Glycyrrhizin improves inflammation and apoptosis via suppressing HMGB1 and PI3K/mTOR pathway in lipopolysaccharide-induced acute liver injury.

OBJECTIVE: Acute liver injury (ALI) is mainly characterized by the symptom of metabolic disorders, homeostasis unbalance, and loss of liver function. There are no effective treatment methods at present stage except the liver transplantation. Effective treatment for early ALI is of great significance for the treatment of liver injury thereof. Glycyrrhizin (GL) is a promising inhibitor of the high-mobility group box-1 gene (HMGB1) which is expressed much higher in an inflammatory injury. However, it is not clear whether GL improves ALI via the inhibition of HMGB1. The present study is to probe the function and mechanism of glycyrrhizin on acute liver injury. MATERIALS AND METHODS: The expression of HMGB1 and inflammation in liver macrophages were analyzed. Lipopolysaccharide (LPS) was used in stimulating the macrophages to activate inflammatory response and recombined human HMGB1 was used to resist the function of GL to explore whether GL acted via the target of HMGB1. Then, LPS injection was utilized to induce ALI in mice, and then we evaluated GL treatment in ALI model. RESULTS: The results showed that the expressions of HMGB1 and inflammatory factors were markedly increased in LPS-activated liver macrophages. GL inhibited the progress of macrophages inflammation by restraining HMGB1, and the administration of GL could reverse the effects of LPS-induced ALI in mice. Moreover, PI3K/mTOR pathway was significantly suppressed by GL application. CONCLUSIONS: These results suggest that GL prevents inflammation in liver macrophages via inhibition of HMGB1. GL restrains inflammation and cell apoptosis by inhibiting HMGB1 via PI3K/mTOR signaling pathway in ALI. GL may become a novel drug for the therapy of ALI in the future.

Nitrate-induced and in situ electrochemical activation synthesis of oxygen deficiencies-rich nickel/nickel (oxy)hydroxide hybrid films for enhanced electrocatalytic water splitting.

Hydrogen produced by electrochemical water splitting offers a hopeful and renewable solution for addressing the global energy crisis; however, development of highly efficient non-noble-metal electrocatalysts remains a big challenge. Herein, we report a facile strategy to fabricate oxygen deficiencies-rich nickel/nickel (oxy)hydroxide hybrid films as efficient electrocatalysts for water splitting by in situ oxygen evolution reaction (OER) activation. Under OER conditions, the originally deposited Ni films from the ethaline-based deep eutectic solvent (DES) undergo a structural rearrangement with a phase transformation in the oxidation state from Ni(ii) to Ni(iii) at the surface. The change is coupled with an increase in oxygen deficiencies and a pronounced defective precursor is induced by the addition of nitrate ions, providing structural disordering and boosting the intrinsic activity of the catalyst, which strongly enhances the water splitting performance.

Liver Transplantation for Biliary Rhabdomyosarcoma With Liver Metastasis: Report of One Case.

BACKGROUND: Liver transplantation in combination with chemotherapy in postoperative biliary rhabdomyosarcoma recurrence of children was evaluated. METHODS: An 8-year-old girl with biliary rhabdomyosarcoma underwent pancreatico-duodenectomy with postoperative vincristine (VCR), adriamycin (Act-D), and cyclophosphamide (CTX) (VAC chemotherapy) (VCR, 1 mg; Act-D, 0.7 mg; CTX, 1500 mg). Two years later, liver metastasis in the left and right lobes was found and was followed by VAC chemotherapy (CTX, 1800 mg; Act-D, 0.9 mg; VCR, 1.2 mg), with no change of the tumor size. One and a half years later, liver transplantation performed with postoperative pathology confirmed embryonal rhabdomyosarcoma recurrence and was followed by VAC chemotherapy (CTX, 1400 mg; Act-D, 0.7 mg; VCR, 1.9 mg) and immunosuppression treatment. RESULTS: The liver transplantation went well, with no major complications. At the time of this report, the patient had survived for 6 months, with a good quality of life and no tumor recurrence. CONCLUSIONS: For unresectable biliary rhabdomyosarcoma without extra-hepatic metastases, liver transplantation could be an effective treatment. Liver transplantation completely removes the tumor and reduces the long-term side effects of chemotherapy drugs.

