Xingchun Zhou

Effect of Feining on bleomycin-induced pulmonary injuries in rats.

ETHNOPHARMACOLOGICAL RELEVANCE The flowers of Gentiana veitchiorum has been widely used in decoction form in the traditional medicine of Tibet against tussis, tracheitis, angina for their anti-inflammatory, antimicrobial and alexipharmic properties. AIM OF THE STUDY The aim of current study was to evaluate the therapeutic effects of Feining, a Chinese herbal formula (national invention patent: ZL200510042636.3) against pulmonary injuries and to clarify the mechanisms involved. MATERIALS AND METHODS Experimental pulmonary injuries were induced by bleomycin (BLM) in rats with or without subsequent treatment of Feining or prednisone as positive control. The pulmonary injuries were evaluated by histological analysis. Also, the levels of superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH) and hydroxyproline (Hyp) in the lung tissue were determined. To clarify one of the possible active principles responsible for Feining, high performance liquid chromatography-diode array detector-mass spectrometry (HPLC-DAD-MS) method was applied to identify the components of Gentiana veitchiorum, one of major ingredients of Feining. RESULTS Feining significantly improved lung alveolitis scores and reduced the Hyp content of lungs, which is an index of collagen accumulation. Moreover, Feining played a role against the oxidative damages by decreasing the MDA level, whereas increasing SOD and GSH activity, which correlated with oxidation resistance and scavenging of free radicals. In addition, Feining alleviated inflammatory lung injury by decreasing tumor necrosis factor-α (TNF-α) expression. HPLC-DAD-MS analysis revealed that there was 1.97% gentiopicroside in Gentiana veitchiorum. CONCLUSION Feining has certain therapeutic effects against pulmonary injuries.

High leukocyte mtDNA content contributes to poor prognosis through ROS-mediated immunosuppression in hepatocellular carcinoma patients

Compelling epidemiological evidences indicate a significant association between leukocyte mitochondrial DNA (mtDNA) content and incidence risk of several malignancies, including hepatocellular carcinoma (HCC). However, whether leukocyte mtDNA content affect prognosis of HCC patients and underlying mechanism has never been explored. In our study, leukocyte mtDNA content was measured in 618 HCC patients and its prognostic value was analyzed. Moreover, we detected the immunophenotypes of peripheral blood mononuclear cells (PBMCs) and plasma concentrations of several cytokines in 40 HCC patients and assessed the modulating effects of mtDNA content on immunosuppression in cell models. Our results showed that HCC patients with high leukocyte mtDNA content exhibited a significantly worse recurrence-free survival (RFS) and overall survival (OS) than those with low leukocyte mtDNA content. Leukocyte mtDNA content and TNM stage exhibited a notable joint effect in prognosis prediction. Furthermore, we found that patients with high leukocyte mtDNA content exhibited a higher frequency of CD4+CD25+FOXP3+ regulatory T (Treg) cells and lower frequency of NK cells in PBMCs and had higher TGF-β1 and lower TNF-α and IFN-γ plasma concentration when compared with those with low leukocyte mtDNA content, which suggests an immunosuppressive status. High leukocyte mtDNA content significantly enhanced the ROS-mediated secretion of TGF-β1, which accounted for higher Treg and lower NK frequency in PBMCs. In a conclusion, our study for the first time demonstrates that leukocyte mtDNA content is an independent prognostic marker complementing TNM stage and associated with an ROS-mediated immunosuppressive phenotype in HCC patients.

Loss of CD155 expression predicts poor prognosis in hepatocellular carcinoma

CD155 is an important ligand in triggering tumour rejection by immune cells. However, the expression of CD155 and its clinical significance in hepatocellular carcinoma (HCC) remains unknown.

