression of inflammatory cytokins (IL-1ß, IL-6, TNF-α) and epidermal damage related factors (Integrin ß1, CXCL9 and Cytokeratin17), as well as significantly down-regulated the protein level of HMGB1 (a key DAMPs factor) in vivo and in vitro. Cell co-culture experiments demonstrated that HMGB1 released from X-ray-induced JB6 cells can promote inflammatory response of macrophage, which then feedback aggravate epithelial cell damage, notably, HJP can significantly improve radiation skin lesion by inhibiting HMGB1-mediated inflammatory interaction between epithelial cells and macrophages. CONCLUSION: In summary, these findings indicated the role of HJP in the treatment of RD by inhibiting the inflammatory interaction between macrophage and JB6 cells mediated by HMGB1, which may provide a reliable therapeutic method for RD. Furthermore, HMGB1 may be an effective target for HJP to inhibit inflammation and ameliorate skin damage in RD.

Impact of Vascular Endothelial Growth Factor Gene Polymorphisms and Their Interactions with Environmental Factors on Susceptibility to Renal Cell Carcinoma.

AIMS: This study aimed to investigate the association of single nucleotide polymorphisms (SNPs) within vascular endothelial growth factor (VEGF) gene and additional gene-environment interaction with renal cell carcinoma (RCC) risk. METHODS: PCR-restriction fragment length polymorphism was performed to detect SNPs. Hardy-Weinberg equilibrium and allele frequencies in cases and controls were calculated using SNPStats (http://bioinfo.iconcologia.net/SNPstats). Generalized multifactor dimensionality reduction (GMDR) was used to screen the best interaction combination among 4 SNPs, smoking, and alcohol drinking. Logistic regression was performed to investigate the association between 4 SNPs within VEGF gene, additional gene-smoking interaction, and RCC risk. RESULTS: RCC risk was significantly higher in carriers with the T allele of rs833061 within VEGF gene than those with CC genotype (CT+TT vs. CC) {adjusted odds ratio (OR) (95% confidence interval [CI]) = 1.71 (1.17-2.32), p = 0.002} and higher in carriers with the A allele of rs699947 within VEGF gene than those with GG genotype (GA+AA vs. GG) (adjusted OR [95% CI] = 1.64 [1.27-2.10], p < 0.001). GMDR analysis indicated a significant 2-locus model (p = 0.0010) involving rs833061 and smoking. The cross-validation consistency of the 2-locus model was 10/10, and the testing accuracy was 60.72%. Current smokers with rs833061-CT+TT genotype had the highest RCC risk, compared to never smokers with rs833061-CC genotype within VEGF gene (OR [95% CI] = 3.02 [1.84-4.23], p < 0.001). CONCLUSIONS: We found that the T allele of rs833061 and the A allele of rs699947 within VEGF gene, and the interaction between rs833061 and smoking were all associated with increased RCC risk.

Salidroside affects proliferation, invasion and apoptosis of cervical squamous cell carcinoma C33Acells through JAK2/STAT3 pathway / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To investigate the effects of salidroside on the proliferation, invasion and apoptosis of cervical squamous cell carcinoma C33A cells and explore its possible mechanism. Methods: C33A cells were divided into 4 groups: control group, low-dose group (salidroside 50 μg/mL), high-dose group (salidroside 150 μg/mL), and AG490 group (inhibitor of JAK2/STAT3 signaling pathway, 50 μmol/L). Effects of salidroside and AG490 on the proliferation, invasion and apoptosis of C33A cells were detected by MTT method, EdU labeling experiment, Transwell assay, Rh123 staining and Flow cytometry, respectively. Western blotting was used to detect the effects of salidroside and AG490 on the expressions of JAK2/STAT3 pathway-related proteins (p-JAK2, p-STAT3) and apoptosis-related proteins (Bax, Bcl-2, caspase-3) in C33A cells. Result: Compared with the control group, the proliferation and DNA synthesis as well as the invasion of C33Acells in the low-dose group were significantly inhibited (all P<0.05), while the apoptosis was significantly enhanced (P<0.05); in the meanwhile, the fluorescence intensity of Rh123 was significantly reduced (all P<0.05) and the membrane structure of C33A cells were destroyed; moreover, the expressions of p-JAK2, p-STAT3 and Bcl-2 were significantly decreased while the expressions of Bax and caspase-3 were significantly increased (all P<0.05). Compared with the low-dose group, the effects of high-dose salidroside and AG490 on the proliferation, invasion, apoptosis and related protein expressions in C33A cells were more significant (all P<0.05), but there was no difference between the high-dose group and the AG490 group. Conclusion: Salidroside can inhibit the proliferation and invasion of C33A cells and promote cell apoptosis. Its mechanism may be related to inhibition of JAK2/ STAT3 signaling pathway.