Moderate swimming suppressed the growth and metastasis of the transplanted liver cancer in mice model: with reference to nervous system.

Physical activity has been shown to suppress tumor initiation and progression. The neurotransmitter dopamine (DA) is closely related to movement and exhibits antitumor properties. However, whether the suppressive effects of physical activity on tumors was mediated by the nervous system via increased DA level remains unknowns. Here we show that regular moderate swimming (8 min/day, 9 weeks) raised DA levels in the prefrontal cortex, serum and tumor tissue, suppressed growth, reduced lung metastasis of transplanted liver cancer, and prolonged survival in a C57BL/6 mouse model, while overload swimming (16 and 32 min/day, 9 weeks) had the opposite effect. In nude mice that were orthotopically implanted with human liver cancer cell lines, DA treatment significantly suppressed growth and lung metastasis by acting on the D2 receptor (DR2). Furthermore, DR2 blockade attenuated the suppressive effect of moderate swimming on liver cancer. Both moderate swimming and DA treatment suppressed the transforming growth factor-beta (TGF-ß1)-induced epithelial-mesenchymal transition of transplanted liver cancer cells. At the molecular level, DR2 signaling inhibited extracellular signal-regulated kinase phosphorylation and expression of TGF-ß1 in vitro. Together, these findings demonstrated a novel mechanism by which the moderate exercise suppressed liver cancer through boosting DR2 activity, while overload exercise had the opposite effect, highlighting the possible importance of the dopaminergic system in tumor growth and metastasis of liver cancer.

Distribution and clinical significance of tumour-associated macrophages in pancreatic ductal adenocarcinoma: a retrospective analysis in China.

BACKGROUND: We aimed to characterize the localization and prognostic significance of tumour-associated macrophages (tams) in pancreatic ductal adenocarcinoma (pdac). METHODS: Tumour specimens from 70 patients with pdac and inflammatory specimens from 13 patients with chronic pancreatitis were collected and analyzed for tam and M2 macrophage counts by immunohistochemistry. Correlations between tam distributions and clinicopathologic features were determined. RESULTS: Immunohistochemical analysis showed that tam and M2 macrophage counts were higher in tissues from pdac than from chronic pancreatitis. The tams and M2 macrophages both infiltrated more into peritumour. Both macrophage types were positively associated with lymph node metastasis (p = 0.041 for tams in peritumour, p = 0.013 for M2 macrophages in introtumour, p = 0.006 for M2 macrophage in peritumour). In addition, abdominal pain was significantly more frequent in pdac patients with a greater tams count. The survival rate was much lower in patients having high infiltration by M2 macrophages than in those having low infiltration. CONCLUSIONS: The tam count might be associated with neural invasion in pdac, and M2 macrophages might play an important role in lymph node metastasis. Higher counts of either macrophage type were associated with increased risk of lymph node metastasis, and the M2 macrophage count could potentially be a marker for evaluating prognosis.

Effects of hypoxia on proliferation and osteogenic differentiation of periodontal ligament stem cells: an in vitro and in vivo study.

