Guoan Xiang

Resveratrol reduces acute lung injury in a LPS‑induced sepsis mouse model via activation of Sirt1.

The development of acute lung injury (ALI) during sepsis almost doubles the mortality rate of patients. The efficacy of current treatment strategies is low as treatment is usually initiated following the onset of symptoms. Inflammation is one of the main mechanisms of autoimmune disorders and is a common feature of sepsis. The suppression of inflammation is therefore an important mechanism for the treatment of sepsis. Sirtuin 1 (Sirt1) has been demonstrated to play a role in the regulation of inflammation. Resveratrol, a potent Sirt1 activator, exhibits anti‑inflammatory properties. However, the role of resveratrol for the treatment of ALI during sepsis is not fully understood. In the present study, the anti‑inflammatory role of Sirt1 in the lipopolysaccharide (LPS)‑induced TC‑1 cell line and its therapeutic role in ALI was investigated in a mouse model of sepsis. The upregulation of matrix metalloproteinase-9, interleukin (IL)‑1β, IL‑6 and inducible nitric oxide synthase was induced by LPS in the mouse model of sepsis and the TC‑1 cell line, and resveratrol suppressed the overexpression of these proinflammatory molecules in a dose‑dependent manner. Resveratrol decreased pulmonary edema in the mouse model of sepsis induced by LPS. In addition, resveratrol improved lung function and reduced pathological alterations in the mouse model of sepsis. Knockdown of Sirt1 by RNA interference resulted in an increased susceptibility of TC‑1 cells to LPS stimulation and diminished the anti‑inflammatory effect of resveratrol. These results demonstrated that resveratrol inhibits LPS‑induced ALI and inflammation via Sirt1, and indicated that Sirt1 is an efficient target for the regulation of LPS‑induced ALI and inflammation. The present study provides insights into the treatment of ALI during sepsis.

SIRT1 promotes tumorigenesis of hepatocellular carcinoma through PI3K/PTEN/AKT signaling

SIRT1 is the human orthologue of SIR2, a conserved NAD-dependent protein deacetylase that regulates longevity in yeast and in Caenorhabditis elegans. Overexpression of SIRT1 in cancer tissue, compared with normal tissue, has been demonstrated, suggesting that SIRT1 may act as a tumor promoter. The function of SIRT1 in liver cancer has not been elucidated. In the present study, SIRT1 re-expression or knockdown was induced in hepatoma cell lines and liver normal cell lines. Our study demonstrated that overexpression of SIRT1 promoted mitotic entry of liver cells, cell growth and proliferation and inhibited apoptosis. The apoptosis involved caspase-3 and caspase-7, and was related to the PTEN/PI3K/AKT signaling pathway. The results demonstrate that SIRT1 promotes tumorigenesis of hepatocellular carcinoma (HCC) through the PTEN/PI3K/AKT signaling pathway. SIRT1 may serve as a novel target for selective killing of cancer versus normal liver cells.

Increased survival in hepatocellular carcinoma with iodine-125 implantation plus radiofrequency ablation: A prospective randomized controlled trial

BACKGROUND & AIMS The purpose of this study was to evaluate whether use of combined radiofrequency ablation (RFA) and percutaneous iodine-125 ((125)I) seed implantation results in better progression-free survival compared with the use of RFA alone in patients with hepatocellular carcinoma. METHODS 136 patients were randomly assigned to undergo HCC treatment with RFA and percutaneous iodine-125 seed implantation (RFA-(125)I, n=68) or RFA-only (n=68). A total of 91 patients had hepatitis B viral infection in both groups. Rates of tumour recurrence and overall survival were evaluated. RESULTS The probabilities of recurrence at 1-, 3-, and 5-years were 4.5%, 22.1%, and 39.8% in the RFA-(125)I group; and 14.8%, 35.3%, and 57.4% in the RFA-only group, respectively. The recurrence rate in the RFA-(125)I group was significantly lower than in the RFA-only group (HR, 0.508; 95% CI, 0.317-0.815; p=0.004 by log-rank test). Local and intrahepatic recurrence was significantly lower in the RFA-(125)I group than in the RFA-only group (7.3% vs. 22.0%, p=0.012 by log-rank test; 17.6% vs. 32.3%, p=0.041 by log-rank test). The probabilities of survival at 1-, 3-, and 5-years were 100%, 86.7%, and 66.1% in the RFA-(125)I group and 95.6%, 75.0%, and 47.0% in the RFA-only group, respectively. The survival rate in the RFA-(125)I group was significantly better than in the RFA-only group (HR, 0.502; 95% CI, 0.313-0.806; p=0.003 by log-rank test). Cox regression model indicated that the treatment group and tumour size were both recurrence-related and overall survival-related prognostic factors. CONCLUSIONS There were significant differences in overall survival and cumulative recurrence between RFA-(125)I and RFA-only for patients with small HCCs (⩽3 cm). Treatment with RFA-(125)I facilitated better local and intrahepatic tumour control and long-term survival compared with treatment of RFA alone. ClinicalTrials.gov Identifier: NCT01717729.

