Hepatocarcinoma Angiogenesis and DNA Damage Repair Response: An Update

Hepatocarcinoma is one of the most common lethal human malignant tumors, mainly because of active angiogenesis. This kind of high angiogenesis often accounts for early metastasis, rapid recurrence, and poor survival. Growing evidence has proved that hepatocarcinoma angiogenesis is closely associated with multiple risk factors, such as DNA damages resulting from hepatitis B and C virus infection, aflatoxin B1 exposure, ethanol intake, and obesity. Genetic alterations and genomic instability, probably resulting from low DNA damage repair response (DRR) and the following unrepaired DNA lesions, are also increasingly recognized as important risk factors of hepatocarcinoma angiogenesis. Dysregulation of DRRs and signaling to cell cycle checkpoints involving in DRR pathways may accelerate the accumulation of DNA damages and trigger the dysregulation of angiogenesis-related genes and the progression of hepatocarcinoma. In this review, we discussed DNA damages/DRRs and angiogenesis during hepatocarcinogenesis and their interactive regulations. Hopefully, the review will also remind the medical researchers and clinic doctors of further understanding and validating the values of DNA damages/DRRs in hepatocarcinoma angiogenesis

Surgical treatment of multivalvular endocarditis: Twenty-one–year single center experience

ObjectiveLittle information is available about surgical outcomes in patients with multivalvular endocarditis. The aim of this article is to review the 21-year experience with surgical treatment of patients with multivalvular endocarditis at our institution and, in particular, to determine the incidence, pathologic status, diagnosis, surgical strategies, and outcomes of patients with this disease.MethodsFrom January 1986 to December 2006, a total of 48 patients (40 men, 8 women), with a mean age of 42 ± 12 years, underwent surgery for multivalvular endocarditis. Endocarditis was active in 32 patients and healed in 16. Preoperative transthoracic echocardiographic evaluation was performed in all 48 patients with addition of transesophageal echocardiography in 22 (45.8%). Intraoperative findings showed that the endocarditis involved mostly the mitral and aortic valves (40/48 patients). Triple or quadruple valve involvement was found in 1 and 2 patients, respectively. Preoperative, perioperative, and postoperative data were retrospectively analyzed and risk factors for early and late survival were determined.ResultsIn only 24 (50.0%) patients was multivalvular endocarditis diagnosed by preoperative transthoracic echocardiography; 17 (77.3%) patients had multivalvular endocarditis confirmed by preoperative transesophageal echocardiography. The 30-day hospital mortality was 12.5% (n = 6). Preoperative renal failure, New York Heart Association class IV, and emergency surgery were identified as independent risk factors for hospital mortality. Overall long-term survival was 74% ± 6% at 5 years and 62% ± 3% at 10 years. Multivariate analysis revealed that renal failure and recurrent endocarditis were associated with increased late mortality. Ten-year freedom from recurrent endocarditis was 74% ± 5% and 10-year freedom from reoperation was 73% ± 6%.ConclusionsIn our institution, multivalvular endocarditis was diagnosed by transthoracic echocardiography in only half of the patients. Intraoperative transesophageal echocardiography provided a more effective means to identify this disease. Radical resection of all infected tissues for patients with multivalvular endocarditis and additional intraoperative interventions, depending on the intraoperative pathologic condition, produced satisfactory in-hospital and long-term results, similar to those in patients with a single infected heart valve

CBX4 Expression and AFB1-Related Liver Cancer Prognosis

Background: Previous studies have shown that chromobox 4 (CBX4) expression may involve in the progression of liver cancer, however, it is unclear whether it affects the prognosis of hepatocellular carcinoma (HCC) related to aflatoxin B1 (AFB1)

Aspirin-triggered lipoxin A4 attenuates LPS-induced pro-inflammatory responses by inhibiting activation of NF-κB and MAPKs in BV-2 microglial cells