Changes in oxygen concentration may influence various innate characteristics of stem cells. The effects of varying oxygen concentration on human periodontal ligament stem cells (HPDLSCs) has not been explored, particularly under hypoxia-related conditions. First, HPDLSCs were cultured from the periodontium of human teeth using the outgrowth method. STRO-1 and CD146 expression of HPDLSCs was investigated by flow cytometry. To detect the multilineage differentiation capacities of HPDLSCs, osteogenic-like and adipogenic-like states were induced in cells. Next, HPDLSCs (passage 3) were exposed to normal oxygen (21% O2) or hypoxia (2% O2) conditions for 7 days and cell proliferation was evaluated. After culture in osteogenic medium for 7 days, osteoblastic differentiation was evaluated by semi-quantitative reverse transcription-polymerase chain reaction analysis to detect 3 osteoblastic markers: core-binding factor a 1/runt-related transcription factor 2, osteocalcin, and osteopontin. In addition, each cell group was incubated with a hydroxyapatite/tricalcium phosphate carrier and transplanted subcutaneously into the back of immunocompromised mice to investigate transplantation differences in vivo. HPDLSCs were isolated, cultured, and successfully identified. After exposure of HPDLSCs to hypoxia for 7 days, the proliferation rate was increased and showed higher osteogenic differentiation potential compared to control cells. After 12 weeks of transplantation, hypoxia-treated HPDLSCs differentiated into osteoblast-like cells that formed bone-like structures. These results suggest that oxygen concentrations affect various aspects of HPDLSC physiology and that hypoxia enhances osteogenic differentiation both in vivo and in vitro. Oxygen concentration may be a critical parameter for HPDLSCs during expansion and differentiation.

Early extraction: a silver bullet to avoid nerve injury in lower third molar removal?

This retrospective study evaluated the effects of early extraction of immature lower third molar on preventing complications, particularly nerve injury following lower third molar removal. Patients were grouped according to age and radiographic results: group A (518 patients, ≤23 years, immature teeth with apical foramen not closed); group B (532 patients, >23 years, mature teeth with closed apical foramen). Group A included 230 males and 288 females (average age 17 years). In group A, 808 lower mandibular third molars were extracted bilaterally in 290 and unilaterally in 228 patients; the incidence of complications was 2.48% (20/808) (all were temporary), the incidence of nerve injury was 0%. Group B included 250 males and 282 females (average age 39 years). In group B, 810 lower third molars were extracted bilaterally in 278 and unilaterally in 254 patients; the incidence of complications was 10% (81/810), the incidence of nerve injury was 1.6% (13/810). All complications were temporary, except two removals of permanent inferior alveolar nerve numbness (>6 months). In this study, early removal of the lower third molar was effective in avoiding some postoperative complications, especially nerve injury. Early extraction of lower third molar in youngsters is recommended following a team consultation.

Establishment of a novel human esophageal squamous cell carcinoma cell line (ESC-410) and its partial biological characterization.

Esophageal cancer exhibits an uneven geographical distribution strikingly, resulting in focal endemic high-incidence areas in several countries worldwide including China, which might be associated with the environmental and genetic risk factors in those areas. Permanent cancer cell lines are invaluable tools in understanding the biology of cancers and experimental therapeutics. To enrich cell line panel and animal models of human esophageal squamous cell carcinoma (ESCC) from different geographical areas and investigate the environmental and genetic risk factors in the carcinogenesis of ESCC, a novel human esophageal squamous cancer cell line (ESC-410) was established. The cell line grew adherent as a monolayer and maintained stable growth rate with a doubling time of 53 h and distinct epithelial morphological appearance; it was maintained in vitro for 18 months and subcultured for more than 50 passages. Ultrastructural examination revealed large irregular nuclei, desmosome, and tonofilaments; karyotype analysis showed a modal number of chromosomes that ranged from 35 to 73, with a median of 57, and 77% of analyzed cells were hyperdiploidy; reverse transcription polymerase chain reaction (RT-PCR) detected the mRNA expressions of CK8, CK18, and CK19 in the established cells; immunofluorescence assay identified the protein expressions of neurotrophin receptor p75 and integrin α6 (CD49f) in the ESC-410 cell line; xenotransplantation of ESC-410 cells into athymic nude mice subcutaneously induced the formation of solid tumor masses in about 2 weeks. By histopathological examination, heterogeneity of xenograft tumor was observed, as same as that of human primary ESCC. All findings and evidence in this experimental study suggested that this cell line might be a useful model in vitro and in vivo in cellular and molecular studies as well as in testing novel therapies for human ESCC.

Reversal of the gastric effects of nicotine by nitric oxide donor treatment.