Genetic variations in monocarboxylate transporter genes as predictors of clinical outcomes in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is characterized by poor prognosis and only a few molecular markers may be potentially used to predict clinical outcomes. Previous studies have demonstrated that monocarboxylate transporters (MCTs) play important roles in the development and progression of many cancers. The purpose of this study was to assess the effects of single nucleotide polymorphisms (SNPs) of MCT genes on prognosis of NSCLC patients in Chinese Han population. Nine functional SNPs in MCT1, MCT2, and MCT4 genes were selected and genotyped using Sequenom iPLEX genotyping system in 500 Chinese NSCLC patients receiving surgery. Multivariate Cox proportional hazards model and Kaplan–Meier curve were used for the prognostic analysis. TT genotype of SNP rs1049434 (MCT1) was significantly associated with better overall survival (OS) (HR = 0.56, P = 0.026) and recurrence-free survival (RFS) (HR = 0.57, P = 0.016) of NSCLC patients. TT genotype of another SNP rs995343 (MCT2) exhibited an association with worse RFS of NSCLC patients (HR = 1.46, P = 0.039). Unfavorable genotypes of SNP rs1049434 and rs995343 showed a significant cumulative effect on OS and RFS of NSCLC patients. Moreover, we found that patients carrying AA+AT genotypes of rs1049434 showed significant OS and RFS benefits from adjuvant chemotherapy, but those with TT genotype did not. Our findings suggest that SNPs in MCT1 and MCT2 genes may affect clinical outcomes and can be used to predict the response to adjuvant chemotherapy in NSCLC patients who received surgical treatment once validated in future study.

Hsp60 exerts a tumor suppressor function by inducing cell differentiation and inhibiting invasion in hepatocellular carcinoma

Heat shock protein 60 (Hsp60), a typical mitochondrial chaperone, is associated with progression of various cancers. However, its expression and significance in hepatocellular carcinoma (HCC) remain largely unclear. In the present study, the mRNA and protein expression of Hsp60 in HCC tissues were detected by quantitative RT-PCR (n=24), western blot (n=7), and immunohistochemical staining (n=295), respectively. The correlation between Hsp60 expression and clinicopathological characteristics of HCC patient was also analyzed. Meanwhile, the influence of Hsp60 on malignant phenotype of HCC cells was further investigated. We found that expression of Hsp60 was significantly downregulated in HCC tissues compared to peritumor tissues. Hsp60 expression was significantly correlated with serum alpha -foetoprotein (AFP) level and tumor differentiation grade. Moreover, high Hsp60 expression cancer/pericancer (C/P) ratio was associated with a better overall survival rate (P=0.035, n=295). The prognostic implication of Hsp60 in HCC was further confirmed in another cohort of 107 HCC patients (P=0.027). Up-regulation of Hsp60 remarkably induced the cell differentiation and inhibited the invasive potential of HCC in vitro and in vivo. Intriguingly, the down-regulation of Hsp60 significantly impaired mitochondrial biogenesis. Although more data are required to clarify the underling mechanism responsible for function of Hsp60, our results suggested that the effect of Hsp60 on differentiation and invasion of HCC cells might be associated with mitochondrial biogenesis. Collectively, our findings indicated that Hsp60 exerted a tumor suppressor function, and might serve as a potential therapeutic target in the treatment of HCC.

Genetic variants in genes of tricarboxylic acid cycle key enzymes are associated with prognosis of patients with non-small cell lung cancer.