<p>Abstract</p> <p>Background</p> <p>Microglial activation plays an important role in neurodegenerative diseases through production of nitric oxide (NO) and several pro-inflammatory cytokines. Lipoxins (LXs) and aspirin-triggered LXs (ATLs) are considered to act as 'braking signals' in inflammation. In the present study, we investigated the effect of aspirin-triggered LXA₄(ATL) on infiammatory responses induced by lipopolysaccharide (LPS) in murine microglial BV-2 cells.</p> <p>Methods</p> <p>BV-2 cells were treated with ATL prior to LPS exposure, and the effects of such treatment production of nitric oxide (NO), inducible nitric oxide synthase (iNOS), interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α) were analysed by Griess reaction, ELISA, western blotting and quantitative RT-PCR. Moreover, we investigated the effects of ATL on LPS-induced nuclear factor-κB (NF-κB) activation, phosphorylation of mitogen-activated protein kinases (MAPKs) and activator protein-1 (AP-1) activation.</p> <p>Results</p> <p>ATL inhibited LPS-induced production of NO, IL-1β and TNF-α in a concentration-dependent manner. mRNA expressions for iNOS, IL-1β and TNF-α in response to LPS were also decreased by ATL. These effects were inhibited by Boc-2 (a LXA₄receptor antagonist). ATL significantly reduced nuclear translocation of NF-κB p65, degradation of the inhibitor IκB-α, and phosphorylation of extracellular signal-regulated kinase (ERK) and p38 MAPK in BV-2 cells activated with LPS. Furthermore, the DNA binding activity of NF-κB and AP-1 was blocked by ATL.</p> <p>Conclusions</p> <p>This study indicates that ATL inhibits NO and pro-inflammatory cytokine production at least in part via NF-κB, ERK, p38 MAPK and AP-1 signaling pathways in LPS-activated microglia. Therefore, ATL may have therapeutic potential for various neurodegenerative diseases.</p

Effects of tourmaline on growth of three kinds of microorganisms

Tourmaline is a kind of widespread minerals and has been used in many fields of society. Owing to the special electric properties, tourmaline can destroy the hydrogen bond between water molecules. The growth of microorganism may be affected with addition of tourmaline; therefore the effects of tourmaline on three different kinds of microorganisms were studied using microcalorimetric method. The kinetic parameters of growth process were obtained through the thermogenic curves. The results show that high concentration tourmaline inhibited the growth of prokaryotic cells (the growth rate constant of Escherichia coli and Staphylococcus aureus decreased 68.77 and 35.25% at tourmaline concentration of 160 g/L), while promoted eukaryotic cell (the growth rate constant of Candida albicans increased 40.73% at tourmaline concentration of 160 g/L). However, the low concentration tourmaline had complex effects on growth of the studied microorganisms.Key words: Microcalorimetric, water cluster, growth rate, inhibitory ratio

Molecular Mechanisms of Hepatocellular Carcinoma Related to Aflatoxins: An Update

Hepatocellular carcinoma (hepatocarcinoma) is a major type of primary liver cancer and one of the most frequent human malignant neoplasms. Aflatoxins are I-type chemical carcinogen for hepatocarcinoma. Increasing evidence has shown that hepatocarcinoma induced by aflatoxins is the result of interaction between aflatoxins and hereditary factor. Aflatoxins can induce DNA damage including DNA strand break, adducts formation, oxidative DNA damage, and gene mutation and determine which susceptible individuals feature cancer. Inheritance such as alterations may result in the activation of proto-oncogenes and the inactivation of tumor suppressor genes and determine individual susceptibility to cancer. Interaction between aflatoxins and genetic susceptible factors commonly involve in almost all pathologic sequence of hepatocarcinoma: chronic liver injury, cirrhosis, atypical hyperplastic nodules, and hepatocarcinoma of early stages. In this review, we discuss the biogenesis, toxification, and epidemiology of aflatoxins and signal pathways of aflatoxin-induced hepatocarcinoma. We also discuss the roles of some important genes related to cell apoptosis, DNA repair, drug metabolism, and tumor metastasis in hepatocarcinogenesis related to aflatoxins