Nicotine intensifies experimental gastric ulceration by reducing gastric mucosal blood flow (GMBF) and mucus. As both these parameters can be improved by nitric oxide (NO), we evaluated the impact of a NO donor in ethanol-induced gastric mucosal injury in rats administered nicotine. A nicotine solution or water was administered for 20 days to Sprague-Dawley rats. NO donor (isosorbide dinitrate) was given 60 and 10 min before preparation of ex vivo gastric chambers and exposure to ethanol. Chronic nicotine intake significantly reduced GMBF and gastric mucus content. Nicotine intensifies ethanol-induced gastric injury and short-term administration of NO donor failed to antagonize the ulcerogenic action from either nicotine or alcohol. In another study, rats drank nicotine solution for 20 days, after which the nicotine was withdrawn and replaced by water for 10 additional days. NO donor was provided during these last 10 days. The gastric effects of nicotine persisted for at least 10 days after nicotine was withdrawn but then these effects could be abolished by prolonged NO treatment. Nicotine reduces plasma nitrite level, but gastric mucosal MPO activity remained unchanged. Our data suggest that nicotine cessation plus a longer period of NO donor administration can completely abolish the gastric effects of nicotine.

Relationship between mucosal levels of Helicobacter pylori-specific IgA, interleukin-8 and gastric inflammation.

Mucosal IgA is important in local immune defence. Helicobacter pylori induces a specific IgA response in antral mucosa, but its immunopathology is unknown. Interleukin-8 (IL-8) has been suggested to be important in H. pylori-induced inflammation. Current information on the relationship between H. pylori-induced IgA and mucosal inflammation is limited. To investigate possible associations between mucosal-specific IgA, the toxinogenicity of H. pylori, mucosal levels of IL-8 and gastric inflammation, 52 endoscoped patients were studied. These comprised 28 patients with peptic ulcer and 24 with non-ulcer dyspepsia. Of these patients, 38 had H. pylori infection: 28 with peptic ulcer and 10 with non-ulcer dyspepsia. Antral biopsies were taken for histology, H. pylori culture and measurement of mucosal levels of IL-8 (pg/mg) and specific IgA (A450x1000) by ELISA. Mucosal H. pylori IgA was detectable in 35 out of 38 patients with H. pylori infection, with a median (interquartile) level of 220 (147, 531) units. There was no significant difference in mucosal levels of the IgA antibodies between patients infected with cytotoxin-positive or cagA-positive strains of H. pylori and those with toxin-negative or cagA-negative strains. The IgA levels in those patients with severe neutrophil infiltration were lower than in those with mild or moderate infiltration (P<0.05). There was a weak inverse correlation between antral mucosal IgA and IL-8 in infected patients (r=-0.36; P=0.04). H. pylori infection induced a significant local mucosal IgA response in most infected patients. The level of IgA antibodies does not appear to be correlated with the toxinogenicity of H. pylori. However, patients with severe active inflammation appear to have decreased levels of IgA. An inverse correlation between mucosal IL-8 and IgA may suggest that IL-8-induced inflammation compromises the mucosal IgA defence and renders the mucosa susceptible to further damage.

Association of antral mucosal levels of interleukin 8 and reactive oxygen radicals in patients infected with Helicobacter pylori.