Adjuvant Iodine-125 Brachytherapy for Hepatocellular Carcinoma after Complete Hepatectomy: A Randomized Controlled Trial

Background Tumor recurrence is a major problem after curative resection of hepatocellular carcinoma (HCC). The current study evaluated the effects of adjuvant iodine-125 (125I) brachytherapy on postoperative recurrence of HCC. Methodology/Principal Findings From July 2000 to June 2004, 68 HCC patients undergoing curative hepatectomy were randomly assigned into a 125I adjuvant brachytherapy group (n = 34) and a group of best care (n = 34). Patients in the 125I adjuvant brachytherapy group received 125I seed implantation on the raw surface of resection. Patients in the best care control group received identical treatments except for the 125I seed implantation. Time to recurrence (TTR) and 1-, 3- and 5-year overall survival (OS) were compared between the two groups. The follow-up ended in January 2010, and lasted for 7.7–106.4 months with a median of 47.6 months. TTR was significantly longer in the 125I group (mean of 60.0 months vs. 36.7 months in the control). The 1-, 3- and 5-year recurrence-free rates of the 125I group were 94.12%, 76.42%, and 73.65% vs. 88.24%, 50.00%, and 29.41% compared with the control group, respectively. The 1-, 3- and 5-year OS rates of the 125I group were 94.12%, 73.53%, and 55.88% vs. 88.24%, 52.94%, and 29.41% compared with the control group, respectively. The 125I brachytherapy decreased the risk of recurrence (HR = 0.310) and the risk of death (HR = 0.364). Most frequent adverse events in the 125I group included nausea, vomiting, arrhythmia, decreased white blood cell and/or platelet counts, and were generally mild and manageable. Conclusions/Significance Adjuvant 125I brachytherapy significantly prolonged TTR and increased the OS rate after curative resection of HCC. Trial Registration Australian New Zealand Clinical Trials Registry ACTRN12610000081011.

Crocetin induces apoptosis of BGC-823 human gastric cancer cells.

Gastric cancer (GC) is one of the most common types of gastrointestinal tumors worldwide, and the side effects of chemotherapeutic drugs and the resistance to chemotherapy remain problematic in its clinical treatment. Therefore, safe and effective novel agents are urgently required. The purpose of the present study was to investigate the crocetin‑sensitive treatment of GC and its possible mechanisms. BGC‑823 human GC cells were treated with crocetin. The effects of crocetin on the viability of the cells were determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Hoechst 33258 dyeing and Rh123 staining were used to detect cell apoptosis. The BGC‑823 cells were subjected to western blotting analysis for detection of cytochrome c and cleaved caspase‑3 protein expression. Crocetin inhibited the proliferation of the GC cell line in a dose‑ and time‑dependent manner. Apoptotic BGC‑823 cells induced by crocetin were stained by Hoechst 33258 and observed under a light microscope for cell membrane staining of dense nuclei, nuclear pyknosis, fragmentation, chromatin condensation and highlighted nuclear membrane staining. This revealed a decline in the mitochondrial membrane potential of the BGC‑823 cells. Crocetin also induced caspase‑3 activation and cytochrome c translocation into the cytosol from the mitochondria. The results of this study indicate that crocetin induces the apoptosis of BGC‑823 cells, and may be used as an effective agent in the treatment of GC.

Towards a Near-Zero Recurrence Rate in Laparoscopic Inguinal Hernia Repair for Pediatric Patients

OBJECTIVE The aim of this study was to assess whether the median or lateral umbilicus ligament covering the internal hernia opening region after the purse-string knot could eliminate recurrence in laparoscopic inguinal hernia repair in pediatric patients of all ages. METHODS About 482 laparoscopic inguinal hernia repairs in 428 children of various ages were prospectively study in our institution from January 2000 to January 2004. The patients were divided into two groups randomly. In group A, the patients were accepted laparoscopic purse-string knot closing the internal hernia opening only; in group B, the patients were accepted the median or lateral umbilicus ligament covering the internal hernia opening region after the laparoscopic purse-string knot. The data from both groups of operations were then compared. RESULTS A total of 239 hernias were repaired in group A (214 patients), whereas 243 in group B (214 patients). The differences between the sex ratio of boys to girls (199:15 versus 197:17) and the mean ages (51.05 ± 49.65 versus 50.59 ± 48.87 months) in the two groups were not statistically significant. The recurrence rate in group B was lower than that in group A and was statistically significant (0.00% versus 4.18%, P < .05). There were no postoperative testicular atrophy in either group of the patients. CONCLUSION It is possible to achieve a near-zero recurrence rate in laparoscopic hernia repair in pediatric patients of all ages, especially for the patients with large hernia sac (diameter >1.5 cm) and the age over 5 years.