INTRODUCTION Non-small cell lung cancer (NSCLC) is characterized by poor prognosis and only a few molecular markers may be potentially used to predict the outcome. Metabolic reprogramming is a hallmark of cancer, including the alterations of tricarboxylic acid (TCA) cycle key enzymes. However, the significance of single nucleotide polymorphisms (SNPs) in genes encoding these key enzymes has not been investigated in NSCLC. PATIENTS AND METHODS In this study, we genotyped 18 potentially functional SNPs in 7 genes belonging to 3 TCA cycle enzyme families (SDH, FH and IDH) using Sequenom iPLEX genotyping system in a cohort of 500 NSCLC patients. Multivariate Cox proportional hazards model and Kaplan-Meier curve were used for the survival analysis. RESULTS Our results showed that SDHC gene: SNP rs12064957, IDH2 gene: SNP rs11540478 and FH gene: SNP rs1414493 were associated with overall survival (OS) and SDHA gene: SNP rs13173911, IDH2 gene: SNP rs4932158 were associated with recurrence-free survival (RFS) of NSCLC patients. Unfavorable genotypes of these SNPs showed a significant cumulative effect on OS and RFS of NSCLC patients (both P<0.001). Furthermore, survival tree analysis indicated that FH: rs1414493 was the primary risk factor contributing to OS of NSCLC patients and the IDH2: rs4932158 was the primary risk factor contributing to RFS of NSCLC patients. CONCLUSION Our data suggest that SNPs in TCA cycle key enzyme genes may serve as potential biomarkers to predict the outcomes of NSCLC. Further studies with different ethnicities are needed to validate our findings and generalize their clinical utility.

Polymorphisms in Genes of Tricarboxylic Acid Cycle Key Enzymes Are Associated with Early Recurrence of Hepatocellular Carcinoma.

Alterations of activity and expression in tricarboxylic acid (TCA) cycle key enzymes have been indicated in several malignancies, including hepatocellular carcinoma (HCC). They play an important role in the progression of cancer. However, the impact of single nucleotide polymorphisms (SNPs) in genes encoding these key enzymes on the recurrence of HCC has not been investigated. In this study, we genotyped 17 SNPs in genes encoding TCA cycle key enzymes and analyzed their association with recurrence-free survival (RFS) in a cohort of 492 Chinese HCC patients by Cox proportional hazard model and survival tree analysis. We identified 7 SNPs in SDHC, SDHD, FH, and IDH2 genes to be significantly associated with the RFS of HCC patients. Moreover, all these SNPs were associated with the early recurrence (within 2 years after surgery) risk of diseases. Cumulative effect analysis showed that these SNPs exhibited a dose-dependent effect on the overall and early recurrence. Further stratified analysis suggested that number of risk genotypes modified the protective effect on HCC recurrence conferred by transcatheter arterial chemoembolization treatment. Finally, the survival tree analysis revealed that SNP rs10789859 in SDHD gene was the primary factor contributing to HCC recurrence in our population. To the best of our knowledge, we for the first time observed the association between SNPs in genes encoding TCA cycle key enzymes and HCC recurrence risk. Further observational and functional studies are needed to validate our findings and generalize its clinical usage.

Low expression of CD112 is associated with poor overall survival in patients with hepatocellular carcinoma

CD112 as an important ligand of CD226 can stimulate the natural killer (NK) cell-mediated target cell lysis. Previous studies have reported that CD112 is involved in cancer initiation and progression. However, its expression and clinical significance in hepatocellular carcinoma (HCC) have never been investigated. In this study, we used immunohistochemistry to examine CD112 expression in cancer and pericancer tissues from 159 HCC cases. Western blot and immunofluorescence were used to detect CD112 expression in HCC cell lines. χ(2) Test was used to assess the association of CD112 expression with clinicopathological characteristics, whereas Kaplan-Meier survival function and Cox proportional hazards regression model were used to explore the association between CD112 expression and clinical outcome of patients with HCC. Overall, CD112 expression was significantly reduced in HCC tissues when compared with adjacent pericancer liver tissues (P < .001). Western blot and immunofluorescence analyses showed that most HCC cell lines had low CD112 expression level. Furthermore, low CD112 expression was significantly associated with high serum α-fetoprotein level (P = .004) in patients with HCC. Kaplan-Meier analysis showed that patients with low CD112 expression had poorer postsurgery overall survival than those with high CD112 expression (log-rank P = .045). In conclusion, our findings demonstrate that the down-regulation of CD112 may be an important mechanism through which HCC cells evade the natural killer cell-mediated immunosurveillance, and thus, CD112 may be a useful biomarker to assess the immunologic niche of HCC.