1. Helicobacter pylori infection is characterized by an infiltration of neutrophils in the gastric mucosa. Neutrophil activation is an important source of reactive oxygen radicals, which cause tissue damage. Studies have shown that in Helicobacter pylori-infected patients there is increased mucosal production of interleukin 8. However, the role of interleukin 8 in the Helicobacter pylori-related inflammatory process and its relationship with reactive oxygen radicals remains to be clarified. The aims of this study were to investigate if there is any association between antral mucosal levels of interleukin 8 and reactive oxygen radicals and their relationship to gastric antral inflammation. 2. Fifty-two patients referred for endoscopy were recruited into the study. Gastric antral biopsies were taken for histology, culture and measurement of interleukin 8 and chemiluminescence (measuring reactive oxygen radicals). Interleukin 8 was measured by ELISA and the result expressed as pg/mg biopsy. Luminol-enhanced chemiluminescence was measured as mV min-1 mg-1 biopsy. Antral inflammation was assessed by a pathologist in a blinded fashion. 3. Antral mucosal levels of interleukin 8 and reactive oxygen radicals were significantly higher in Helicobacter pylori-colonized mucosa than in Helicobacter pylori-negative mucosa. After the eradication of Helicobacter pylori in patients with duodenal ulcer the median values (ranges) of interleukin 8 and reactive oxygen radicals fell from 1.21 (0.10-2.40) to 0.65 (0.00-1.60) and from 110.0 (10.0-959.0) to 14.5 (0.0-85.0) respectively. There was a positive correlation between interleukin 8 concentration and chemiluminescence response in the antral mucosa (r = 0.72). A higher interleukin 8 concentration was associated with greater neutrophil infiltration (r = 0.72) and mononuclear cell infiltration (r = 0.55); the magnitude of the chemiluminescence response was also positively associated with neutrophil (r = 0.77) and mononuclear cell infiltration (r = 0.59). 4. Interleukin 8 concentration is associated with an infiltration of neutrophils and mononuclear cells and is correlated with the production of reactive oxygen radicals in antral gastric mucosa infected with Helicobacter pylori. These findings suggest that interleukin 8 may be important in attracting and activating phagocytes to release reactive oxygen radicals, thereby causing mucosal damage.

Effect of omeprazole therapy on the survival of Helicobacter pylori, urease activity, and antral gastric histology in patients with duodenal ulcer.

BACKGROUND: Helicobacter pylori is associated with chronic active gastritis and peptic ulceration (PU). Omeprazole is a proton pump inhibitor that is effective in healing PU and reducing gastritis. Previously it has been found that omeprazole has some bacteriostatic activity against H. pylori both in vitro and in vivo and in inhibiting urease activity in vitro. Our aim was to evaluate the effect of omeprazole on H. pylori colonization of the gastric mucosa, urease activity in vivo, and the presence of associated gastritis in patients with duodenal ulcer (DU). MATERIALS AND METHODS: We studied 12 patients (7 men and 5 women, ages 22-68 yr) with Du larger than 5 mm in diameter with a positive CLOtest (Delta West Ltd., Australia). Omeprazole, 20 mg bid, was given for 8 weeks to each patient, patients were endoscoped at the end of this period to check for healing of DU, and repeat biopsies were obtained from the gastric antrum for histological analysis, CLOtest, and culture. RESULTS: DU healed completely in all patients. Likewise in all patients there was significant reduction in the urease activity, from 22.1 +/- 4.17 to 1.58 +/- 0.92 units/ml (p < .001; 95% confidence interval of the difference between means, 32.7-14.1), and reduced H. pylori density, from 1,403.46 +/- 128.23 to 422.5 +/- 172.39 colony-forming units (CFU) per milligram of tissue biopsy (p < .001; 95% confidence interval of the difference between means, 1,486.1-590.5). The numbers of H. pylori were reduced on the gastric mucosa after omeprazole therapy and disappeared in six patients, a result that correlated with a negative CLOtest reading after 24 hours. CONCLUSION: Omeprazole, 20 mg bid, is capable of reducing H. pylori numbers and urease activity in vivo. There was no significant reduction in the severity of antral gastritis in DU patients studied.

Vaginal radical hysterectomy for uterine cervical cancer.

The incidence of uterine cervical carcinoma, though decreasing in many cities of China, dose not show any diminution in the rural areas where it appears to be high in some regions. Therefore, radical hysterectomy is particularly important for the patients with cervical adenocarcinoma and squamous adenocarcinoma which are insensitive to chemotherapy and radiotherapy. The operation is effective in the treatment of early cervical carcinoma and even late carcinoma when the procedure is combined with extraperitoneal radical lymphadenectomy, radiotherapy and chemotherapy reinforced by the traditional Chinese medicine. This operation gets rid of technical difficulties in manipulating the deep pelvic cavities of obese patients, and is suitable for those patients with general weakness, heart and renal diseases, hypertension, severe tuberculosis complicated by the poor tolerance of the abdomen or fear to transabdominal procedures. The detailed procedures of the operation and its results are described.