Single-walled carbon nanohorn (SWNH) aggregates inhibited proliferation of human liver cell lines and promoted apoptosis, especially for hepatoma cell lines

Single-walled carbon nanohorns (SWNHs) may be useful as carriers for anticancer drugs due to their particular structure. However, the interactions between the material itself and cancerous or normal cells have seldom been studied. To address this problem, the effects of raw SWNH material on the biological functions of human liver cell lines were studied. Our results showed that unmodified SWNHs inhibited mitotic entry, growth, and proliferation of human liver cell lines and promoted their apoptosis, especially in hepatoma cell lines. Individual spherical SWNH particles were found inside the nuclei of human hepatoma HepG2 cells and the lysosomes of normal human liver L02 cells, implying that SWNH particles could penetrate into human liver cells_and the different interacted mechanisms on human normal cell lines compared to hepatoma cell lines. Further research on the mechanisms and application in treatment of hepatocellular carcinoma with SWNHs is needed.

siRNA suppression of hTERT using activatable cell-penetrating peptides in hepatoma cells.

Activatable cell-penetrating peptides (aCPPs) allow non-viral, low cytotoxic and selective delivery of compounds into target cells for cancer therapy. In tumour cells, up-regulation of human telomerase reverse transcriptase (hTERT) frequently occurs and is being considered as a target in cancer diagnosis and treatment. siRNA sequence that target hTERT mRNA can silence the gene and reduce hTERT protein expression to reduce cell proliferation and inhibit cell growth. In our study, we tested a matrix metalloproteinase-2 (MPP2) aCPP in delivering hTERT siRNA into hepatocellular carcinoma cells (SMMC-7721) to silence the hTERT gene. Cultured SMMC-7721 cells were transfected with a complex of aCPPs and hTERT-specific siRNA-encoding or control plasmids. Compared with cells treated with the complex of control plasmid–CPPs, cells treated with the hTERT-specific siRNA-encoding plasmid–CPP complex had a prolonged G1-phase, but a shorter G2/S-phase, indicating a G1-arrest. Treatment with the hTERT-specific siRNA resulted in a significant decrease (by 26%; P<0.05) in hTERT mRNA levels. The aCPPs tested in this study provides a non-viral delivery of siRNA into cancer cells to silence target genes in cancer therapy.

Adiponectin and its receptors in chronic hepatitis B patients with steatosis in china.

Background HBV infection is a serious public health problem worldwide, which can contribute to the incidence of chronic hepatitis B (CHB), cirrhosis, and hepatocellular carcinoma (HCC). Objectives In the present report, we assessed the association between adiponectin, its receptors and hepatic steatosis, fibrosis, and inflammation with hepatitis B virus. Patients and Methods Liver biopsies from 89 patients with untreated chronic hepatitis B (34 steatosis vs. 55 without steatosis) were analyzed; liver biopsies from 50 healthy adults were used as control. The liver biopsies were subjected to routine histological examination, and stained immunohistochemically for adiponectin and adiponectin receptor2 (adipoR2). Results The two groups were found to be comparable with respect to demographic, biochemical, metabolic, histological, and viral characteristics. BMI, γ-GT, FPG, insulin, and insulin sensitivity estimated by the HOMA index were significantly higher in patients with steatosis. The viral load of HBV and HBeAg positivity was higher in patients with steatosis than those without steatosis. High serum adiponectin levels were significantly correlated with abnormal serum ALT level (vs. normal ALT, P = 0.000), and HBV genotype C (vs. genotype B, P = 0.018). In patients with chronic HBV, the insulin sensitizing adipokine adiponectin, and its receptor AdipoR2were associated with steatosis. While adiponectin may becorrelated with inflammation, adiponectin, and its receptors were not associated with viral factors. Conclusions Our results suggest that the role of adiponectin might be impaired in chronic hepatitis B with steatosis. Reduced hepatic expression of adiponectin and adipoR2 might be of pathophysiological relevance in CHB patients with steatosis. These findings indicated that reduced liver adiponectin expression may play an important role in the pathogenesis, and progression of CHB patients with steatosis. However, hepatic expression of adiponectin, and adipoR2 was not associated with various measures of HBV infection.

MicroRNA-132 cause apoptosis of glioma cells through blockade of the SREBP-1c metabolic pathway related to SIRT1

BACKGROUND The inhibition role of miRNA (microRNA or miR) on cancer signaling pathways has been used to prospective cancer treatment. SIRT1 might promote tumorigenesis in human glioma. METHODS Here, we investigated whether miR-132 regulate the expression of SIRT1 and its downstream SREBP (Sterol regulatory element-binding protein)-lipogenesis-cholesterogenesis metabolic pathway in human glioma cells. Furthermore, we studied the effect on biology function of glioma cell induced by miR-132. RESULTS MiR-132 inhibited SIRT1 and SREBP-1c expression and downregulated their targeted genes, including HMGCR and FASN. MiR-132 suppressed the cell growth, tumorigenicity, the invasion of glioma cells and migration as well as promoted their apoptosis. The pathways associated with cancer progression and tumorigenicity, and induce glioma cell apoptosis has been inhibited by miR-132 involving in a caspase-dependent apoptotic mechanism. CONCLUSIONS The recovery of miR-132 resulted in caspase-dependent apoptotic death in glioma cells. MiR-132 that was newly discovered represents a newly targeting mechanism in treatment for glioma.