The Serum MicroRNA Expression Modified the Genic Toxicity Caused by Aflatoxin B1

The serum microRNAs have been reported as potential biomarkers for hepatocellular carcinoma (HCC); however, their role in genic toxicity related to aflatoxin B1 (AFB1), such as TP53 mutation and DNA damage, has not yet been evaluated. Here, we conducted a hospital-based case-control study, including 558 patients with pathologically diagnosed HCC and positive AFB1 and healthy controls (n = 630) without any evidence of liver diseases. Genic toxicity related to AFB1 was evaluated using the hot-spot mutation at the codon 269 of TP53 gene (TP53M) and AFB1-DNA adducts. Through serum microRNA PCR microarray screening analysis, we observed 10 differentially expressed microRNAs (including miR-7-2-3p, miR-4651, miR-127-3p, miR-192-5p, miR-382-5p, miR-10b-5p, miR-532-3p, miR-16-5p, miR-106b-5p, and miR-4688) among HCC cases with positive AFB1 and controls with positive AFB1. The miR-4651 and miR-382-5p were further identified to be significantly higher in AFB1-positive HCC cases compared to controls. This kind of increasing serum levels was significantly and positively associated with frequency of TP53M and the levels of AFB1-DNA adduct. Furthermore, these microRNAs also modified the prognosis of HCC related to AFB1. These results suggest that the serum levels of microRNAs might be able to modify AFB1-induced genic toxicity, and microRNA-4651 and miR-382-5p, are such potential candidates

The Diagnostic and Prognostic Potential of MicroRNAs for Hepatocellular Carcinoma

Hepatocellular carcinoma (also termed hepatocarcinoma) is the third cancer-related cause of death worldwide. To our knowledge, markers such as α-fetoprotein display poor performance in the early diagnosis and prognosis prediction of hepatocarcinoma. MicroRNAs are an evolutionarily conserved class of small noncoding single-stranded RNA typically consisting of 18–24 nucleotides. They have been reported to act as tumor suppressors or oncogenes via reversely regulating gene expression. Recent evidence has revealed that microRNAs, especially in body fluids such as the blood and urine, display important diagnostic and prognostic potential for hepatocarcinoma. Here, we reviewed currently available data on microRNAs and hepatocarcinoma, with emphasis on the biogenesis and function of microRNAs and their potential diagnostic and prognostic value for hepatocarcinoma. We also discussed the clinical utility perspectives of microRNAs in hepatocarcinoma and possible challenges

Gastrodin attenuates renal injury and collagen deposition via suppression of the TGF-β1/Smad2/3 signaling pathway based on network pharmacology analysis

Background: Gastrodin has been widely used clinically in China as an antihypertensive drug. However, its effect on hypertensive renal injury is yet to be elucidated. The current study aimed to investigate the effects of gastrodin on hypertensive renal injury and its underlying mechanisms by network pharmacology analysis and validation in vivo and in vitro.Methods: A total of 10 spontaneously hypertensive rats (SHRs) were randomly categorized into the following two groups: SHR and SHR + Gastrodin groups. Wistar Kyoto (WKY) rats were used as the control group (n = 5). The SHR + Gastrodin group was intragastrically administered gastrodin (3.5 mg/kg/day), and the rats in both WKY and SHR groups were intragastrically administered an equal amount of double-distilled water for 10 weeks. Hematoxylin-eosin, Masson’s trichrome, and Sirius red staining were used to detect the pathological changes and collagen content in the renal tissues. Network pharmacology analysis was performed to explore its potential targets and related pathways. In vitro, the CCK-8 assay was used to determine the cell viability. Immunohistochemistry and western-blotting analyses were employed to assess the protein expression associated with renal fibrosis and transforming growth factor-β1 (TGF-β1) pathway-related proteins in the renal tissues or in TGF-β1-stimulated rat kidney fibroblast cell lines (NRK-49F).Results: Gastrodin treatment attenuates renal injury and pathological alterations in SHRs, including glomerular sclerosis and atrophy, epithelial cell atrophy, and tubular dilation. Gastrodin also reduced the accumulation of collagen in the renal tissues of SHRs, which were confirmed by downregulation of α-SMA, collagen I, collagen III protein expression. Network pharmacology analysis identified TGFB1 and SMAD2 as two of lead candidate targets of gastrodin on against hypertensive renal injury. Consistently, gastrodin treatment downregulated the increase of the protein expression of TGF-β1, and ratios of both p-Smad2/Smad2 and p-Samd3/Smad3 in renal tissues of SHRs. In vitro, gastrodin (25–100 μM) treatment significantly reversed the upregulation of α-SMA, fibronectin, collagen I, as well as p-Smad2 and p-Smad3 protein expressions without affecting the cell viability of TGF-β1 stimulated NRK-49F cells.Conclusion: Gastrodin treatment significantly attenuates hypertensive renal injury and renal fibrosis and suppresses TGF-β1/Smad2/3 signaling in vivo and in vitro